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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: In this challenging field , aflibercept offers a good option for oxaliplatin-refractory mCRC patients when combined with irinotecan and 5-fluorouracil irrespective of prior anti-angiogenic treatment . Paragraph: Pharmacokinetic and pharmacodynamic evaluation of aflibercept for the treatment of colorectal cancer. Colorectal cancer (CRC) is currently one of the most lethal and prevalent tumors worldwide. Prognosis in the metastatic setting remains poor despite therapeutic advances. In addition to chemotherapy, new drugs have recently been developed targeting signaling pathways involved in tumor growth, differentiation and angiogenesis. aflibercept , a recombinant protein derived from VEGF receptors 1 and 2, also targets this angiogenesis pathway but via a different mechanism, acting as VEGF decoy, thus blocking other VEGFs. ### Areas Covered A comprehensive review of preclinical studies with aflibercept in cell lines and xenografts of different tumor types is presented. aflibercept safety, pharmacokinetics and pharmacodynamics data from Phase I studies in solid tumor patients are discussed. Implications of Phase II studies and the pivotal Phase III VELOUR trial of second-line treatment in metastatic CRC (mCRC) patients evaluating aflibercept alone or combined with chemotherapy are also described. ### Expert Opinion In this challenging field , aflibercept offers a good option for oxaliplatin-refractory mCRC patients when combined with irinotecan and 5-fluorouracil irrespective of prior anti-angiogenic treatment . Therapeutic management may be further advanced by characterization of patients with predictive biomarkers and molecular profiles to improve benefit with this treatment. ### Assistant: [{"class": "POS", "spans_text": ["aflibercept", "irinotecan", "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: The combination of 1-hour paclitaxel , carboplatin , and extended oral schedule etoposide is feasible and well tolerated at the doses administered in this phase II trial . Paragraph: Paclitaxel, carboplatin, and oral etoposide in the treatment of small cell lung cancer. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is active in previously untreated patients with small cell lung cancer (SCLC). We evaluated the toxicity and efficacy of a 1-hour infusion of paclitaxel added to a combination regimen of carboplatin and etoposide in a phase II trial for the treatment of patients with SCLC. Thirty-eight patients with previously untreated SCLC were treated with paclitaxel 135 mg/m2 (1-hour intravenous infusion), day 1; carboplatin at area under the concentration-time curve of 5, day 1; and oral etoposide 100 and 50 mg (alternating days), days 1 to 10. Treatment cycles were repeated every 21 days for a total of four courses. Patients with limited-stage disease received radiation therapy (4,500 cGy in 25 fractions) concurrently with the last two courses of chemotherapy. This outpatient combination was easily tolerated. Grade 3 or 4 leukopenia was experienced in only 8% of courses; grades 3 and 4 thrombocytopenia and anemia were also infrequent. Nonhematologic toxicity was uncommon, with the exception of transient esophagitis, which occurred in six of 15 patients (grade 3 in five patients, grade 4 in one) receiving concurrent chemoradiotherapy. Of 35 evaluable patients, 29 (83%) achieved a response to treatment. The complete response rate was 29% (40% in patients with limited-stage disease). Median survival was 7 months for patients with extensive-stage disease and 17 months in limited-stage patients. Prophylactic whole brain irradiation was not used, and seven patients developed brain metastases as their initial site of relapse. The combination of 1-hour paclitaxel , carboplatin , and extended oral schedule etoposide is feasible and well tolerated at the doses administered in this phase II trial . This treatment was highly active and the results are comparable to other standard regimens. Increased doses of both paclitaxel and carboplatin could probably be tolerated and are currently being evaluated. Precise definition of the role of paclitaxel in the treatment of SCLC will require randomized studies. ### Assistant: [{"class": "POS", "spans_text": ["paclitaxel", "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: In this regard , we have synthesized Pem-PEG-Gem , wherein pemetrexed ( Pem ) and gemcitabine ( Gem ) are conjugated to a heterobifunctional polyethylene glycol ( PEG ) polymer for the effective treatment of Non-Small Cell Lung Cancer ( NSCLC ) . Paragraph: Synergistic activity of combination therapy with PEGylated pemetrexed and gemcitabine for an effective cancer treatment. Combination therapy in cancer is now opted as a potential therapeutic strategy for cancer treatment. However, effective delivery of drugs in combination at the tumor site is marred by low bioavailability and systemic toxicity of individual drugs. Polymer therapeutics is indeed an upcoming approach for the combinational drug delivery in favor of better cancer management. Hence, the objective of our investigation was to develop a dual drug PEGylated system that carries two chemotherapeutic drugs simultaneously for effective treatment of cancer. In this regard , we have synthesized Pem-PEG-Gem , wherein pemetrexed ( Pem ) and gemcitabine ( Gem ) are conjugated to a heterobifunctional polyethylene glycol ( PEG ) polymer for the effective treatment of Non-Small Cell Lung Cancer ( NSCLC ) . Our results demonstrate enhanced bioavailability of the individual drugs in Pem-PEG-Gem in comparison with the drugs in their native form. The developed Pem-PEG-Gem showed enhanced cell death with respect to their native counterparts when treated singly or in combination against NSCLC cells. This might be attributed to better cellular internalization through the process of macropinocytosis and synergistic cytotoxic action of Pem-PEG-Gem in NSCLC cells. Hence, we propose the above dual drug based polymer therapeutic approach suitable for better clinical application in the treatment of NSCLC. ### Assistant: [{"class": "POS", "spans_text": ["pemetrexed", "gemcitabine"]}]

### 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 the initiation of antimalarial treatment with artesunate and mefloquine , his clinical condition gradually improved . Paragraph: An 11-year-old boy with Plasmodium falciparum malaria and dengue co-infection. Malaria and dengue fever are major mosquito-borne public health problems in tropical countries. The authors report a malaria and dengue co-infection in an 11-year-old boy who presented with sustained fever for 10 days. The physical examination revealed a flushed face, injected conjunctivae and left submandibular lymphadenopathy. His peripheral blood smear showed few ring-form trophozoites of Plasmodium falciparum. His blood tests were positive for dengue NS-1 antigen and IgM antibody, and negative for IgG antibody. After the initiation of antimalarial treatment with artesunate and mefloquine , his clinical condition gradually improved . However, he still had low-grade fever that persisted for 6 days. Finally, he recovered well without fluid leakage, shock or severe bleeding. This case report emphasises that early recognition and concomitant treatment of malaria and dengue co-infection in endemic areas can improve clinical outcome and prevent serious complications. ### Assistant: [{"class": "POS", "spans_text": ["artesunate", "mefloquine"]}]

### 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: For those few patients who do not respond to first-line therapy , the combination of vinblastine , ifosfamide , and cisplatin is the most popular regimen for the subset of platinum-sensitive tumors . Paragraph: Update on malignant ovarian germ cell tumors. The evolution of therapy for malignant ovarian germ cell tumors has been one of the true success stories in oncology. This article reviews the major advances in this field, with emphasis on more recent developments. During the past two decades, the nomenclature and histologic criteria for the major histologic subtypes have been standardized. Although the role of secondary debulking is uncertain, it probably has merit in selected patients. The use of second-look laparotomy should be limited as much as possible. Chemotherapeutic regimens have evolved to the current "gold standard"--the combination of bleomycin, etoposide, and cisplatin, with overall disease-free survival rates of greater than 95%. For patients with metastatic dysgerminoma, chemotherapy has replaced radiation therapy as the treatment of choice. For those few patients who do not respond to first-line therapy , the combination of vinblastine , ifosfamide , and cisplatin is the most popular regimen for the subset of platinum-sensitive tumors . For those with platinum-resistant tumors, dose intensification with autologous bone marrow rescue or Phase II drugs are being investigated. Studies on the late effects of treatment reveal that reproductive potential can be preserved in most young patients. In summary, although the progress in this field has been phenomenal, small incremental advances will continue to occur during the 1990s. ### Assistant: [{"class": "POS", "spans_text": ["vinblastine", "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: Patients received once-daily vandetanib ( planned dosing levels of 100 , 200 , and 300 mg ) with concomitant daily radiotherapy ( 1.8 Gy/d , 45 Gy total ) and chemotherapy , consisting of infusional 5-FU ( 225 mg/m/d over 96 h , weekly ) , paclitaxel ( 50 mg/m , days 1 , 8 , 15 , 22 , 29 ) and carboplatin ( AUC of 5 , days 1 , 29 ) . Paragraph: Induction Therapy for Locally Advanced, Resectable Esophagogastric Cancer: A Phase I Trial of Vandetanib (ZD6474), Paclitaxel, Carboplatin, 5-Fluorouracil, and Radiotherapy Followed by Resection. Preoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates. ### methods Patients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib ( planned dosing levels of 100 , 200 , and 300 mg ) with concomitant daily radiotherapy ( 1.8 Gy/d , 45 Gy total ) and chemotherapy , consisting of infusional 5-FU ( 225 mg/m/d over 96 h , weekly ) , paclitaxel ( 50 mg/m , days 1 , 8 , 15 , 22 , 29 ) and carboplatin ( AUC of 5 , days 1 , 29 ) . ### results A total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d. ### conclusions vandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study. ### Assistant: [{"class": "POS", "spans_text": ["vandetanib", "5-FU", "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: The calcium channel blocker verapamil has been previously shown to augment the chemosensitivity of pancreatic adenocarcinoma cell lines to doxorubicin by mechanisms other than changes in the intracellular accumulation , retention , or metabolism of doxorubicin . Paragraph: Inhibitory effects of a calcium antagonist on ornithine decarboxylase induction in pancreatic cancer cell lines. The calcium channel blocker verapamil has been previously shown to augment the chemosensitivity of pancreatic adenocarcinoma cell lines to doxorubicin by mechanisms other than changes in the intracellular accumulation , retention , or metabolism of doxorubicin . Because of our interest in polyamine biosynthesis and metabolism and the known involvement of calcium in the induction of ornithine decarboxylase (ODC) by serum refeeding of cultured cells, the effects of verapamil on the serum-stimulated ODC activity in two hamster pancreatic adenocarcinoma cell lines were examined. In plateau phase well-differentiated (WD) PaCa and poorly differentiated (PD) PaCa cells, a dose-dependent inhibition of the 4-h serum induction of ODC was seen at concentrations of 1, 5, and 10 microM verapamil. At the higher concentrations of verapamil, the inhibition of ODC induction was comparable to that achieved with 5 mM alpha-difluoromethylornithine (DFMO, a specific enzyme inhibitor of ODC) and greater than that seen with 2 mM EGTA plus calcium-depleted serum. Log phase PD PaCa cells, included for comparison, showed less ODC induction with serum and lesser degrees of inhibition of the response to serum refeeding with verapamil, DFMO, and calcium depletion. No direct inhibition of the ODC enzyme was found when verapamil was added at the time the activity was measured. Based on our present data, a possible influence of intracellular calcium pools in the verapamil effect on ODC activity is unclear. Nevertheless, the present findings suggest that verapamil's effects on cytotoxicity may be mediated (at least in part) by inhibition of the serum-mediated induction of ODC. ### Assistant: [{"class": "COMB", "spans_text": ["verapamil", "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: The results of a randomized phase II trial have demonstrated that the addition of cetuximab to irinotecan in patients with irinotecan-resistant tumors represents another active treatment option for these patients . Paragraph: Current status of second-line therapy for metastatic colorectal cancer. Decisions regarding the optimal systemic therapy for patients with metastatic colorectal cancer (CRC) have become more complex with the identification and development of multiple effective agents for this disease. Multiple treatment options are now available in the second-line setting for patients with metastatic CRC who have progressed despite prior chemotherapy. The exact choice of second-line therapy depends on the first-line treatment that was administered. irinotecan as a salvage therapy for patients with metastatic CRC who have progression following front-line 5-fluorouracil (5-FU)-based therapies was confirmed in a number of phase II/III studies. Many patients who received irinotecan/5-FU-based therapy as first-line treatment benefit from the combination of oxaliplatin and 5-FU/leucovorin (FOLFOX) in terms of response, time to progression, and relief of tumor-related symptoms. Other considerations include the integration of targeted therapies into chemotherapy regimens. The results of a randomized phase II trial have demonstrated that the addition of cetuximab to irinotecan in patients with irinotecan-resistant tumors represents another active treatment option for these patients . The activity of bevacizumab as part of second-line therapy is currently under investigation and results from phase III trials are expected within the next year. In summary, the availability of 5 drugs that are active in CRC provides us, for the first time, with choice--and dilemma--regarding optimal second-line therapy in patients with metastatic CRC. ### Assistant: [{"class": "POS", "spans_text": ["cetuximab", "irinotecan"]}]

### 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: Normal heart rate and rhythm were then preserved temporarily with digoxin and flecainide . Paragraph: Direct fetal administration of adenosine for the termination of incessant supraventricular tachycardia. Adenosine terminates supraventricular reentry tachycardia safely and effectively in the pediatric age group. ### case The recurrence of pretreated incessant tachycardia led to severe hydrops in a 28-week-old fetus. The tachycardia was terminated instantly with direct fetal administration of adenosine via the umbilical vein. Normal heart rate and rhythm were then preserved temporarily with digoxin and flecainide . ### conclusion Direct fetal adenosine administration might be helpful in the treatment of fetal reentry tachycardias if the sinus rhythm achieved quickly can be preserved by long-acting antiarrhythmic drugs. Such a combined therapeutic approach might be especially advantageous in hydropic fetuses. ### Assistant: [{"class": "POS", "spans_text": ["digoxin", "flecainide"]}]

