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zx2045284

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llama2_medicine

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### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: m2 on day 1 , oxaliplatin 85 mg/m² day 1 and capecitabine twice-daily dose of 625 mg/ m2 , p.o . for 2 weeks ) every 3 Paragraph: A Modified Epirubicin and Oxaliplatin Plus Capecitabine (EOX) Regimen as a Second- Line Therapy in Patients with Advanced Gastric Cancer Objective: We aimed to evaluate the effectiveness of an mEOX (modified epirubicin, oxaliplatin plus capecitabine) regimen as second line therapy after failure of mDCF (modified docetaxel, cisplatin plus fluorouracil). Methods: Gastic cancer patients for whom first-line therapy was unsuccessful and who subsequently received mEOX (epirubicin 50 mg/ m2 on day 1 , oxaliplatin 85 mg/m² day 1 and capecitabine twice-daily dose of 625 mg/ m2 , p.o . for 2 weeks ) every 3 weeks until disease progression or unacceptable toxicity, were retrospectively analyzed. Results: The study population comprised 129 cases with a median age of 55 years (range= 27-78), the majority being male (76 %). Most (75.2%) had ≥ 2 sites of metastasis. The median number of chemotherapy courses was five (range= 2–9). Forty-nine achieved a partial response and 33 showed stable disease, resulting in a ORR (overall response rate) of 38% and a DCR (disease control rate) of 63.6%. The most frequent features of grade 3-4 hematological and non-hematological toxicity were neutropenia (8.5%) and nausea/vomiting (5.4%). None of the patients suffered death due to toxicity. The median PFS was 4.7 months (95% CI, 4.1–5.3) and the OS was 7.4 months (95% CI, 6.3–8.5). On multivariate analysis, age ≥ 60 years and ECOG performance status (0-1) were independent prognostic factors affecting PFS and OS. Conslusions: In advanced gastric cancer patients, who progress after first line chemotherapy and have an ECOG performance status of 0-1, mEOX is a well tolerated triple regimen associated with a promising OS and PFS. ### Assistant: [{"class": "POS", "spans_text": ["oxaliplatin", "capecitabine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: However , two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and , by contrast , increased toxicity . Paragraph: The role of capecitabine in locally advanced rectal cancer treatment: an update. Preoperative infusional 5-fluorouracil (5-FU) and concurrent radiation therapy (RT) followed by total mesorectal surgery is the current standard of care for locally advanced rectal cancer (LAR). When compared with postoperative 5-FU-based chemoradiation, this strategy is associated with significantly lower rates of local relapse, lower toxicity and better compliance. capecitabine is a rationally designed oral prodrug that is converted into 5-FU by intracellular thymidine phosphorylase. Substitution of infusional 5-FU with capecitabine is an attractive option that provides a more convenient administration schedule and, possibly, increased efficacy. Indeed, incorporation of capecitabine in combined modality neoadjuvant therapy for LAR has been under intense investigation during the last 10 years. Phase I and II clinical trials showed that a regimen consisting of capecitabine 825mg/m(2) twice daily for 7 days/week continuous oral administration in combination with RT is an active and well tolerated regimen, thereby being the preferred concurrent regimen. The definitive demonstration that efficacy of capecitabine/RT is similar to 5-FU/RT has been provided by the NSABP-R-04 and the German Margit trials. One approach to improve outcomes in rectal cancer is to deliver a second RT-sensitizing drug with effective systemic activity. oxaliplatin and irinotecan are therefore good candidates. However , two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and , by contrast , increased toxicity . capecitabine has also been combined with irinotecan. This regimen showed encouraging results in phase I and II clinical trials, which led to an ongoing phase III clinical trial. New strategies with induction chemotherapy with or without chemoradiation prior to surgery are currently under investigation. Whether or not capecitabine has a role in this setting is being investigated in ongoing trials. Incorporation of agents directed towards new targets, such as anti-epidermal growth factor receptor (EGFR) antibodies or antiangiogenic agents, in combination preoperative regimens, is being hampered by results of early trials in which efficacy outcomes with cetuximab were poor and an excessive rate of surgical complications with bevacizumab was observed. The lack of improvements in efficacy with the addition of cetuximab or bevacizumab in the adjuvant treatment of colon cancer led to concerns about further development of these agents in rectal cancer. The role of capecitabine in the postoperative adjuvant setting is the aim of the ongoing Dutch SCRIPT trial. The prediction of response associated with capecitabine has been based on expression of thymidylate synthase and dihydropyrimidine dehydrogenase, as well as on gene expression arrays. All these procedures require further validation and should be considered as investigational. In conclusion, capecitabine can safely and effectively replace intravenous continuous infusion of 5-FU in the preoperative chemoradiation setting for rectal cancer management. The addition of other new antineoplastic agents to a fluoropyrimidine-based regimen remains investigational. ### Assistant: [{"class": "NEG", "spans_text": ["oxaliplatin", "capecitabine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes . Paragraph: Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR. To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-resistant PCa models. ### Experimental Design Androgen-dependent (LNCaP) and castration-resistant PCa (HP-LNCaP) cells were grown as tumours in SCID mice. Once tumours reached 500 mm(3), animals were grouped and injected subcutaneous with vehicle, our novel anti-androgen/androgen synthesis inhibitor, VN/124-1, bicalutamide, and everolimus. Tumour volumes were measured biweekly. The PSA and protein analyses were performed after completion of the treatment. ### results The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes . Anti-androgen treatment also increased protein expression of multiple signal transduction pathways earlier than vehicle-treated control xenografts. VN/124-1 plus everolimus acted in concert to reduce tumour growth rates in our castration-resistant xenograft model. ### conclusions This study suggests that dual inhibition of AR and mTOR in castration-resistant xenograft models can restore sensitivity of tumours to anti-androgen therapy. Furthermore, after bicalutamide failure, dual inhibition with VN/124-1 and everolimus was the most effective treatment. ### Assistant: [{"class": "POS", "spans_text": ["everolimus", "bicalutamide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: To assess plasma steady-state pharmacokinetics ( PK ) of rifampicin , isoniazid , saquinavir and ritonavir in HIV and tuberculosis ( TB ) co-infected patients , and investigate potential interactions between TB drugs and protease inhibitors ( PIs ) . Paragraph: Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis. To assess plasma steady-state pharmacokinetics ( PK ) of rifampicin , isoniazid , saquinavir and ritonavir in HIV and tuberculosis ( TB ) co-infected patients , and investigate potential interactions between TB drugs and protease inhibitors ( PIs ) . ### methods Open-label, single-arm, sequential PK study including 22 patients with HIV infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between PI parameters in the second and third PK studies were used to assess interactions. ### results Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C(max) and C(trough), respectively, was seen with rifampicin and isoniazid. ritonavir AUC(0-24), C(max) and C(trough) decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid. ### conclusions There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels. ### Assistant: [{"class": "COMB", "spans_text": ["isoniazid", "saquinavir", "ritonavir", "rifampicin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel ( control group ) or pertuzumab plus trastuzumab plus docetaxel ( pertuzumab group ) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed . Paragraph: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer. ### methods We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel ( control group ) or pertuzumab plus trastuzumab plus docetaxel ( pertuzumab group ) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed . The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. ### results The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. ### conclusions The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.). ### Assistant: [{"class": "POS", "spans_text": ["pertuzumab", "trastuzumab", "docetaxel"]}, {"class": "COMB", "spans_text": ["trastuzumab", "docetaxel"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Toxicological studies revealed that the oral LD50 for thiabendazole in mice was 2200 mg/kg , and when combined with 140 mg/kg of aspirin , the LD50 was reduced to 900 mg/kg . Paragraph: The effect of thiabendazole on pain threshold. thiabendazole significantly increased the reaction time to thermal stimulus. However, in mice treated with morphine, the reaction time was not in any way different from those treated with combined doses of thiabendazole and morphine. thiabendazole was found to have an antinociceptive action. The protective dose for 50% of animal (ED50) against p-benzoquinone-induced writhing reflex was found to be 310 mg/kg. The ED50 for aspirin alone was 140 mg/kg. When the ED50 of aspirin was determined in combination with different dose levels of thiabendazole, it showed a marked reduction in the values reaching 50 mg/kg, when 300 mg of thiabendazole was used in combination. Toxicological studies revealed that the oral LD50 for thiabendazole in mice was 2200 mg/kg , and when combined with 140 mg/kg of aspirin , the LD50 was reduced to 900 mg/kg . These findings indicate that thiabendazole possesses an analgesic activity which is potentiated by aspirin, though aspirin was found to significantly enhance its toxicity. ### Assistant: [{"class": "NEG", "spans_text": ["thiabendazole", "aspirin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Azacitidine and enasidenib are two therapies available for treatment of acute myelogenous leukemia ( AML ) , and the mechanisms of action of these drugs involve alteration of aberrant DNA methylation . Paragraph: Combination of azacitidine and enasidenib enhances leukemic cell differentiation and cooperatively hypomethylates DNA. Azacitidine and enasidenib are two therapies available for treatment of acute myelogenous leukemia ( AML ) , and the mechanisms of action of these drugs involve alteration of aberrant DNA methylation . We hypothesized that a combination of these agents could have interactive effects on DNA methylation and enhance differentiation in mIDH2 cells. Combination treatment enhanced cellular differentiation in TF-1 cells overexpressing IDJ2R140Q through increased hemoglobinization and increased hemoglobin γ RNA expression compared with the effects of single agents. Furthermore, in primary AML samples (IDH2R140Q or R172K), combination treatment reduced CD34+ cells and increased CD15+ cells to a greater extent than attained with single agents. To explore the mechanism of enhanced differentiation with combination treatment, the TF-1 epigenome was analyzed by profiling 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) DNA methylation changes. enasidenib treatment alone increased 5hmC, consistent with reactivation of ten-eleven-translocation (TET) enzyme activity. Compared with treatment with azacitidine alone, combination treatment reduced 5mC levels at greater numbers of sites and these loci were significantly enriched in regions with increased 5hMC (25.8% vs. 7.4%). Results are consistent with a model in which enasidenib-mediated reactivation of ten-eleven-translocation enzymes cooperates with azacitidine-mediated inhibition of DNA methyltransferase enzymes, leading to greater reductions in DNA methylation and enhanced erythroid differentiation. ### Assistant: [{"class": "COMB", "spans_text": ["Azacitidine", "enasidenib"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Good , moderate and mild pain relief were noted in 19 ( 41 % ) , six ( 13 % ) and seven ( 15 % ) patients on lamotrigine and 13 ( 28 % ) , five ( 11 % ) and 15 ( 33 % ) patients on amitriptyline , respectively , by patient 's global assessment of efficacy and safety . Paragraph: Randomized double-blind study comparing the efficacy and safety of lamotrigine and amitriptyline in painful diabetic neuropathy. To compare the efficacy and safety of lamotrigine and amitriptyline in controlling chronic painful peripheral neuropathy in diabetic patients. ### methods A randomized, double-blind, crossover, active-control, clinical trial with variable dose titration was carried out (n = 53). amitriptyline orally, at doses of 10, 25 and 50 mg at night-time, each dose for 2 weeks, and lamotrigine orally, at doses of 25, 50 and 100 mg twice daily, each dose for 2 weeks, by optional titration were used. There was a placebo washout period for 2 weeks between the two drugs. Assessment for pain relief, overall improvement and adverse events were carried out. ### results Good , moderate and mild pain relief were noted in 19 ( 41 % ) , six ( 13 % ) and seven ( 15 % ) patients on lamotrigine and 13 ( 28 % ) , five ( 11 % ) and 15 ( 33 % ) patients on amitriptyline , respectively , by patient 's global assessment of efficacy and safety . Patient and physicians global assessment, McGill pain questionnaire and Likert pain scale showed no significant difference between the treatments, although improvement with both treatments was seen from 2 weeks. Of the 44 adverse events reported, 33 (75%) were with amitriptyline, sedation being the commonest [in 19 (43%) patients]. lamotrigine caused adverse events in 11 (25%), of which rash in three (7%) and elevations of creatinine in four (9%) were the most common. The preferred lamotrigine dose was 25 mg twice daily. ### conclusions As there are few differences between the two treatments in efficacy, lamotrigine 25 mg twice daily might be the first choice as it is associated with fewer adverse effects in our population. ### Assistant: [{"class": "NEG", "spans_text": ["lamotrigine", "amitriptyline"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The majority of the evidence comes from studies of bevacizumab and triamcinolone used as primary therapy for DMO . Paragraph: Anti-vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema. The combination of steroid and anti-vascular endothelial growth factor (VEGF) intravitreal therapeutic agents could potentially have synergistic effects for treating diabetic macular oedema (DMO). On the one hand, if combined treatment is more effective than monotherapy, there would be significant implications for improving patient outcomes. Conversely, if there is no added benefit of combination therapy, then people could be potentially exposed to unnecessary local or systemic side effects. ### objectives To assess the effects of intravitreal agents that block vascular endothelial growth factor activity (anti-VEGF agents) plus intravitreal steroids versus monotherapy with macular laser, intravitreal steroids or intravitreal anti-VEGF agents for managing DMO. ### Search Methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 1); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 21 February 2018. ### Selection Criteria We included randomised controlled trials (RCTs) of intravitreal anti-VEGF combined with intravitreal steroids versus intravitreal anti-VEGF alone, intravitreal steroids alone or macular laser alone for managing DMO. We included people with DMO of all ages and both sexes. We also included trials where both eyes from one participant received different treatments. ### Data Collection And Analysis We used standard methodological procedures recommended by Cochrane.Two authors independently reviewed all the titles and abstracts identified from the electronic and manual searches against the inclusion criteria. Our primary outcome was change in best corrected visual acuity (BCVA) between baseline and one year. Secondary outcomes included change in central macular thickness (CMT), economic data and quality of life. We considered adverse effects including intraocular inflammation, raised intraocular pressure (IOP) and development of cataract. ### Main Results There were eight RCTs (703 participants, 817 eyes) that met our inclusion criteria with only three studies reporting outcomes at one year. The studies took place in Iran (3), USA (2), Brazil (1), Czech Republic (1) and South Korea (1). Seven studies used the unlicensed anti-VEGF agent bevacizumab and one study used licensed ranibizumab. The study that used licensed ranibizumab had a unique design compared with the other studies in that included eyes had persisting DMO after anti-VEGF monotherapy and received three monthly doses of ranibizumab prior to allocation. The anti-VEGF agent was combined with intravitreal triamcinolone in six studies and with an intravitreal dexamethasone implant in two studies. The comparator group was anti-VEGF alone in all studies; two studies had an additional steroid monotherapy arm, another study had an additional macular laser photocoagulation arm. Whilst we judged these studies to be at low risk of bias for most domains, at least one domain was at unclear risk in all studies.When comparing anti-VEGF/steroid with anti-VEGF monotherapy as primary therapy for DMO, we found no meaningful clinical difference in change in BCVA (mean difference (MD) -2.29 visual acuity (VA) letters, 95% confidence interval (CI) -6.03 to 1.45; 3 RCTs; 188 eyes; low-certainty evidence) or change in CMT (MD 0.20 μm, 95% CI -37.14 to 37.53; 3 RCTs; 188 eyes; low-certainty evidence) at one year. There was very low-certainty evidence on intraocular inflammation from 8 studies, with one event in the anti-VEGF/steroid group (313 eyes) and two events in the anti-VEGF group (322 eyes). There was a greater risk of raised IOP (Peto odds ratio (OR) 8.13, 95% CI 4.67 to 14.16; 635 eyes; 8 RCTs; moderate-certainty evidence) and development of cataract (Peto OR 7.49, 95% CI 2.87 to 19.60; 635 eyes; 8 RCTs; moderate-certainty evidence) in eyes receiving anti-VEGF/steroid compared with anti-VEGF monotherapy. There was low-certainty evidence from one study of an increased risk of systemic adverse events in the anti-VEGF/steroid group compared with the anti-VEGF alone group (Peto OR 1.32, 95% CI 0.61 to 2.86; 103 eyes).One study compared anti-VEGF/steroid versus macular laser therapy. At one year investigators did not report a meaningful difference between the groups in change in BCVA (MD 4.00 VA letters 95% CI -2.70 to 10.70; 80 eyes; low-certainty evidence) or change in CMT (MD -16.00 μm, 95% CI -68.93 to 36.93; 80 eyes; low-certainty evidence). There was very low-certainty evidence suggesting an increased risk of cataract in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 4.58, 95% 0.99 to 21.10, 100 eyes) and an increased risk of elevated IOP in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 9.49, 95% CI 2.86 to 31.51; 100 eyes).One study provided very low-certainty evidence comparing anti-VEGF/steroid versus steroid monotherapy at one year. There was no evidence of a meaningful difference in BCVA between treatments at one year (MD 0 VA letters, 95% CI -6.1 to 6.1, low-certainty evidence). Likewise, there was no meaningful difference in the mean CMT at one year (MD - 9 μm, 95% CI -39.87μm to 21.87μm between the anti-VEGF/steroid group and the steroid group. There was very low-certainty evidence on raised IOP at one year comparing the anti-VEGF/steroid versus steroid groups (Peto OR 0.75, 95% CI 0.16 to 3.55).No included study reported impact of treatment on patients' quality of life or economic data. None of the studies reported any cases of endophthalmitis. ### Authors Conclusions Combination of intravitreal anti-VEGF plus intravitreal steroids does not appear to offer additional visual benefit compared with monotherapy for DMO; at present the evidence for this is of low-certainty. There was an increased rate of cataract development and raised intraocular pressure in eyes treated with anti-VEGF plus steroid versus anti-VEGF alone. Patients were exposed to potential side effects of both these agents without reported additional benefit. The majority of the evidence comes from studies of bevacizumab and triamcinolone used as primary therapy for DMO . There is limited evidence from studies using licensed intravitreal anti-VEGF agents plus licensed intravitreal steroid implants with at least one year follow-up. It is not known whether treatment response is different in eyes that are phakic and pseudophakic at baseline. ### Assistant: [{"class": "COMB", "spans_text": ["bevacizumab", "triamcinolone"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Doxorubicin and ifosfamide are currently the two main drugs for the treatment of soft tissue sarcomas in adults . Paragraph: Perspectives on anthracyclines plus ifosfamide in advanced soft tissue sarcomas. Doxorubicin and ifosfamide are currently the two main drugs for the treatment of soft tissue sarcomas in adults . Given in combination at full doses, with or without dacarbazine, these agents have induced higher response rates than were obtained with single-agent therapy. Because they involve considerable myelotoxicity, however, full-dose regimens should be reserved for patients with good performance status and without potential septic foci. Obviously, higher response rates do not automatically translate into improved survival. In soft tissue sarcomas, full-dose polychemotherapy will most probably provide a survival benefit only in selected patients in whom surgery can be performed in combination with chemotherapy. Prospective trials in such patients, although difficult to carry out, would be highly desirable. The information they would provide might help the clinician tailor treatment in a more rational way and improve chances of cure or long-term survival in at least some patient subgroups. ### Assistant: [{"class": "POS", "spans_text": ["Doxorubicin", "ifosfamide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The skin and oral mucous membrane lesions recurred after effective treatments with methylprednisolone pulse therapy and combination therapy with prednisolone and cyclosporine . Paragraph: Successful treatment of adolescent pemphigus vulgaris by immunoadsorption method. A 15-year-old girl with pemphigus vulgaris did not respond to oral administration of prednisolone at 45 mg/day. The skin and oral mucous membrane lesions recurred after effective treatments with methylprednisolone pulse therapy and combination therapy with prednisolone and cyclosporine . The finally successful treatment involved eleven cycles of immunoadsorption using a tryptophan column and administration of a moderate dose of prednisolone. Serum gamma-globulin level and anti-intercellular antibody titer decreased from 1.08 g/dl to 0.5 g/dl and 1:320 to 1:20, respectively. She has been well controlled with 21.5 mg/day prednisolone for 8 months after the final adsorption. Considering the physical, mental and social situation of adolescent student patients, immunoadsorption is a highly preferable choice among a variety of treatment modalities for pemphigus vulgaris because it makes the term of hospitalization shorter and avoids undesirable side effects from initial high dose corticosteroids. ### Assistant: [{"class": "COMB", "spans_text": ["prednisolone", "cyclosporine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Incorporation of colistin significantly accelerated the release of ciprofloxacin from the DMPG anionic liposomes . Paragraph: Co-Delivery of Ciprofloxacin and Colistin in Liposomal Formulations with Enhanced In Vitro Antimicrobial Activities against Multidrug Resistant Pseudomonas aeruginosa. This study aims to develop liposomal formulations containing synergistic antibiotics of colistin and ciprofloxacin for the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa. ### methods colistin (Col) and ciprofloxacin (Cip) were co-encapsulated in anionic liposomes by ammonium sulfate gradient. Particle size, encapsulation efficiency, in vitro drug release and in vitro antibiotic activities were evaluated. ### results The optimized liposomal formulation has uniform sizes of approximately 100 nm, with encapsulation efficiency of 67.0% (for colistin) and 85.2% (for ciprofloxacin). Incorporation of anionic lipid (DMPG) markedly increased encapsulation efficiency of colistin (from 5.4 to 67.0%); however, the encapsulation efficiency of ciprofloxacin was independent of DMPG ratio. Incorporation of colistin significantly accelerated the release of ciprofloxacin from the DMPG anionic liposomes . In vitro release of ciprofloxacin and colistin in the bovine serum for 2 h were above 70 and 50%. The cytotoxicity study using A549 cells showed the liposomal formulation is as non-toxic as the drug solutions. Liposomal formulations of combinations had enhanced in vitro antimicrobial activities against multidrug resistant P. aeruginosa than the monotherapies. ### conclusions Liposomal formulations of two synergistic antibiotics was promising against multidrug resistant P. aeruginosa infections. ### Assistant: [{"class": "POS", "spans_text": ["colistin", "ciprofloxacin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin 's lymphomas . Paragraph: Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin 's lymphomas . PURPOSE: This phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary efficacy of the combination of decitabine with vorinostat. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied. RESULTS: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg three times a day on days 6-12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1-5 with vorinostat 200 mg twice a day on days 3-9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg twice a day on days 6-12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12/42 (29%) patients evaluable for toxicity. The most common ≥ grade 3 adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for ≥ 4 cycles was observed in 11/38 (29%) evaluable patients. CONCLUSION: The combination of decitabine with vorinostat is tolerable on both concurrent schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types. ### Assistant: [{"class": "POS", "spans_text": ["decitabine", "vorinostat"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Epirubicin ( 35 mg/m(2 ) ) and cyclophosphamide ( 400 mg/m(2 ) ) were administered from day 2 to day 4 , every 4 weeks . Paragraph: Combined 5-fluorouracil infusion with fractionated epirubicin and cyclophosphamide in advanced breast cancer. 5-fluorouracil (5-FU) given by continuous infusion (c.i.) allows higher dose delivery, causes less myelosuppression, and may interfere with repair of DNA damage caused by epirubicin and cyclophosphamide. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-FU c.i., epirubicin, and cyclophosphamide in patients with metastatic breast cancer (MBC). Twenty-eight patients with MBC were entered in the trial. 5-FU (200 mg/m(2)) was administered by c.i. from day 1 to day 20. Epirubicin ( 35 mg/m(2 ) ) and cyclophosphamide ( 400 mg/m(2 ) ) were administered from day 2 to day 4 , every 4 weeks . All patients were evaluable for response and toxicity. A total of 125 courses of chemotherapy were administered, with a median of 4 per patient (range: 2--6). Toxicity, assessed using World Health Organization criteria, was as follows: nausea and vomiting grade III--IV occurred in 36%, alopecia (grade III) in 86%, neutropenia (grade III--IV) in 50%, and cardiac toxicity grade I--II in 11% of patients. Five patients (17.9%) had a complete response to therapy, and 16 (57.1%) had a partial response (response rate 75%, 95% CI 55--89%). Disease stability and progression occurred in 4 (14.3%) and 3 (10.7%) patients, respectively. Median time to progression was 13.1 months (range: 3.4--66.9+), and median survival time was 27.7 months (range: 5.4--67.1+). Outpatient treatment with combined 5-FU c.i., epirubicin, and cyclophosphamide shows high activity in advanced breast cancer and gives prolonged remission with acceptable toxicity. ### Assistant: [{"class": "POS", "spans_text": ["Epirubicin", "cyclophosphamide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Our patient could be weaned from LVAD probably due to the combination management strategy employing mitral valvuloplasty , use of cardiac resynchronization therapy , and taking carvedilol with spironolactone . Paragraph: Successful bridge to recovery with VAD implantation for anthracycline-induced cardiomyopathy. Anthracyclines are effective antineoplastic drugs, but they are known to be cardiotoxic. Recovery of cardiac function is rare. A few studies on implantation of a ventricular assist device (VAD) have been performed for anthracycline-induced cardiomyopathy. Recovery of left ventricular (LV) function with an LVAD is also rare. Recently, several adjunctive therapies were attempted to restore ventricular function. We report a successful bridge to recovery of ventricular function using VAD implantation for anthracycline-induced cardiomyopathy. The patient was a 57-year-old man who had been diagnosed with diffuse large B-cell lymphoma (DLBCL) at age 52. Combination chemotherapy including hydroxydaunorubicin was started. Complete remission was achieved after chemotherapy. Heart failure symptoms such as fatigue, dyspnea on exertion, and weight gain appeared 5 months later. A cardiac resynchronization device was implanted. His heart function deteriorated. He underwent implantation of a Toyobo LVAD and mitral annuloplasty. After implantation, he was prescribed carvedilol with spironolactone. He was weaned from the LVAD on postoperative day (POD) 239 and discharged on POD 37 after weaning. He remained in New York Heart Association classes within the first- to second-degree range, the LV dimention diastolic/systolic ratio was 56/46 mm, ejection fraction 38%, and mitral regurgitation mild at 3 years after weaning from the LVAD. Our patient could be weaned from LVAD probably due to the combination management strategy employing mitral valvuloplasty , use of cardiac resynchronization therapy , and taking carvedilol with spironolactone . Further studies will be needed to clarify the efficacy of these adjunctive therapies. ### Assistant: [{"class": "POS", "spans_text": ["carvedilol", "spironolactone"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Serum hydroxyzine and cetirizine concentrations were above the limit of quantitation ( 0.1 ng/ml ) of the assay Paragraph: Pharmacokinetics of hydroxyzine and cetirizine following oral administration of hydroxyzine to exercised Thoroughbred horses. hydroxyzine is a first-generation antihistamine and cetirizine, a second-generation antihistamine and active metabolite of hydroxyzine. hydroxyzine is commonly used in performance horses and as such its use in closely regulated; however, there are no published studies suitable for establishing appropriate regulatory recommendations. In the current study, 12 exercised Thoroughbred research horses received a single oral administration of 500 mg of hydroxyzine. Blood and urine samples were collected prior to and up to 96 hr postdrug administration and concentrations of hydroxyzine and cetirizine determined using liquid chromatography-tandem mass spectrometry. A joint parent/metabolite population 2-compartment pharmacokinetic model with first-order absorption and elimination was utilized to describe the pharmacokinetics of both compounds. Serum hydroxyzine and cetirizine concentrations were above the limit of quantitation ( 0.1 ng/ml ) of the assay at 96 hr (the last time point sampled). The terminal half-life was 7.41 and 7.13 hr for hydroxyzine and cetirizine, respectively. Findings from this study suggest that a prolonged withdrawal time should be observed if this compound is used in performance administered to performance horses and is classified as prohibited substance by the applicable regulatory body. ### Assistant: [{"class": "NEG", "spans_text": ["hydroxyzine", "cetirizine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Although well tolerated , the efficacy of everolimus and vinorelbine combination therapy was not superior to vinorelbine monotherapy . Paragraph: VicTORia: a randomised phase II study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line chemotherapy in advanced HER2-negative breast cancer. Improving the outcome of patients with HER2-negative metastatic breast cancer experiencing tumour progression following first-line chemotherapy remains an urgent medical need. The purpose of the VicTORia trial was to show superiority of everolimus in combination with vinorelbine versus vinorelbine monotherapy as second-line chemotherapy for patients with advanced HER2 negative breast cancer. ### methods In this randomised phase II trial, 133 patients were recruited in 32 centres in Germany. Patients were randomised 1:1 to second-line chemotherapy either with vinorelbine plus everolimus (arm1) or vinorelbine alone (arm2). Primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS rate at 6 months, overall survival (OS), overall response rate (ORR) and safety. Baseline PI3 K mutational status was determined in plasma samples. ### results Median progression-free survival was not different between arms (arm1 vs. arm2: 4.01 months, 95% CI 2.40-6.09 vs. 4.08, 95% CI 2.80-5.33). PFS rate at 6 months (arm1 vs. arm2: 39.4%, 95% CI 27.6-50.9% vs. 36.6%, 95% CI 24.6-48.6%), median OS (arm1 vs. arm2: 16.3 months, 95% CI 11.4-19.0 vs. 13.8 months, 95% CI 10.2-19.1) and ORR were not different between arms. Most frequent grade 3/4 adverse events were neutropenia (50% vs. 40%), gastrointestinal toxicities (19.1% vs. 6.1%), and infections (19.1% vs. 7.7%). PI3 K mutational status was neither associated with PFS nor with OS. ### conclusion Although well tolerated , the efficacy of everolimus and vinorelbine combination therapy was not superior to vinorelbine monotherapy . There was no correlation between PI3 K mutational status and efficacy. EudracCT No 2011-001024-38, ClinicalTrials.gov No NCT01520103. ### Assistant: [{"class": "NEG", "spans_text": ["everolimus", "vinorelbine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In addition , biochemical examinations revealed that docetaxel could induce phosphorylation of both bcl-2 and c-raf-1 , but these changes were inhibited when tumor cells were pretreated or simultaneously treated with doxorubicin . Paragraph: In vitro evaluation of schedule-dependent interactions between docetaxel and doxorubicin against human breast and ovarian cancer cells. docetaxel, a novel member of the taxoid family, has shown greater potency than paclitaxel in the treatment of advanced breast cancer and certain other solid tumors. The promising clinical activity of docetaxel has also promoted considerable interest in combining this drug with other antitumor agents. In this study, we assessed the cytotoxic interaction between docetaxel and doxorubicin administered at various schedules to human breast and ovarian cancer cells. Through a series of in vitro assays including DNA fragmentation analyses, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and flow cytometric analyses, we found that the antagonistic interaction occurred when tumor cells were exposed to the two drugs simultaneously or exposed to doxorubicin before docetaxel. However, no antagonism was observed when docetaxel was added before doxorubicin. Further analyses demonstrated that doxorubicin could interfere with the cytotoxic effect of docetaxel on both mitotic arrest and apoptotic cell death. In addition , biochemical examinations revealed that docetaxel could induce phosphorylation of both bcl-2 and c-raf-1 , but these changes were inhibited when tumor cells were pretreated or simultaneously treated with doxorubicin . These results indicate that the interaction between docetaxel and doxorubicin is highly schedule dependent. Exposure of tumor cells to doxorubicin before docetaxel could result in pronounced antagonism. The optimal schedule for this combination might be sequential exposure to docetaxel followed by doxorubicin. ### Assistant: [{"class": "NEG", "spans_text": ["docetaxel", "doxorubicin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy . Paragraph: Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy . To determine if fluorouracil (5-FU) plus high-dose leucovorin (LV) enhances local response in patients receiving preoperative radiation therapy (RT) for adenocarcinoma of the rectum, we compared the degree of downstaging in patients receiving preoperative RT with or without chemotherapy. ### Patients And Methods For this comparison, three groups of patients who were treated with identical doses and techniques of preoperative pelvic RT (total dose of 5,040 cGy) were examined. Group 1 included 20 patients with unresectable disease who received combined RT and LV/5-FU. Group 2 included 11 patients with unresectable disease who received preoperative RT. Group 3 included 21 patients with invasive, resectable, primary disease who received preoperative RT. ### results Patients with unresectable disease who received LV/5-FU had a higher rate of pathologic complete response (20% v 0%) and a lower incidence of positive nodes (30% v 64%) compared with those who did not receive chemotherapy. Even when the most favorable group of patients was included (group 3), patients who received LV/5-FU still had a higher complete response rate (20% v 6%) and a lower incidence of positive nodes (30% v 53%) compared with those who received RT without LV/5-FU. Of those patients with initially unresectable disease, the resectability rate was higher in those who received LV/5-FU compared with those who did not receive LV/5-FU (90% v 64%). Patients who received LV/5-FU experienced slightly more grade 1 to 2 fatigue, stomatitis, nausea, and grade 3 diarrhea, tenesmus, and dysuria. ### conclusions Despite the fact that patients who received chemotherapy (group 1) had more advanced disease compared with those with resectable disease (group 3), the addition of LV/5-FU increased the resectability and downstaging rates. The ultimate impact of a complete response as well as a decrease in the incidence of pelvic nodes on local control and survival remains to be determined. However, given the enhancement of down-staging in patients with unresectable rectal cancer, we are encouraged by the combined modality approach. ### Assistant: [{"class": "POS", "spans_text": ["fluorouracil", "leucovorin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Final analysis of a phase II study of nivolumab in combination with ipilimumab for unresectable chemotherapy-naive advanced melanoma . Paragraph: Final analysis of a phase II study of nivolumab in combination with ipilimumab for unresectable chemotherapy-naive advanced melanoma . nivolumab plus ipilimumab combination is currently one of the preferred regimens for advanced melanoma in recently updated clinical practice guidelines. However, the evidence on the efficacy of the combination for acral or mucosal subtypes remains less robust. This is the final analysis of a multicenter, open-label, uncontrolled phase II study that investigated the long-term efficacy and safety in treatment-naive Japanese patients with advanced melanoma, including acral or mucosal subtypes, and subsequent therapy after discontinuation of the investigational agents. Patients received four doses of nivolumab (1 mg/kg i.v.) in combination with ipilimumab (3 mg/kg i.v.) at 3-week intervals, followed by doses of nivolumab (3 mg/kg i.v.) at 2-week intervals. The median follow-up period was 20.8 months (range, 5.2-35.0). The centrally and locally assessed objective response rates were both 43.3% (13/30; 95% confidence interval [CI], 25.5-62.6). Median progression-free survival was not reached (95% CI, 3.02-not reached), and median overall survival was also not reached (95% CI, 19.52-not reached). The 30-month progression-free survival and overall survival rates were 50.3% and 54.2%, respectively. No new safety concerns were detected. After discontinuation of the investigational agents, 83.3% of patients received some form of subsequent therapy including 43.3% of patients who received nivolumab monotherapy and 26.7% of patients who received radiotherapy. Of the four patients who discontinued the investigational agents because of immune-related adverse events, two received subsequent therapy (nivolumab and ipilimumab, respectively) and the other two showed long-term treatment-free survival (659 and 590 days, respectively). Long-term survival with nivolumab plus ipilimumab was observed in Japanese patients with melanoma including acral and mucosal subtypes, which is consistent with the CheckMate 067 study. Many patients continued to receive some form of treatment safely after stopping treatment with nivolumab plus ipilimumab. ### Assistant: [{"class": "NEG", "spans_text": ["nivolumab", "ipilimumab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In some relatively developed regions in China , infliximab and rituximab may be a favorable cost-effective alternative for moderate to severe RA . Paragraph: Cost effectiveness of different treatment strategies in the treatment of patients with moderate to severe rheumatoid arthritis in china. To analyse the cost-effectiveness of traditional disease-modifying anti-rheumatic drugs (tDMARDs) compared to biological therapies from the perspective of Chinese society. ### Methodology Principal Findings A mathematical model was developed by incorporating the clinical trial data and Chinese unit costs and treatment sequences from a lifetime perspective. Hypothetical cohorts with moderate to severe RA were simulated. The primary outcome measure-quality-adjusted life years (QALYs)-was derived from disease severity (HAQ scores). Primary analysis included drug costs, monitoring costs, and other costs. Probabilistic and one-way sensitivity analyses were performed. Treatment sequences that included TNF antagonists and rituximab produced a greater number of QALYs than tDMARDs alone or TNF antagonists plus DMARDs. In comparison with tDMARDs, the incremental cost-effectiveness ratios (ICERs) for etanercept, infliximab, and adalimumab without rituximab were $77,357.7, $26,562.4 and $57,838.4 per QALY and $66,422.9, $28,780.6 and $50,937.6 per QALY, for etanercept, infliximab, and adalimumab with rituximab. No biotherapy was cost-effective under the willingness to pay threshold when the threshold was 3 times the per capita GDP of China. When 3 times the per capita GDP of Shanghai used as the threshold, infliximab and rituximab could yield nearly 90% cost-effective simulations in probabilistic sensitivity analysis. ### Conclusions Significance tDMARD was the most cost-effective option in the Chinese healthcare setting. In some relatively developed regions in China , infliximab and rituximab may be a favorable cost-effective alternative for moderate to severe RA . ### Assistant: [{"class": "POS", "spans_text": ["infliximab", "rituximab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Topiramate CR treatment produced significant weight loss and meaningful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated with diet and exercise or in combination with metformin . Paragraph: A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. This is a randomized, placebo-controlled study of the weight-loss efficacy and safety of a controlled-release (CR) formulation of topiramate in overweight and obese patients with type 2 diabetes treated with diet and exercise alone or in combination with metformin. ### Research Design And Methods Patients with type 2 diabetes, BMI > or =27 kg/m2, A1C >6.5 and <11.0%, treated with diet and exercise alone or in combination with metformin monotherapy were enrolled. Patients were randomized to placebo or topiramate CR titrated up to 175 mg/day. Treatment consisted of a 7-week titration phase followed by a 9-week maintenance phase. ### results A total of 111 subjects were randomized and analyzed. By the end of week 16, patients in the placebo and topiramate groups lost 2.5 and 6.0 kg, which represented 2.3 and 5.8%, respectively, of their baseline body weight (P < 0.001 vs. placebo). A1C improved from a baseline of 7.4% in the placebo and 7.6% in the topiramate groups to 7.1 and 6.7%, respectively, representing a 0.4 and 0.9% reduction from baseline, respectively (P < 0.001 vs. placebo). topiramate also significantly reduced blood pressure and urinary albumin excretion. Adverse events were predominantly neuropsychiatric or central and peripheral nervous system related. ### conclusions Topiramate CR treatment produced significant weight loss and meaningful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated with diet and exercise or in combination with metformin . However, the central nervous system and psychiatric adverse event profile of topiramate CR makes it unsuitable for the treatment of obesity and diabetes. ### Assistant: [{"class": "POS", "spans_text": ["Topiramate", "metformin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: To compare efficacy and toxicity of bolus application of chemotherapy protocol , oxaliplatin , fluorouracil ( bolus ) , leucovorin ( folfox ) between two groups of patients in the therapy of metastatic colorectal carcinoma ( mCRC ) . Paragraph: Therapeutic efficacy and toxicity of bolus application of chemotherapy protocol in the treatment of metastatic colorectal cancer. To compare efficacy and toxicity of bolus application of chemotherapy protocol , oxaliplatin , fluorouracil ( bolus ) , leucovorin ( folfox ) between two groups of patients in the therapy of metastatic colorectal carcinoma ( mCRC ) . ### methods A total of 63 patients were treated for mCRC in the period January 2009 - January 2010 at the Department of Oncology of the Cantonal Hospital Zenica, Bosnia and Herzegovina (first group, 30 patients) and at the Department of Oncology of the Clinical Hospital Centre Bežanijska kosa in Belgrade, Serbia, in the period January 2005 - January 2006 (second group, 33 patients). The patients were treated according the same protocol, i.v. bolus infusion, but in different day intervals (D), 1, 8, 15/28 days or D1-D5/28 days, respectively. In all patients the following factors were analyzed: tumor response, overall survival (OS), progression free survival, hematological and non-hematological toxicity . ### results Colon was the primary localization in almost two thirds of patients. There was no statistically significant difference between the groups according to the age, hematological and non-hematological toxicity, as well as in achieved OS. Progression free survival expressed in months was in average 5 months though with a large range between minimal and maximal survival time. ### conclusion Both groups have shown equivalent efficacy to applied chemotherapy protocols. Overall survival in the two groups matched data from the literature. Further research should confirm success of the combination of chemotherapy protocols and their combination with the biological therapy. ### Assistant: [{"class": "COMB", "spans_text": ["oxaliplatin", "fluorouracil", "leucovorin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Verapamil and quinine were added in patients with tumors failing to respond or progressing on CVAD alone . Paragraph: Combination chemotherapy with cyclophosphamide, vincristine, adriamycin, and dexamethasone (CVAD) plus oral quinine and verapamil in patients with advanced breast cancer. We evaluated the question of whether the chemosensitizers verapamil and quinine given orally to breast cancer patients failing combination chemotherapy alone would result in additional clinical responses. In vitro studies reported here showed verapamil sensitization of Adriamycin resistance in 18.8% of fresh human breast cancer specimens tested. Patients (27) were first treated with cyclophosphamide, vincristine, Adriamycin and dexamethasone (CVAD) alone. Verapamil and quinine were added in patients with tumors failing to respond or progressing on CVAD alone . Following treatment with CVAD alone there were no complete remissions and 3 patients (11%) developed partial remissions lasting 5.5, 8, 10.5 months. With the addition of verapamil and quinine to the CVAD regimen, one patient (4%) developed a complete remission of 11.8 months duration and 4 additional patients (15%) developed partial remissions lasting 2.8, 17.3, 19 and > 40 months. Thus, the overall rate of CVAD sensitization by verapamil and quinine was 19%. Treatment with CVAD plus verapamil and quinine was generally well tolerated with observed toxicities including: myelosuppression, neuropathy, Cushingoid symptoms and tinnitus and/or dizziness due to quinine. We conclude that addition of the non-cytotoxic chemosensitizers verapamil and quinine to CVAD in patients failing CVAD alone results in additional clinical responses in a small percentage of patients, some with long term durations. The results of this study lend credence to the notion that non-cytotoxic chemosensitizers can enhance the clinical activity of combination chemotherapy and the search for more effective and less toxic chemosensitizers continues. ### Assistant: [{"class": "POS", "spans_text": ["Verapamil", "quinine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: However , dipyridamole had no effect on both the influx and efflux of epirubicin in doxorubicin-sensitive cells . Paragraph: [Studies on reversing effect of multidrug resistance by dipyridamole. II. Inhibition of epirubicin efflux from resistant cells by dipyridamole and its pharmacological effect]. We have previously reported that dipyridamole increases the cytotoxicity of epirubicin and alters the cell cycle in doxorubicin-resistant (P388/DOX) cells, increasing the accumulation of G2/M phase by blocking the cell cycle. In