### 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 phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer . Paragraph: A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer . The aim of this study was to determine in patients with previously untreated advanced colorectal cancer the maximum tolerated dose (MTD) and safety profile of irinotecan in combination with capecitabine, to identify a recommended dose and to determine the response rate and time to disease progression. In addition, we aimed to explore the pharmacokinetic parameters of irinotecan and capecitabine when used in different sequences of administration, with irinotecan infusion either prior to or after the first intake of capecitabine. ### Patients And Methods One hundred patients were included: 43 patients were recruited into an extended phase I trial of alternating escalation in dose of both drugs where irinotecan was administered intravenously (i.v) on day 1 after first intake of capecitabine taken from days 1-14 twice daily, with cycles repeated every 3 weeks. After the determination of recommended dose a further 57 patients were treated in a phase II evaluation with the reverse sequence of drugs on day 1. Pharmacokinetic analysis was performed in patients treated at the recommended dose in two cohorts of patients in which the sequence of the first administration of each drug was reversed. ### results The MTD of the combination was determined as irinotecan 300 mg/m2, with capecitabine 2000 mg/m2/day. Dose limiting toxicities were neutropenia and diarrhoea. The recommended dose is irinotecan intravenous (i.v.) 250 mg/m2 day 1 and capecitabine 2000 mg/m2/day days 1-14, every 3 weeks. Treatment was well tolerated, with diarrhoea the most common serious toxicity. Response rate in the phase II cohort was 42% [95% confidence interval (CI) 29% to 56%]. Median duration of response was 7.7 months (95% CI 7.5-8.9). Median time to progression was 8.3 months (95% CI 5.8-10). No significant effect on irinotecan pharmacokinetics was observed whatever the intake of capecitabine before or after irinotecan infusion. An effect of irinotecan on capecitabine and some capecitabine metabolites was observed, but irinotecan did not effect 5-fluorouracil (5-FU) pharmacokinetics. ### conclusions irinotecan in combination with capecitabine is a well tolerated regimen with an activity comparable to, but more convenient than, irinotecan-5-FU i.v. combinations in patients with previously untreated advanced colorectal cancer. The pharmacokinetic data suggest that the sequence of administration does not impact significantly on the metabolism of the two drugs. ### Assistant: [{"class": "POS", "spans_text": ["irinotecan", "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 purpose of this study was to determine whether combination therapy with vancomycin and TZP is associated with an incidence of AKI in pediatric patients higher than that in those on combination therapy with vancomycin and cefepime . Paragraph: Incidence of Nephrotoxicity Among Pediatric Patients Receiving Vancomycin With Either Piperacillin-Tazobactam or Cefepime: A Cohort Study. Recent studies in adults have found an incidence of acute kidney injury (AKI) in patients treated with a combination of vancomycin and piperacillin-tazobactam (TZP) that is greater than that expected with either medication alone. The purpose of this study was to determine whether combination therapy with vancomycin and TZP is associated with an incidence of AKI in pediatric patients higher than that in those on combination therapy with vancomycin and cefepime . ### methods We performed a retrospective single-center matched-cohort study of pediatric patients who received vancomycin in combination with TZP or cefepime between January 2015 and June 2016. The patients were matched according to chronic disease, age, sex, and number of concomitant nephrotoxic medications at the time of combination antibiotic therapy. The primary outcome was incidence of AKI. Secondary outcomes included differences between groups in time to AKI, resolution of AKI, and effect of vancomycin trough levels on the incidence of nephrotoxicity. Conditional logistic regression was used to compare categorical and continuous variables between treatment groups. Conditional Poisson regression was used to assess the association between AKI and treatment groups. Stratified log-rank tests and Cox proportional hazards models with shared frailty were used to compare the times to AKI according to treatment group. ### results Two hundred twenty-eight matched patients were included. AKI developed in 9 (7.9%) of 114 and 33 (28.9%) of 114 patients in the cefepime and TZP groups, respectively (P < .001). Type of combination therapy remained a significant predictor for AKI in multivariate conditional Poisson analysis in which adjustments were made for age, sex, use of concomitant nephrotoxins, and vancomycin dose (relative risk, 2.5 [95% confidence interval, 1.1-5.8]; P = .03). AKI developed almost 3 times sooner in the TZP group than in the cefepime group (hazard ratio, 2.9 [95% confidence interval, 1.3-6.1]; P = .006). Sensitivity analyses in which adjustment was made for antibiotic indication in addition to the aforementioned variables and excluding those with gastrointestinal infection revealed similar results. ### conclusion Among hospitalized children at our institution, combination therapy with vancomycin and TZP was associated with an incidence of AKI higher than that associated with vancomycin and cefepime. ### Assistant: [{"class": "NEG", "spans_text": ["vancomycin", "TZP"]}, {"class": "POS", "spans_text": ["vancomycin", "cefepime"]}]

### 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 patients who experience disease progression after etoposide , doxorubicin , cisplatin with mitotane ( EDP-M ) , gemcitabine and metronomic capecitabine , or the less used streptozotocin , represent a second-line chemotherapy option . Paragraph: Adrenocortical carcinoma: current treatment options. In this article, we focus on the current and future treatment options for adrenocortical carcinoma (ACC). ### Recent Findings Radical surgery remains the only curative treatment for ACC. Recent reports showed a longer overall survival (OS) in patients with high risk of recurrence treated with adjuvant mitotane; the time in target range (14-20 mg/l) is related to low risk of relapse both in adjuvant and in palliative setting. In patients who experience disease progression after etoposide , doxorubicin , cisplatin with mitotane ( EDP-M ) , gemcitabine and metronomic capecitabine , or the less used streptozotocin , represent a second-line chemotherapy option . temozolomide can be employed as a third-line chemotherapy. To date, unsatisfactory results have been obtained on the efficacy of targeted therapies. Clinical trials are ongoing to evaluate the efficacy of tyrosine kinase and immune checkpoint inhibitors. ### summary ACC is a rare disease with a poor prognosis. The main therapy is represented by radical surgery conducted by an expert surgeon. Adjuvant mitotane has to be started in patients with high risk of recurrence. In patients with inoperable disease, the scheme EDP-M is the most employed. Few data are available on second-line and third-line chemotherapy in patients with disease progression after EDP-M. Currently, the role of targeted therapies is under evaluation. ### Assistant: [{"class": "POS", "spans_text": ["gemcitabine", "capecitabine"]}, {"class": "POS", "spans_text": ["gemcitabine", "streptozotocin"]}]

### 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 conclude that ropivacaine alone injected into the pterygomandibular region does not affect the cardiovascular system and that the addition of epinephrine has no beneficial effect . Paragraph: Effects of regional anesthesia with ropivacaine on arterial pressure and heart rate in healthy subjects. The anesthetic, ropivacaine, has been used extensively in clinical practice, but few studies have evaluated this long-acting local anesthetic in dentistry. In this study we evaluated the effects of ropivacaine alone and ropivacaine + vasoconstrictor on the cardiovascular system when used as a dental anesthetic in volunteers. Thirty-two healthy subjects received two consecutive infiltrations of 1.8 ml of either 0.75% ropivacaine or ropivacaine + epinephrine into the pterygomandibular region. Pain sensation, numbness of the lip, arterial pressure, heart rate, and electrocardiogram changes were monitored for 2 h. The onset of anesthesia was 10 min after the injection and lasted for more than 2 h, and numbness of the lip lasted for approximately 8 h. ropivacaine alone did not cause significant changes in the cardiovascular parameters, but ropivacaine + epinephrine caused a transient increase in arterial pressure and heart rate 2 min postinjection. We conclude that ropivacaine alone injected into the pterygomandibular region does not affect the cardiovascular system and that the addition of epinephrine has no beneficial effect . This finding may be relevant to dentists endeavoring to find an anesthetic of minimal cardiovascular risk to produce regional anesthesia for long-lasting procedures without the need of a vasoconstrictor. ### Assistant: [{"class": "COMB", "spans_text": ["ropivacaine", "epinephrine"]}]

### 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 next broad-spectrum drug was ethionamide , followed by ansamycin , rifampin , capreomycin , kanamycin , streptomycin and ethambutol . Paragraph: Spectrum of drugs against atypical mycobacteria: how valid is the current practice of drug susceptibility testing and the choice of drugs? The in vitro activity of 13 drugs against 552 clinical isolates of atypical mycobacteria representing 12 species was performed in 7H11 agar medium at the National Reference Laboratory for Mycobacteria, using the 1% proportion method. All the species tested were resistant to isoniazid and pyrazinamide. In general, clofazimine and d-cycloserine showed the widest spectrum of activity except in the case of Mycobactrium fortuitum and M. chelonei which were resistant to both drugs, and the M. szulgai and M. terrae complex which was resistant to d-cycloserine. The next broad-spectrum drug was ethionamide , followed by ansamycin , rifampin , capreomycin , kanamycin , streptomycin and ethambutol . Among the fluoroquinolones, both ciprofloxacin and ofloxacin were active against M. xenopi, M. gordonae and M. fortuitum whereas M. kansasii and M. gastri were sensitive to ofloxacin only. When the species were listed in respect of the number of drugs to which they were susceptible (less than 10% of resistant strains), they were classified as follows; 7/13 drugs for M. kansasii, M. gastri and M. xenopi; 6/13 for M. gordonae; 5/13 for M. marinum; 3/13 for M. szulgai; 2/13 for M. fortuitum; 1/13 for the M. avium, M. scrofulaceum, M. simiae, and M. terrae complex, and none of the 13 in the case of M. chelonei. These results are discussed in relation to the multiple drug resistance of atypical mycobacteria. We conclude that the critical concentrations of drugs established for M. tuberculosis are not appropriate for atypical mycobacteria. ### Assistant: [{"class": "COMB", "spans_text": ["ethionamide", "rifampin", "capreomycin", "kanamycin", "streptomycin", "ethambutol", "ansamycin"]}]

### 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/II study of gefitinib and capecitabine in patients with colorectal cancer . Paragraph: Phase I/II study of gefitinib and capecitabine in patients with colorectal cancer . The objectives of this phase I/II study were to determine the maximum tolerated dose (MTD), characterise the principal toxicities in the phase I part and assess the efficacy in the phase II part of gefitinib, an oral selective inhibitor of the epidermal growth factor receptor, in combination with capecitabine in patients with advanced colorectal cancer (CRC). ### Methods And Patients Patients with advanced CRC were treated with gefitinib administered daily for 21 days and capecitabine administered twice daily for 14 days of a 21-day cycle. The dose levels of gefitinib (mg) and capecitabine (mg/m(2) bid) assessed were 250/1000 and 250/ 1250. An expanded cohort was enrolled at the MTD to better characterise toxicity and efficacy. A total of 32 previously treated patients were accrued. In the phase I part 10 subjects were treated, with one dose-limiting toxicity. Overall 26 patients were treated at the MTD of the combination, which was gefitinib 250 mg/day and capecitabine 1250 mg/m(2) twice daily. ### results The most frequent treatment-related adverse events included asthenia, diarrhoea, nausea, rash and anorexia. The incidence profile was very similar in phases I and II. No objective responses were documented but 53% of the patients achieved stable disease as best response to therapy. ### conclusions capecitabine 1250 mg/m(2) twice daily 14 of 21 days and gefitinib at 250 mg/day can be safely administered in combination. The combination is relatively well tolerated. There were no objective responses, although an interesting stabilisation rate was documented, in previously treated advanced CRC patients. ### Assistant: [{"class": "POS", "spans_text": ["gefitinib", "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: Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma . Paragraph: Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma . Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination. ### methods We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood. ### results The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%). ### conclusions In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .). ### Assistant: [{"class": "POS", "spans_text": ["ibrutinib", "venetoclax"]}]

### 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 group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6 . Paragraph: Population pharmacokinetics of ifosfamide and its 2- and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients. The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide. 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6 . The concentration-time profiles of ifosfamide were described by an ifosfamide concentration-dependent development of autoinduction of ifosfamide clearance. Metabolite compartments were linked to the ifosfamide compartment enabling description of the concentration-time profiles of 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide. The Bayesian estimates of the pharmacokinetic parameters were used to calculate the systemic exposure to ifosfamide and its metabolites for the four ifosfamide schedules. Fractionation of the dose over 2 days resulted increased metabolite formation, especially of 2-dechloroethylifosfamide, probably due to increased autoinduction. Renal recovery was only minor with 6.6% of the administered dose excreted unchanged and 9.8% as dechloroethylated metabolites. In conclusion, ifosfamide pharmacokinetics were described with an ifosfamide concentration-dependent development of autoinduction and allowed estimation of the population pharmacokinetics of the metabolites of ifosfamide. Fractionation of the dose resulted in increased exposure to 2-dechloroethylifosfamide, probably due to increased autoinduction. ### Assistant: [{"class": "COMB", "spans_text": ["ifosfamide", "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: Ticlopidine and clopidogrel achieve antiplatelet effects by inhibiting the binding of adenosine 5'-disphosphate to its platelet receptor . Paragraph: The antiplatelet effects of ticlopidine and clopidogrel. Ticlopidine and clopidogrel achieve antiplatelet effects by inhibiting the binding of adenosine 5'-disphosphate to its platelet receptor . ticlopidine was first shown to decrease major events compared with placebo or aspirin in patients with stroke or recent transient ischemic attack. Randomized studies in patients undergoing coronary artery stenting have shown that ticlopidine reduces the risk for subacute stent thrombosis compared with warfarin-based regimens. Smaller studies have also shown this drug to have benefit during follow-up in patients with unstable angina, peripheral arterial disease, saphenous vein coronary bypass grafts, and diabetic retinopathy. clopidogrel was recently approved by the U.S. Food and Drug Administration for the reduction of ischemic events in patients with recent myocardial infarction, stroke, or peripheral arterial disease (incidence, 5.32% per year compared with 5.83% per year for aspirin; P = 0.043) with no added risk for neutropenia. The combination of clopidogrel and aspirin, as well as the utility of clopidogrel in other patient populations and in stenting, requires further study. ticlopidine and clopidogrel seem to have beneficial effects compared with aspirin (the current standard) in a broad range of patients. These observations highlight the importance of antiplatelet therapy in cardiovascular disease. ### Assistant: [{"class": "POS", "spans_text": ["Ticlopidine", "clopidogrel"]}]

### 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: Irinotecan plus gemcitabine induces both radiographic and CA 19 - 9 tumor marker responses in patients with previously untreated advanced pancreatic cancer . Paragraph: Irinotecan plus gemcitabine induces both radiographic and CA 19 - 9 tumor marker responses in patients with previously untreated advanced pancreatic cancer . This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. ### Patients And Methods Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. ### results Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). ### conclusion irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity. ### Assistant: [{"class": "POS", "spans_text": ["Irinotecan", "gemcitabine"]}]

### 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 patient was treated with a combination of cyclophosphamide , doxorubicin , vincristine , and prednisone as initial management immediately after diagnosis . Paragraph: Lymphomatoid granulomatosis. Successful treatment with CHOP combination chemotherapy. A patient with lymphomatoid granulomatosis is reported. The patient was treated with a combination of cyclophosphamide , doxorubicin , vincristine , and prednisone as initial management immediately after diagnosis . She obtained a complete remission and remains free of disease 3 1/2 years from the time of diagnosis. The favorable outcome in this patient may be related to her initial limited disease or to the use of initial intensive chemotherapy; nonetheless, the generally unfavorable prognosis of this disease appears to mandate early trials of intensive therapy in most patients. ### Assistant: [{"class": "POS", "spans_text": ["cyclophosphamide", "doxorubicin", "vincristine", "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: To our knowledge , we present the first reported case of SS associated with linezolid and methadone with a brief review of the literature . Paragraph: Serotonin syndrome due to co-administration of linezolid and methadone. Serotonin syndrome (SS), a potentially life-threatening adverse drug reaction caused by excessive serotonergic agonism in central and peripheral nervous system serotonergic receptors, may be caused by a single drug or a combination of drugs with serotonergic activity. The syndrome results in a variety of mental, autonomic and neuromuscular changes, which can range in severity from mild to life-threatening. To our knowledge , we present the first reported case of SS associated with linezolid and methadone with a brief review of the literature . ### Assistant: [{"class": "NEG", "spans_text": ["linezolid", "methadone"]}]

### 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: Recent clinical trials have reported improved survival for two novel agents ; ipilimumab , a humanized , IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 ( CTLA-4 ) and vemurafenib , a BRAF ( v-raf murine sarcoma viral oncogene homolog B1 ) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene . Paragraph: Vemurafenib for the treatment of melanoma. Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents ; ipilimumab , a humanized , IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 ( CTLA-4 ) and vemurafenib , a BRAF ( v-raf murine sarcoma viral oncogene homolog B1 ) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene . ### Areas Covered The authors reviewed preclinical and clinical data examining the safety of vemurafenib in melanoma. MEDLINE and EMBASE were searched using the medical subject heading 'vemurafenib' and the following text terms: melanoma, BRAF inhibition, vemurafenib. This review provides the reader with an overview of current data examining the efficacy and safety of vemurafenib in metastatic melanoma. ### Expert Opinion vemurafenib is an oral agent licensed for patients with BRAF V600E mutation-positive inoperable and metastatic melanoma. The most common adverse effects observed in Phase III clinical trials were dermatological events, arthralgia and fatigue. Specific dermatological toxicities included development of cutaneous squamous cell cancers and keratoacanthomas. Prolongation of the QT interval was also reported. Regular dermatological assessments and electrocardiograms are recommended. Ongoing trials are examining vemurafenib in both the adjuvant setting and metastatic setting in combination with ipilimumab and MEK inhibitors (mitogen-activated protein kinase/extracellular signal-regulated kinase). Understanding and overcoming mechanisms of resistance to BRAF inhibitors is the focus of ongoing research. ### Assistant: [{"class": "POS", "spans_text": ["ipilimumab", "vemurafenib"]}]

### 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: Three interventions exhibited significantly improved OS results over chemotherapy ( all HR < 1 ): Ipilimumab , Nivolumab and Ipilimumab + Chemotherapy . Paragraph: Pharmacological interventions for melanoma: Comparative analysis using bayesian meta-analysis. We conducted a network meta-analysis in order to compare different strategies for managing melanoma patients. Electronic databases were searched for eligible randomized trials that compared different strategies in efficacy and tolerability. Five interventions were associated with a significant improvement in PFS over chemotherapy (all HR < 1): ipilimumab, tremelimumab, nivolumab, pembrolizumab 2 mg/kg and ipilimumab + nivolumab. Three interventions exhibited significantly improved OS results over chemotherapy ( all HR < 1 ): Ipilimumab , Nivolumab and Ipilimumab + Chemotherapy . Four interventions were superior to chemotherapy in CR and PR (all OR > 1): nivolumab, pembrolizumab 10 mg/kg, pembrolizumab 2 mg/kg and ipilimumab + nivolumab. However, the other seven interventions were associated with an increased risk of pruritus compared to chemotherapy (all OR > 1). ipilimumab, tremelimumab, ipilimumab + nivolumab and ipilimumab + Chemotherapy might result in a higher risk of diarrhea compared to chemotherapy (all OR > 1). Immune checkpoint therapy or combined interventions might be more effective than chemotherapy for managing melanoma patients. However, chemotherapy appears to be more tolerable than these combined strategies with respect to adverse events. ### Assistant: [{"class": "POS", "spans_text": ["Ipilimumab", "Nivolumab", "Ipilimumab", "Chemotherapy"]}]

### 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 breast trial participants studied were those elderly enrolled between 1995 and 1997 and treated with doxorubicin and cyclophosphamide or this combination with paclitaxel . Paragraph: Criterion validity of Medicare chemotherapy claims in Cancer and Leukemia Group B breast and lung cancer trial participants. To determine the accuracy with which Medicare claims data measure chemotherapy use in elderly Medicare beneficiaries with cancer, we performed a criterion validation study. We compared gold-standard clinical trial data for 175 elderly cancer patients treated in two Cancer and Leukemia Group B (CALGB) breast and lung cancer trials (i.e., 45 from trial 9344 and 130 from trial 9730) with contemporaneous ambulatory and in-patient Medicare health insurance claims data from Centers for Medicare and Medicaid Services (CMS). The breast trial participants studied were those elderly enrolled between 1995 and 1997 and treated with doxorubicin and cyclophosphamide or this combination with paclitaxel . The lung trial participants studied were those elderly enrolled between 1998 and 2000 and treated with paclitaxel and carboplatin or paclitaxel alone. Comparing CALGB data with Medicare claims, we found the crude sensitivity for chemotherapy administration was 93% (95% confidence interval [CI] = 88% to 96%). Individual chemotherapy agents had similarly high sensitivities, ranging from 81% (95% CI = 70% to 89%) for carboplatin to 91% (95% CI = 79% to 98%) for cyclophosphamide. Agent-specific specificities were 100%. CMS data reliably captured repeat administration of chemotherapy to within one cycle. Administrative Medicare claims data appear to be a valid source of information for chemotherapy administered to elderly Medicare beneficiaries with cancer. ### Assistant: [{"class": "COMB", "spans_text": ["doxorubicin", "cyclophosphamide"]}, {"class": "COMB", "spans_text": ["doxorubicin", "cyclophosphamide", "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: The intensive polychemotherapy regimen eBEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone in escalated doses ) is very active in patients with advanced-stage Hodgkin 's lymphoma , albeit at the expense of severe toxicities . Paragraph: PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. The intensive polychemotherapy regimen eBEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone in escalated doses ) is very active in patients with advanced-stage Hodgkin 's lymphoma , albeit at the expense of severe toxicities . Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. ### methods In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m ### findings Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4-94·0) with eBEACOPP and 88·1% (83·5-92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9-93·7) and 92·2% (89·4-95·0), respectively (difference 1·4%, 95% CI -2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8 × eBEACOPP group, three [1%] in the 8 × R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8 × eBEACOPP or 6 × eBEACOPP group). ### interpretation The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma. ### funding Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG. ### Assistant: [{"class": "COMB", "spans_text": ["bleomycin", "etoposide", "doxorubicin", "cyclophosphamide", "vincristine", "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: Systemic treatments , and here in particular a combined therapeutic regimen of chemotherapy and electron beam , bexarotene , or denileukin diftitox , showed more adverse effects than topical or skin-directed treatments . Paragraph: Interventions for mycosis fungoides. Mycosis fungoides is the most common type of cutaneous T-cell lymphoma, a malignant, chronic disease initially affecting the skin. Several therapies are available, which may induce clinical remission for a time. ### objectives To assess the effects of interventions for mycosis fungoides in all stages of the disease. ### Search Methods We searched the following databases up to January 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2010), and LILACS (from 1982). We also checked reference lists of included studies for further references to relevant RCTs. We searched online trials registries for further references to unpublished trials and undertook a separate search for adverse effects of interventions for mycosis fungoides in non-RCTs in MEDLINE in May 2011. ### Selection Criteria Randomised controlled trials (RCTs) of interventions for mycosis fungoides in people with any stage of the disease. At least 90% of participants in the trials must have been diagnosed with mycosis fungoides (Alibert-Bazin-type). ### Data Collection And Analysis Two authors independently assessed eligibility and methodological quality for each study and carried out data extraction. We resolved any disagreement by discussion. Primary outcomes were the impact on quality of life and the safety of interventions. When available, we reported on our secondary outcomes, which were the improvement or clearance of skin lesions, disease-free intervals, survival rates, relapse rates, and rare adverse effects. When possible, we combined homogeneous studies for meta-analysis. We used The Cochrane Collaboration's 'Risk of bias' tool to assess the internal validity of all included studies in six different domains. ### Main Results The review included 14 RCTs involving 675 participants, covering a wide range of interventions. Eleven of the included trials assessed participants in clinical stages IA to IIB only (please see Table 1 for definitions of these stages).Internal validity was considerably low in studies with a high or unclear risk of bias. The main reasons for this were low methodological quality or missing data, even after we contacted the study authors, and a mean dropout rate of 26% (0% to 72%). Study size was generally small with a minimum of 4 and a maximum of 103 participants. Only one study provided a long enough follow-up for reliable survival analysis.Included studies assessed topical treatments, such as imiquimod, peldesine, hypericin, nitrogen mustard, as well as intralesional injections of interferon-α (IFN-α). The light therapies investigated included psoralen plus ultraviolet A light (PUVA), extracorporeal photopheresis (photochemotherapy), and visible light. Oral treatments included acitretin, bexarotene, and methotrexate. Treatment with parenteral systemic agents consisted of denileukin diftitox; a combination of chemotherapy and electron beam radiation; and intramuscular injections of active transfer factor. Nine studies evaluated therapies by using an active comparator; five were placebo-controlled RCTs.Twelve studies reported on common adverse effects, while only two assessed quality of life. None of these studies compared the health-related quality of life of participants undergoing different treatments. Most of the reported adverse effects were attributed to the interventions. Systemic treatments , and here in particular a combined therapeutic regimen of chemotherapy and electron beam , bexarotene , or denileukin diftitox , showed more adverse effects than topical or skin-directed treatments .In the included studies, clearance rates ranged from 0% to 83%, and improvement ranged from 0% to 88%. The meta-analysis combining the results of 2 trials comparing the effect of IFN-α and PUVA versus PUVA alone showed no significant difference in the relative risk of clearance: 1.07 (95% confidence interval 0.87 to 1.31). None of the included studies demonstrated a significant increase in disease-free intervals, relapse, or overall survival. ### Authors Conclusions This review identified trial evidence for a range of different topical and systemic interventions for mycosis fungoides. Because of substantial heterogeneity in design, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be established on the basis of the included RCTs. Taking into account the possible serious adverse effects and the limited availability of efficacy data, topical and skin-directed treatments are recommended first, especially in the early stages of disease. More aggressive therapeutic regimens may show improvement or clearance of lesions, but they also result in more adverse effects; therefore, they are to be considered with caution. Larger studies with comparable, clearly-defined end points for all stages of mycosis fungoides, and a focus on safety, quality of life, and duration of remission as part of the outcome measures, are necessary. ### Assistant: [{"class": "NEG", "spans_text": ["bexarotene", "denileukin diftitox"]}]

### 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: Risk factors associated with cardiotoxicity within 2 years of doxorubicin administration included age [ adjusted hazard ratio ( aHR ) = 1.02 , 95 % confidence interval ( CI ) 1.00 - 1.04 ; p = 0.05 ] , metastasis ( aHR = 2.66 ; 95 % CI 1.36 - 5.20 ; p < 0.01 ) , and concomitant trastuzumab ( aHR = 4.08 ; 95 % CI 2.31 - 7.21 ; p Paragraph: Cumulative incidence of chemotherapy-induced cardiotoxicity during a 2-year follow-up period in breast cancer patients. Cardiotoxicities are adverse effects often reported in chemotherapy-treated breast cancer patients. This study evaluated the potential risk factors and cumulative incidence of doxorubicin-induced cardiotoxicity in Korean breast cancer patients. ### methods We retrospectively analyzed the data of 613 breast cancer patients who underwent a multigated acquisition (MUGA) scan or echocardiography prior to chemotherapy and at least one post-chemotherapy follow-up MUGA scan/echocardiography between 2007 and 2016 at National Cancer Center, Korea. The Cox proportional hazards models were used to evaluate cardiotoxicity risks. Competing risks analyses were performed to estimate cumulative incidence of cardiotoxicity. ### results Risk factors associated with cardiotoxicity within 2 years of doxorubicin administration included age [ adjusted hazard ratio ( aHR ) = 1.02 , 95 % confidence interval ( CI ) 1.00 - 1.04 ; p = 0.05 ] , metastasis ( aHR = 2.66 ; 95 % CI 1.36 - 5.20 ; p < 0.01 ) , and concomitant trastuzumab ( aHR = 4.08 ; 95 % CI 2.31 - 7.21 ; p < 0.01). The cumulative incidence of patients with cardiotoxicity was 6.1% at 2 years (without substantial change from about 9 months)and 20.2% at 2 years (without substantial change from about 15 months) after initiation of doxorubicin-containing therapy without and with trastuzumab, respectively. ### conclusions Susceptibility to chemotherapy-induced cardiotoxicity within 2 years of doxorubicin initiation in breast cancer patients was elevated with old age, metastasis, and concomitant trastuzumab. Regular imaging monitoring at least up to 9 months after doxorubicin initiation in patients treated without concomitant trastuzumab, and 15 months in patients treated with concomitant trastuzumab, is needed for early detection of chemotherapy-induced cardiotoxicity. ### Assistant: [{"class": "NEG", "spans_text": ["doxorubicin", "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: Twenty-four patients have been treated to date , and the maximum tolerated dose has been reached at paclitaxel 185 mg/m2 and carboplatin 350 mg/m2 . Paragraph: Preliminary results of a dose-finding study of paclitaxel and carboplatin in patients with advanced non-small cell lung cancer. This ongoing phase I study sought to establish the maximum tolerated dose of the combination of carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. paclitaxel was administered as a 3-hour intravenous infusion. The carboplatin infusion was administered over 30 minutes immediately afterward. Patients were assigned sequentially to one of eight treatment groups in which paclitaxel and carboplatin were administered in doses ranging from 130 to 185 mg/m2 and from 230 to 350 mg/m2, respectively. Twenty-four patients have been treated to date , and the maximum tolerated dose has been reached at paclitaxel 185 mg/m2 and carboplatin 350 mg/m2 . The combination has an excellent safety profile, with only a few, short-lasting episodes of neutropenia observed and no evidence of infection. At the doses tested, thrombocytopenia has not occurred. ### Assistant: [{"class": "POS", "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: [ Aztreonam or gentamicin combined with piperacillin as empiric antibiotic therapy during neutropenia of patients with hematologic diseases ] . Paragraph: [ Aztreonam or gentamicin combined with piperacillin as empiric antibiotic therapy during neutropenia of patients with hematologic diseases ] . Fourty-two febrile episodes of 32 patients with hematologic disease during neutropenia were treated with two randomly assigned antibiotic combinations of either piperacillin plus gentamicin or piperacillin plus aztreonam. Eleven of the 22 febrile episodes treated with piperacillin plus gentamicin and 12 of the 20 febrile episodes treated with piperacillin plus aztreonam responded. Addition of cefamandole to non-responders improved the outcome in 2 of the 16 febrile episodes. Mean nadir leucocyte count, age, sex, and underlying disease were not significantly different in both groups. Side effects were tolerable in both groups, although 1 patient treated with piperacillin plus gentamicin showed severe renal impairment. piperacillin plus aztreonam is as effective as piperacillin plus gentamicin as an empiric antibiotic combination in the treatment of febrile episodes with hematologic disease during neutropenia. ### Assistant: [{"class": "POS", "spans_text": ["Aztreonam", "piperacillin"]}, {"class": "POS", "spans_text": ["gentamicin", "piperacillin"]}]