cultured cells, dipyridamole increased dose-dependently the intracellular accumulation of epirubicin in the resistant cells. Simultaneous exposure of the resistant cells to epirubicin and 100 microM dipyridamole resulted in a 4.2-fold increase in proportion to the control level of epirubicin after 60 min. dipyridamole inhibited the enhanced efflux of epirubicin in doxorubicin-resistant cells. However , dipyridamole had no effect on both the influx and efflux of epirubicin in doxorubicin-sensitive cells . In mice, lethal and bone marrow toxicity induced by epirubicin were potentiated by administration of high-dose of dipyridamole. In addition, in vivo results also demonstrated that dipyridamole in combination with epirubicin produced a significant reversal of the in vivo antitumor activity of epirubicin in mice bearing P388/DOX cells. These data imply the enhancement effects of dipyridamole on the efficacy and toxicity of epirubicin. ### Assistant: [{"class": "NEG", "spans_text": ["dipyridamole", "epirubicin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: This study aims to evaluate the potential role of combination therapy with docetaxel , flavopiridol , or 5-FU in modulating chemosensitivity and better understand how they might be used clinically . Paragraph: Efficacy of sequential treatment of HCT116 colon cancer monolayers and xenografts with docetaxel, flavopiridol, and 5-fluorouracil. Clinical treatment of solid tumors with docetaxel, flavopiridol, or 5-fluorouracil (5-FU) often encounters undesirable side effects and drug resistance. This study aims to evaluate the potential role of combination therapy with docetaxel , flavopiridol , or 5-FU in modulating chemosensitivity and better understand how they might be used clinically . ### methods HCT116 colon cancer cells were treated with docetaxel, flavopiridol, and 5-FU in several different administrative schedules in vitro, either sequentially or simultaneously. Cell survival was measured by MTT assay. The activity of caspase-3 was determined by caspase-3 assays and the soft agar colony assay was used to test the colony formation of HCT116 cells in soft agar. We also established xenograft models to extend in vitro observations to an in vivo system. ### results The maximum cytotoxicity was found when human colon cancer HCT116 cells were treated with docetaxel for 1 h followed by flavopiridol for 24 h and 5-FU for another 24 h. This sequential combination therapy not only inhibits tumor cell growth more strongly compared to other combination therapies but also significantly reduces colony formation in soft agar and augments apoptosis of HCT116 cells. Sequencing of docetaxel followed 1 h later by flavopiridol, followed 24 h later by 5-FU in xenograft models, also resulted in delayed tumor growth and higher survival rate. ### conclusion These results highlight the importance of an administrative schedule when combining docetaxel with flavopiridol and 5-FU, providing a rationale explanation for its development in clinical trials. ### Assistant: [{"class": "POS", "spans_text": ["docetaxel", "flavopiridol"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Dipyridamole or dipyridamole and acetylsalicyclic acid were used in 22 pregnancies . Paragraph: The course of pregnancy in patients with artificial heart valves. Twenty-five women with prosthetic heart valves (PHV) became pregnant 28 times. Twenty-six of the pregnancies occurred while the patients were receiving oral anticoagulants and these were continued throughout in 25 pregnancies. Dipyridamole or dipyridamole and acetylsalicyclic acid were used in 22 pregnancies . Eighteen infants were delivered, one with a congenital corneal leukoma; none had hemorrhagic complications; their psychomotor development was normal. Nine women aborted 10 times, including patients with two PHV, pelvic trauma and self-induced abortion. We could not detect excess anticoagulation in eight of the nine who had spontaneous losses; excess anticoagulation occurred five weeks before an abortion. There were no maternal deaths despite numerous complications; in two women, brain embolism was related to short interruptions of anticoagulation. The details of management are mentioned. We lack enough evidence to suggest routine sterilization, routine interruption of coumarin therapy during pregnancy or routine interruption of pregnancy in women with certain types and models of PHV; however, pregnancy under such conditions, plus antithrombotic therapy, carries a high risk for the product and a potential teratogenic effect. Women with one or two PHV can have children if their management is closely supervised and if extreme care is taken with the use of oral anticoagulants. ### Assistant: [{"class": "COMB", "spans_text": ["dipyridamole", "acetylsalicyclic acid"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Bevacizumab and trastuzumab are efficacious for treatment of advanced or HER2-positive metastatic breast cancer ; however , few data exist for this regimen in inflammatory breast cancer . Paragraph: Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study. Bevacizumab and trastuzumab are efficacious for treatment of advanced or HER2-positive metastatic breast cancer ; however , few data exist for this regimen in inflammatory breast cancer . In our phase 2 trial, we aimed to assess efficacy and safety of neoadjuvant bevacizumab combined with trastuzumab and chemotherapy in patients with primary HER2-positive inflammatory breast cancer. ### methods In our phase 2, multicentre, open-label, single-arm, non-comparative trial, we enrolled women (aged ≥ 18 years) with histologically confirmed HER2-positive non-metastatic inflammatory breast cancer at private or public oncology centres in France. Before surgery, patients were treated with fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1-4) and docetaxel, bevacizumab, and trastuzumab (cycles 5-8) in 3-week cycles. After surgery, patients received adjuvant radiotherapy, trastuzumab, and bevacizumab. For the primary endpoint, we assessed the proportion of patients who achieved a pathological complete response (defined by central review of surgical specimens according to Sataloff classification, counting missing data as failure) and adverse events in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00717405. ### findings Between Oct 23, 2008, and Oct 28, 2009, we enrolled 52 patients at 21 centres. 42 (81%) of 52 patients received all eight cycles of neoadjuvant therapy and 49 (94%) underwent surgery. After neoadjuvant therapy, 33 of 52 patients had a pathological complete response according to central review (63·5%, 95% CI 49·4-77·5). The most common adverse events were asthenia and nausea (both occurred in 36 [69%] of 52 patients). 25 (48%) patients had grade 3-4 neutropenia, which was the most common grade 3-4 adverse event. Only one grade 3 or worse adverse event regarded as related to bevacizumab was reported (hypertension, one patient). Four patients (8%) had cardiac failure. ### interpretation Neoadjuvant treatment with bevacizumab, trastuzumab, and chemotherapy was efficacious and well tolerated in patients with previously untreated primary inflammatory breast cancer. Further confirmation of use of bevacizumab in inflammatory breast cancer is needed. ### funding Roche (France). ### Assistant: [{"class": "COMB", "spans_text": ["Bevacizumab", "trastuzumab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Rats were distributed into three groups ( n = 5 ) according to the drug studied namely , 50 % enantiomeric excess bupivacaine mixture ( 5 μg/mL ) ; pancuronium ( 2 μg/mL ) ; 50 % enantiomeric excess bupivacaine mixture + pancuronium . Paragraph: Effect of 50% enantiomeric excess bupivacaine mixture combined with pancuronium on neuromuscular transmission in rat phrenic nerve-diaphragm preparation; a pilot study. Local anaesthetics are drugs that are widely used in clinical practice. However, the effects of these drugs on the neuromuscular junction and their influence on the blockade produced by non-depolarising neuromuscular blocking drugs are still under investigation. The aim of this study was to evaluate, in vitro, the influence of a 50% enantiomeric excess bupivacaine mixture on neuromuscular transmission and neuromuscular block produced by pancuronium. ### methods Rats were distributed into three groups ( n = 5 ) according to the drug studied namely , 50 % enantiomeric excess bupivacaine mixture ( 5 μg/mL ) ; pancuronium ( 2 μg/mL ) ; 50 % enantiomeric excess bupivacaine mixture + pancuronium . The following parameters were evaluated: (1) Effects of a 50% enantiomeric excess bupivacaine mixture on membrane potential (MP) and miniature endplate potentials (MEPPs); (2) amplitude of diaphragmatic response before and 60 min after the addition of a 50% enantiomeric excess bupivacaine mixture; the degree of neuromuscular block with pancuronium and pancuronium combined with a 50% enantiomeric excess bupivacaine mixture. ### results A 50% enantiomeric excess bupivacaine mixture did not alter the amplitude of muscle response (MP) but decreased the frequency and amplitude of MEPP. The block produced by pancuronium was potentiated by a 50% enantiomeric excess bupivacaine mixture. ### conclusion A 50% enantiomeric excess bupivacaine mixture used alone did not affect neuromuscular transmission, but potentiated the neuromuscular block produced by pancuronium. No action was shown on the muscle fibre, and alterations on MEPPs demonstrated a presynaptic action. ### Assistant: [{"class": "COMB", "spans_text": ["bupivacaine", "pancuronium"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Blood was sampled immediately prior to premedication ( temazepam ) , after induction of anaesthesia ( fentanyl and thiopentone ) and at 10-minute intervals until the end of the procedure ( N2O maintenance , vecuronium relaxation ) . Paragraph: The plasma ACTH, AVP, CRH and catecholamine responses to conventional and laparoscopic cholecystectomy. We compared the responses of the stress hormones, cortisol, ACTH, vasopressin (AVP), corticotrophin releasing hormone (CRH) and catecholamines to elective conventional and laparoscopic cholecystectomy. ### design A right upper quadrant transverse incision was used for conventional cholecystectomy, and four 1-2-cm incisions for the laparoscopic procedure (for insertion of surgical instruments, diathermy, fibreoptic telescope and light source, and carbon dioxide insufflation). Blood was sampled immediately prior to premedication ( temazepam ) , after induction of anaesthesia ( fentanyl and thiopentone ) and at 10-minute intervals until the end of the procedure ( N2O maintenance , vecuronium relaxation ) . A blood sample was taken after reversal, and then at 10-minute intervals for 50 minutes. Plasma sodium and blood pressure were measured at similar intervals. Results are expressed as mean +/- standard error. ### patients Twelve patients were studied (six in each group). ### measurements Peptide hormones were measured by radioimmunoassay, cortisol by ELISA and catecholamines by HPLC. ### results The mean premedication hormone values for the conventional and laparoscopic procedures did not increase significantly after induction of anaesthesia. Within 10 minutes of the first incision, however, there was a marked concordant rise in mean plasma ACTH and AVP levels for both procedures (conventional: ACTH, from a premedication value of 10.2 +/- 1.7 to 80.1 +/- 14.3 pmol/l, AVP from 1.2 +/- 0.4 to 117 +/- 24 pmol/l, P < 0.01 for both hormones; laparoscopic: ACTH from 5.8 +/- 2.6 to 55.1 +/- 26.0 pmol/l, AVP from 1.6 +/- 0.11 to 49.2 +/- 27.09 pmol/l). At the end of both types of operation mean levels of ACTH and AVP were still elevated, although the ACTH: AVP ratio had increased. Greater variability in ACTH and AVP responses was seen in the laparoscopic than in the conventional procedure, three patients showing a relatively small response to surgery. Total secretion of ACTH during both types of surgery was not significantly less both during (P < 0.05), and after (P < 0.01) laparoscopic surgery. For both procedures, the timing of AVP and ACTH peaks was significantly related (P < 0.002). A small but significant rise in CRH was observed 30 minutes after the start of surgery for both procedures P < 0.05). The timing of CRH and ACTH peaks was unrelated. The maximum mean plasma cortisol level for the conventional procedure (1268 +/- 147 nmol/l) was reached 20 minutes after reversal of anaesthesia and remained at this level until the end of sampling. The cortisol response was comparable during the laparoscopic procedure but was beginning to fall at 60 minutes post-operatively. Plasma adrenaline responses to the two types of surgery were not significantly different, but the plasma total noradrenaline response to laparoscopic surgery as indicated by the response area during the first 20 minutes was significantly increased (P < 0.02). Plasma sodium, renin activity and initial systolic blood pressure fall were not significantly different during the two procedures. ### conclusions For both procedures, the peak of ACTH secretion after incision is likely to be AVP dependent, and the timing of peak levels of these two hormones was significantly related. Subsequent ACTH secretion may be the result of an interaction between AVP and CRH. Laparoscopic cholecystectomy results in a smaller AVP rise than does the conventional procedure, and plasma AVP falls more rapidly post-operatively. During the period of observation, ACTH, CRH, cortisol and adrenaline responses were not significantly lessened by the laparoscopic approach, but there was a significant increase in the noradrenaline response. Stress hormone monitoring may assist further improvements in surgical technique. ### Assistant: [{"class": "COMB", "spans_text": ["temazepam", "fentanyl", "thiopentone", "vecuronium"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The planned concomitant treatment in group B was : bleomycin 5 units twice a week i.m . , total dose 70 units , mitomycin C 15 mg/m2 i.v . after delivery of 10 Gy , and 10 mg/m2 i.v . on the last day of radiotherapy . Paragraph: Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report. To compare the efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone. ### Methods And Materials Between March 1991 and December 1993, 64 patients with inoperable head and neck carcinoma (41 with oropharyngeal site) were randomized to radiotherapy alone (group A) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin (group B). In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66-70 Gy. The planned concomitant treatment in group B was : bleomycin 5 units twice a week i.m . , total dose 70 units , mitomycin C 15 mg/m2 i.v . after delivery of 10 Gy , and 10 mg/m2 i.v . on the last day of radiotherapy . To enhance the effect of these two drugs, patients received also nicotinamide, chlorpromazine, and dicoumarol. Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma, the study was closed and such patients were after December 1993 routinely treated with the combined therapy (as in arm B). Until October 1996, we treated and followed up 48 such consecutive patients. ### results Median follow-up of our study patients is 42 months. Complete remission (CR) rate in group A was 31% and in group B 59% (p = 0.04); disease-free survival (DFS) in group A was 8% and in group B 37% (P = 0.01); and overall survival (OS) was 7% in group A and 26% in group B (p = 0.08). CR rate for patients with oropharyngeal carcinoma was 29% in group A (N = 21) and 75% in group B (N = 20) (p = 0.007); DFS in group A was 10% and in group B 48% (p = 0.001); and the OS was 10% in group A and 38% in group B (p = 0.019). In patients with inoperable oropharyngeal carcinoma treated after December 1993, complete remission was achieved in 32/48 (67%, 95% CI: 52%-80%). DFS at the median follow-up of 14 months was 60% (95% CI 43-77%) and OS 58% (95% CI 42-74%). ### conclusion From the results of our study it seems that the concomitant treatment significantly improves CR rate, DFS, and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone. ### Assistant: [{"class": "POS", "spans_text": ["bleomycin", "mitomycin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The study objectives were to evaluate the safety , tolerability , and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced , recurrent , or metastatic colorectal cancer . Paragraph: A phase 1B study of dulanermin in combination with modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer. The study objectives were to evaluate the safety , tolerability , and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced , recurrent , or metastatic colorectal cancer . ### Patients And Methods A total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed. ### results In the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7). ### conclusions Overall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population. ### Assistant: [{"class": "POS", "spans_text": ["dulanermin", "FOLFOX6", "bevacizumab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The study was conducted in 90 patients operated on for unilateral breast cancer who were then assigned to receive either 12 intravenous cycles of cyclophosphamide , methotrexate and fluorouracil ( CMF ) every three weeks , or no further treatment . Paragraph: Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-negative and estrogen receptor-negative breast cancer. Updated results. Node-negative breast cancers are considered to comprise a subgroup which is amenable to cure with local-regional therapy alone. However, approximately 30% of affected patients present new disease manifestations within 10 years after surgery. To test the hypothesis that node-negative and estrogen receptor-negative breast cancer patients can benefit from adjuvant chemotherapy, a prospective randomized study was activated at the Istituto Nazionale Tumori of Milan in 1980. ### Patients And Methods The study was conducted in 90 patients operated on for unilateral breast cancer who were then assigned to receive either 12 intravenous cycles of cyclophosphamide , methotrexate and fluorouracil ( CMF ) every three weeks , or no further treatment . Adjuvant chemotherapy was administered in the outpatient clinic of the Division of Medical Oncology. Patient characteristics were fairly well balanced between the two treatment groups except for primary tumor size: 58% of those with a primary tumor measuring > 2 cm in its largest diameter were randomized in the control group compared with 38% in the CMF regimen (P = 0.06). ### results At 12 years after surgery treatment outcome was significantly superior for patients given adjuvant CMF. The relapse-free survival rate was 71% (95% confidence limits (CL): 56-86) versus 43% (95% CL: 28-58), and total survival was 80% (95% CL: 68-92) versus 50% (95% CL: 34-66), respectively. The benefit from the administration of CMF was evident in all patient subsets and was not influenced by menopausal status. ### conclusions The long-term results of this trial of adjuvant combination chemotherapy confirm our previous observations on the efficacy of adjuvant chemotherapy in node-negative breast cancer patients at high risk of early disease relapse. ### Assistant: [{"class": "POS", "spans_text": ["cyclophosphamide", "methotrexate", "fluorouracil"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: This study compared the efficacy of topical emedastine 0.05 % ophthalmic solution with that of oral loratadine 10 mg and their combination in the conjunctival allergen challenge model of allergic conjunctivitis . Paragraph: A randomized, double-blind, placebo-controlled comparison of emedastine 0.05% ophthalmic solution with loratadine 10 mg and their combination in the human conjunctival allergen challenge model. When selecting treatment for allergic conjunctivitis, a primary concern is whether to choose local or systemic therapy. ### objective This study compared the efficacy of topical emedastine 0.05 % ophthalmic solution with that of oral loratadine 10 mg and their combination in the conjunctival allergen challenge model of allergic conjunctivitis . ### methods This was a single-center, randomized, double-masked, placebo-controlled, parallel-group study. At visit 1, eligible subjects underwent conjunctival allergen challenge to identify the dose required to elicit a positive allergic reaction. After 7 days, subjects returned for visit 2, at which the allergen dose was confirmed. At visit 3, which took place 2 weeks later, subjects were randomized to receive either emedastine plus placebo capsules, loratadine plus placebo eyedrops, or both emedastine and loratadine. One hour after receiving study drug, subjects were challenged with allergen in both eyes. Allergic signs and symptoms were graded using standardized 5-point scales. The primary efficacy variables were itching and conjunctival hyperemia. Secondary efficacy variables were ciliary and episcleral hyperemia, chemosis, lid swelling, and tearing. Itching was graded subjectively at 3, 5, and 10 minutes after challenge. All other variables were assessed at 5, 10, and 20 minutes after challenge. ### results Eighty subjects (mean age, 43.68 years) were randomized to receive study treatment. Forty subjects (20 men, 20 women) received emedastine plus placebo capsules, 20 (7 men, 13 women) received loratadine plus placebo eyedrops, and 20 (12 men, 8 women) received both active treatments. In the between-group efficacy comparison at visit 3, the difference in itching and hyperemia scores between emedastine and loratadine was statistically significant at all time points (all, P < 0.05). Efficacy scores for the combination of emedastine and loratadine were significantly better than those for loratadine alone at 2 of 3 time points for itching and all time points for hyperemia (P < 0.05). The combination was significantly better than emedastine alone at I of 3 time points for itching and 6 of 9 time points for hyperemia (P < 0.05). ### conclusion In this study, emedastine was more efficacious than loratadine for reducing the itching and redness associated with allergic conjunctivitis in the human conjunctival allergen challenge model. ### Assistant: [{"class": "POS", "spans_text": ["emedastine", "loratadine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Mycophenolate mofetil resulted in rapid improvement of steroid-refractory immune-related adverse event hepatitis , induced by nivolumab plus ipilimumab . Paragraph: Successful mycophenolate mofetil treatment of a patient with severe steroid-refractory hepatitis evoked by nivolumab plus ipilimumab treatment for relapsed bladder cancer. Mycophenolate mofetil resulted in rapid improvement of steroid-refractory immune-related adverse event hepatitis , induced by nivolumab plus ipilimumab . ### Assistant: [{"class": "COMB", "spans_text": ["nivolumab", "ipilimumab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Resistant isolates emerged quickly and uniformly in all patients administered nevirapine either as monotherapy or in combination with zidovudine ( AZT ) . Paragraph: Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. Drug susceptibility and mutations in the reverse transcriptase (RT) gene were analyzed with 167 virus isolates from 38 patients treated with nevirapine, a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) RT. Resistant isolates emerged quickly and uniformly in all patients administered nevirapine either as monotherapy or in combination with zidovudine ( AZT ) . Resistance developed as early as 1 week, indicating rapid turnover of the virus population. The development of resistance was associated with the loss of antiviral drug activity as measured by CD4 lymphocyte counts and levels of HIV p24 antigen and RNA in serum. In addition to mutations at amino acid residues 103, 106, and 181 that had been identified by selection in cell culture, mutations at residues 108, 188, and 190 were also found in the patient isolates. Sequences from patient clones documented cocirculating mixtures of populations of different mutants. The most common mutation with monotherapy, tyrosine to cysteine at residue 181, was prevented from emerging by coadministration of AZT, which resulted in the selection of alternative mutations. The observations documented that, under selective drug pressure, the circulating virus population can change rapidly, and many alternative mutants can emerge, often in complex mixtures. The addition of a second RT inhibitor, AZT, significantly altered the pattern of mutations in the circulating population of HIV. ### Assistant: [{"class": "COMB", "spans_text": ["nevirapine", "zidovudine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Postoperative combination chemotherapy for six cycles with cisplatin ( 100 mg/m2 per day for 1 day every 3 weeks ) , bleomycin ( 15 units intravenously weekly for 18 weeks ) and etoposide ( 100 mg/m2 per day for 3 days every 3 weeks ) were given and the tumor responded dramatically . Paragraph: Huge retroperitoneal germinoma presenting with pathological fracture of the spine. Primary retroperitoneal germ cell tumors are extremely rare