### 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 present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man . Paragraph: Effect of salbutamol on digoxin pharmacokinetics. A single dose of the beta 2-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the phenomenon is a beta 2-adrenoceptor-mediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man . Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutamol, 4 micrograms.kg-1.h-1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i.v. injection of digoxin 15 micrograms.kg-1, was given 20 min after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the AUC 0-6 h was 15% lower during salbutamol infusion than during saline infusion. salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol compared to placebo treatment. The serum potassium concentration was significantly lower after salbutamol compared to placebo, as was the rate of renal excretion of potassium.(ABSTRACT TRUNCATED AT 250 WORDS) ### Assistant: [{"class": "COMB", "spans_text": ["salbutamol", "digoxin"]}]

### 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: Mecamylamine reversed the effects of nicotine on SHR performance . Paragraph: Nicotine-induced behavioral sensitization in an adult rat model of attention deficit/hyperactivity disorder (ADHD). Attention deficit hyperactivity disorder (ADHD) is associated with increased risk of tobacco dependence. nicotine, the main psychoactive component of tobacco, appears to be implicated in ADHD-related tobacco dependence. However, the behavioral responsiveness to nicotine of the prevalent animal model of ADHD, the spontaneously hypertensive rat (SHR), is currently underinvestigated. The present study examined the activational effects of acute and chronic nicotine on the behavior of adult male SHRs, relative to Wistar Kyoto (WKY) controls. Experiment 1 verified baseline strain differences in open-field locomotor activity. Experiment 2 tested for baseline strain differences in rotational behavior using a Rotorat apparatus. Adult SHR and WKY rats were then exposed to a 7-day regimen of 0.6mg/kg/d s.c. nicotine, or saline, prior to each assessment. A separate group of SHRs underwent similar training, but was pre-treated with mecamylamine, a cholinergic antagonist. nicotine sensitization, context conditioning, and mecamylamine effects were then tested. Baseline strain differences were observed in open-field performance and in the number of full rotations in the Rotorat apparatus, but not in the number of 90° rotations or direction changes. In these latter measures, SHRs displayed weaker nicotine-induced rotational suppression than WKYs. Both strains expressed nicotine-induced sensitization of rotational activity, but evidence for strain differences in sensitization was ambiguous; context conditioning was not observed. Mecamylamine reversed the effects of nicotine on SHR performance . These findings are consistent with the hypothesis that a reduced aversion to nicotine (expressed in rats as robust locomotion) may facilitate smoking among adults with ADHD. ### Assistant: [{"class": "POS", "spans_text": ["Mecamylamine", "nicotine"]}]

### 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 sub-effective doses of leflunomide and cyclosporin A resulted in significant inhibition of chronic arthritis . Paragraph: Immunomodulation of rat antigen-induced arthritis by leflunomide alone and in combination with cyclosporin A. The effects of the new immunomodulating isoxazol derivative leflunomide, in comparison with cyclosporin A, on established antigen-induced arthritis in rats as well as serum antibody levels were determined. When treatment with leflunomide, at concentrations from 2.5 to 10 mg/kg/d, was started on day 3 of arthritis, the acute and chronic phases of arthritis were effectively inhibited. This was demonstrated by decreased joint swelling and reduced histopathological arthritis score at the end of experiment (day 26). Furthermore, the treatment resulted in a significantly reduced level of serum antibodies to the matrix components collagen type I, type II and proteoglycans. Neither leflunomide nor cyclosporin A, at doses of 1 mg/kg/d, had an effect on the severity of arthritis and antibody levels. However, when both drugs were used together, at these non-effective doses, the histopathological score of chronic arthritis was significantly reduced. The results of our experiments demonstrate that leflunomide has a strong suppressive effect on both acute and chronic phases of antigen-induced arthritis and formation of autoantibodies in rats. Furthermore, orally administered doses of leflunomide were as effective as doses of cyclosporin A given intraperitoneally. The combination of sub-effective doses of leflunomide and cyclosporin A resulted in significant inhibition of chronic arthritis . ### Assistant: [{"class": "POS", "spans_text": ["leflunomide", "cyclosporin"]}]

### 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 metastatic setting , FOLFIRINOX ( folinic acid , 5-fluorouracil , irinotecan , and oxaliplatin ) , and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival . Paragraph: Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Pancreatic cancer is expected to be the second deadliest malignancy in the USA by 2020. The survival rates for patients with other gastrointestinal malignancies have increased consistently during the past 30 years; unfortunately, however, the outcomes of patients with pancreatic cancer have not changed significantly. Although surgery remains the only curative treatment for pancreatic cancer, therapeutic strategies based on initial resection have not substantially improved the survival of patients with resectable disease over the past 25 years; presently, more than 80% of patients suffer disease relapse after resection. Preclinical evidence that pancreatic cancer is a systemic disease suggests a possible benefit for early administration of systemic therapy in these patients. In locally advanced disease, the role of chemoradiotherapy is increasingly being questioned, particularly considering the results of the LAP-07 trial. Novel biomarkers are clearly needed to identify subsets of patients likely to benefit from chemoradiotherapy. In the metastatic setting , FOLFIRINOX ( folinic acid , 5-fluorouracil , irinotecan , and oxaliplatin ) , and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival . Thus, new treatments are urgently needed for patients with pancreatic cancer. Herein, we review the state-of-the-art of pancreatic cancer treatment, and the upcoming novel therapeutics that hold promise in this disease are also discussed. ### Assistant: [{"class": "COMB", "spans_text": ["folinic", "5-fluorouracil", "irinotecan", "oxaliplatin"]}, {"class": "COMB", "spans_text": ["nab-paclitaxel", "gemcitabine"]}]

### 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 in arm 1 ( n = 88 ) received 4 cycles of paclitaxel and carboplatin followed by 2 to 4 cycles of gemcitabine-based combination chemotherapy . Paragraph: Effects of sequential paclitaxel-carboplatin followed by gemcitabine-based chemotherapy compared with paclitaxel-carboplatin therapy administered to patients with advanced epithelial ovarian cancer: A retrospective, STROBE-compliant study. We aimed to compare the efficacy of paclitaxel and carboplatin followed by gemcitabine-based combination chemotherapy with paclitaxel-carboplatin for treating advanced epithelial ovarian cancer in this retrospective, STROBE-compliant study. Patients' tolerance to treatment was also assessed.We retrospectively analyzed the records of 178 women who underwent initial optimal debulking surgery between January 2003 and December 2011 to treat FIGO stage IIIc epithelial ovarian cancer. Patients in arm 1 ( n = 88 ) received 4 cycles of paclitaxel and carboplatin followed by 2 to 4 cycles of gemcitabine-based combination chemotherapy . Patients in arm 2 (n = 90) received 6 to 8 cycles of paclitaxel and carboplatin. The granulocyte-colony stimulating factor was administered prophylactically to all patients.The median follow-up for both arms was 62 months. Medianprogression-free survival (PFS) between arms 1 and 2 (28 and 19 months [P = 0.003]) as well as 5-year OS (34.1% and 18.9% [P = 0.021]) differed significantly. The neurotoxicity rate was significantly higher in arm 2 than in arm 1 (45.2% vs 27.1%, P = 0.026). There was no significant difference between study arms in hematological toxicity.The sequential regimen significantly improved PFS and 5-year OS with tolerable toxicity compared with the single regimen, and offers an alternative for treating patients with advanced epithelial ovarian cancer. ### Assistant: [{"class": "POS", "spans_text": ["paclitaxel", "carboplatin", "gemcitabine-based"]}]

### 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 patients receiving digoxin and propafenone simultaneously , the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity . Paragraph: Interaction between digoxin and propafenone. The pharmacokinetic and pharmacodynamic interactions between digoxin and propafenone were investigated in 10 hospitalized patients with heart disease and cardiac arrhythmias. During steady state (0.25 mg/day) the glycoside was combined with 600 mg of propafenone daily for 1 week. The mean +/- SD serum digoxin concentration (SDC) was 0.97 +/- 0.29 ng/ml before and 1.54 +/- 0.65 ng/ml (p less than 0.003) during propafenone administration. propafenone induced a mean decrease in 31.1 and 31.7% in total and renal digoxin clearances, respectively. The increase in SDCs was accompanied by a decrease in heart rate (HR) and shortening of QTC (QT interval corrected for HR). In patients receiving digoxin and propafenone simultaneously , the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity . ### Assistant: [{"class": "COMB", "spans_text": ["digoxin", "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: To review the clinical effectiveness and cost-effectiveness evidence base for lapatinib ( LAP ) in combination with an aromatase inhibitor ( AI ) and trastuzumab ( TRA ) in combination with an AI for the first-line treatment of patients who have hormone receptor-positive (HR+)/human epidermal growth factor 2-positive ( HER2 + ) mBC . Paragraph: Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor-positive breast cancer which over-expresses human epidermal growth factor 2 (HER2): a systematic review and economic analysis. Breast cancer is the uncontrolled, abnormal growth of malignant breast tissue affecting predominantly women. Metastatic breast cancer (mBC) is an advanced stage of the disease when the disease has spread beyond the original organ. Hormone receptor status and human epidermal growth factor 2 (HER2) status are two predictive factors that are taken into consideration when estimating the prognosis of patients with breast cancer. ### objectives To review the clinical effectiveness and cost-effectiveness evidence base for lapatinib ( LAP ) in combination with an aromatase inhibitor ( AI ) and trastuzumab ( TRA ) in combination with an AI for the first-line treatment of patients who have hormone receptor-positive (HR+)/human epidermal growth factor 2-positive ( HER2 + ) mBC . ### Data Sources Relevant electronic databases and websites, including MEDLINE, EMBASE and the Cochrane Library, were searched until May 2010. Further data were derived from the manufacturers' submissions for LAP + AI and TRA + AI. ### Review Methods A systematic review of the clinical effectiveness and cost-effectiveness of LAP + AI and TRA + AI was undertaken. As it was deemed inappropriate to compare LAP + AI with TRA + AI, two separate assessments of cost-effectiveness versus AIs alone were undertaken. ### results Three trials were included in the systematic review [the patient populations of the efficacy and safety of lapatinib combined with letrozole (EGF30008) trial, the efficacy and safety of trastuzumab combined with anastrozole (TAnDEM) trial and the efficacy and safety of letrozole combined with trastuzumab (eLEcTRA) trial]. As a result of differences in the exclusion criteria and because one trial was halted prematurely, comparisons across trials were believed to be inappropriate and meta-analysis was not possible. Individually, however, the findings from the trials all suggest that LAP + AI or TRA + AI results in improved progression-free survival and/or time to progression when compared with AIs alone. The trials do not show a statistically significant benefit in terms of overall survival. Two separate economic analyses were conducted based on the completed trials; neither LAP + AI nor TRA + AI was found to be cost-effective when compared with AI monotherapy. ### limitations Because of differences in the EGF30008 and the TAnDEM trials, the Assessment Group believes the indirect comparisons analyses conducted by the manufacturers are inappropriate and, for the same reason, chooses not to compare LAP + AI with TRA + AI in an economic evaluation. ### conclusions LAP + AI and TRA + AI appear to be clinically more effective than AI monotherapy, but neither is cost-effective compared with AIs alone. It was not possible to compare LAP + AI with TRA + AI. Future research should include research into treating mBC in the HR+/HER2+ population who are not TRA (or LAP) naive and into comparing the clinical effectiveness of AIs as monotherapy in patients with HER2+ and human epidermal growth factor 2-negative breast cancer. ### funding The National Institute for Health Research Technology Assessment programme. ### Assistant: [{"class": "POS", "spans_text": ["lapatinib", "AI"]}, {"class": "POS", "spans_text": ["AI", "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: Since combination therapy with nateglinide and vildagliptin restored the decrease in pancreatic beta cell mass , our present findings suggest that combination therapy could be a promising therapeutic strategy for postprandial dysmetabolism associated with obese and insulin resistance . Paragraph: Combination therapy with nateglinide and vildagliptin improves postprandial metabolic derangements in Zucker fatty rats. Postprandial metabolic derangements are one of the risk factors of cardiovascular disease in humans. Insulin resistance and/or impaired early-phase insulin secretion are major determinants of postprandial metabolic derangements. In this study, we investigated the potential utility of combination therapy with vildagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor and nateglinide, a rapid-onset/short-duration insulinotropic agent, for the treatment of postprandial metabolic derangements in Zucker Fatty (ZF) rats, an animal model of obesity with insulin resistance. ZF rats fed twice daily with or without high fat diet (HFD) were given vehicle, 50 mg/kg of nateglinide, 10 mg/kg of vildagliptin, or both for 6 weeks. Combination therapy with nateglinide and vildagliptin for 2 weeks ameliorated postprandial hyperglycemia, hypertriglyceridemia, and elevation of free fatty acid in ZF rats fed with HFD. 6-week treatment with nateglinide and vildagliptin not only increased hepatic levels of phosphorylated forkhead box protein 1A (FOXO1A), but also reduced triglyceride contents in the liver. Combination therapy also prevented the loss of pancreatic islet mass in ZF rats fed with HFD. These observations demonstrate that combination therapy with nateglinide and vildagliptin may improve postprandial metabolic derangements probably by ameliorating early phase of insulin secretion and hepatic insulin resistance, respectively, in ZF rats fed with HFD. Since combination therapy with nateglinide and vildagliptin restored the decrease in pancreatic beta cell mass , our present findings suggest that combination therapy could be a promising therapeutic strategy for postprandial dysmetabolism associated with obese and insulin resistance . ### Assistant: [{"class": "POS", "spans_text": ["nateglinide", "vildagliptin"]}]

### 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 were randomised to receive either four or eight courses of cytotoxic chemotherapy with cyclophosphamide , vincristine and etoposide and also randomised to receive , on disease progression , either second line chemotherapy ( methotrexate and doxorubicin ) or symptomatic treatment only . Paragraph: Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. A total of 610 patients with small cell lung cancer were entered into a randomised trial designed to assess the effect of duration of initial chemotherapy on survival. Patients were randomised to receive either four or eight courses of cytotoxic chemotherapy with cyclophosphamide , vincristine and etoposide and also randomised to receive , on disease progression , either second line chemotherapy ( methotrexate and doxorubicin ) or symptomatic treatment only . In the whole study 196 (32.1%) had limited disease and 414 (67.9%) extensive disease. During initial chemotherapy the response rate (complete and partial responses) after four courses of treatment was 61% with no significant increase in patients receiving eight courses (63%). In those randomised to receive relapse chemotherapy the response rate was improved slightly for those who had originally received four courses of chemotherapy (25.6%) over those receiving eight (18.7%). The overall results show that of the four possible treatment randomizations, four courses of chemotherapy alone is inferior in terms of overall survival (30 weeks median survival) to the other three treatment options (39 weeks median survival, P less than 0.01). In patients responding to initial chemotherapy the disadvantage of four courses of chemotherapy alone was apparent (median survival of 40 weeks versus 49 weeks, P = 0.003) but not if drug treatment was given on relapse. The study shows that limiting treatment to four courses of chemotherapy alone is associated with inferior survival, but this is not the case if chemotherapy is given at relapse. ### Assistant: [{"class": "POS", "spans_text": ["cyclophosphamide", "vincristine", "etoposide"]}, {"class": "COMB", "spans_text": ["methotrexate", "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: Tazobactam has inhibitory activity , and therefore protects piperacillin against Richmond and Sykes types II , III , IV and V beta-lactamases , staphylococcal penicillinase and extended-spectrum beta-lactamases . Paragraph: Piperacillin/tazobactam. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Combining tazobactam, a beta-lactamase inhibitor, with the ureidopenicillin, piperacillin, successfully restores the activity of piperacillin against beta-lactamase-producing bacteria. Tazobactam has inhibitory activity , and therefore protects piperacillin against Richmond and Sykes types II , III , IV and V beta-lactamases , staphylococcal penicillinase and extended-spectrum beta-lactamases . However, tazobactam has only species-specific activity against class I chromosomally-mediated enzymes. Resistant organisms include some Citrobacter spp., Enterobacter spp., Serratia spp., Xanthomonas maltophilia and Enterococcus faecium. Consistent with its in vitro activity, preliminary clinical data indicate that the fixed combination of piperacillin/tazobactam (dose ratio 8:1) is effective in the treatment of moderate to severe polymicrobial infections, including intra-abdominal, skin and soft-tissue and lower respiratory tract infections. In limited comparative trials, piperacillin/tazobactam demonstrated equivalent or better efficacy than standard comparator regimens in these infections. piperacillin/tazobactam in combination with an aminoglycoside was effective in the empirical treatment of fever in patients with neutropenia and compared favourably with ceftazidime in combination with an aminoglycoside, although second-line therapy with a glycopeptide antibiotic may be indicated in unresponsive episodes. Data from phase III trials indicate that piperacillin/tazobactam has a tolerability profile typical of a penicillin agent. piperacillin/tazobactam provides a broad spectrum of antibacterial activity in a convenient single formulation suitable for use in the treatment of polymicrobial infections. Possible limitations concern its restricted activity against class I beta-lactamases, enzymes that are becoming increasingly important in the nosocomial environment. Combined therapy with an aminoglycoside may be necessary in more serious infections. ### Assistant: [{"class": "POS", "spans_text": ["Tazobactam", "piperacillin"]}]

### 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 diagnosis was stage IIIA HHV-8-LBL , and he was treated with 6 cycles of R-EPOCH ( rituximab , etoposide , vincristine , doxorubicin , cyclophosphamide , and prednisone ) infusion chemotherapy . Paragraph: Human Herpesvirus Type 8-associated Large B-cell Lymphoma: A Nonserous Extracavitary Variant of Primary Effusion Lymphoma in an HIV-infected Man: A Case Report and Review of the Literature. Primary effusion lymphoma (PEL) is a rare non-Hodgkin lymphoma subtype primarily seen in human immunodeficiency virus (HIV)-infected individuals with low CD4(+) cell counts and elevated HIV viral loads. It has always been associated with human herpesvirus type 8 (HHV-8) and in 80% of cases has also been associated with Epstein-Barr virus (EBV). Less commonly, PEL has presented in patients with advanced age and other conditions associated with an altered immunity, including malignancy, liver cirrhosis, and immunosuppressive medications. It is a tumor of B-cell lineage; however, it shows a "null" phenotype, rarely expressing pan-B cell surface antigens. It will usually express CD45, CD30, CD38, CD138, and MUM1 and is characterized by lymphomatous effusions in body cavities but not lymphadenopathy. It is an aggressive lymphoma, with an average median survival of < 1 year. HHV-8-associated large B-cell lymphoma (HHV-8-LBL) is a second variant of PEL that is both solid and extracavitary. It has immunoblastic and/or anaplastic morphologic features and a distinct immunohistochemical staining pattern. It could also have a different clinical presentation than that of classic PEL. ### Materials And Methods We describe the case of a 57-year-old HIV-infected man who presented with a slow-growing and asymptomatic abdominal mass. Examination of an excisional biopsy specimen showed malignant large cells with prominent cytoplasm that were positive for pan-B cell antigen CD20, HHV-8, and EBV and negative for CD138, CD10, BCL-6, CD3, and CD30. The Ki-67 labeling index was 90%. The diagnosis was stage IIIA HHV-8-LBL , and he was treated with 6 cycles of R-EPOCH ( rituximab , etoposide , vincristine , doxorubicin , cyclophosphamide , and prednisone ) infusion chemotherapy . At 12 months after treatment, he was in complete remission. We also performed a Medline and Embase search to better understand the clinical findings of our patient and the unique attributes of HHV-8-LBL. Focusing our search on English language studies, we identified 83 cases of HHV-8-LBL without an effusion component. We compared these 83 cases with 118 reported cases of classic PEL. ### results The median age of the patients with HHV-8-LBL was 41 years (range, 24-77), and 96% of the cases were associated with HIV. The median age of the patients with classic PEL was 41 years (range, 26-86), and 96% of the cases were associated with HIV. Of those with HHV-8-LBL, 31 of 61 (51%) had a pre-existing diagnosis of acquired immunodeficiency syndrome (AIDS) and 47 of 63 (75%) were coinfected with EBV. In contrast, 69 of 96 patients (72%) with classic PEL had a pre-existing AIDS diagnosis and 40 of 49 (82%) were coinfected with EBV. The mean CD4(+) count of the HHV-8-LBL patients was 256 cells/μL (range, 18-1126 cells/μL) compared with 139 cells/μL (range, 2-557 cells/μL) in the classic PEL patients. The median survival time for both groups was similar at 5.5 months (range, 25 days to ≥ 25 months) for patients with HHV-8-LBL and 4 months (range, 2 days to ≥ 113 months) for those with classic PEL. More patients with HHV-8-LBL were alive at the last follow-up point (59% vs. 18%). The percentage of patients achieving complete remission was 54% (30 of 56) and 36% (32 of 89) for HHV-8-LBL and classic PEL, respectively. ### conclusion Our patient's high CD4(+) cell count, the lack of a pre-existing AIDS diagnosis, and the excellent response to chemotherapy highlights that HHV-8-LBL might have distinct clinical features and possibly a better response to chemotherapy than classic PEL. HHV-8-LBL should be included in the differential diagnosis of HIV patients with solid lesions. It is essential that patients' Centers for Disease Control and Prevention HIV clinical status and HIV viral load at the diagnosis of PEL and HHV-8-LBL be reported and that the reported clinical results include longer term follow-up data. Only then will a more complete clinical picture of this little-appreciated and little-understood PEL variant be defined. ### Assistant: [{"class": "POS", "spans_text": ["rituximab", "etoposide", "vincristine", "doxorubicin", "cyclophosphamide", "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: Our objective was to define the maximum tolerated dose of an escalating dose of ifosfamide in combination with a fixed dose of doxorubicin supported by granulocyte colony-stimulating factor ( Neupogen ) . Paragraph: A phase I study of ifosfamide and doxorubicin with recombinant human granulocyte colony-stimulating factor in stage IV breast cancer. Our objective was to define the maximum tolerated dose of an escalating dose of ifosfamide in combination with a fixed dose of doxorubicin supported by granulocyte colony-stimulating factor ( Neupogen ) . Eighteen women with stage IV breast cancer were enrolled in a Phase I study of an escalating dose of ifosfamide (1.2 g/m2/day for 5 days-2.75 g/m2/day for 5 days) with doxorubicin 20 mg/m2/day for 3 days. Granulocyte colony-stimulating factor was used at 5 microgram/kg on day 6 until hematological recovery. Prophylactic antibiotics were also used. The maximum tolerated dose of ifosfamide in combination with doxorubicin was 2.75 g/m2/day for 5 days. The objective response rate was 83% with a complete response rate of 33% (6/18 patients); the median time to treatment failure was 11.5 months. The median survival has not been reached and will exceed 18 months. We concluded that the recommended dose of ifosfamide in combination with doxorubicin is 2.5 g/m2/day for 5 days. This combination shows promise in stage IV breast cancer. ### Assistant: [{"class": "POS", "spans_text": ["ifosfamide", "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 combined analysis of two pivotal randomized trials of a single dose of pegfilgrastim per chemotherapy cycle and daily Filgrastim in patients with stage II-IV breast cancer . Paragraph: A combined analysis of two pivotal randomized trials of a single dose of pegfilgrastim per chemotherapy cycle and daily Filgrastim in patients with stage II-IV breast cancer . This combined, retrospective analysis compared once-per-chemotherapy-cycle pegfilgrastim with daily filgrastim in breast cancer patients undergoing myelosuppressive chemotherapy enrolled in two similarly designed, randomized, double-blind, pivotal trials. On day 2 of each chemotherapy cycle, a single subcutaneous (SC) injection of pegfilgrastim [either 6 mg (n=77) or 100 microg/kg (n=149)] was administered, or daily filgrastim SC injections (5 microg/kg/day; n=222) were initiated and continued until either absolute neutrophil count (ANC) > or =10 x 10(9)/l after the expected nadir or for up to 14 days, whichever occurred first. Individually, each of these trials demonstrated that a single pegfilgrastim injection per cycle is as effective at reducing the duration of severe neutropenia as daily injections of filgrastim. Clinical efficacy data from the two trials were combined for analysis (n=448). The risk of febrile neutropenia (FN; absolute neutrophil count <0.5 x 10(9)/l with fever > or =38.2 degrees C) was significantly lower [11% vs 19%, respectively; relative risk = 0.56 (95% confidence interval: 0.35, 0.89)] in patients receiving pegfilgrastim than for those receiving filgrastim. Trends towards lower risks of hospitalization and intravenous anti-infective use were also observed. These observations were consistent irrespective of risk factors, including age, disease stage, performance status and prior treatment. Pegfilgrastim may offer patients more effective protection against neutropenic complications of chemotherapy with fewer injections and less disruption to their lives. ### Assistant: [{"class": "POS", "spans_text": ["pegfilgrastim", "Filgrastim"]}]

### 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: At initial treatment with dabrafenib plus trametinib , three patients achieved a partial response and one patient achieved a complete response . Paragraph: Dabrafenib plus trametinib rechallenge in four melanoma patients who previously progressed on this combination. In unresectable or metastatic melanoma with a BRAF V600 mutation, combined BRAF/MEK targeted therapy improves clinical outcomes. Yet, disease progression because of acquired resistance occurs in the majority of patients. There is emerging evidence that resistance to BRAF-inhibitor-based targeted therapy can be reversible in some cases. We retrospectively analyzed four patients with BRAF-mutant stage IV cutaneous melanoma who were treated with dabrafenib plus trametinib and rechallenged with the same combination after previously experiencing progression. At initial treatment with dabrafenib plus trametinib , three patients achieved a partial response and one patient achieved a complete response . Progression-free survival varied from 9.9 to 24.3 (median 19.8) months. The targeted therapy-free interval ranged from 2.3 to 11.7 (median 8.8) months. At rechallenge, all four patients had a partial response, with progression-free survival ranging from 3.6 to 6.8 (median 5.2) months. Clinical benefit and a second radiological response can be obtained upon readministration of dabrafenib plus trametinib after previously acquiring resistance to this combination. A better understanding of the biological underpinnings of genomic and nongenomic mechanisms of resistance to BRAF-inhibitor-based targeted therapy is needed to identify patients who may benefit from this rechallenge approach. ### Assistant: [{"class": "POS", "spans_text": ["dabrafenib", "trametinib"]}]