neoplasms. The most common presenting features are abdominal pain and palpable abdominal masses. Pathological fractures of the spine presenting as bilateral lower leg weakness are exceptionally rare. We describe a 16-year-old girl who developed progressive paraplegia after a minor falling injury. Radiological study demonstrated a huge retroperitoneal tumor with invasion of the T12 vertebral body and spinal canal. A posterior surgical approach was used to perform laminectomy (T12, L1), removal of the intraspinal tumor and internal fixation with transpedical screws (T10, T11 to L2,3), and posterolateral fusion. Postoperative combination chemotherapy for six cycles with cisplatin ( 100 mg/m2 per day for 1 day every 3 weeks ) , bleomycin ( 15 units intravenously weekly for 18 weeks ) and etoposide ( 100 mg/m2 per day for 3 days every 3 weeks ) were given and the tumor responded dramatically . The patient had fully recovered without evidence of sequelae or recurrence at 2 years after operation. To the authors' knowledge, this is the first case in which a huge retroperitoneal germinoma presented as pathological fracture of the spine and spinal cord compression. The effectiveness of the postoperative cisplatin-based chemotherapy against this tumor made major retroperitoneal surgery to remove the main tumor mass unnecessary is also demonstrated. ### Assistant: [{"class": "POS", "spans_text": ["cisplatin", "bleomycin", "etoposide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The other received chemotherapy including prednisone , vincristine , cytarabine and L-asparaginase , combined with intrathecal injections of methotrexate , dexamethasone and Ara-C and supporting treatment . Paragraph: [Renal tubular acidosis as an initial manifestation in children with malignant lymphoma]. Primary renal lymphoma is one of the malignant lymphomas that initially presents in the extra lymphonode, which is rarely seen in children. This study reported two cases of primary renal lymphoma in children who were definitively diagnosed by renal biopsy. Renal tubular acidosis was the initial manifestation in both cases. They were referred to the hospital with chief complaints of polydipsia, polyuria, debilitation, vomiting and anemia. Imaging and laboratory examinations showed bilateral renomegaly, hypocalcemia, hypophosphatemia, and metabolic acidosis. One of the patients discontinued therapy. The other received chemotherapy including prednisone , vincristine , cytarabine and L-asparaginase , combined with intrathecal injections of methotrexate , dexamethasone and Ara-C and supporting treatment . Twenty-three days after treatment, polydipsia and polyuria were relieved, and acidosis, kaliopenia and anemia were improved in the patient. There were no abnormal findings in the renal B-ultrasound re-examination. It was concluded that when a patient is suspected of renal lymphoma, diagnostic puncture and renal biopsy should be performed early. Early combined therapeutics including chemotherapy, radiation therapy, surgery and supporting treatments may result in a favorable prognosis in patients with this disease. ### Assistant: [{"class": "POS", "spans_text": ["prednisone", "vincristine", "cytarabine", "L-asparaginase"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Then , neoadjuvant chemotherapy ( NAC ) consisting of a combination of 5-fluorouracil ( 5-FU ) , oxaliplatin , irinotecan , and leucovorin ( FOLFOXIRI ) was planned , followed by primary tumor resection . Paragraph: A pathological complete response after neoadjuvant triplet chemotherapy for locally advanced transverse colon cancer. Perioperative chemotherapy could improve oncological outcomes for patients with advanced colon cancer. However, the effectiveness of triplet chemotherapy in the neoadjuvant setting is still unknown. ### Presentation Of Case A 61-year-old man was referred to our hospital due to abdominal distention. Abdominal computed tomography showed a huge, 18-cm mass in the right upper abdomen. Biopsy showed well-differentiated adenocarcinoma. Locally advanced transverse colon cancer T4b N2a M0 Stage IIIC was diagnosed. Considering the extensive invasion to surrounding organs and difficulties in achieving margin-negative surgery, an emergency ileostomy was performed first. Then , neoadjuvant chemotherapy ( NAC ) consisting of a combination of 5-fluorouracil ( 5-FU ) , oxaliplatin , irinotecan , and leucovorin ( FOLFOXIRI ) was planned , followed by primary tumor resection . After 6 courses of treatment, the primary tumor shrank remarkably. Finally, laparoscopic radical extended right hemi-colectomy was performed. There were no residual tumor cells in resected specimens, including the primary tumor and surrounding lymph nodes. The pathological diagnosis was complete response. ### conclusion A case of pathological complete response after neoadjuvant treatment followed by radical resection was reported. Further research is needed to confirm the appropriate indications for neoadjuvant FOLFOXIRI therapy for patients with LACC. ### Assistant: [{"class": "POS", "spans_text": ["5-fluorouracil", "oxaliplatin", "irinotecan", "leucovorin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Interestingly , aspirin not only significantly inhibited the growth of TNBC cells , but also attenuated YAP and β-catenin expression by upregulating the E3 ubiquitin ligase β-TrCP to abolished docetaxel and vinorelbine resistance . Paragraph: Aspirin attenuates YAP and β-catenin expression by promoting β-TrCP to overcome docetaxel and vinorelbine resistance in triple-negative breast cancer. The use of aspirin has been associated with reduced breast cancer risk, but it is litter known if aspirin overcomes chemoresistance in triple-negative breast cancer (TNBC). Herein, we demonstrated that changes in the expression of Yes-associated protein (YAP) and β-catenin might be a promising predictive biomarker for neoadjuvant chemotherapy sensitivity in TNBC patients. Inhibition of YAP or β-catenin enhanced the cytotoxicity of the anti-microtubule agents docetaxel and vinorelbine against drug-resistant TNBC cells as well as the sensitivity of these cells to the agents in vitro and in vivo. Interestingly , aspirin not only significantly inhibited the growth of TNBC cells , but also attenuated YAP and β-catenin expression by upregulating the E3 ubiquitin ligase β-TrCP to abolished docetaxel and vinorelbine resistance . The combination of aspirin and docetaxel or vinorelbine remarkably inhibited the growth of drug-resistant TNBC cells in vitro and in vivo. Moreover, TNBC patients with high YAP and/or β-catenin expression had a higher risk of relapse or mortality than patients with low YAP and/or β-catenin expression. Collectively, our study discovered a novel role of aspirin based on its anticancer effect, and put forward some possible mechanisms of chemoresistance in TNBC. The combined use of aspirin and anti-microtubule drugs presented several promising therapeutic approaches for TNBC treatment. ### Assistant: [{"class": "POS", "spans_text": ["aspirin", "docetaxel", "vinorelbine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: No alterations in paclitaxel or doxorubicin pharmacokinetics were observed when the drugs were administered alone versus in combination . Paragraph: Combination paclitaxel (Taxol) and doxorubicin therapy for metastatic breast cancer. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a very active agent for the treatment of breast cancer, with associated complete response rates of 12% in patients with minimally pretreated metastatic disease. Simultaneous paclitaxel and doxorubicin administration by 72-hour continuous infusion in patients with previously untreated metastatic breast cancer has yielded an overall response rate of 72% with 8% complete responses. No alterations in paclitaxel or doxorubicin pharmacokinetics were observed when the drugs were administered alone versus in combination . Two phase I studies from the M.D. Anderson Cancer Center (Houston, TX) and the University of Indiana (Indianapolis, IN) have shown that administration of a 24-hour paclitaxel infusion prior to doxorubicin results in a significantly higher incidence of mucositis than the reverse sequence. Preliminary pharmacokinetic studies from M.D. Anderson suggest that peak plasma concentration and clearance of doxorubicin are altered by pretreatment with 24-hour paclitaxel. In contrast, in an ongoing phase I study at the Istituto Nazionale Tumori in Milan, Italy, no differences in toxicities have been observed with the combination of intravenous bolus doxorubicin and 3-hour infusional paclitaxel administered by either sequence. Preclinical in vitro and in vivo studies suggest that the combination of paclitaxel and doxorubicin is associated with no or minimal additive antitumor effects. The modest complete response rates that have been observed in patients with metastatic breast cancer to date are in agreement with these observations. A randomized study of paclitaxel versus doxorubicin versus intravenous bolus doxorubicin followed by 24-hour paclitaxel is now being conducted by the Eastern Cooperative Oncology Group. ### Assistant: [{"class": "COMB", "spans_text": ["paclitaxel", "doxorubicin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Twenty-seven received rituximab mainly in addition to high-dose cytarabine and etoposide ( n = 18 ) and/or ifosfamide , carboplatin , and etoposide ( n = 7 ) . Paragraph: Outcome of relapse in children and adolescents with B-cell non-Hodgkin lymphoma and mature acute leukemia: A report from the French LMB study. In order to describe relapsed B-cell non-Hodgkin lymphoma and mature acute leukemia in children/adolescents treated with the Lymphomes Malins B (LMB) regimen and their outcome in the rituximab era, relapses in the French LMB2001 study were reviewed. ### methods Between February 2001 and December 2011, 33 patients out of 773 (4.3%) relapsed; 27 had Burkitt lymphoma and six large B-cell histology. Median age at diagnosis was 10.1 years. One patient was initially treated in risk group A, 21 in group B, and 11 in group C. ### results Median time to relapse after diagnosis was 4.5 months (range 2.4-13.6). Thirty-two patients received salvage therapy. Twenty-seven received rituximab mainly in addition to high-dose cytarabine and etoposide ( n = 18 ) and/or ifosfamide , carboplatin , and etoposide ( n = 7 ) . First-line salvage chemotherapy response rate was 66% with 47% being complete remission (CR). Twenty-one patients received high-dose chemotherapy (HDC) followed by autologous (n = 13) or allogeneic (n = 8) transplant. With a median follow-up of 6.8 years, the 5-year survival rate after relapse was 36.4% (95% confidence interval [CI] 22-53%). Twelve patients were still alive; all but one (group A) received consolidation treatment. Achieving CR before consolidation was significantly associated with better survival, with a 5-year survival rate of 75% (95% CI 46.8-91.1%) for patients in CR before HDC, 33% (95% CI 9.7-70%) for patients in partial remission, and 0% for nonresponders (P = .033). ### conclusion Survival of children/adolescents with mature B-cell lymphoma/leukemia remains poor after relapse with no apparent improvement with rituximab. Response rates to salvage chemo-immunotherapies are insufficient and new drugs are urgently needed to improve disease control. ### Assistant: [{"class": "COMB", "spans_text": ["rituximab", "cytarabine", "etoposide", "ifosfamide", "carboplatin", "etoposide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Both mono and combination therapies achieved the primary efficacy parameters : lowered diastolic blood pressure ( at trough ) more than placebo , p < 01 ( except the 120 mg verapamil SR , NS , 0.5 mg trandolapril , 0.5/180 and 2/120 combinations , p < 05 ) , yielded a trough to peak ratio of > 0.52 and had higher percentages of responders compared to placebo . Paragraph: Efficacy of combination therapy with trandolapril and verapamil sr in primary hypertension: a 4 x 4 trial design. The Trandolapril Study Group. The Joint National Committee V suggested that combination therapy can provide effective blood pressure control in patients with stage I-IV hypertension. This 4 x 4 factorial trial design assessed the efficacy of monotherapy with trandolapril-an ACE inhibitor, and verapamil SR-a calcium antagonist, each in a range of 3 doses as monotherapy, and in combination therapy in patients with stage I-III diastolic hypertension. After a 4-week, single-blind placebo treatment period, 746 patients in 39 study centers were randomized to 1 of the 16 double-blind treatments for 6 weeks (placebo, verapamil SR monotherapy 120, 180, or 240 mg; trandolapril monotherapy 0.5, 2, or 8 mg; and trandolapril/verapamil SR combinations 0.5/120, 0.5/180, 0.5/240, 2/120, 2/180, 2/240, 8/120, 8/180, or 8/240 mg. Both mono and combination therapies achieved the primary efficacy parameters : lowered diastolic blood pressure ( at trough ) more than placebo , p < 01 ( except the 120 mg verapamil SR , NS , 0.5 mg trandolapril , 0.5/180 and 2/120 combinations , p < 05 ) , yielded a trough to peak ratio of > 0.52 and had higher percentages of responders compared to placebo . Combination therapy was more effective than monotherapy for sitting diastolic blood pressure 2/180, p < 01; 2/240 and 8/240, p < 05. There were no differences between active treatment groups and placebo as a percentage of patients having adverse reactions. trandolapril, 2 and 8 mg, appeared to have a greater incremental effect on the systolic blood pressure reduction of the combination than verapamil SR 180 and 240 mg. ### Assistant: [{"class": "POS", "spans_text": ["verapamil", "trandolapril"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In metastastic patients , the combination of gemcitabine and cisplatin has become the new standard regimen due to a lower toxicity in comparison to the combination of methotrexate , vinblastine , doxorubicin , and cisplatin ( MVAC ) . Paragraph: [Neoadjuvant or Adjuvant Chemotherapy for Bladder Cancer?]. Advanced urothelial carcinoma of the bladder is associated with a high metastatic potential. Life expectancy for metastatic patients is poor and rarely exceeds more than one year without further therapy. Neoadjuvant chemotherapy can decrease the tumour burden while reducing the risk of death. Adjuvant chemotherapy has been discussed controversially. Patients with lymph node-positive metastases seem to benefit the most from adjuvant chemotherapy. In selected patients, metastasectomy can prolong survival. In metastastic patients , the combination of gemcitabine and cisplatin has become the new standard regimen due to a lower toxicity in comparison to the combination of methotrexate , vinblastine , doxorubicin , and cisplatin ( MVAC ) . For second-line treatment, vinflunine is the only approved therapeutic agent. ### Assistant: [{"class": "POS", "spans_text": ["gemcitabine", "cisplatin"]}, {"class": "COMB", "spans_text": ["methotrexate", "vinblastine", "doxorubicin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: A randomized clinical trial of adjuvant chemotherapy with doxorubicin , ifosfamide , and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas ( SARCGYN study ) . Paragraph: A randomized clinical trial of adjuvant chemotherapy with doxorubicin , ifosfamide , and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas ( SARCGYN study ) . There is no proven benefit of adjuvant treatment of uterine sarcoma (US). SARCGYN phase III study compared adjuvant polychemotherapy followed by pelvic radiotherapy (RT) (arm A) versus RT alone (arm B) conducted to detect an increase ≥ 20% of 3-year PFS. ### methods Patients with FIGO stage ≤ III US, physiological age ≤ 65 years; chemotherapy: four cycles of doxorubicin 50 mg/m&sup2; d1, ifosfamide 3 g/m&sup2;/day d1-2, cisplatin 75 mg/m&sup2; d3, (API) + G-CSF q 3 weeks. Study was stopped because of lack of recruitment. ### results Eighty-one patients were included: 39 in arm A and 42 in arm B; 52 stage I, 16 stage II, 13 stage III; 53 leiomyosarcomas, 9 undifferenciated sarcomas, 19 carcinosarcomas. Gr 3-4 toxicity during API (/37 patients): thrombopenia (76%), febrile neutropenia (22%) with two toxic deaths; renal gr 3 (1 patient). After a median follow-up of 4.3 years, 41/81 patients recurred, 15 in arm A, 26 in arm B. The 3 years DFS is 55% in arm A, 41% in arm B (P = 0.048). The 3-year overall survival (OS) is 81% in arm A and 69% in arm B (P = 0.41). ### conclusion API adjuvant CT statistically increases the 3 year-DFS of patients with US. ### Assistant: [{"class": "POS", "spans_text": ["doxorubicin", "ifosfamide", "cisplatin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Combination therapy with irinotecan ( CPT-11 ) , 5-fluorouracil ( 5-FU ) and leucovorin is widely used for the treatment of metastatic colorectal cancer . Paragraph: Pharmacodynamic study of the Saltz regimen for metastatic colorectal cancer in a hemodialyzed patient. Combination therapy with irinotecan ( CPT-11 ) , 5-fluorouracil ( 5-FU ) and leucovorin is widely used for the treatment of metastatic colorectal cancer . However, little is known about the safety of chemotherapy of malignancies in hemodialysis (HD) patients. We encountered a patient with colorectal carcinoma on HD. We decided to administer combination chemotherapy while monitoring the pharmacodynamics of the patient. ### Case Report A 74-year-old male received regular HD 3 times a week because of type 1 diabetes mellitus. He was diagnosed with stage IV colorectal cancer in November 2004. After sigmoidectomy, the patient received chemotherapy: a weekly schedule of CPT-11 (50 mg/m(2)) was administered followed by l-leucovorin (10 mg/m(2)) and 5-FU (400 mg/m(2)) just after HD. During the course, the plasma concentrations of both SN-38, an active metabolite of CPT-11, and 5-FU were not increased compared with those of patients with normal renal function. Our patient presented with grade III hematological toxicity that was easily recovered by granulocyte colony-stimulating factor. ### conclusion These data suggest that the dose-reduced Saltz regimen can be feasible for colorectal cancer patients receiving dialysis as postoperative adjuvant chemotherapy. ### Assistant: [{"class": "POS", "spans_text": ["irinotecan", "leucovorin", "5-fluorouracil"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Long-term safety and outcome of fludarabine , cyclophosphamide and mitoxantrone ( FCM ) regimen in previously untreated patients with advanced follicular lymphoma : 12 years follow-up of a phase 2 trial . Paragraph: Long-term safety and outcome of fludarabine , cyclophosphamide and mitoxantrone ( FCM ) regimen in previously untreated patients with advanced follicular lymphoma : 12 years follow-up of a phase 2 trial . fludarabine combinations are very affective in follicular lymphoma (FL) with high rates of complete response and prolonged survival. However, late toxicities could be a concern. The aim of the present study was to analyze the long-term impact on survival, relapse and late toxicities of a trial of treatment with fludarabine, mitoxantrone and cyclophosphamide (FCM regimen) for untreated patients with advanced stage FL. One hundred and twenty patients enrolled in a phase 2 trial of treatment with FCM regimen between 2000 and 2003 were evaluated. After a median follow-up of 12 years, 52 patients eventually relapsed/progressed with 10 year progression-free survival (PFS) of 46 %. Ten patients showed histological transformation to aggressive lymphoma with a risk of transformation of 2 and 9 % at 5 and 10 years, respectively. Three patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) and seven solid neoplasms with an overall risk of 3 and 8 % at 5 and 10 years, respectively. Twenty-six patients eventually died during the follow-up. Overall survival at 10 years was 83 %. In conclusion, FCM regimen allows excellent long-lasting response in previously untreated patients with FL. The incidence of late events including histological transformation and secondary neoplasia is low but not negligible. ### Assistant: [{"class": "POS", "spans_text": ["fludarabine", "cyclophosphamide", "mitoxantrone"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: After clinical improvement under vemurafenib monotherapy , four cycles of ipilimumab were additionally administered . Paragraph: 18F-FDG PET/CT longitudinal studies in patients with advanced metastatic melanoma for response evaluation of combination treatment with vemurafenib and ipilimumab. Sixteen BRAF-mutation positive, metastatic melanoma patients with highly advanced disease received combination therapy of vemurafenib and ipilimumab as an individual treatment decision. Our aim was to assess the role of fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (PET/CT) in the evaluation of the clinical benefit (CB) of this combination treatment. After clinical improvement under vemurafenib monotherapy , four cycles of ipilimumab were additionally administered . F-FDG PET/CT was performed before the start, after two cycles and after completion of the combined ipilimumab/vemurafenib treatment. PET-based patient response evaluation to treatment was based on the European Organization for Research and Treatment of Cancer and the PET Response Evaluation Criteria for Immunotherapy criteria. Progression-free survival (PFS) from the end of combination treatment was calculated. According to their best clinical response at the end of combination treatment, eight patients showed CB and eight patients had no-CB. Two patients revealed extraordinary good clinical outcome with PFS of more than 5 years. Overall, 13 out of 16 patients were correctly classified by the European Organization for Research and Treatment of Cancer and 15 out of 16 by the PET Response Evaluation Criteria for Immunotherapy criteria. Median PFS was 8.8 months among PET-responders and 3.6 months among nonresponders. During immunotherapy administration seven patients developed radiologic signs of immune-related adverse events (irAEs), with colitis and arthritis being the most frequent ones; these patients had a significantly longer PFS than those without irAEs (P=0.036). F-FDG PET/CT is a valuable tool for the evaluation of patients receiving a combination of targeted treatment and immunotherapy. The appearance of irAEs on PET/CT might correlate with benefit to immunotherapy. ### Assistant: [{"class": "POS", "spans_text": ["vemurafenib", "ipilimumab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer ( TURANDOT ): primary endpoint results of a randomised , open-label , non-inferiority , phase 3 trial . Paragraph: Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer ( TURANDOT ): primary endpoint results of a randomised , open-label , non-inferiority , phase 3 trial . The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1·04; 97·5% repeated CI [RCI] -∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. ### methods In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. ### findings Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6-32·6 months) versus 26·1 months (22·3-29·0), respectively. The stratified HR was 1·02 (97·5% RCI -∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 [97·5% RCI -∞ to 1·39]; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. ### interpretation bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles. ### funding Roche. ### Assistant: [{"class": "POS", "spans_text": ["bevacizumab", "capecitabine"]}, {"class": "COMB", "spans_text": ["Bevacizumab", "paclitaxel"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: She underwent rectectomy and adjuvant chemotherapy with fluorouracil , leucovorin plus oxaliplatin for stage IIIB rectal cancer . Paragraph: Esophageal Metastasis from Rectal Cancer Successfully Treated with Fluorouracil-Based Chemotherapy with Bevacizumab: A Case Report and Review of the Literature. Esophageal metastasis from colorectal carcinoma is uncommon, and diagnosis of esophageal metastasis is difficult. We report a case of a 54-year-old woman with postoperative recurrence of rectal cancer metastasizing to the esophagus. She underwent rectectomy and adjuvant chemotherapy with fluorouracil , leucovorin plus oxaliplatin for stage IIIB rectal cancer . Three years later, she presented with dysphagia and cough. Computed tomography showed thickening of the esophagus wall, enlargement of the lymph nodes in the mediastinum and abdomen, and ground-glass opacities in the right lung. Endoscopy revealed a submucosal tumor of the midthoracic esophagus. Histopathological analysis of the tumor biopsy showed infiltration of adenocarcinoma cells into the stroma of the esophagus; tumor cells were positive for caudal type homeobox 2 and negative for thyroid transcription factor 1. A transbronchial biopsy indicated pulmonary lymphangitic carcinomatosis of rectal adenocarcinoma. Based on those findings, she was diagnosed with recurrent rectal cancer. She received fluorouracil-based chemotherapy plus bevacizumab, which ameliorated her symptoms and induced a durable response without severe adverse events. Diagnosis of esophageal metastasis from rectal cancer can thus be made