### 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 this meta-analysis to evaluate the clinical efficacy and safety of gemcitabine plus cisplatin ( GP ) and paclitaxel plus cisplatin ( TP ) combined with thermotherapy in the treatment of NSCLC , as well as to provide reference for clinical practice and future research . Paragraph: [Thermo-chemotherapy of GP or TP for advanced non-small cell lung cancer: a systematic review]. Advanced non-small cell lung cancer (NSCLC) is characterized by poor treatment efficacy and short survival time. Clinical trials have shown that the combination of chemotherapy with thermotherapy exhibits strong efficacy. We performed this meta-analysis to evaluate the clinical efficacy and safety of gemcitabine plus cisplatin ( GP ) and paclitaxel plus cisplatin ( TP ) combined with thermotherapy in the treatment of NSCLC , as well as to provide reference for clinical practice and future research . ### methods We searched international (Cochrane Library, PubMed, and EMBASE) and Chinese (CBM, CNKI, VIP and Wanfang) databases for relevant articles and imported other retrievable sources, such as tracing-related references. We also corresponded with other authors to obtain certain inaccessible information. Data from all relevant randomized controlled trials (RCT) were collected to compare GP or TP thermochemotherapy with GP or TP chemotherapy alone. The quality of the included studies was assessed by adequate outcome-based standards and clinical circumstances. The meta-analysis was conducted using RevMan 5.1. ### results Fifteen RCTs involving 952 patients were included in this meta-analysis. The results showed that the thermochemotherapy group had higher rates of improvement in quality of life (OR=3.84, 95%CI: 2.61-5.64), survival at 1 year (HR=1.94, 95%CI: 1.21-3.12), and survival at 2 years (HR=2.05, 95%CI: 1.18-3.58) compared with the chemotherapy group, with the differences between them being significant. However, these groups did not differ in other indicators of treatment effectiveness, such as myelosuppression, alimentary canal reactions, hepatic lesions, and diarrhea. ### conclusions Compared with chemotherapy alone, thermochemotherapy can improve survival rates and curative effects, ameliorate symptoms, and enhance the quality of life of patients with advanced NSCLC, and it has an acceptable safety profile. The results of this meta-analysis warrant further investigation with a larger sample size and using a high-quality RCT design. ### Assistant: [{"class": "POS", "spans_text": ["gemcitabine", "cisplatin", "thermotherapy"]}, {"class": "POS", "spans_text": ["paclitaxel", "cisplatin", "thermotherapy"]}]

### 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 pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor . Paragraph: Pharmacodynamic effects during the transition between cangrelor and ticagrelor. This study sought to determine pharmacodynamic effects during transition from intravenous cangrelor to oral ticagrelor and from oral ticagrelor to intravenous cangrelor. ### background cangrelor is an intravenous antagonist of P2Y12 and its use will require transition to and from oral agents. ### methods Patients (n = 12) with stable coronary artery disease who were taking aspirin 81 mg daily were recruited. On study day 1, they received a bolus plus 2-h infusion of cangrelor plus a 180-mg dose of ticagrelor at either 0.5 h (n = 6) or 1.25 h (n = 6). Pharmacodynamic effects (light transmission platelet aggregation in response to 20 and 5 μmol/l adenosine diphosphate, VerifyNow, P2Y12 assay (Accumetrics, San Diego, California), vasodilator-stimulated phosphoprotein index, and flow cytometry) were assessed during and after the cangrelor infusion. Patients took 90 mg of ticagrelor twice daily for either 6 (n = 6) or 7 (n = 6) doses. On study day 5, pharmacodynamic effects were assessed before and during a bolus plus 2-h infusion of cangrelor. ### results During cangrelor infusion, extensive inhibition of platelet function reflected by limited residual platelet reactivity was apparent. After cangrelor was stopped, the antiplatelet effects of ticagrelor were preserved despite a modest increase in platelet reactivity. ### conclusions ticagrelor given before or during infusion of cangrelor did not attenuate the pharmacodynamic effects of cangrelor. The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor . Consistent with the reversible binding of ticagrelor, this oral P2Y12 antagonist can be administered before, during, or after treatment with cangrelor. ### Assistant: [{"class": "POS", "spans_text": ["ticagrelor", "cangrelor"]}]

### 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 49-year-old woman diagnosed with International Federation of Obstetricians and Gynecologists stage 2018 IIIC2 locally advanced undifferentiated cervical cancer received first-line chemoradiotherapy followed by carboplatin , paclitaxel , and bevacizumab with partial response . Paragraph: Complete pathological response to olaparib and bevacizumab in advanced cervical cancer following chemoradiation in a BRCA1 mutation carrier: a case report. Homologous recombination deficiency is a marker of response to poly(ADP-ribose) polymerase inhibitors in different cancer types including ovary, prostate, and pancreatic cancer. To date, no report about poly(ADP-ribose) polymerase inhibitors has been published on cervical cancer. ### Case Presentation Here we present the case of a patient with cervical cancer treated in this setting. A 49-year-old woman diagnosed with International Federation of Obstetricians and Gynecologists stage 2018 IIIC2 locally advanced undifferentiated cervical cancer received first-line chemoradiotherapy followed by carboplatin , paclitaxel , and bevacizumab with partial response . Because of a family history of cancers, the patient was tested and found positive for a pathogenic BRCA1 germline and somatic mutation, which motivated bevacizumab plus olaparib maintenance treatment. A simple hysterectomy was performed after 2 years stable disease; pathological report showed complete pathological response, and 12 months follow-up showed no recurrence. ### conclusion Poly(ADP-ribose) polymerase inhibitors could be an alternative maintenance treatment for patients with persistent advanced cervical cancer previously treated with platinum, especially when familial history of cancers is reported. Clinical trials using poly(ADP-ribose) polymerase inhibitors for advanced cervical cancer are warranted. ### Assistant: [{"class": "POS", "spans_text": ["carboplatin", "paclitaxel", "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: Sipuleucel-T , cabazitaxel , abiraterone , enzalutamide and radium-223 have been approved in the pre- or post-docetaxel setting in metastatic CRPC during the last few years . Paragraph: SEOM clinical guidelines for the treatment of metastatic prostate cancer. Androgen deprivation treatment is the current standard first-line treatment for metastatic prostate cancer. For several years, docetaxel was the only treatment with a proven survival benefit for castration-resistant prostate cancer (CRPC). Since docetaxel became standard of care for men with symptomatic metastatic castration-resistant prostate cancer (CRPC), three treatment virtual spaces, for treatment and drug development in CPRC, have emerged: pre-docetaxel, docetaxel combinations and post-docetaxel. Sipuleucel-T , cabazitaxel , abiraterone , enzalutamide and radium-223 have been approved in the pre- or post-docetaxel setting in metastatic CRPC during the last few years . Patients are now living longer and experiencing better quality of life. Strategies for patient selection and treatment sequencing are therefore urgently required. ### Assistant: [{"class": "POS", "spans_text": ["Sipuleucel-T", "cabazitaxel", "abiraterone", "enzalutamide", "radium-223"]}]

### 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: Therefore , we conducted this phase II study to evaluate the activity and toxicity of the combination paclitaxel and gemcitabine in advanced NSCLC . Paragraph: A phase II study of weekly gemcitabine and paclitaxel in patients with previously untreated stage IIIb and IV non-small cell lung cancer. Platinum-based combination chemotherapy has become the standard treatment for good performance patients with stage IIIb and IV non-small cell lung cancer (NSCLC). However, newer agents such as gemcitabine and paclitaxel appear to have superior single agent activity and are more easily tolerated in comparison to the older platinum compounds. Therefore , we conducted this phase II study to evaluate the activity and toxicity of the combination paclitaxel and gemcitabine in advanced NSCLC . gemcitabine was given at 1,000 mg/m(2) intravenously over 30 min followed by paclitaxel at 110 mg/m(2) intravenously over 1 h on days 1, 8 and 15 every 28 days for a maximum of 6 cycles. Between April 1998 and June 1999, 40 of 42 patients entered were eligible and received chemotherapy. Data was available on 39 patients. Toxicities included Grade 3/4 neutropenia in 43% of patients, while thrombocytopenia (13%) and anemia (7%) were less frequent. Five (12.5%) patients developed neutropenic fever. Four (10%) patients developed bilateral interstitial shadows with hypoxia suggestive of a drug-induced pneumonitis. There were 4 treatment-related deaths (1 from pneumonitis, 3 from neutropenic complications). Five patients were not evaluable due to early death. Therefore, 34 patients were evaluable with 12 (35.3%) achieving a partial remission and 1 achieving a complete remission for an overall response rate of 38.2% (32.5% on an intention-to-treat basis). The median progression free survival was 107 days (range, 14-391), median survival was 148 days (range, 12-495) and 1-year survival was 26%. In conclusion, weekly gemcitabine with paclitaxel in patients with advanced NSCLC is an active regimen; however, toxicity and poor survival precludes the use of this regimen as an experimental arm on a future phase III study. ### Assistant: [{"class": "NEG", "spans_text": ["paclitaxel", "gemcitabine"]}]

### 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: Ciprofloxacin , 500 mg orally twice a day plus antifungal prophylaxis , fluconazole 50 mg once daily plus amphotericin B tablets or suspension and tablets , each 200 mg four times a day , was given . Paragraph: Infection prevention in autologous bone marrow transplantation and the role of protective isolation. The efficacy of an antimicrobial regimen for prevention of infections was prospectively evaluated in 113 patients undergoing autologous bone marrow transplantation (BMT). Ciprofloxacin , 500 mg orally twice a day plus antifungal prophylaxis , fluconazole 50 mg once daily plus amphotericin B tablets or suspension and tablets , each 200 mg four times a day , was given . In addition all patients received streptococcal prophylaxis for 10 days after BMT. Documented infections occurred in 39% (44 of 113) of patients and unexplained fever in 27% (30 of 113). The efficacy of this regimen was reflected in a low mortality rate (3.5%) from infections and in the low need for intravenous amphotericin B (7%). No benefit of protective isolation was found in 59 patients compared with 54 patients treated without isolation measures. ### Assistant: [{"class": "POS", "spans_text": ["Ciprofloxacin", "fluconazole", "amphotericin"]}]

### 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 recently updated clinical guidelines , the fully humanized monoclonal antibody panitumumab , combined with irinotecan , has been recommended as an optional third-line chemotherapy for KRAS wild-type metastatic colorectal cancer ( mCRC ) . Paragraph: A Prospective, Multicenter Phase II Study of the Efficacy and Feasibility of 15-minute Panitumumab Infusion Plus Irinotecan for Oxaliplatin- and Irinotecan-refractory, KRAS Wild-type Metastatic Colorectal Cancer (Short Infusion of Panitumumab Trial). In some recently updated clinical guidelines , the fully humanized monoclonal antibody panitumumab , combined with irinotecan , has been recommended as an optional third-line chemotherapy for KRAS wild-type metastatic colorectal cancer ( mCRC ) . The present prospective, multicenter phase II study evaluated the effectiveness and safety of short 15-minute panitumumab infusions. ### Patients And Methods From January 2011 to December 2011, patients with KRAS wild-type mCRC were enrolled at 8 centers. The key eligibility criteria were age ≥ 20 years and resistance or intolerance to irinotecan, fluoropyrimidine, and oxaliplatin. All patients received 6 mg/kg of panitumumab and 150 mg/m ### results Of the 43 patients, the median age was 62 years (range, 32-75 years), 58% were male, and the Eastern Cooperative Oncology Group performance status was 0 to 1. The total response rate was 37.2% (95% confidence interval [CI], 23.0-53.3), and the confirmed response rate was 18.6% (95% CI, 8.4-33.4). The median progression-free and overall survival were 5.8 months (95% CI, 3.3-8.4 months) and 13.6 months (95% CI, 10.8-16.5 months), respectively. The most frequent grade 3/4 toxicities were anorexia (12%), leukopenia (9%), and neutropenia (9%). Nine patients did not reach the 15-minute infusion, primarily because of disease progression. No infusion-related reactions were observed. ### conclusion The short 15-minute panitumumab infusion regimen was well tolerated, without compromising safety or efficacy in patients with KRAS wild-type, oxaliplatin- and irinotecan-refractory mCRC. ### Assistant: [{"class": "POS", "spans_text": ["panitumumab", "irinotecan"]}]

### 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 monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon ( VEMUPLINT ) in advanced melanoma patients harboring the V600BRAF mutation . Paragraph: A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon ( VEMUPLINT ) in advanced melanoma patients harboring the V600BRAF mutation . Studies carried out in vitro and in a mouse model have shown that BRAF inhibitors enhance the effects of IFN-α on BRAFV600E melanoma cells through the inhibition of ERK. Therefore, the combination of vemurafenib and IFN-α in patients with BRAFV600E melanoma may provide therapeutic benefits; MEK inhibition may prevent the reactivation of the MAPK pathway induced by BRAF inhibitor resistance. ### Patients And Methods In a phase I study, adult patients with advanced BRAFV600-mutated melanoma were treated with vemurafenib + PEG-IFN-α-2b or vemurafenib + cobimetinib + PEG-IFN-α-2b, to assess the safety of the combination and the upregulation of IFN-α/β receptor-1 (IFNAR1). ### results Eight patients were treated; 59 adverse events with four serious ones (three related to study treatments) were reported. Patients with a pre-treatment IFNAR1 expression on ≤ 35% melanoma cells had a median progression-free survival of 12.0 months (range: 5.6-18.4 months) and a median overall survival of 31.0 months (range: 19.8-42.2 months), while patients with a pre-treatment IFNAR1 expression on > 35% of melanoma cells had a median progression-free survival of 4.0 months (range: 0-8.8; p = 0.03), and a median overall survival of 5 months (p = 0.02). Following treatment, responders had higher levels of growth-suppressor genes, including GAS1 and DUSP1, and genes involved in a metabolically robust immune response, including FAP. ### conclusion Our study supports the overall safety of the vemurafenib + PEG-IFN-α-2b + cobimetinib combination. IFNAR1 expression levels correlated with response to treatment, including survival. vemurafenib + PEG-IFN-α-2b + cobimetinib would have difficulty finding a niche in the current treatment scenario for advanced melanoma, but we speculate that our findings may contribute to identify subjects particularly responsive to treatment. ### Trial Registration The study was registered at clinicaltrials.gov (NCT01959633). Registered 10 October 2013, https://clinicaltrials.gov/ct2/show/NCT01959633. ### Assistant: [{"class": "POS", "spans_text": ["vemurafenib", "cobimetinib", "VEMUPLINT"]}]

### 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 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma . Paragraph: Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma . On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated. ### methods Adult patients with mRCC who had received ≤ 1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics. ### results Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report. ### conclusions In this study of tremelimumab plus sunitinib, rapid-onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses > 6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity. ### Assistant: [{"class": "NEG", "spans_text": ["tremelimumab", "sunitinib"]}]