by repeated biopsy. Furthermore, aggressive systemic treatment with fluorouracil-containing chemotherapy and bevacizumab is a treatment option for colorectal cancer patients with esophageal metastasis. ### Assistant: [{"class": "COMB", "spans_text": ["fluorouracil", "leucovorin", "oxaliplatin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We designed this phase II trial to evaluate the safety , tolerability , and efficacy of the combination of carboplatin , paclitaxel , cetuximab , and bevacizumab in chemotherapy-naive patients with advanced , nonsquamous NSCLC . Paragraph: Phase II trial of carboplatin, paclitaxel, cetuximab, and bevacizumab followed by cetuximab and bevacizumab in advanced nonsquamous non-small-cell lung cancer: SWOG S0536. cetuximab and bevacizumab have each been demonstrated to prolong survival when added to chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). However, the potential benefit of combining cetuximab and bevacizumab together with a platinum-based doublet had not been explored. We designed this phase II trial to evaluate the safety , tolerability , and efficacy of the combination of carboplatin , paclitaxel , cetuximab , and bevacizumab in chemotherapy-naive patients with advanced , nonsquamous NSCLC . ### methods Patients received with up to six cycles of carboplatin (area under curve 6), paclitaxel (200 mg/m(2)), cetuximab (400 mg/m(2) day 1 then 250 mg/m(2) weekly), and bevacizumab (15 mg/kg) every 21 days. Patients with an objective response or stable disease received maintenance cetuximab (250 mg/m(2) weekly) and bevacizumab (15 mg/kg every 21 days) until disease progression. The primary endpoint was safety as defined by the frequency and severity of hemorrhagic toxicities. Secondary endpoints included response rate, progression-free survival, overall survival, and toxicity. Molecular biomarkers were assessed in an exploratory manner. ### results The primary endpoint of grade 4 or higher hemorrhage of 2% (95% confidence interval: 0%-7%) met prespecified criteria for safety. One hundred ten patients were enrolled. There were four treatment-related deaths including lung hemorrhage (2), infection (1), and unknown (1). Median progression-free survival was 7 months and median overall survival was 15 months. The response rate was 56% with an overall disease control rate of 77%. ### conclusion This regimen was safe, feasible, and effective as a frontline treatment of advanced NSCLC, providing the basis for the ongoing phase III trial S0819. ### Assistant: [{"class": "POS", "spans_text": ["carboplatin", "paclitaxel", "cetuximab", "bevacizumab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: All patients underwent mexiletine monotherapy ( M-mono ) , propafenone monotherapy ( P-mono ) , low dose combination therapy ( low M+P ) , and full dose combination therapy ( full M+P ) . Paragraph: Mexiletine and propafenone: a comparative study of monotherapy, low, and full dose combination therapy. The electrophysiological effects of combination therapy of mexiletine and propafenone were assessed using standard 12-lead electrocardiogram (standard ECG), signal-averaged ECG (SAECG), and ambulatory ECG in 31 patients with ventricular arrhythmias. All patients underwent mexiletine monotherapy ( M-mono ) , propafenone monotherapy ( P-mono ) , low dose combination therapy ( low M+P ) , and full dose combination therapy ( full M+P ) . Full M+P increased the PQ interval and QRS duration to the same extent as P-mono did. Low M+P increased PQ interval and QRS duration to a lesser extent than P-mono and full M+P did. P-mono and full M+P significantly decreased root mean square (RMS) and increased f-QRS in SAECG, while M-mono and low M+P showed only a weak trend. SAECGs with late potentials increased in number with treatments; 9 in predrug control, 11 on M-mono, 15 on P-mono, 10 on low M+P, and 14 on full M+P. The percent suppression of frequent premature ventricular contractions (PVCs) (> 1,000/day) with M-mono, P-mono, low M+P, and full M+P were 46.4 +/- 9.0, 56.6 +/- 10.4, 64.4 +/- 9.2, and 71.4 +/- 7.1, respectively, and those of frequent couplets (> 10/day) were 58.3 +/- 17.7, 62.6 +/- 23.6, 87.5 +/- 6.2, and 92.1 +/- 4.0, respectively. Thus, full dose combination of mexiletine and propafenone exhibited the maximum antiarrhythmic efficacy without enhancement of effects on standard ECG and SAECG. Low dose combination therapy showed better antiarrhythmic efficacy in association with lesser effects on standard ECG and SAECG compared with propafenone monotherapy. ### Assistant: [{"class": "POS", "spans_text": ["mexiletine", "propafenone"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Cephalexin , 500 mg 4 times daily , plus trimethoprim-sulfamethoxazole , 320 mg/1600 mg twice daily , for 7 days ( n = 248 participants ) or cephalexin plus placebo for 7 days ( n = 248 participants ) . Paragraph: Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial. Emergency department visits for skin infections in the United States have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). For cellulitis without purulent drainage, β-hemolytic streptococci are presumed to be the predominant pathogens. It is unknown if antimicrobial regimens possessing in vitro MRSA activity provide improved outcomes compared with treatments lacking MRSA activity. ### objective To determine whether cephalexin plus trimethoprim-sulfamethoxazole yields a higher clinical cure rate of uncomplicated cellulitis than cephalexin alone. ### Design Setting And Participants Multicenter, double-blind, randomized superiority trial in 5 US emergency departments among outpatients older than 12 years with cellulitis and no wound, purulent drainage, or abscess enrolled from April 2009 through June 2012. All participants had soft tissue ultrasound performed at the time of enrollment to exclude abscess. Final follow-up was August 2012. ### interventions Cephalexin , 500 mg 4 times daily , plus trimethoprim-sulfamethoxazole , 320 mg/1600 mg twice daily , for 7 days ( n = 248 participants ) or cephalexin plus placebo for 7 days ( n = 248 participants ) . ### Main Outcomes And Measures The primary outcome determined a priori in the per-protocol group was clinical cure, defined as absence of these clinical failure criteria at follow-up visits: fever; increase in erythema (>25%), swelling, or tenderness (days 3-4); no decrease in erythema, swelling, or tenderness (days 8-10); and more than minimal erythema, swelling, or tenderness (days 14-21). A clinically significant difference was defined as greater than 10%. ### results Among 500 randomized participants, 496 (99%) were included in the modified intention-to-treat analysis and 411 (82.2%) in the per-protocol analysis (median age, 40 years [range, 15-78 years]; 58.4% male; 10.9% had diabetes). Median length and width of erythema were 13.0 cm and 10.0 cm. In the per-protocol population, clinical cure occurred in 182 (83.5%) of 218 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 165 (85.5%) of 193 in the cephalexin group (difference, -2.0%; 95% CI, -9.7% to 5.7%; P = .50). In the modified intention-to-treat population, clinical cure occurred in 189 (76.2%) of 248 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 171 (69.0%) of 248 in the cephalexin group (difference, 7.3%; 95% CI, -1.0% to 15.5%; P = .07). Between-group adverse event rates and secondary outcomes through 7 to 9 weeks, including overnight hospitalization, recurrent skin infections, and similar infection in household contacts, did not differ significantly. ### Conclusions And Relevance Among patients with uncomplicated cellulitis, the use of cephalexin plus trimethoprim-sulfamethoxazole compared to cephalexin alone did not result in higher rates of clinical resolution of cellulitis in the per-protocol analysis. However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed. ### Trial Registration clinicaltrials.gov Identifier: NCT00729937. ### Assistant: [{"class": "COMB", "spans_text": ["Cephalexin", "trimethoprim-sulfamethoxazole"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In the NALA trial , neratinib plus capecitabine led to increased PFS and time to intervention for central nervous system disease over the standard regimen of lapatinib plus capecitabine . Paragraph: Neratinib plus capecitabine for the treatment of advanced HER2-positive breast cancer. Several agents are being developed for advanced HER2-positive breast cancer, such as potent tyrosine kinase inhibitors (TKI) targeting ErbB family receptors, novel antibody-drug conjugates, higher affinity anti-HER2 antibodies, among others. neratinib is an irreversible pan-HER (EGFR, ERBB2, and ERBB4) TKI being tested in early and advanced HER2-positive breast cancer. In the NALA trial , neratinib plus capecitabine led to increased PFS and time to intervention for central nervous system disease over the standard regimen of lapatinib plus capecitabine . The main adverse event in the neratinib arm was diarrhea, which mandates for prophylactic treatment with loperamide. ### Areas Covered In this review, we analyze and discuss preclinical and clinical data with neratinib plus capecitabine. We summarize efficacy and safety results from phase I/II and III trials, and discuss this regimen within the landscape of treatment for patients with HER2-positive metastatic breast cancer progressing after two lines of HER2-directed treatment. ### Expert Opinion neratinib plus capecitabine is a valid treatment option for patients with advanced HER2-positive breast cancer, after progression to at least two anti-HER2-based regimens. Given the multiple options that are being developed in this context, efforts should be employed to establish strong predictive biomarkers of efficacy to each drug and combination. ### Assistant: [{"class": "POS", "spans_text": ["neratinib", "capecitabine"]}, {"class": "POS", "spans_text": ["lapatinib", "capecitabine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Since the patient had anemia , aspirin and cilostazol were discontinued after diagnosis . Paragraph: [A Case of Ascending Colon Cancer with Essential Thrombocythemia]. Essential thrombocythemia(ET)is a rare myeloproliferative disorder characterized by thrombocytosis and a risk of thrombotic and hemorrhagic events. ET rarely occurs simultaneously with colorectal cancer. Including our case, only 5 cases of c o l orectal cancer with ET have been reported in Japan. Herein, we report a case of colon cancer in an ET patient who underwent laparoscopic right hemicolectomy. Our perioperative management avoided complications such as thrombosis or bleeding. An 81-year-old woman developed bloody stools. She was previously diagnosed with ET 9 years ago. aspirin, cilostazol, and hydroxyurea(HU)were prescribed. Colonoscopy revealed a tumor at the ascending colon. Histopathological examination showed a well-differentiated tubular adenocarcinoma. Since the patient had anemia , aspirin and cilostazol were discontinued after diagnosis . HU was discontinued from the day before surgery to 2 days after surgery. enoxaparin was subcutaneously administered for 1 to 3 days after surgery. aspirin and cilostazol were resumed on the fourth day post-surgery. The patient could be discharged when her condition stabilizes with no thrombosis and bleeding after 8 days. ### Assistant: [{"class": "NEG", "spans_text": ["aspirin", "cilostazol"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: This case report describes a patient with O-NHL which was possibly linked to the combination of methotrexate and etanercept for the treatment of her rheumatoid arthritis . Paragraph: Oral non-Hodgkin's lymphoma in a patient with rheumatoid arthritis treated with etanercept and methotrexate. Oral non-Hodgkin's lymphomas (O-NHLs) are a rare group of diverse lymphoid tissue malignancies and represent less than 5% of the oral cavity malignancies and 2% of all extra-nodal NHLs. Oral-NHLs affect the Waldeyer's-ring, the salivary glands, the bone of the jaws and the oral mucosa, their clinical appearance is very heterogeneous. Among the risk factors for NHLs are immunosuppression (primary or secondary), autoimmunity and inflammation. O-NHLs share the same risk factors. This case report describes a patient with O-NHL which was possibly linked to the combination of methotrexate and etanercept for the treatment of her rheumatoid arthritis . To our knowledge this is probably among the first cases of O-NHL with possible relation to the use of a Tumor Necrosis Factor (TNF) antagonist biological agent (etanercept). This case could contribute to the sensitization of the dentists for the signs and symptoms of this rare malignancy. It also underlines the need for thorough medical history and medication recording for all the dental patients. Key words:Lymphoma (oral) methotrexate, etanercept. ### Assistant: [{"class": "NEG", "spans_text": ["methotrexate", "etanercept"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In a prospective , pragmatic , randomised , parallel group study , 170 patients of mean ( SD ) age 37 ( 12 ) years with acute asthma ( peak expiratory flow ( PEF ) 212 ( 80 ) l/min ) presenting to hospital received treatment with either high dose prednisolone and continuous nebulised salbutamol as recommended in the US or lower dose prednisolone and bolus nebulised salbutamol as recommended in the UK by the BTS . Paragraph: Randomised pragmatic comparison of UK and US treatment of acute asthma presenting to hospital. Systemic corticosteroids and inhaled beta(2) agonists are accepted first line treatments for acute severe asthma, but there is no consensus on their optimum dosage and frequency of administration. American regimens include higher initial dosages of beta(2) agonists and corticosteroids than UK regimens. ### methods In a prospective , pragmatic , randomised , parallel group study , 170 patients of mean ( SD ) age 37 ( 12 ) years with acute asthma ( peak expiratory flow ( PEF ) 212 ( 80 ) l/min ) presenting to hospital received treatment with either high dose prednisolone and continuous nebulised salbutamol as recommended in the US or lower dose prednisolone and bolus nebulised salbutamol as recommended in the UK by the BTS . ### results Outcome measures were: deltaPEF at 1 hour (BTS 89 l/min, US 106 l/min, p=0.2, CI -8 to 41) and at 2 hours (BTS 49 l/min, US 101 l/min, p<0.0001, CI 28 to 77); time to discharge if admitted (BTS 4 days, US 4 days); rates of achieving discharge PEF (>60%) at 2 hours (BTS 64%, US 78%, p=0.04); time to regain control of asthma as measured by PEF >/=80% best with salbutamol leads to a greater immediate improvement in PEF but the degree of recovery at 24 hours and speed of recovery thereafter is achieved as effectively with lower corticosteroid doses as recommended in the British guidelines. ### Assistant: [{"class": "POS", "spans_text": ["prednisolone", "salbutamol"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We report a case of a 78-year-old white male ( weight , 90 kg ) presented to the Department of Medical Oncology and Hematology , Istituto Clinico Humanitas , Rozzano , Milan , Italy , with refractory MM immunoglobulin G kappa ( IgGkappa ) , Durie-Salmon Stage IIA , with progressive renal failure after an oral melphalan , prednisone , and thalidomide regimen ( 4 mg/m2.d , 40 mg/m2.d for 7 days every 6 weeks , and 100 mg/d , respectively ) . Paragraph: Bortezomib-dexamethasone combination in a patient with refractory multiple myeloma and impaired renal function. Multiple myeloma (MM) is a hematologic neoplasia characterized by the monoclonal proliferation of bone marrow plasma cells. Renal failure occurs in 20% to 30% of MM patients at diagnosis and in >50% with an advanced form of the disease. For those with advanced MM, often a high-risk group of patients with poor prognosis, salvage treatment for renal failure needs to avoid nephrotoxic drugs. ### Case Summary We report a case of a 78-year-old white male ( weight , 90 kg ) presented to the Department of Medical Oncology and Hematology , Istituto Clinico Humanitas , Rozzano , Milan , Italy , with refractory MM immunoglobulin G kappa ( IgGkappa ) , Durie-Salmon Stage IIA , with progressive renal failure after an oral melphalan , prednisone , and thalidomide regimen ( 4 mg/m2.d , 40 mg/m2.d for 7 days every 6 weeks , and 100 mg/d , respectively ) . The patient had documented increments of serum monoclonal component (M-protein), anemia, and renal failure with Bence Jones proteinuria (serum creatinine, 2.9 mg/dL; creatinine clearance, 30 mL/min; hemoglobin, 10.9 g/dL; serum IgGkappa M-protein, 3.9 g/dL; proteinuria 3.5 g/d;light-chain level in urine, 1.2 g/L). After 2 cycles with bortezomib at a reduced dose (1.0 mg/m2 twice weekly for 2 weeks followed by a 10-day rest period) to evaluate tolerability and renal toxicity, the patient completed another 3 cycles at the standard dose (1.3 mg/m2) in combination with dexamethasone (20 mg on the day of bortezomib administration and the day after). This led to an improvement of the renal function with a reduction of serum and urinary M-protein (serum creatinine 1.4 mg/dL; serum IgGkappa M-protein, 2.9 g/dL; proteinuria, 2 g/d; kappa light-chain level in urine, 0.7 g/L). The patient developed thrombocytopenia but did not suffer from some of the more severe adverse events associated with bortezomib, such as infection or peripheral neuropathy, even at full dose. ### conclusion We report an elderly patient with refractory MM and progression with renal failure who responded to bortezomib treatment. bortezomib was well tolerated in this patient. ### Assistant: [{"class": "NEG", "spans_text": ["melphalan", "prednisone", "thalidomide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Following an intravitreal injection of ranibizumab , off-label administration of intravitreal dexamethasone was considered to reduce the edema . Paragraph: Effect of intravitreal dexamethasone on macular edema in von Hippel-Lindau disease assessed using swept-source optical coherence tomography: a case report. Von Hippel-Lindau disease is a rare hereditary syndrome caused by germinal mutations in a von Hippel-Lindau tumor-suppressing gene. Retinal hemangioblastoma is the ocular hallmark lesion of von Hippel-Lindau disease. ### Case Presentation A 20-year-old Caucasian woman presented to our institution with painless visual impairment in the right eye. A fundus ophthalmoscopic evaluation and swept-source optical coherence tomographic examination revealed a retinal hemangioblastoma associated with cystoid macular edema. On the basis of the clinical ocular findings and genetic analysis, von Hippel-Lindau disease was diagnosed. Following an intravitreal injection of ranibizumab , off-label administration of intravitreal dexamethasone was considered to reduce the edema . An almost complete resolution of the edema in the macular area was observed 1 week after the injection. Finally, laser photocoagulation and transconjunctival cryotherapy were performed; the patient developed "ablatio fugax" after cryotherapy. ### conclusions In our experience, intravitreal dexamethasone administration has proven to be a useful tool for reducing retinal hemangioblastoma-related macular edema in von Hippel-Lindau disease and may be considered a potentially valuable treatment that can be used in combination with other therapies. ### Assistant: [{"class": "POS", "spans_text": ["ranibizumab", "dexamethasone"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We performed a prospective , preplanned , pooled analysis of six randomized , phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX ( fluorouracil , leucovorin , and oxaliplatin ) or CAPOX ( capecitabine and oxaliplatin ) administered for 3 months , as compared with 6 months . Paragraph: Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. ### methods We performed a prospective , preplanned , pooled analysis of six randomized , phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX ( fluorouracil , leucovorin , and oxaliplatin ) or CAPOX ( capecitabine and oxaliplatin ) administered for 3 months , as compared with 6 months . The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. ### results After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). ### conclusions Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.). ### Assistant: [{"class": "POS", "spans_text": ["capecitabine", "oxaliplatin"]}, {"class": "COMB", "spans_text": ["fluorouracil", "leucovorin", "oxaliplatin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Growth inhibition and apoptosis were significantly ( P < 0.05 ) higher in BxPC-3 , HPAC , and PANC-1 cells treated with celecoxib and erlotinib than cells treated with either celecoxib or erlotinib . Paragraph: Simultaneous targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic cancer therapy. The aims of this study were to determine the effects of (a) combining the epidermal growth factor receptor (EGFR) blocker (erlotinib) and the cyclooxygenase-2 inhibitor (celecoxib) on cell growth and apoptosis in human pancreatic cancer cell lines, (b) baseline EGFR expression on the potentiation of erlotinib-induced apoptosis by celecoxib, and (c) the effects of the combination on the expression of the COX-2, EGFR, HER-2/neu, and nuclear factor-kappaB (NF-kappaB). Baseline expression of EGFR was determined by Western blot analysis in five human pancreatic cancer cell lines. BxPC-3, PANC-1, and HPAC had high EGFR and MIAPaCa had low EGFR. Cells were grown in culture and treated with erlotinib (1 and 10 micromol/L), celecoxib (1 and 10 micromol/L), and the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. Reverse transcriptase-PCR was used to evaluate COX-2 and EGFR mRNA. EGFR, COX-2, and HER-2/neu expression was determined by Western immunoblotting. Electrophoretic mobility shift assay was used to evaluate NF-kappaB activation. Growth inhibition and apoptosis were significantly ( P < 0.05 ) higher in BxPC-3 , HPAC , and PANC-1 cells treated with celecoxib and erlotinib than cells treated with either celecoxib or erlotinib . However, no potentiation in growth inhibition or apoptosis was observed in the MIAPaCa cell line with low expression of the EGFR. Significant down-regulation of COX-2 and EGFR expression was observed in the BxPC-3 and HPAC cells treated with the combination of erlotinib (1 micromol/L) and celecoxib (10 micromol/L) compared with celecoxib- or erlotinib-treated cells. celecoxib significantly down-regulated HER-2/neu expression in BxPC-3 and HPAC cell lines. Significant inhibition of NF-kappaB activation was observed in BxPC-3 and HPAC cell lines treated with erlotinib and celecoxib. (a) celecoxib can potentiate erlotinib-induced growth inhibition and apoptosis in pancreatic cell lines, (b) high baseline EGFR expression is a predictor of this potentiation, and (c) the down-regulation of EGFR, COX-2, and HER-2/neu expression and NF-kappaB inactivation contributes to the potentiation of erlotinib by celecoxib. ### Assistant: [{"class": "POS", "spans_text": ["celecoxib", "erlotinib"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: These results indicate that low-dose 100 microg levonorgestrel and 20 microg ethinyl estradiol given for 21 days is effective in suppressing ovarian activity and they confirm the contraceptive efficacy observed in clinical trials ( Pearl index of 0.8 ) . Paragraph: The effects on ovarian activity of a monophasic oral contraceptive with 100 microg levonorgestrel and 20 microg ethinyl estradiol. An open-label, single-center, noncomparative study was conducted to determine the effects of a monophasic oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol on ovarian activity. The subjects were 26 healthy women 20 to 35 years of age who had normal ovulatory cycles and were not at risk for becoming pregnant. For 3 treatment cycles, they took 1 tablet of active drug daily for 21 days followed by placebo tablets for 7 days. Follicle diameters and serum progesterone and 17beta-estradiol levels were measured before, during, and after treatment. In 2 (2.7%) of 73 cycles, luteinized unruptured follicles were present and in another 2 (2.7%) cycles, ovulation was confirmed by the disappearance of the enlarged follicle. Ovarian activity, as reflected by mean serum progesterone levels, was restored after treatment. The results of this study are in agreement with those of other studies that showed suppression of ovarian activity in women treated with a monophasic oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol. These results indicate that low-dose 100 microg levonorgestrel and 20 microg ethinyl estradiol given for 21 days is effective in suppressing ovarian activity and they confirm the contraceptive efficacy observed in clinical trials ( Pearl index of 0.8 ) . ### Assistant: [{"class": "POS", "spans_text": ["levonorgestrel", "ethinyl"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The combination of ixabepilone and capecitabine in the phase II study resulted in an ORR of 23 % in triple-negative patients . Paragraph: Efficacy of ixabepilone in ER/PR/HER2-negative (triple-negative) breast cancer. Patients with ER/PR/HER2-negative (triple negative) breast cancer are not candidates for hormonal therapy or HER2-targeted agents. Ongoing research is aimed at identifying and understanding the benefit of established and emerging therapies in this disease setting. Triple-negative patients may achieve early responses to anthracyclines and taxanes, but novel strategies are also eagerly sought. The epothilone B analog ixabepilone acts to stabilize microtubules and demonstrates antitumor activity in recent breast cancer studies. Herein, we have analyzed efficacy and safety data of ixabepilone specifically for the treatment of women with triple-negative disease. A retrospective analysis was completed using activity and toxicity data in the triple-negative subsets from 5 phase II studies. In addition, a prospective pooled analysis of triple-negative patients from 2 phase III trials is also reviewed. Of 2,261 patients evaluated in these trials, 556 (24.5%) had triple-negative tumors. In the neoadjuvant setting, ixabepilone produced a pathologic complete response rate in the breast of 26% in triple-negative patients (vs. 15% in the non-triple-negative population). In patients with metastatic breast cancer whose pretreatment status ranged from no prior therapy to progression on several classes of agents, overall response rates (ORR) in the phase II ixabepilone monotherapy trials ranged from 6 to 55%, comparable to rates seen in patients with non-triple-negative tumors. The combination of ixabepilone and capecitabine in the phase II study resulted in an ORR of 23 % in triple-negative patients . A similar ORR (31%) was observed for a preplanned pooled analysis of triple-negative patients in the phase III trials of ixabepilone plus capecitabine. The median progression-free survival (PFS) was significantly longer for triple-negative patients treated with ixabepilone plus capecitabine (4.2 months) compared with treatment with capecitabine alone (1.7 months). No increase in toxicity was noted in the triple-negative subgroup compared with other patients. ixabepilone shows notable antitumor activity in patients with triple-negative breast cancer when used in a variety of settings. The addition of ixabepilone to capecitabine results in an approximately twofold increase in median PFS for triple-negative patients versus capecitabine alone and responses to ixabepilone in triple-negative disease are comparable to those seen in patients with non-triple-negative tumors. ### Assistant: [{"class": "POS", "spans_text": ["ixabepilone", "capecitabine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We report the rare case of a 27-year-old premenopausal woman with locally advanced breast cancer that was marked by rapid tumor necrosis followed by massive hemorrhage shortly after bevacizumab and paclitaxel administration . Paragraph: Rapid tumor necrosis and massive hemorrhage induced by bevacizumab and paclitaxel combination therapy in a case of advanced breast cancer. bevacizumab when combined with chemotherapy exerts significant activity against many solid tumors through tumor angiogenesis inhibition; however, it can induce severe side effects. We report the rare case of a 27-year-old premenopausal woman with locally advanced breast cancer that was marked by rapid tumor necrosis followed by massive hemorrhage shortly after bevacizumab and paclitaxel administration . On the basis of histopathological examination of a biopsy specimen and computed tomography findings, she was diagnosed with stage IV estrogen and progesterone receptor-negative and human epidermal growth factor receptor type 2-positive breast cancer with multiple organ metastases when she had entered gestational week 24. cyclophosphamide, Adriamycin®, fluorouracil therapy was initiated, but multiple liver metastases continued to progress. A healthy fetus was delivered by induced delivery and trastuzumab-based treatment was initiated. Although the multiple liver metastases were controlled successfully by trastuzumab combined with paclitaxel, the primary tumor continued to expand even after subsequent administration of three other treatment regimens including anti-human epidermal growth factor receptor type 2 agents and cytotoxic drugs. To inhibit primary tumor growth, a combination therapy with paclitaxel and bevacizumab was subsequently initiated. Following therapy initiation, however, the large tumor occupying the patient's entire left breast became necrotic and ulcerated rapidly. Furthermore, massive hemorrhage from the tumor occurred 5 weeks after bevacizumab-based therapy initiation. Although hemostasis was achieved by manual compression, the patient required blood transfusion for the massive blood loss. She eventually succumbed to respiratory failure. This case report demonstrates that primary breast cancer lesions with skin involvement have the potential to cause massive hemorrhage after bevacizumab-based treatment. ### Assistant: [{"class": "NEG", "spans_text": ["bevacizumab", "paclitaxel"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: More recently , paclitaxel plus carboplatin also has been evaluated in previously untreated patients . Paragraph: Current status of chemotherapy for ovarian cancer. Standard treatment for patients with advanced ovarian cancer has been cytoreductive surgery followed by combination chemotherapy. Until recently, platinum-based chemotherapy was considered optimal and patients were treated with regimens built around either cisplatin or carboplatin. Recently, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been shown to be a highly active agent in refractory ovarian cancer patients. Subsequently, the Gynecologic Oncology Group performed a prospective randomized trial of paclitaxel plus cisplatin compared with cisplatin plus cyclophosphamide in suboptimal stage III and IV ovarian cancer patients. Based on higher response rates, longer time to progression, and marked improvement in median survival (37.5 months compared with 24.4 months), the Gynecologic Oncology Group currently considers paclitaxel plus cisplatin to be the new standard regimen for patients with advanced disease. More recently , paclitaxel plus carboplatin also has been evaluated in previously untreated patients . Using area under the curve dosing for carboplatin, it was demonstrated that this agent could be combined with paclitaxel (175 mg/m2 in a 3-hour infusion) with acceptable toxicity. All current Gynecologic Oncology Group protocols for untreated patients with ovarian cancer use a paclitaxel-based regimen. These clinical trials are evaluating the relative efficacy of carboplatin plus paclitaxel versus cisplatin plus paclitaxel as well as differences in dose and schedule and number of cycles of treatment. Investigational studies are continuing with high-dose chemotherapy that requires hematologic support as well as with intraperitoneal therapy (cisplatin or paclitaxel). ### Assistant: [{"class": "COMB", "spans_text": ["paclitaxel", "carboplatin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Mitoxantrone and cyclophosphamide in advanced breast cancer : a pilot study . Paragraph: Mitoxantrone and cyclophosphamide in advanced breast cancer : a pilot study . A trial of combination chemotherapy using mitoxantrone-cyclophosphamide was started in 1983. Sixteen patients with widely metastatic cancer of the breast, including one man, received mitoxantrone, 10 mg/m2 intravenously (IV) over 30 minutes on day 1, followed by cyclophosphamide, 200 mg/m2 by mouth (PO) daily in divided doses on days 3 to 6. It is too early to evaluate four patients at present. The remaining 12 received three or more courses of treatment, and three of these patients achieved a complete response. Another four patients went into partial remission, amounting to an overall response rate of 58%. The other evaluable patients showed stable disease with improved symptoms. Hematologic toxicity was mainly granulocytopenia, but thrombocytopenia occurred in two patients. Alopecia, nausea, and vomiting were attributed to the cyclophosphamide component of the therapy. mitoxantrone appeared to have no cardiac toxicity. It was concluded that mitoxantrone-cyclophosphamide is an effective chemotherapeutic combination with minimal toxicity and should be further studied in larger controlled trials. ### Assistant: [{"class": "POS", "spans_text": ["Mitoxantrone", "cyclophosphamide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We retrospectively analyzed the data of 37 patients who had postprandial hyperglycemia ( ≥10.0 mmol/L ) with BOT ( long-acting insulin plus glimepiride ) with their insulin titrated enough to keep preprandial glycemia < 7.2 mmol/L , and who had their treatment changed to liraglutide monotherapy , with the subsequent addition of glimepiride , when required . Paragraph: Efficacy of liraglutide therapy in Japanese type 2 diabetic patients insufficiently controlled with basal-supported oral therapy. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00223.x, 2012) Aims/Introduction:  We assessed the efficacy of liraglutide therapy in Japanese type 2 diabetic patients insufficiently controlled with basal-supported oral therapy (BOT). ### Materials And Methods We retrospectively analyzed the data of 37 patients who had postprandial hyperglycemia ( ≥10.0 mmol/L ) with BOT ( long-acting insulin plus glimepiride ) with their insulin titrated enough to keep preprandial glycemia < 7.2 mmol/L , and who had their treatment changed to liraglutide monotherapy , with the subsequent addition of glimepiride , when required . Those who achieved the glycemic target at all points (preprandial glycemia <7.2 mmol/L and postprandial glycemia <10.0 mmol/L) were regarded as responders and the efficacy of liraglutide therapy was assessed. We also explored the predictive clinical characteristics associated with its efficacy. ### results Daily doses of insulin and glimepiride with BOT were 14 ± 9 units and 1.5 ± 0.9 mg, respectively. After the change to liraglutide therapy, 37% of the patients appeared to be responders to the therapy, whereas 12% had their glycemic control rather deteriorated. Efficacy of liraglutide therapy was significantly associated with baseline insulin dosage and post-breakfast glycemia with BOT. The C-statistic of the model was calculated to be 0.90. ### conclusions There were responders and non-responders to liraglutide therapy in Japanese BOT failures. It is likely that baseline insulin dosage and post-breakfast glycemia with BOT are clinically useful indicators for the efficacy of liraglutide therapy. ### Assistant: [{"class": "COMB", "spans_text": ["liraglutide", "glimepiride"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: It was shown that the H2 receptor antagonist cimetidine when combined with N , N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine-HCl ( DPPE ) , a tamoxifen derivate , inhibits the proliferation of HT168 cells . Paragraph: Cimetidine and a tamoxifen derivate reduce tumour formation in SCID mice xenotransplanted with a human melanoma cell line. Histamine is produced by many cells expressing histidine decarboxylase (HDC), the enzyme responsible for the synthesis of histamine. Since melanoma cells and tissue contain relatively large amounts of histamine, the functional significance of histamine was examined using specific antihistamines in vitro and in vivo in the human melanoma cell line HT168 and severe combined immunodeficiency (SCID) mice. It was shown that the H2 receptor antagonist cimetidine when combined with N , N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine-HCl ( DPPE ) , a tamoxifen derivate , inhibits the proliferation of HT168 cells . Furthermore, it is suggested that there is a factor(s) that interferes with the exponential growth of HT168 cells xenografted to immunodeficient mice, and cimetidine and DPPE together significantly influence this factor(s). This combination of antihistamines also increases the survival of human melanoma-grafted mice. These changes are accompanied by enhanced infiltration of interferon-gamma- producing mouse macrophages into the tumour tissue. These findings suggest that two different mechanisms are probably acting concordantly: direct inhibition of tumour cell proliferation by the H2 receptor antagonists, and activation of the local immune response characterized by interferon-gamma production. These findings may help to elucidate the possibility of a rationally designed antihistamine strategy in melanoma therapy. ### Assistant: [{"class": "POS", "spans_text": ["cimetidine", "DPPE", "N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine-HCl"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We report here on a case of successful treatment of a patient suffering with severe liver dysfunction and metastatic gastric cancer ; the patient was treated with a combination of capecitabine and oxaliplatin ( XELOX ) . Paragraph: Capecitabine and oxaliplatin (XELOX) for the treatment of patients with metastatic gastric cancer and severe liver dysfunction. Gastric cancer patients with severe liver dysfunction secondary to hepatic metastases have limited treatment options. Most cytotoxic drugs have a narrow therapeutic index. Although both capecitabine and oxaliplatin have been well tolerated as single agents for patients with severe hepatic dysfunction, the combination of these drugs has not been investigated. We report here on a case of successful treatment of a patient suffering with severe liver dysfunction and metastatic gastric cancer ; the patient was treated with a combination of capecitabine and oxaliplatin ( XELOX ) . The initial bilirubin level of the patient was 10.9 mg/dL. After two cycles of treatment, his bilirubin level decreased to 2.1 mg/dL. He has experienced an excellent radiological response and he has received six cycles of XELOX chemotherapy. XELOX chemotherapy is feasible and it can be associated with positive outcomes for the patients suffering with metastatic gastric cancer and severe liver dysfunction. ### Assistant: [{"class": "POS", "spans_text": ["capecitabine", "oxaliplatin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: From 1987 to 1991 , 194 previously untreated patients received vincristine and ifosfamide plus dactinomycin or etoposide for 1 - 2 years . Paragraph: Renal toxicity of ifosfamide in pilot regimens of the intergroup rhabdomyosarcoma study for patients with gross residual tumor. The purpose of this review is to characterize the nephrotoxicity noted in newly diagnosed patients under 21 years of age after treatment with ifosfamide-containing chemotherapy regimens and local irradiation for localized gross residual rhabdomyosarcoma or undifferentiated sarcoma. ### Patients And Methods From 1987 to 1991 , 194 previously untreated patients received vincristine and ifosfamide plus dactinomycin or etoposide for 1 - 2 years . ifosfamide was given at 1.8 g/m2/day for 5 days with sodium mercaptoethane sulfonate, or 9 g/m2 of ifosfamide per course. The three-drug regimen was repeated every 3-4 weeks. ### results Twenty-eight patients (14%) developed renal toxicity: 19 had renal tubular dysfunction (RTD) characterized by low serum phosphate (< or = 3 mg/dl) or bicarbonate (< 20 or = mEq/L) levels, five had decreased glomerular function (DGF), and four had both RTD and DGF. When nine or more courses of ifosfamide (> 72 g/m2) were given, children < 3 years of age had a higher incidence of RTD than did children > or = 3 years of age (34% versus 6%; p < 0.001). A similar age difference was observed even when eight or fewer courses (< or = 72 g/m2) were given (p = 0.03). A matched case-control comparison showed that renal abnormalities at diagnosis, chiefly hydronephrosis, also increased the risk of renal tubular injury by ifosfamide by a factor of 13 (p < 0.001). Patients with DGF tended to be older than those with RTD, and all but one received > 72 g/m2 of ifosfamide. ### conclusions Patients who are < 3 years of age who receive more than eight courses (> 72 g/m2) of ifosfamide and who have a preexisting renal abnormality have an increased risk of RTD and DGF. The renal function of patients being considered for ifosfamide treatment must be carefully monitored. ifosfamide should be avoided in patients with renal abnormalities at diagnosis unless the potential benefit clearly exceeds the risk of further renal impairment. ### Assistant: [{"class": "NEG", "spans_text": ["vincristine", "ifosfamide", "dactinomycin"]}, {"class": "NEG", "spans_text": ["vincristine", "ifosfamide", "etoposide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: This nested substudy of the AVALON trial assessed the effects of coadministered amlodipine and atorvastatin vs. either therapy alone or placebo on arterial compliance , to evaluate the vascular benefits of coadministered therapy . Paragraph: Coadministered amlodipine and atorvastatin produces early improvements in arterial wall compliance in hypertensive patients with dyslipidemia. Combining statins with antihypertensive therapy has been demonstrated to provide an early reduction in cardiovascular events. This nested substudy of the AVALON trial assessed the effects of coadministered amlodipine and atorvastatin vs. either therapy alone or placebo on arterial compliance , to evaluate the vascular benefits of coadministered therapy . ### methods During an initial 8-week, double-blind phase, patients with concomitant hypertension and dyslipidemia were randomized into four treatment groups (placebo, amlodipine 5 mg, atorvastatin 10 mg, or coadministered amlodipine 5 mg and atorvastatin 10 mg). The sustained effect of combined therapy was evaluated during subsequent 8-week, single-blind, and 12-week, open-label periods. In the single-blind phase, all patients were coadministered amlodipine 5 mg and atorvastatin 10 mg, which were then titrated to optimize blood pressure and low-density lipoprotein cholesterol control during the open-label phase. Arterial compliance was assessed every 4 weeks using the HDI/Pulsewave CR-2000. ### results Overall, 668 patients (61% male, mean age 55 years) were randomized to treatment. A 19% improvement in small artery compliance (C2) was observed with coadministered amlodipine and atorvastatin from baseline to week 8, which was significantly greater than with either treatment alone or with placebo (P = 0.03 to 0.0001). After 28 weeks, C2 was increased from baseline in all groups, but the overall improvement was greatest in the group receiving coadministered drugs for the entire study period (P < 0.05). ### conclusions Early and sustained improvement in small artery compliance was observed following coadministration of amlodipine and atorvastatin, thus demonstrating a vascular benefit with simultaneous treatment of hypertension and dyslipidemia. ### Assistant: [{"class": "POS", "spans_text": ["amlodipine", "atorvastatin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We analysed the serial dermatoscopic photographs of atypical melanocytic lesions taken from patients with advanced metastatic melanoma on four different systemic therapies ( selective BRAF-inhibitor monotherapy , dabrafenib combined with trametinib [ D&T ] , anti-programmed cell death protein 1 [ anti-PD1 ] therapies , and anti-PD1 combined with ipilimumab ) seen from February 2013 to May 2016 . Paragraph: Melanocytic lesion evolution patterns with targeted therapies and immunotherapies for advanced metastatic melanoma: An observational study. Various cutaneous side-effects have been reported with anti-melanoma systemic therapies. This study investigated the changes in melanocytic lesion pigmentation in patients on four different therapies. ### methods We analysed the serial dermatoscopic photographs of atypical melanocytic lesions taken from patients with advanced metastatic melanoma on four different systemic therapies ( selective BRAF-inhibitor monotherapy , dabrafenib combined with trametinib [ D&T ] , anti-programmed cell death protein 1 [ anti-PD1 ] therapies , and anti-PD1 combined with ipilimumab ) seen from February 2013 to May 2016 . We compared these changes with the melanocytic lesions of 10 control patients. ### results In the control group, 19% of naevi lightened, 64% did not change and 17% darkened. Only the BRAF inhibitor group showed more darkened lesions than controls (37%, P < 0.001). Meanwhile, there were more lightened naevi in the D&T therapy group (86%, P < 0.001) as well as the anti-PD1 and ipilimumab groups (59%, P < 0.001) than controls. Patients on anti-PD1 monotherapy had more lightened (49%) and fewer darkened naevi (9%) than controls, but differences were not significant. ### conclusions Our study showed that different anti-melanoma systemic therapies have different effects on the pigmentation of melanocytic lesions. BRAF inhibitor may have the propensity to cause darkening while D&T therapy and anti-PD1 caused lightening compared with controls. The findings emphasise the importance of regular dermatological monitoring in specialised clinics for patients on anti-melanoma systemic therapy. Clinicians should expect changes in the global pigmentation of melanocytic lesions but be suspicious of lesions with structural changes. ### Assistant: [{"class": "COMB", "spans_text": ["dabrafenib", "trametinib"]}, {"class": "COMB", "spans_text": ["anti-PD1", "ipilimumab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: He received six cycles MOPP-induction therapy followed by a chlorambucil maintenance therapy with procarbazine and prednisone reinforcements . Paragraph: Acute erythroleukemia following chemotherapy for Hodgkin's disease. A case of erythroleukemia developing in a patient 6.5 years after therapy for Hodgkin's disease (HD) is described. The patient had chemotherapy alone for a stage III B lymphocyte-predominant HD. He received six cycles MOPP-induction therapy followed by a chlorambucil maintenance therapy with procarbazine and prednisone reinforcements . To our knowledge this is the first case of erythroleukemia following HD treated with chemotherapy alone. ### Assistant: [{"class": "NEG", "spans_text": ["chlorambucil", "procarbazine", "prednisone"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma : a multicentre phase II study . Paragraph: Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma : a multicentre phase II study . There is a lack of published data examining non-cytotoxic options for the frontline treatment of patients with high-tumour burden (HTB) indolent non-Hodgkin lymphoma (iNHL). We completed a multicentre phase II study for patients with untreated HTB iNHL (NCT00369707) consisting of three induction cycles of weekly bortezomib and rituximab followed by an abbreviated consolidation. Forty-two patients were treated and all were evaluable; the most common histology was follicular lymphoma (FL) (n = 33, 79%). Patient characteristics included median age 62 years (40-86); 38% bulky disease; 19% malignant effusions; 91% advanced-stage disease; and median FL International Prognostic Index (FLIPI) score was 3. Therapy was well tolerated with few grade 3/4 toxicities including minimal neurotoxicity. On intent-to-treat, the overall response rate (ORR) at end of therapy was 70% with a complete remission (CR) rate of 40% (FL: ORR 76%, CR 44%). With 50-month median follow-up, 4-year progression-free survival (PFS) was 44% with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Four-year PFS for FLIPI 0-2 vs. 3-5 was 60% vs. 26% respectively (P = 0·02), with corresponding OS rates of 92% and 81% respectively (P = 0·16). Collectively, bortezomib/rituximab is a non-cytotoxic therapeutic regimen that was well tolerated and resulted in long-term survival rates approximating prior rituximab/cytotoxic chemotherapy series for untreated HTB FL. ### Assistant: [{"class": "POS", "spans_text": ["bortezomib", "rituximab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The ifosfamide , carboplatin and etoposide ( ICE ) regimen was developed to address these challenges . Paragraph: Ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy for the management of relapsed and refractory aggressive non-Hodgkin's lymphoma. Despite advances in the management of aggressive non-Hodgkin's lymphoma, the treatment of relapsed and primary refractory disease remains a major challenge. High-dose chemotherapy or radio-chemotherapy followed by autologous or allogeneic stem cell transplantation (SCT) is a potentially curative treatment approach; however, the applicability of this approach is restricted to patients responding to second-line chemotherapy. Thus, second-line therapy must be both efficacious and without stem cell or organ toxicity that would compromise the ability to proceed to SCT. The ifosfamide , carboplatin and etoposide ( ICE ) regimen was developed to address these challenges . In a series of prospective clinical trials, 222 patients were treated with the ICE regimen. with an overall response rate of 72%. The mobilization of stem cells with this regimen was excellent,with 86% of patients mobilizing at least 2.0 x 10(6) CD34+ cells/kg. The incidence of treatment-related toxicity precluding SCT after ICE is very low. Herein, we report the clinical results of this treatment program for 222 patients with 5-year median follow-up for surviving patients. rituximab