### 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 working group convened by the Centers for Disease Control recommended three antibiotics for the treatment of recurrent and persistent acute otitis media : ( 1 ) amoxicillin/clavulanate in combination with amoxicillin ( high dose amoxicillin regimen , 80 to 90 mg/kg/day ) ; ( 2 ) cefuroxime axetil ( standard dose , 30 mg/kg/day ) ; and ( 3 ) ceftriaxone ( possibly requiring up to three injections to optimize clinical success ) . Paragraph: Recurrent and persistent otitis media. Recurrent acute otitis media occurs during the first several years of life in approximately 20 to 30% of the pediatric population. A clinical challenge closely related to recurrent otitis media is persistent otitis media, manifested by persistence during antimicrobial therapy of symptoms and signs of middle ear infection (treatment failure) and/or relapse of acute otitis media within 1 month of completion of antibiotic therapy. Recurrent and persistent otitis media infections are early childhood problems with identifiable risk factors. Differentiation of these infections from otitis media with effusion is important in avoiding misdiagnosis and overtreatment with antibiotics. The predominant pathogens of recurrent and persistent acute otitis media are antibiotic-resistant Streptococcus pneumoniae and beta-lactamase-producing Haemophilus influenzae. A working group convened by the Centers for Disease Control recommended three antibiotics for the treatment of recurrent and persistent acute otitis media : ( 1 ) amoxicillin/clavulanate in combination with amoxicillin ( high dose amoxicillin regimen , 80 to 90 mg/kg/day ) ; ( 2 ) cefuroxime axetil ( standard dose , 30 mg/kg/day ) ; and ( 3 ) ceftriaxone ( possibly requiring up to three injections to optimize clinical success ) . Other antibiotics were considered suboptimal or had accumulated insufficient data upon which to base a judgment. Conclusions. Optimal management of recurrent and persistent acute otitis media is a clinical challenge. Accurate diagnosis of acute otitis media is the first step in optimal management. Selection of appropriate antibiotic therapy should take into account the major pathogens (S. pneumoniae, H. influenzae and Moraxella catarrhalis) and the occurrence of antibiotic resistance. ### Assistant: [{"class": "POS", "spans_text": ["amoxicillin/clavulanate", "amoxicillin"]}]

### 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 who had failed only one prior chemotherapy regimen and had Eastern Cooperative Oncology Group ( ECOG ) Performance Status ( PS ) ≤2 were randomised to either : pemetrexed 500 mg/m(2 ) on day 1 plus erlotinib 150 mg daily on days 2 - 14 ; erlotinib 150 mg daily ; or pemetrexed 500 mg/m(2 ) on day 1 of a 21-day cycle until discontinuation criteria were met . Paragraph: Three-arm randomised controlled phase 2 study comparing pemetrexed and erlotinib to either pemetrexed or erlotinib alone as second-line treatment for never-smokers with non-squamous non-small cell lung cancer. This randomised controlled phase 2 study compared pemetrexed and erlotinib in combination with either agent alone in terms of efficacy and safety as second-line treatment in a clinically selected population of never-smokers with non-squamous non-small cell lung cancer (NSCLC). ### methods Patients who had failed only one prior chemotherapy regimen and had Eastern Cooperative Oncology Group ( ECOG ) Performance Status ( PS ) ≤2 were randomised to either : pemetrexed 500 mg/m(2 ) on day 1 plus erlotinib 150 mg daily on days 2 - 14 ; erlotinib 150 mg daily ; or pemetrexed 500 mg/m(2 ) on day 1 of a 21-day cycle until discontinuation criteria were met . The primary endpoint, progression-free survival (PFS), was analysed using a multivariate Cox model. Firstly, a global comparison across the three arms was performed. If the global null hypothesis was rejected at a two-sided 0.2 significance level, pairwise comparisons of pemetrexed-erlotinib versus erlotinib or pemetrexed were then conducted using the same model. Statistical significance was claimed only if both global and pairwise null hypotheses were rejected at a two-sided 0.05 significance level. ### findings A total of 240 patients (male, 35%; East Asian, 55%; ECOG PS 0-1, 93%) were included. A statistically significant difference in PFS was found across the three arms (global p=0.003), with pemetrexed-erlotinib significantly better than either single agent: HR=0.57, 95% confidence interval (CI): 0.40-0.81, p=0.002 versus erlotinib; HR=0.58, 95% CI: 0.39-0.85, p=0.005 versus pemetrexed. Median PFS (95% CI) was 7.4 (4.4, 12.9) months in pemetrexed-erlotinib, 3.8 (2.7, 6.3) months in erlotinib and 4.4 (3.0, 6.0) months in pemetrexed. Safety analyses showed a higher incidence of drug-related grade 3/4 toxicity in pemetrexed-erlotinib (60.0%) than in pemetrexed (28.9%) or erlotinib (12.0%); the majority being neutropenia, anaemia, rash and diarrhoea. ### interpretation pemetrexed-erlotinib significantly improved PFS compared to either drug alone in this clinically selected population. The combination had more toxicity, but was clinically manageable. ### Assistant: [{"class": "POS", "spans_text": ["pemetrexed", "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: This study was conducted to test the feasibility of reducing the interval between cycles of doxorubicin , cyclophosphamide , etoposide ( ACE ) chemotherapy to 2 weeks , thereby increasing dose intensity , by adding granulocyte colony-stimulating factor ( G-CSF ) to reduce the duration of neutropenia following a cycle . Paragraph: The feasibility of using glycosylated recombinant human granulocyte colony-stimulating factor (G-CSF) to increase the planned dose intensity of doxorubicin, cyclophosphamide and etoposide (ACE) in the treatment of small cell lung cancer. Medical Research Council Lung Cancer Working Party. This study was conducted to test the feasibility of reducing the interval between cycles of doxorubicin , cyclophosphamide , etoposide ( ACE ) chemotherapy to 2 weeks , thereby increasing dose intensity , by adding granulocyte colony-stimulating factor ( G-CSF ) to reduce the duration of neutropenia following a cycle . 20 patients with small cell lung cancer (SCLC) were prescribed six cycles of 2-weekly ACE, with G-CSF on the intermediate days. 3 patients died during the treatment period and a further 5 had ACE terminated, 3 for toxicity and 2 for progressive disease. Of the 71 intervals between cycles, 42 (59%) were of the prescribed 14 days, 9 (13%) of 15-20 days, 15 (21%) of 21 days and five (7%) longer, but during the first four cycles, 36 (77%) of 47 intervals were of 14 days. The main reason for delay was haematological toxicity. All 20 patients experienced WHO grade 3 or 4 neutropenia, but at 2 weeks after a cycle only 3 had grade 4 and 1 grade 3. 17 patients required blood transfusion and 12 platelet transfusion. The only potentially serious adverse reaction to G-CSF was an episode of rash with facial oedema. Adding G-CSF allows ACE chemotherapy to be intensified by reducing the interval between cycles. ### Assistant: [{"class": "POS", "spans_text": ["doxorubicin", "cyclophosphamide", "etoposide", "G-CSF"]}]

### 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 rate of down-stage to pT1 or less was 59 % for methotrexate , vinblastine , doxorubicin and cisplatin , and 53 % for gemcitabine and carboplatin ( P = 0.624 ) . Paragraph: Neoadjuvant gemcitabine plus carboplatin for locally advanced bladder cancer. Although cisplatin-based neoadjuvant chemotherapy followed by cystectomy was demonstrated to improve the survival among patients with locally advanced bladder cancer, its severe adverse events, including nephrotoxicity, are critical issues. We investigated the safety and activity of carboplatin, a mild nephrotoxic agent, combined with gemcitabine as a neoadjuvant chemotherapy compared with methotrexate, vinblastine, doxorubicin and cisplatin for patients with locally advanced bladder cancer. ### methods We retrospectively evaluated 68 patients with locally advanced bladder cancer who received neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (n = 34) or gemcitabine and carboplatin (n = 34) followed by cystectomy at our institute. The adverse events, chemotherapy delivery profile, rate of down-stage and recurrence-free survival were assessed for methotrexate, vinblastine, doxorubicin and cisplatin compared with gemcitabine and carboplatin. ### results The mean cycles of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, were 2.5 and 2.7, respectively. The hematologic adverse events of Grade 3 or 4 neutropenia, anemia and thrombocytopenia for methotrexate, vinblastine, doxorubicin and cisplatin were 15, 18 and 0%, respectively. The occurrences for gemcitabine and carboplatin were 53, 21 and 50%, respectively. Grade 3 or 4 non-hematologic toxicities for methotrexate, vinblastine, doxorubicin and cisplatin were nausea and vomiting in 24%, and were not observed for gemcitabine and carboplatin. The lowest median estimated glomerular filtration rate during methotrexate, vinblastine, doxorubicin, and cisplatin and gemcitabine and carboplatin was 55.8 and 70.6 ml/min/1.73 m(2), respectively (P = 0.002). The rate of down-stage to pT1 or less was 59 % for methotrexate , vinblastine , doxorubicin and cisplatin , and 53 % for gemcitabine and carboplatin ( P = 0.624 ) . The recurrence-free survival of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, at 36 months from the diagnosis was 79 and 75%, respectively (P = 0.85). ### conclusions Neoadjuvant gemcitabine and carboplatin showed less non-hematologic toxicity than methotrexate, vinblastine, doxorubicin and cisplatin, and especially less nephrotoxicity was demonstrated for gemcitabine and carboplatin. Although observed during the short term, the recurrence-free survival for gemcitabine and carboplatin was comparable to that for methotrexate, vinblastine, doxorubicin and cisplatin. ### Assistant: [{"class": "POS", "spans_text": ["gemcitabine", "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: The combined irrigation of bupivacaine and ketorolac showed a clinically significant reduction of pain in the first postoperative hour and on postoperative day 5 . Paragraph: The Role of Local Bupivacaine Irrigation in Postoperative Pain Control After Augmentation Mammoplasty: A Systematic Review and Meta-Analysis. The objective of this study is to analyze the efficacy of local bupivacaine irrigation after augmentation mammoplasty for the control of postoperative pain. ### methods A systematic review and meta-analysis was conducted including all randomized controlled trials (RCTs) that compared the irrigation of bupivacaine (±ketorolac) versus normal saline or no irrigation for pain control after breast augmentation. The primary outcome was postoperative pain measured by visual analog scale. The study protocol was established a priori according to the recommendations of the Cochrane Collaboration. A bibliographical search was conducted in September 2015 in the following Cochrane Library databases: CENTRAL, MEDLINE, EMBASE, and Scielo. The strategy used for the search was ((augmentation AND ("mammoplasty"[MeSH Terms] OR "mammoplasty")) OR (("breast"[MeSH Terms] OR "breast") AND augmentation)) AND (("pain, postoperative"[MeSH Terms])). ### results Four RCTs with a total of 264 participants were included. Two trials compared bupivacaine alone versus placebo (normal saline or no irrigation) and 3 trials compared bupivacaine plus ketorolac versus placebo. The combined irrigation of bupivacaine and ketorolac showed a clinically significant reduction of pain in the first postoperative hour and on postoperative day 5 . The irrigation with bupivacaine compared with placebo significantly reduced pain assessed on postoperative day 4. ### conclusion The irrigation of bupivacaine with or without ketorolac was associated with a reduction of postoperative pain compared with control groups for the first 5 postoperative days. Due to the few number of trials included, these results should be correlated further clinically. ### Assistant: [{"class": "POS", "spans_text": ["bupivacaine", "ketorolac"]}]

### 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 group I , clinical response was observed in 10 of 19 febrile episodes ( 52.6 % ) treated with carbenicillin plus gentamicin and in 10 of 14 ( 71.4 % ) treated with latamoxef ( p greater than 0.05 ) . Paragraph: Latamoxef versus carbenicillin plus gentamicin or carbenicillin plus mecillinam in leukopenic, febrile patients with solid tumors. Sixty-six febrile episodes associated with leukopenia were observed in 56 patients with solid tumors, WBC less than 1.5 X 10(9)/l and temperature greater than or equal to 38.5 degrees C. Stratification to antibiotic treatment regimen was made with regard to prior cis-dichlorodiamineplatinum (cis-platinum) treatment or not. Patients who had received no cis-platinum were randomized between carbenicillin 10 g every 8 h plus gentamicin 80 mg every 8 h or latamoxef 2 g every 8 h (group I). Patients having received cis-platinum were treated with carbenicillin 10 g every 8 h plus mecillinam 800 mg every 8 h or latamoxef 2 g every 8 h (group II). The first dose of latamoxef was preceded by 10 mg of vitamin K i.v. In group I , clinical response was observed in 10 of 19 febrile episodes ( 52.6 % ) treated with carbenicillin plus gentamicin and in 10 of 14 ( 71.4 % ) treated with latamoxef ( p greater than 0.05 ) . In group II, 6 of 14 febrile episodes treated with carbenicillin plus mecillinam responded (42.9%) while 11 of 19 (57.9%) responded to latamoxef (p greater than 0.05). No bleeding due to antibiotic treatment was observed. No statistical difference between standard antibiotic therapy and latamoxef was seen in this subset of patients. ### Assistant: [{"class": "COMB", "spans_text": ["carbenicillin", "gentamicin"]}]