was subsequently added to the ICE regimen for patients with diffuse large B-cell lymphoma (DLBCL) to improve upon these favorable results. This resulted in an increased complete remission rate. Additional follow-up is necessary to determine if this improvement in the complete remission rate will confer an increase in the overall survival following SCT. ### Assistant: [{"class": "POS", "spans_text": ["ifosfamide", "carboplatin", "etoposide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Effect of sequential treatments with alendronate , parathyroid hormone ( 1 - 34 ) and raloxifene on cortical bone mass and strength in ovariectomized rats . Paragraph: Effect of sequential treatments with alendronate , parathyroid hormone ( 1 - 34 ) and raloxifene on cortical bone mass and strength in ovariectomized rats . Anti-resorptive and anabolic agents are often prescribed for the treatment of osteoporosis continuously or sequentially for many years. However their impact on cortical bone quality and bone strength is not clear. ### methods Six-month old female rats were either sham operated or ovariectomized (OVX). OVX rats were left untreated for two months and then were treated with vehicle (Veh), hPTH (1-34) (PTH), alendronate (Aln), or raloxifene (Ral) sequentially for three month intervals, for a total of three periods. Mid-tibial cortical bone architecture, mass, mineralization, and strength were measured on necropsy samples obtained after each period. Bone indentation properties were measured on proximal femur necropsy samples. ### results Eight or more months of estrogen deficiency in rats resulted in decreased cortical bone area and thickness. Treatment with PTH for 3months caused the deposition of endocortical lamellar bone that increased cortical bone area, thickness, and strength. These improvements were lost when PTH was withdrawn without followup treatment, but were maintained for the maximum times tested, six months with Ral and three months with Aln. Pre-treatment with anti-resorptives was also somewhat successful in ultimately preserving the additional endocortical lamellar bone formed under PTH treatment. These treatments did not affect bone indentation properties. ### summary Sequential therapy that involved both PTH and anti-resorptive agents was required to achieve lasting improvements in cortical area, thickness, and strength in OVX rats. Anti-resorptive therapy, either prior to or following PTH, was required to preserve gains attributable to an anabolic agent. ### Assistant: [{"class": "POS", "spans_text": ["alendronate", "parathyroid hormone", "raloxifene"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Atorvastatin and metformin both have pleiotropic effects . Paragraph: Atorvastatin Plus Metformin Confer Additive Benefits on Subjects with Dyslipidemia and Overweight/Obese via Reducing ROCK2 Concentration. Atorvastatin and metformin both have pleiotropic effects . Whether atorvastatin combined with metformin could provide additive benefits on subjects with dyslipidemia and overweight/obese is unknown. And the mechanism is also not fully clear yet. ### methods A cross-sectional research was performed and 130 subjects with dyslipidemia and overweight/obese were enrolled and randomly assigned into combined group (20 mg of atorvastatin daily plus 500 mg of metformin twice daily) and control group (20 mg of atorvastatin daily). At baseline and 8 weeks later, parameters of interest were recorded and fasting venous blood was drawn for laboratory examination. ### results The rates of overweight (76.9% vs. 73.8%) and obese (23.1% vs. 26.2%) in both group were comparable. Dyslipidemia in both groups were featured by increased serum levels of triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Serum level of high sensitivity C-reactive protein (Hs-CRP) was comparably elevated in both groups at baseline, and leukocyte rho-associated kinase 2 (ROCK2) and serum nitric oxide (NO) concentrations were also comparable. Generally, the baseline characteristics between these 2 groups were no significant differences. 8 weeks later, compared to baseline, body mass index (BMI), the rates of overweight and obese, daily exercise time, smoking status, lipid profiles, Hs-CRP level, leukocyte ROCK2 and serum NO concentrations in both groups were improved. Notably, compared to control group, the rate of obese, Hs-CRP level, leukocyte ROCK2 and serum NO concentrations were improved more profoundly in the combined group (p<0.05). After adjusted for age, gender, BMI, TG, LDL-C, Hs-CRP and exercise time, atorvastatin plus metformin was positively associated with serum NO concentration, with odds ratio (OR) of 1.146 (95% confidence interval (CI) 1.089-1.164, combined group vs. control group, p<0.05), and inversely associated with leukocyte ROCK2 concentration, with OR of 0.853 (95% CI 0.834-0.872, combined group vs. control group, p<0.05). ### conclusion In subjects with dyslipidemia and overweight/obese, atorvastatin plus metformin may confer additive benefits through reducing leukocyte ROCK2 concentration. ### Assistant: [{"class": "POS", "spans_text": ["Atorvastatin", "metformin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Bevacizumab , a monoclonal antibody targeting vascular endothelial growth factor , is the first antiangiogenic drug to show improved efficacy when used in combination with irinotecan and oxaliplatin for first- and second-line treatment of CRC . Paragraph: Targeted agents for adjuvant therapy of colon cancer. Among patients with colorectal cancer (CRC) diagnosed in the United States, 37.2% are diagnosed with stage III and 27.9% with stage II disease. In locoregionally advanced CRC, surgery is the primary treatment modality and has a curative intent. The survival depends on the pathologic stage and varies from 30%-60% for stage III to 60%-80% for stage II. However, as much as 40%-50% of patients will relapse and require additional treatment of the disease. Clinical failure after resection of CRC is predominantly secondary to the clinical progression of previously undetected distant metastatic disease. Until very recently, the absolute benefit for survival obtained with adjuvant therapy compared with control was about 6%. Introduction of oxaliplatin in the adjuvant setting has shown a reduction of 23% in the risk of relapse when compared with 5-fluorouracil alone (MOSAIC). Recent phase III studies have shown that targeted agents improved survival in patients with advanced-stage CRC. Bevacizumab , a monoclonal antibody targeting vascular endothelial growth factor , is the first antiangiogenic drug to show improved efficacy when used in combination with irinotecan and oxaliplatin for first- and second-line treatment of CRC . cetuximab, another monoclonal antibody targeting epidermal growth factor receptor, has shown efficacy in third-line therapy and promising results in first-line phase II studies. There is great interest in whether the biologic agents bevacizumab and cetuximab can improve survival in the adjuvant-therapy setting. This article reviews the adjuvant therapy for colon cancer and discusses the potential role and current trials involving the targeted agents. ### Assistant: [{"class": "POS", "spans_text": ["Bevacizumab", "irinotecan", "oxaliplatin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Between Oct 24 , 2016 , and Jan 24 , 2018 , 861 patients were randomly assigned to receive pembrolizumab plus axitinib ( n=432 ) or sunitinib monotherapy ( n=429 ) . Paragraph: Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. ### methods In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. ### findings Between Oct 24 , 2016 , and Jan 24 , 2018 , 861 patients were randomly assigned to receive pembrolizumab plus axitinib ( n=432 ) or sunitinib monotherapy ( n=429 ) . With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. ### interpretation With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma. ### funding Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. ### Assistant: [{"class": "POS", "spans_text": ["pembrolizumab", "axitinib"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Patients received 175 mg/m of paclitaxel over a 3 h infusion , followed by nedaplatin 80 mg/m in a 1 h infusion on day 1 every 3 weeks for up to 6 treatment cycles . Paragraph: A retrospective study of paclitaxel combining nedaplatin chemotherapy for esophageal cancer. The aim of this study was to evaluate the efficacy and tolerability of the combination of paclitaxel and nedaplatin in patients with advanced esophageal cancer. Patients (n = 310) with recurrent or metastatic esophageal squamous cell carcinoma, who had a maximum of one previous chemotherapy regimen, were enrolled in this study. All patients had bidimensionally measurable disease. Patients received 175 mg/m of paclitaxel over a 3 h infusion , followed by nedaplatin 80 mg/m in a 1 h infusion on day 1 every 3 weeks for up to 6 treatment cycles . The overall response rate was 47.7%, with complete and partial response rates of 6.1 and 41.7%, respectively. The median time to progression for all patients was 6.8 months (95% confidence interval, 6.2-7.4 months) and the 3-year disease-free survival probability was 3 (15.8%). The major toxicity observed was cumulative neutropenia, with 29% patients developing grade 4 toxicity. There was no treatment-related death. The most common nonhematologic toxicity encountered with this regimen was pain and cumulative peripheral neuropathy, with 26% patients experiencing grade 2 or 3 toxicity. The combination of paclitaxel and nedaplatin shows significant antitumor activity and a favorable toxicity profile in patients with metastatic carcinoma of esophageal cancer. ### Assistant: [{"class": "POS", "spans_text": ["paclitaxel", "nedaplatin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: After a median follow-up of 9.5 years , 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin ( LV5FU2 ) and LV5FU2 plus oxaliplatin ( FOLFOX4 ) arms were 67.1 % versus 71.7 % ( hazard ratio [ HR ] , 0.85 ; P = .043 ) in the whole population , 79.5 % versus 78.4 % for stage II ( HR , 1.00 ; P = .980 ) , and 59.0 % versus 67.1 % for stage III ( HR , 0.80 ; P = .016 ) disease . Paragraph: Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. The MOSAIC (Multicenter International Study of oxaliplatin/fluorouracil/leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation. ### methods Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens. ### results After a median follow-up of 9.5 years , 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin ( LV5FU2 ) and LV5FU2 plus oxaliplatin ( FOLFOX4 ) arms were 67.1 % versus 71.7 % ( hazard ratio [ HR ] , 0.85 ; P = .043 ) in the whole population , 79.5 % versus 78.4 % for stage II ( HR , 1.00 ; P = .980 ) , and 59.0 % versus 67.1 % for stage III ( HR , 0.80 ; P = .016 ) disease . Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation. ### conclusion The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation. ### Assistant: [{"class": "POS", "spans_text": ["fluorouracil", "leucovorin"]}, {"class": "POS", "spans_text": ["LV5FU2", "oxaliplatin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: [ Effects of combined use of dofetilide and verapamil on the action potential of papillary muscles in guinea pigs ] . Paragraph: [ Effects of combined use of dofetilide and verapamil on the action potential of papillary muscles in guinea pigs ] . To test the effects of combined use of dofetilide and verapamil on the action potential of papillary muscles in guinea pigs. ### methods Under the stimulation of different frequencies (0.2, 0.5, 1.0, 1.25 or 2.0 Hz), the action potential of papillary muscles in guinea pigs was recorded with the standard microelectrode techniques. The impacts of different concentrations of amiodarone (1, 5 or 10 micromol/L), dofetilide (10, 50, 100 nmol/L), and a combination of 100 nmol/L dofetilide and 1 micromol/L verapamil on the action potential were tested. ### results amiodarone prolonged the action potential duration (APD) significantly, measured both at 50% (APD50) and 90% (APD90) of repolarization, in a concentration-dependent manner independent from stimulation frequencies. dofetilide prolonged APD in a concentration-dependent manner, which was negatively dependent on stimulation frequencies. The frequency-dependent effect was ameliorated by adding 1 micromol/L verapamil to dofetilide. ### conclusion Both amiodarone and dofetilide prolong APD in a concentration-dependent manner. The class III antiarrhythmic compounds, amiodarone, has less frequency-dependent effect than the pure class III antiarrhythmic drug. A combined use of potassium and calcium antagonists may reduce the frequency-dependence of the pure class III antiarrhythmic drug. ### Assistant: [{"class": "POS", "spans_text": ["dofetilide", "verapamil"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Patients with pancreatic adenocarcinoma , pre-treated with gemcitabine-based chemotherapy , were treated with capecitabine ( 800 mg/m(2 ) orally , twice a day for 14 days ) and docetaxel ( 75 mg/m(2 ) i.v , on day 1 ) , every 3 weeks . Paragraph: Second-line chemotherapy with capecitabine (Xeloda) and docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial. To investigate the efficacy and toxicity of the docetaxel and capecitabine combination in patients with previously treated, unresectable adenocarcinoma of the pancreas. ### Patients And Methods Patients with pancreatic adenocarcinoma , pre-treated with gemcitabine-based chemotherapy , were treated with capecitabine ( 800 mg/m(2 ) orally , twice a day for 14 days ) and docetaxel ( 75 mg/m(2 ) i.v , on day 1 ) , every 3 weeks . The primary end-point was overall response rate (RR). ### results Thirty-one patients were enrolled in the study; 93.6% of them had a performance status (PS) of 0-1 and 96.8% had stage IV disease. Patients received a median of 4 cycles/patient, and the main reason for treatment discontinuation was disease progression. Partial response was observed in three (9.7%) patients, stable disease in seven (22.6%) (disease control rate: 32.3%, 95% CI: 15.80-48.71%) and disease progression in 21 (67.6%). The median progression-free survival (PFS) was 2.4 months (95% CI: 1.6-3.13) and the median overall survival (OS) was 6.3 months (95% CI: 3.38-9.23); the estimated 1-year survival rate was 14.7%. Grade III/IV neutropenia occurred in 10 (32.2%) patients and febrile neutropenia in one patient. Other severe non-hematologic toxicities were mild and manageable. After 2 chemotherapy cycles, pain control occurred in 20% of patients and stabilization of body weight in 40%. ### conclusion The combination of docetaxel/capecitabine may confer good disease control associated with improvement of quality of life as second-line chemotherapy in patients with metastatic pancreatic cancer. ### Assistant: [{"class": "POS", "spans_text": ["capecitabine", "docetaxel"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Comparative study of dose escalation versus interval reduction to obtain dose-intensification of epirubicin and cyclophosphamide with granulocyte colony-stimulating factor in advanced breast cancer . Paragraph: Comparative study of dose escalation versus interval reduction to obtain dose-intensification of epirubicin and cyclophosphamide with granulocyte colony-stimulating factor in advanced breast cancer . A potential application of hematopoietic growth factors is to obtain an increased dose-intensity. This can be achieved by either higher doses of chemotherapy with standard intervals, or by standard doses with shorter intervals. The potential of these approaches has not been investigated systematically. ### Patients And Methods In a randomized, multicenter study, 49 advanced breast cancer patients were treated with granulocyte colony-stimulating factor (G-CSF) and either increasing doses of epirubicin and cyclophosphamide with fixed intervals (arm one) or progressively shorter intervals with fixed doses of epirubicin and cyclophosphamide (arm two). A cohort of at least six patients was studied at each interval/dose. A more intensified interval/dose was given if less than 50% of patients encountered a dose-intensity limiting criterium (DILC) in the first three courses. ### results In arm one, epirubicin 140 mg/m2 and cyclophosphamide 800 mg/m2 every 21 days was too toxic. Subsequently, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 was tested with two of 10 patients encountering a DILC. All initial DILCs consisted of febrile neutropenia. In arm two, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely with 14- and 12-day intervals. In the 10-day interval, eight of 12 patients completed the first three cycles without a DILC. In the 8-day interval, seven of eight patients encountered a DILC. Incomplete neutrophil recovery, and to a lesser extent stomatitis, were dose-limiting. ### conclusion In combination with G-CSF, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 every 21 days was feasible (projected dose-intensity, 40 mg/m2/wk and 233 mg/m2/wk, respectively). epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely every 10 days, allowing a projected dose-intensity of 52.5 mg/m2/wk and 350 mg/m2/wk, respectively. ### Assistant: [{"class": "POS", "spans_text": ["epirubicin", "cyclophosphamide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The hearts were treated during the whole procedure either with vehicle , 0.5 μM flecainide ( sodium channel blocker ) or 100 μM streptomycin ( here used as stretch-activated ion-channel blocker ) . Paragraph: Arrhythmogenic effects by local left ventricular stretch: effects of flecainide and streptomycin. Mechanical stretch has been shown to provoke arrhythmia. We wanted to analyze ventricular arrhythmia induced by local left ventricular stretch in order to find out, where arrhythmias originate and whether they can be prevented pharmacologically. Isolated rabbit hearts (Langendorff technique) were submitted to increased left ventricular stretch at the left wall by insertion of an additional intraventricular balloon and adjusting the end-diastolic pressure (EDP) to 25 mmHg for 10 min followed by 20 min recovery at normal EDP of 5-8 mmHg. Activation and repolarization processes were investigated by ventricular 256 electrode epicardial mapping. The hearts were treated during the whole procedure either with vehicle , 0.5 μM flecainide ( sodium channel blocker ) or 100 μM streptomycin ( here used as stretch-activated ion-channel blocker ) . In addition, we performed a series of experiments, in which we enhanced EDP to 30 mmHg (global stretch instead of local stretch) by inflating the left ventricular pressure balloon (strain, 0.148 ± 0.034). Each series was performed with n = 6. Stretch resulted in local strain of 25% at the left wall together with a local slowing of the activation process at the left wall, in a change in the activation pattern, and in ventricular arrhythmia. Coronary flow was not affected. Ventricular arrhythmias originated from the border between the stretched area and the non-stretched region. flecainide and streptomycin reduced the prolongation of the activation process at the stretched left wall and mitigated the difference in total activation time between left and front wall but only partially prevented arrhythmia. In the additional global stretch experiments relative coronary flow and the other parameters remained unchanged, in particular TAT. Thus, in contrast to the local stretch series, there was no difference in the change in TAT between left and front wall. Only rare single ventricular extrasystoles (<1/min; originating from LV (front and left wall) i.e. from within the stretched region) were seen during stretch (but not at the beginning) and during recovery. Local left ventricular stretch can elicit ventricular arrhythmias. Local slowing of electrical activation seems involved so that the difference in total activation time of the stretched free left wall and the non-stretched increased. ### Assistant: [{"class": "COMB", "spans_text": ["flecainide", "streptomycin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In the APHINITY study ( NCT01358877 , BIG 4 - 11/BO25126/TOC4939 G ) , pertuzumab added to trastuzumab and chemotherapy significantly improved invasive disease-free survival as adjuvant treatment for patients with HER2-positive early breast cancer . Paragraph: Pharmacokinetics of pertuzumab administered concurrently with trastuzumab in Chinese patients with HER2-positive early breast cancer. In the APHINITY study ( NCT01358877 , BIG 4 - 11/BO25126/TOC4939 G ) , pertuzumab added to trastuzumab and chemotherapy significantly improved invasive disease-free survival as adjuvant treatment for patients with HER2-positive early breast cancer . The objective of this analysis was to assess the pharmacokinetics of pertuzumab in combination with trastuzumab in Chinese patients with early breast cancer. Samples for pertuzumab and trastuzumab pharmacokinetic analysis were taken from Chinese patients during cycle 1 of treatment and at steady-state in cycle 10. Noncompartmental analysis was used to estimate minimum and maximum serum concentrations (Cmax and Cmin), area under the concentration-time curve, clearance, and other pharmacokinetic parameters. In 15 patients, mean steady-state Cmax and Cmin pertuzumab serum concentrations (368 ± 177 μg/ml, and 122 ± 47 μg/ml, respectively) were numerically higher than observed previously in a pharmacokinetic analysis of the global population in APHINITY and in patients treated in the metastatic setting. The geometric mean ratio and corresponding 90% confidence interval for trastuzumab Cmax and Cmin in the presence (n = 15) or absence (n = 17) of pertuzumab were 104.6 (91.09-120) and 98.23 (84.58-114), respectively, indicating no apparent impact of pertuzumab on the pharmacokinetics of trastuzumab. Increases in pertuzumab Cmax and Cmin were not associated with an increase in adverse events. The APHINITY Chinese pharmacokinetic substudy analysis supports the dosing regimen for pertuzumab (840 mg loading dose followed by 420 mg maintenance doses every 3 weeks administered by intravenous infusion) in a Chinese HER2-positive early breast cancer patient population. ### Assistant: [{"class": "POS", "spans_text": ["pertuzumab", "trastuzumab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In two trials , an anti-EGFR antibody ( panitumumab or cetuximab ) reduced median survival when added to bevacizumab in previously untreated patients . Paragraph: Chemotherapy of metastatic colorectal cancer. Without treatment, patients with inoperable or metastatic colorectal cancer have a median life expectancy of about 8 months. The following article is an update of our 2005 review of chemotherapy regimens used in metastatic colorectal cancer, based on the standard Prescrire methodology. In 2005, the de Gramont protocol, based on fluorouracil (always combined with folinic acid) plus either oxaliplatin (Folfox protocol) or irinotecan (Folfiri protocol), was the standard first-line chemotherapy in this setting. Four trials comparing monotherapy versus combination therapy in previously untreated patients showed that initial fluorouracil (or fluorouracil precursor) monotherapy, followed by the Folfox or Folfiri protocol in case of failure, was not associated with shorter overall survival. Two trials compared first-line treatment with the Folfiri regimen versus the Folfoxiri regimen (fluorouracil + oxaliplatin + irinotecan). One of these studies showed an increase in median survival with the Folfoxiri protocol (24 versus 17 months), but at a cost of greater neurotoxicity. The only tangible advantage of capecitabine and tegafur, two oral fluorouracil precursors, is their convenience of use. pemetrexed was less effective and more toxic than the Folfiri protocol in one trial. bevacizumab and panitumumab have yielded disappointing results in previously untreated patients. Neither of these monoclonal antibodies has yet been shown to improve overall survival. Three trials have assessed the addition of cetuximab to combinations consisting of fluorouracil or capecitabine plus oxaliplatin or irinotecan. In two of these trials, the median survival time of patients whose tumours carried the wild-type KRAS gene was about 3 months longer in the cetuximab arms, although the increase was statistically significant in only one trial. cetuximab had no impact on survival time in the third trial. In two trials , an anti-EGFR antibody ( panitumumab or cetuximab ) reduced median survival when added to bevacizumab in previously untreated patients . When progression occurs after treatment with the Folfiri protocol (or equivalent), a combination of the Folfox protocol and bevacizumab seems to increase median survival time by about 2 months versus Folfox alone, but it is also more toxic. In patients who progress after receiving the fluorouracil + oxaliplatin combination (Folfox) or the fluorouracil+ irinotecan combination (Folfiri), neither panitumumab nor cetuximab has been shown to provide a clinically meaningful increase in overall survival. It remains to be shown whether these drugs are more effective in patients with the wild-type KRAS gene than in patients with KRAS mutations. In early 2010, the standard cytotoxic drugs for treatment of metastatic colorectal cancer are fluorouracil (combined with folinic acid), oxaliplatin and irinotecan. Initial combination therapy may be beneficial when the metastases are borderline operable. When the metastases are inoperable and are unlikely to become operable after chemotherapy, it seems best to begin treatment with single-agent fluorouracil (+ folinic acid) or capecitabine. The use of monoclonal antibodies in first-line treatment of patients with colorectal cancer is not justified. Further trials of these drugs are warranted as second-line treatment for patients with KRAS wild-type tumours. ### Assistant: [{"class": "NEG", "spans_text": ["panitumumab", "bevacizumab"]}, {"class": "NEG", "spans_text": ["cetuximab", "bevacizumab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The results of the APPEARANCE trial indicate that adapalene does not prevent acne-like rash over placebo when added to topical moisturizer and oral minocycline but instead may have a detrimental effect . Paragraph: Adapalene Gel 0.1% Versus Placebo as Prophylaxis for Anti-Epidermal Growth Factor Receptor-Induced Acne-Like Rash: A Randomized Left-Right Comparative Evaluation (APPEARANCE). The results of the APPEARANCE trial indicate that adapalene does not prevent acne-like rash over placebo when added to topical moisturizer and oral minocycline but instead may have a detrimental effect . Therefore, adapalene is not recommended as prophylaxis against acne-like rash induced by anti-epidermal growth factor receptor therapies.Given that acne-like rash was completely controlled with placebo in approximately half of patients, predictive measures to identify patients needing intensive prophylaxis are required. ### background Anti-epidermal growth factor receptor (EGFR) therapies are frequently associated with acne-like rash. To evaluate the prophylactic efficacy of adapalene, a topical retinoid used as first-line therapy for acne vulgaris, we conducted a randomized, placebo-controlled, evaluator-blinded, left-right comparative trial. ### methods Patients with non-small cell lung, colorectal, or head and neck cancer scheduled to receive anti-EGFR therapies were randomly assigned to once-daily adapalene application on one side of the face, with placebo on the other side. All patients had topical moisturizer coapplied to both sides of the face, and received oral minocycline. The primary endpoint was the difference in total facial lesion count of acne-like rash at 4 weeks. Secondary endpoints included complete control rate (CCR) of acne-like rash (≤5 facial lesions) and global skin assessment (Investigator's Global Assessment [IGA] scale, grade 0-4) at 4 weeks. Two blinded dermatologists independently evaluated the endpoints from photographs. ### results A total of 36 patients were enrolled, of whom 26 were evaluable. adapalene treatment was associated with a greater lesion count than placebo at 4 weeks, although the difference was not statistically significant (mean, 12.6 vs. 9.8, ### conclusion adapalene is not recommended as prophylaxis against acne-like rash induced by anti-EGFR therapies. ### Assistant: [{"class": "NEG", "spans_text": ["adapalene", "minocycline"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Both regimens included cyclophosphamide , methotrexate , 5-FU , prednisone , and doxorubicin . Paragraph: Randomized comparison of two combination chemotherapy regimens containing doxorubicin in patients with metastatic breast cancer: a Western Cancer Study Group trial. Ninety-six patients with metastatic breast cancer were entered in a prospectively randomized trial comparing a five-drug doxorubicin (Adriamycin)-containing regimen given in two different schedules. Both regimens included cyclophosphamide , methotrexate , 5-FU , prednisone , and doxorubicin . On one schedule, referred to as "combination" treatment, doxorubicin was given every 21 days and cyclophosphamide was given daily. On the less intensive "fixed-rotation" schedule, doxorubicin was given on alternative cycles every 42 days and cyclophosphamide was given for 21 days of the 42-day cycle. Response frequency and survival were comparable among patients receiving either regimen. Significantly less (P < 0.05) nausea and leukopenia occurred on the fixed-rotation schedule. Therefore, similar therapeutic benefit along with decreased toxicity was obtained by use of combination chemotherapy involving doxorubicin and cyclophosphamide given in the less intensive schedule. ### Assistant: [{"class": "POS", "spans_text": ["cyclophosphamide", "doxorubicin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: A Randomized , Multicenter , Double-blind , Phase III Study to Evaluate the Efficacy on Allergic Rhinitis and Safety of a Combination Therapy of Montelukast and Levocetirizine in Patients With Asthma and Allergic Rhinitis . Paragraph: A Randomized , Multicenter , Double-blind , Phase III Study to Evaluate the Efficacy on Allergic Rhinitis and Safety of a Combination Therapy of Montelukast and Levocetirizine in Patients With Asthma and Allergic Rhinitis . The aim of this study was to evaluate the efficacy and safety of a fixed-dose combination of montelukast and levocetirizine in patients with perennial allergic rhinitis with mild to moderate asthma compared with the efficacy and safety of montelukast alone. ### methods This study was a 4-week, randomized, multicenter, double-blind, Phase III trial. After a 1-week placebo run-in period, the subjects were randomized to receive montelukast (10 mg/day, n = 112) or montelukast (10 mg/day)/levocetirizine (5 mg/day) (n = 116) treatment for 4 weeks. The primary efficacy end point was mean daytime nasal symptom score. Other efficacy end points included mean nighttime nasal symptom score, mean composite symptom score, overall assessment of allergic rhinitis by both subjects and physicians, forced expiratory volume in 1 second (FEV ### findings Of 333 patients screened for this study, 228 eligible patients were randomized to treatment. The mean (SD) age of patients was 43.32 (15.02) years, and two thirds of subjects were female (66.67%). The demographic characteristics were similar between the treatment groups. Compared with the montelukast group, the montelukast/levocetirizine group reported significant reductions in mean daytime nasal symptom score (least squares mean [SE] of combination vs montelukast, -0.98 [0.06] vs -0.81 [0.06]; P = 0.045). For all other allergic rhinitis efficacy end points, the montelukast/levocetirizine group showed greater improvement than the montelukast group. Similar results were observed in overall assessment scores and in FEV ### implications The fixed-dose combination of montelukast and levocetirizine was effective and safe in treating perennial allergic rhinitis in patients with asthma compared with montelukast alone. ClinicalTrials.gov identifier: NCT02552667. ### Assistant: [{"class": "POS", "spans_text": ["Montelukast", "Levocetirizine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Intravenous administration of cefoperazone and sulbactam given as individual agents compared with the combination did not show pharmacokinetic differences that are likely to produce clinically relevant effects . Paragraph: Multiple-dose pharmacokinetics and toleration of intravenously administered cefoperazone and sulbactam when given as single agents or in combination. The multiple-dose pharmacokinetics and toleration of cefoperazone (3 g every 12 h) and sulbactam (1.5 g every 12 h) were studied when these antimicrobial agents were administered continuously over 7 days as a 15-min infusion of individual agents and as a 3/1.5-g cefoperazone-sulbactam combination. Fourteen male volunteers participated in an open, three-way crossover study of Latin Square design with a 1-week washout period between phases. On days 1 and 7 of each phase, serial serum samples and urine were collected for drug assay over a 12-h period. Hematological and clinical chemistry determinations were made within 10 days before the first antibiotic dose and for each treatment phase just before the first dose, on day 4 of treatment, and within 24 h of the last dose. For cefoperazone as a single agent on days 1 and 7, the average maximal concentration in serum (Cmax) was approximately 430 micrograms/ml, the terminal elimination half-life (t1/2) was 1.8 h, and the average percentage of dose excreted unchanged in the urine (%Ur) was 30%. For sulbactam as a single agent, the Cmax was approximately 90 micrograms/ml, the t1/2 was 1 h, and the %Ur was 89% on days 1 and 7. When comparing individual versus simultaneous drug administration, the only pharmacokinetic alteration observed was a statistically significant but minor (about 10%) decrease in sulbactam renal clearance, on both days 1 and 7, resulting in a similar decrease in total body clearance (CL). The area under the curve, apparent volume of distribution by the area method (V), t1/2, and Cmax were not significantly altered. Although cefoperazone pharmacokinetic parameters were not significantly altered when comparing single-agent to combination drug administration, the area under the curve was slightly lower and CL, nonrenal clearance, and V were modestly higher from day 1 to day 7. Because Cmax and t1/2 were unaffected, these minor day effects would not be of clinical significance. Intravenous administration of cefoperazone and sulbactam given as individual agents compared with the combination did not show pharmacokinetic differences that are likely to produce clinically relevant effects . The combination of cefoperazone and sulbactam was well tolerated, and the safety profile of the combination was similar to that either drug given alone under the conditions of this study. ### Assistant: [{"class": "COMB", "spans_text": ["cefoperazone", "sulbactam"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: HDC with cyclophosphamide , carmustine and thiotepa was given from day -7 to -5 . Paragraph: Interleukin-2 and granulocyte-macrophage-colony-stimulating factor immunomodulation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer. Immunomodulation with cytokines was used to improve the result of high-dose chemotherapy (HDC)/autologous hematopoietic stem cell transplantation (AHST). We examined the use of IL-2 and growth factors for mobilization, ex vivo activation of peripheral blood stem cell (PBSC) and maintenance therapy after HDC/AHST in metastatic breast cancer. Eligible patients with metastatic breast cancer for HDC/AHST were assigned to 1 of 3 protocols for PBSC mobilization: G-CSF (group 1); IL-2 + G-CSF (group 2); or IL-2 + G-CSF + GM-CSF (group 3). HDC with cyclophosphamide , carmustine and thiotepa was given from day -7 to -5 . PBSCs were treated ex vivo with IL-2 for 24 h and reinfused on day 0. Maintenance therapy included low-dose IL-2, followed by 2 courses of intermediate-dose IL-2. GM-CSF was given from day 1 until neutrophil recovery. Thirty-four patients (10 in group 1, 14 in group 2, and 10 in group 3) were included. Comparable numbers of CD34(+) cells were collected from all 3 groups; incremental increases of CD3(+) cells were collected from groups 1 to 2 and to 3 (p = 0.03). Major adverse effects from IL-2 were fever, hypotension and fatigue; no treatment-related mortality was seen. At a median follow-up of 790.5 days (range 150-2,722 days), median progression-free survival was 434 days and median overall survival was 1,432 days. Estimated 3-year progression-free and overall survival rates were 31 and 57%. Our study suggested that the use of IL-2 and growth factors immunomodulation with HDC/AHST was feasible with comparable survival rates. ### Assistant: [{"class": "COMB", "spans_text": ["cyclophosphamide", "carmustine", "thiotepa"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: A recently reported phase II trial has demonstrated that trastuzumab plus vinorelbine is both effective ( overall response rate 75 % ) and well tolerated , with the major side effects being typical of single-agent vinorelbine . Paragraph: New combinations with Herceptin in metastatic breast cancer. Preclinical data indicate that trastuzumab (Herceptin) has the potential for synergistic or additive effects in combination with therapies including chemotherapy and hormonal agents, providing the rationale for a number of clinical trials in women with HER2-positive metastatic breast cancer. A recently reported phase II trial has demonstrated that trastuzumab plus vinorelbine is both effective ( overall response rate 75 % ) and well tolerated , with the major side effects being typical of single-agent vinorelbine . Other combinations of trastuzumab with a variety of other chemotherapeutic and hormonal agents are also being assessed. In an effort to overcome the cardiotoxicity observed with trastuzumab plus doxorubicin in the pivotal phase III trial, combination regimens involving potentially less toxic anthracyclines such as epirubicin and liposomal formulations of doxorubicin are ongoing. In addition, trials are investigating whether trastuzumab can reverse the resistance to hormonal therapy that develops in most women with metastatic breast cancer. These and other studies will identify the regimens that produce the best outcomes with the fewest possible side effects in women with HER2-positive breast cancer. ### Assistant: [{"class": "POS", "spans_text": ["trastuzumab", "vinorelbine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Differences were observed when palbociclib or ribociclib was used in combination with letrozole or anastrozole or fulvestrant . Paragraph: First clinical experience with CDK4/6 inhibitors in breast cancer therapy. For hormone receptor-positive, HER2-negative breast cancer patients with metastatic or advanced disease, therapy with CDK4/6 inhibitors in addition to aromatase inhibitors (AIs) or to the estrogen receptor (ER) downregulator fulvestrant has resulted in an additional therapy option and a longer progression-free survival. In the Gynecologic-Oncology Clinic, Diakonie-Klinikum Schwäbisch Hall, we followed and registered our initial clinical experience with CDK4/6 inhibitors, following the side effects and tumor response over two years since they were officially approved for general use in Germany. Differences were observed when palbociclib or ribociclib was used in combination with letrozole or anastrozole or fulvestrant . The dynamic side effects and tumor response under therapy with palbociclib or ribociclib were found to be comparable with the main reported data in the official drug information. The CDK4/6 inhibitors have an important and promising role in the therapy of breast cancer patients. Patient age and therapy duration do not influence the use of palbociclib or ribociclib, although it may be important which AI is used in combination with palbociclib. ### Assistant: [{"class": "COMB", "spans_text": ["palbociclib", "letrozole"]}, {"class": "COMB", "spans_text": ["palbociclib", "anastrozole"]}, {"class": "COMB", "spans_text": ["palbociclib", "fulvestrant"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Resolution of muscle damage followed discontinuation of cyclosporine and lovastatin therapy . Paragraph: Rhabdomyolysis and renal injury with lovastatin use. Report of two cases in cardiac transplant recipients. Hyperlipidemia, particularly hypercholesterolemia, occurs in cardiac transplant recipients both as a preexisting condition and as a consequence of immunosuppressive therapy. lovastatin (Mevacor) has emerged as an agent that may effectively manage this condition. Few serious side effects of this drug have been observed. We describe two cardiac transplant recipients treated with lovastatin in conjunction with their other medications, including cyclosporine, who developed acute renal failure and rhabdomyolysis. Resolution of muscle damage followed discontinuation of cyclosporine and lovastatin therapy . We postulate that hepatic dysfunction secondary to cyclosporine predisposed these patients to lovastatin-induced muscle damage. Use of this drug in cardiac and other organ transplant recipients should be accompanied by close surveillance of creatine kinase, hepatic transaminases, and cyclosporine levels. ### Assistant: [{"class": "NEG", "spans_text": ["cyclosporine", "lovastatin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Primary chemotherapy with gemcitabine , liposomal doxorubicin and docetaxel in patients with locally advanced breast cancer : results of a phase I trial . Paragraph: Primary chemotherapy with gemcitabine , liposomal doxorubicin and docetaxel in patients with locally advanced breast cancer : results of a phase I trial . The primary objective was to determine the optimal doses for gemcitabine (prolonged infusion), liposomal doxorubicin (Myocet) and docetaxel as primary (neoadjuvant) chemotherapy for locally advanced breast cancer. Secondary objectives included evaluation of the safety and efficacy of the regimen. Patients (n=19) with histologically confirmed stage II or III breast cancer were treated with liposomal doxorubicin (50-60 mg/m2) and docetaxel (60-75 mg/m2) on day 1, and gemcitabine as 4-h infusion (350-400 mg/m2) on day 4. Treatment was repeated every 3 weeks for a maximum of 6 cycles. The maximum tolerated doses were gemcitabine 350 mg/m2, liposomal doxorubicin 60 mg/m2 and docetaxel 75 mg/m2. Dose-limiting toxicities were stomatitis, diarrhea and infection. The predominant hematologic toxicity was mild-to-moderate myelosuppression with grade 3/4 neutropenia in 20% of cycles. Non-hematologic toxicity was generally mild, with no grade 4 toxicities being observed. Predominant non-hematologic toxicity was stomatitis, which occurred in 95% of patients. Grade 3 toxicities were reported for stomatitis, nausea, diarrhea, infection and constipation. No cases of cardiac, renal, pulmonary or neurotoxicity were observed. The clinical response rate was 83% and histologically confirmed, clinically complete remissions occurred in two patients (11%). We conclude that the combination of gemcitabine (prolonged infusion), liposomal doxorubicin and docetaxel is safe and highly effective in patients with locally advanced breast cancer as defined by maximum tolerated doses. The evaluated schedule is suitable for phase II studies. ### Assistant: [{"class": "POS", "spans_text": ["gemcitabine", "doxorubicin", "docetaxel"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The aim of this single-blind , randomized , controlled trial was to investigate treatment efficacy and safety of aripiprazole as an adjunct to valproic acid ( Ari+Val ) , compared with haloperidol plus valproic acid ( Hal+Val ) , in acute manic patients . Paragraph: Combination treatment with aripiprazole and valproic acid for acute mania: an 8-week, single-blind, randomized controlled trial. Despite the fact that combination treatment for patients with acute bipolar is prevalent in clinical practice, the outcomes of adjunct treatment with aripiprazole and a mood stabilizer have rarely been reported. The aim of this single-blind , randomized , controlled trial was to investigate treatment efficacy and safety of aripiprazole as an adjunct to valproic acid ( Ari+Val ) , compared with haloperidol plus valproic acid ( Hal+Val ) , in acute manic patients . ### methods Treatment efficacy was prospectively assessed for 8 weeks in 42 patients with acute mania using the Young Mania Rating Scale and the Clinical Global Impression-Severity of illness scale. Emergent adverse events were assessed by the Drug-Induced Extrapyramidal Symptoms Scale and the Liverpool University Neuroleptic Side Effect Rating Scale. ### results Both Ari+Val and Hal+Val produced a high rate of response (85.7% and 92.9%, respectively) and remission (82.1% and 85.7%, respectively) after the 8-week trial. Changes in the Young Mania Rating Scale and the Clinical Global Impression-Severity of illness scale over the study period and time to remission and response were not significantly different between the 2 groups. Patients treated with Ari+Val showed significantly fewer extrapyramidal adverse events than those treated with Hal+Val (t = -2.048, F = 40, P = 0.048). However, significant weight gain was more prevalent in the Ari+Val group than the Hal+Val group (t = 2.055, F = 40, P = 0.046). ### conclusions Our findings suggest that both combination strategies with Ari+Val and Hal+Val are beneficial for acute manic episode. Although patients receiving Ari+Val showed fewer extrapyramidal symptoms than those taking Hal+Val, careful consideration of adverse events such as weight gain and sedation is warranted. ### Assistant: [{"class": "POS", "spans_text": ["aripiprazole", "valproic"]}, {"class": "POS", "spans_text": ["haloperidol", "valproic"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Because the incidence of nausea and vomiting is significantly reduced when ketorolac is used in place of opioids to attenuate postoperative pain , it would appear to be an appropriate choice of agent to use following propofol anesthesia . Paragraph: Ketorolac and propofol administration for prevention of nausea and vomiting in patients undergoing minor gynecologic surgery. This clinical review explores the efficacy of the nonsteroidal antiinflammatory agent, ketorolac tromethamine, added to an anesthetic regimen utilizing intravenous propofol. Both agents have been shown to reduce the incidence of nausea and vomiting postoperatively when administered to patients undergoing minor gynecologic surgery. Because the incidence of nausea and vomiting is significantly reduced when ketorolac is used in place of opioids to attenuate postoperative pain , it would appear to be an appropriate choice of agent to use following propofol anesthesia . The use of this combination of drugs may not only reduce the incidence of postoperative nausea and vomiting in patients undergoing minor gynecologic surgery, but could reduce the duration of hospitalization and enhance recovery from anesthesia. ### Assistant: [{"class": "POS", "spans_text": ["ketorolac", "propofol"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone . Paragraph: A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer. To investigate the efficacy and safety of combining vandetanib, an orally available multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), with bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC). ### methods This was an open-label, randomized phase II multi-center study. Eligible patients had rising PSA on androgen deprivation therapy, minimal symptoms and were chemotherapy-naïve. Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily (Arm A) or bicalutamide 50 mg oral daily alone (Arm B) with cross-over to vandetanib monotherapy at progression. The primary endpoint was PSA response (≥ 50 % decline from baseline). ### results Thirty-nine patients were recruited, 19 in Arm A and 20 in Arm B. PSA response was comparable in Arm A and Arm B (18 vs. 19 %). Time to PSA progression was 3.16 months (95 % confidence interval (CI): 1.09, not reached (NR)) for Arm A and 3.09 months (95 % CI: 1.22, NR) for Arm B. Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B (42 vs. 5 %; p = 0.019). Treatment with vandetanib was associated with a reduction in soluble VEGFR-2 levels after two cycles but an increase in plasma VEGF levels. ### conclusion The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone . Further evaluation of this combination is not warranted in mCRPC. ### Assistant: [{"class": "NEG", "spans_text": ["vandetanib", "bicalutamide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control , and that this activity is likely due to effects on both BC and microenvironment cells . Paragraph: Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells. metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since metformin is frequently used along with aspirin or beta-blockers, we investigated the effect of metformin, aspirin and the beta-blocker atenolol in several BC models. In vitro, aspirin synergized with metformin in inducing apoptosis of triple negative and endocrine-sensitive BC cells, and in activating AMPK in BC and in white adipose tissue (WAT) progenitors known to cooperate to BC progression. Both aspirin and atenolol added to the inhibitory effect of metformin against complex I of the respiratory chain. In both immune-deficient and immune-competent preclinical models, atenolol increased metformin activity against angiogenesis, local and metastatic growth of HER2+ and triple negative BC. aspirin increased the activity of metformin only in immune-competent HER2+ BC models. Both aspirin and atenolol, when added to metformin, significantly reduced the endothelial cell component of tumor vessels, whereas pericytes were reduced by the addition of atenolol but not by the addition of aspirin. Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control , and that this activity is likely due to effects on both BC and microenvironment cells . ### Assistant: [{"class": "POS", "spans_text": ["Aspirin", "Metformin"]}, {"class": "POS", "spans_text": ["Atenolol", "Metformin"]}]