### 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 lapatinib and trastuzumab , the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest ( 44.5 % , 95 % confidence interval [ CI ] = 35.4 % to 53.9 % vs 11.6 % , 95 % CI = 6.9 % to 18.0 % ; adjusted odds ratio [ OR ] = 6.05 , 95 % CI = 3.10 to 11.80 , P < .001 ) . Paragraph: HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade. Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy. ### methods A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated. ### results A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab , the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest ( 44.5 % , 95 % confidence interval [ CI ] = 35.4 % to 53.9 % vs 11.6 % , 95 % CI = 6.9 % to 18.0 % ; adjusted odds ratio [ OR ] = 6.05 , 95 % CI = 3.10 to 11.80 , P < .001 ) . Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01). ### conclusions Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer. ### Assistant: [{"class": "POS", "spans_text": ["lapatinib", "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: A Synergistic Anti-Cancer Effect of Troglitazone and Lovastatin in a Human Anaplastic Thyroid Cancer Cell Line and in a Mouse Xenograft Model . Paragraph: A Synergistic Anti-Cancer Effect of Troglitazone and Lovastatin in a Human Anaplastic Thyroid Cancer Cell Line and in a Mouse Xenograft Model . Anaplastic thyroid cancer (ATC) is a malignant subtype of thyroid cancers and its mechanism of development remains inconclusive. Importantly, there is no effective strategy for treatment since ATC is not responsive to conventional therapies, including radioactive iodine therapy and thyroid-stimulating hormone suppression. Here, we report that a combinational approach consisting of drugs designed for targeting lipid metabolism, lovastatin (an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, HMGCR) and troglitazone (an agonist of peroxisome proliferator-activated receptor gamma, PPARγ), exhibits anti-proliferation in cell culture systems and leads to tumor regression in a mouse xenograft model. The composition contains a sub-lethal concentration of both drugs and exhibits low toxicity to certain types of normal cells. Our results support a hypothesis that the inhibitory effect of the combination is partly through a cell cycle arrest at G0/G1 phase, as evidenced by the induction of cyclin-dependent kinase inhibitors, p21 ### Assistant: [{"class": "POS", "spans_text": ["Troglitazone", "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: Fingolimod sensitizes EGFR wild‑type non‑small cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest . Paragraph: Fingolimod sensitizes EGFR wild‑type non‑small cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest . Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase and mutations in this gene are major drivers of lung cancer development. EGFR tyrosine kinase inhibitors (TKIs) are standard first‑line therapies for patients with advanced non‑small cell lung cancer (NSCLC) with activating EGFR mutations, but are not effective in patients with wild‑type EGFR. In the present study, the cytotoxic effects of various TKIs against EGFR were investigated in wild‑type NSCLC cells as single treatments or in combination with fingolimod (FTY720), which has been approved for treating multiple sclerosis and has cytotoxic effects against several tumor cell lines. It was found that the combined treatment with TKIs lapatinib (Lap) or sorafenib (Sor) and FTY720 synergistically suppressed the viability of the NSCLC cell lines A549 and H596. Additionally, FTY720 inhibited lysosomal acidification and suppressed autophagy flux. Immunoblotting and reverse transcription‑quantitative polymerase chain reaction showed that FTY720 combined with Lap or Sor, enhanced endoplasmic reticulum (ER) stress loading and cell cycle arrest in A549 cells. The enhancement of ER stress loading and cell cycle arrest induced by combined treatment with Lap or Sor and FTY720, which was associated with the cytotoxicity induced by the combination of these drugs. These findings suggested that FTY720 improved TKI therapy in NSCLC patients with wild‑type EGFR, by sensitizing NSCLC cells to TKIs. ### Assistant: [{"class": "POS", "spans_text": ["Fingolimod", "lapatinib"]}, {"class": "POS", "spans_text": ["Fingolimod", "sorafenib"]}]

### 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: Bacteriological , histopathologic , and clinical outcomes after treatment using moxifloxacin , moxifloxacin and dexamethasone combination , and vancomycin were comparable . Paragraph: Effects of intravitreal moxifloxacin and dexamethasone in experimental Staphylococcus aureus endophthalmitis. To evaluate the effects of intravitreal moxifloxacin and moxifloxacin and dexamethasone combination in an experimental rabbit model of Staphylococcus aureus endophthalmitis. ### methods The right eyes of 24 rabbits weighing 2 to 3 kg were used. Ten thousand colony-forming units (CFU) of S. aureus in 0.1 ml saline solution were inoculated into the vitreous cavity. The eyes were randomly assigned to one of the four groups equally. Twenty-four hours after the inoculation of S. aureus, group 1 received 50 microg moxifloxacin, group 2 received 50 microg moxifloxacin plus 400 microg dexamethasone, and group 3 received 1 mg vancomycin intravitreally. No treatment was given to group 4. Clinical examination scores were recorded. Vitreous aspirates were obtained for microbiological analysis just before sacrifice, and the eyes were enucleated for histopathologic examination. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests. ### results In all treatment groups, mean number of CFU and histopathologic score were significantly lower compared with control group (p<0.05), and the difference between treatment groups was not statistically significant (p>0.05). The clinical score was not significantly different between groups (p>0.05). ### conclusions Intravitreal injection of 50 microg moxifloxacin was effective in the treatment of S. aureus endophthalmitis. Bacteriological , histopathologic , and clinical outcomes after treatment using moxifloxacin , moxifloxacin and dexamethasone combination , and vancomycin were comparable . Intravitreal moxifloxacin may be an option in the treatment of S. aureus endophthalmitis. ### Assistant: [{"class": "COMB", "spans_text": ["moxifloxacin", "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: Combining erythromycin , clarithromycin , or azithromycin with rifampin resulted in a significant ( P≤0.005 ) decrease in MPC and MPC/MIC ratio . Paragraph: Mutant prevention concentration and mutant selection window for 10 antimicrobial agents against Rhodococcus equi. The objectives of this study were to determine the mutant prevention concentration (MPC), time above the MPC and mutant selection window for 10 antimicrobial agents against Rhodococcus equi and to determine if the combination of a macrolide with rifampin would decrease emergence of resistant mutants. Antimicrobial agents investigated (erythromycin, clarithromycin, azithromycin, rifampin, amikacin, gentamicin, enrofloxacin, vancomycin, imipenem, and doxycycline) were selected based on in vitro activity and frequency of use in foals or people infected with R. equi. Each antimicrobial agent or combination of agents was evaluated against four virulent strains of R. equi. MPC were determined using an agar plate assay. Pharmacodynamic parameters were calculated using published plasma and pulmonary pharmacokinetic variables. There was a significant (P<0.001) effect of the type of antimicrobial agent on the MPC. The MPC of clarithromycin (1.0 μg/ml) was significantly lower and the MPC of rifampin and amikacin (512 and 384 μg/ml, respectively) were significantly higher than that of all other antimicrobial agents tested. Combining erythromycin , clarithromycin , or azithromycin with rifampin resulted in a significant ( P≤0.005 ) decrease in MPC and MPC/MIC ratio . When MIC and MPC were combined with pharmacokinetic variables, only gentamicin and vancomycin were predicted to achieve plasma concentrations above the MPC for any given periods of time. Only clarithromycin and the combination clarithromycin-rifampin were predicted to achieve concentrations in bronchoalveolar cells and pulmonary epithelial lining fluid above the MPC for the entire dosing interval. In conclusion, the combination of a macrolide with rifampin considerably decreases the emergence of resistant mutants of R. equi. ### Assistant: [{"class": "POS", "spans_text": ["erythromycin", "rifampin"]}, {"class": "POS", "spans_text": ["clarithromycin", "rifampin"]}, {"class": "POS", "spans_text": ["azithromycin", "rifampin"]}]

### 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 was confirmed and show that the dCK levels are retained upon co-treatment , indicating a clinical use for bortezomib treatment in combination with cytarabine to avoid development of resistance . Paragraph: Bortezomib prevents cytarabine resistance in MCL, which is characterized by down-regulation of dCK and up-regulation of SPIB resulting in high NF-κB activity. The addition of high-dose cytarabine to the treatment of mantle cell lymphoma (MCL) has significantly prolonged survival of patients, but relapses are common and are normally associated with increased resistance. To elucidate the mechanisms responsible for cytarabine resistance, and to create a tool for drug discovery investigations, we established a unique and molecularly reproducible cytarabine resistant model from the Z138 MCL cell line. ### methods Effects of different substances on cytarabine-sensitive and resistant cells were evaluated by assessment of cell proliferation using [methyl-14C]-thymidine incorporation and molecular changes were investigated by protein and gene expression analyses. ### results Gene expression profiling revealed that major transcriptional changes occur during the initial phase of adaptation to cellular growth in cytarabine containing media, and only few key genes, including SPIB, are deregulated upon the later development of resistance. Resistance was shown to be mediated by down-regulation of the deoxycytidine kinase (dCK) protein, responsible for activation of nucleoside analogue prodrugs. This key event, emphasized by cross-resistance to other nucleoside analogues, did not only effect resistance but also levels of SPIB and NF-κB, as assessed through forced overexpression in resistant cells. Thus, for the first time we show that regulation of drug resistance through prevention of conversion of pro-drug into active drug are closely linked to increased proliferation and resistance to apoptosis in MCL. Using drug libraries, we identify several substances with growth reducing effect on cytarabine resistant cells. We further hypothesized that co-treatment with bortezomib could prevent resistance development. This was confirmed and show that the dCK levels are retained upon co-treatment , indicating a clinical use for bortezomib treatment in combination with cytarabine to avoid development of resistance . The possibility to predict cytarabine resistance in diagnostic samples was assessed, but analysis show that a majority of patients have moderate to high expression of dCK at diagnosis, corresponding well to the initial clinical response to cytarabine treatment. ### conclusion We show that cytarabine resistance potentially can be avoided or at least delayed through co-treatment with bortezomib, and that down-regulation of dCK and up-regulation of SPIB and NF-κB are the main molecular events driving cytarabine resistance development. ### Assistant: [{"class": "POS", "spans_text": ["bortezomib", "cytarabine"]}]

### 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 fenofibrate and its combination with lovastatin on the expression of genes involved in skeletal muscle atrophy , including FoxO1 and its targets . Paragraph: Effects of fenofibrate and its combination with lovastatin on the expression of genes involved in skeletal muscle atrophy , including FoxO1 and its targets . Fibrates and statins have been widely used to reduce triglyceride and cholesterol levels, respectively. Besides its lipid-lowering effect, the side effect of muscle atrophy after fibrate administration to humans has been demonstrated in some studies. Combination therapy with fibrates and statins also increases the risk of rhabdomyolysis. FoxO1, a member of the FoxO forkhead type transcription factor family, is markedly upregulated in skeletal muscle in energy-deprived states and induces muscle atrophy via the expression of E3-ubiquitine ligases. In this study, we investigated the changes in FoxO1 and its targets in murine skeletal muscle with fenofibrate treatment. High doses of fenofibrate (greater than 0.5% (wt/wt)) over one week increased the expression of FoxO1 and its targets in the skeletal muscles of mice and decreased skeletal muscle weight. These fenofibrate-induced changes were diminished in the PPARα knockout mice. When the effect of combination treatment with fenofibrate and lovastatin was investigated, a significant increase in FoxO1 protein levels was observed despite the lack of deterioration of muscle atrophy. Collectively, our findings suggest that a high dose of fenofibrate over one week causes skeletal muscle atrophy via enhancement of FoxO1, and combination treatment with fenofibrate and lovastatin may further increase FoxO1 protein level. ### Assistant: [{"class": "NEG", "spans_text": ["fenofibrate", "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: Idasanutlin was tolerable alone and in combination with cytarabine . Paragraph: Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: Results from an idasanutlin phase 1/1b study⋆. The prognosis remains poor for patients with relapsed or refractory (r/r) acute myeloid leukemia; thus, novel therapies are needed. We evaluated idasanutlin-a new, potent murine double minute 2 antagonist-alone or with cytarabine in patients with r/r acute myeloid leukemia, de novo untreated acute myeloid leukemia unsuitable for standard treatment or with adverse features, or secondary acute myeloid leukemia in a multicenter, open-label, phase 1/1b trial. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) and characterize the safety profile of idasanutlin monotherapy and combination therapy. Clinical activity and pharmacokinetics were secondary objectives. Two idasanutlin formulations were investigated: a microprecipitate bulk powder (MBP) and optimized spray-dried powder (SDP). Following dose escalation, patients (N = 122) received idasanutlin at the RDE in the extension cohorts. No formal MTD was identified. Idasanutlin was tolerable alone and in combination with cytarabine . The RDE was determined as 600 mg twice a day for the MBP formulation and 300 mg twice a day for the SDP formulation. Adverse events were mostly grade 1/2 (76.2 %). The most common any-grade adverse events were gastrointestinal (including diarrhea [90.2 %]). The early death rate across all patients was 14.8 %. Plasma idasanutlin exposure was dose related. In TP53 wild-type patients, composite complete remission rates were 18.9 % with monotherapy and 35.6 % with combination therapy. Based on these results, idasanutlin development continued with further investigation in the treatment of acute myeloid leukemia. ClinicalTrials.gov: NCT01773408. ### Assistant: [{"class": "POS", "spans_text": ["Idasanutlin", "cytarabine"]}]

### 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 seven days of chemotherapy with 5-fluorouracil , oxaliplatin and bevacizumab , exploratory surgery revealed a perforation at the ileum . Paragraph: Intestinal perforation in colorectal cancers treated with bevacizumab (Avastin). bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), and it has shown promise as a clinical agent against metastatic colorectal cancer, and particularly in combination with chemotherapy. Bowel perforation is a known risk that's associated with bevacizumab use, but the etiology is unknown. Here we report on two cases of metastatic colorectal cancer in which the patients suffered from intestinal perforation after chemotherapy with bevacizumab. For the first case, a 47 year-old man had rectal cancer with concurrent liver and lung metastasis. He underwent chemotherapy with 5-fluorouracil, irinotecan and bevacizumab. Fever and abdominal pain developed seven days later, and rectal perforation was identified upon exploration 13 days later. For the second case, a 48 year-old woman had sigmoid colon cancer with peritoneal and ovary metastases. After seven days of chemotherapy with 5-fluorouracil , oxaliplatin and bevacizumab , exploratory surgery revealed a perforation at the ileum . ### Assistant: [{"class": "NEG", "spans_text": ["5-fluorouracil", "oxaliplatin", "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: Nausea graded none or mild 24 h after the start of cisplatin infusion was reported in 71 and 69 % of patients in the 8- and 32-mg ondansetron groups , respectively , and in 73 % of patients in the granisetron group . Paragraph: Ondansetron compared with granisetron in the prophylaxis of cisplatin-induced acute emesis: a multicentre double-blind, randomised, parallel-group study. The Ondansetron and Granisetron Emesis Study Group. This is the first international, multi-centre, double-blind, randomised, parallel group study to directly compare the efficacy and safety profile of a single intravenous dose of ondansetron (8 or 32 mg) with granisetron (3 mg) in the control of cisplatin-induced acute emesis. A total of 496 patients were randomised to receive one of three anti-emetic treatments prior to cisplatin chemotherapy (> or = 50 mg/m2). Of these, 165 and 162 patients received 8 and 32 mg of ondansetron, respectively, and 169 patients received 3 mg of granisetron. Complete control of emesis (0 emetic episodes) over 24 h was reported in 59% of patients in the 8-mg ondansetron group, 51% of patients in the 32-mg ondansetron group and 56% of patients in the granisetron group. Complete or major control (< or = 2 emetic episodes) was achieved in 76 and 74% of patients in the 8- and 32-mg ondansetron group, respectively, compared with 78% of patients in the granisetron group. Nausea graded none or mild 24 h after the start of cisplatin infusion was reported in 71 and 69 % of patients in the 8- and 32-mg ondansetron groups , respectively , and in 73 % of patients in the granisetron group . There were no significant differences between the treatment groups when global satisfaction scores were compared. Logistic regression models were fitted to assess any interaction between treatments and prognostic factors (age, gender, alcohol use, cisplatin dose or concomitant chemotherapy) on complete or major response, but there was no evidence of interaction for any factor. All three anti-emetic treatments were well tolerated and no severe or unexpected drug-related adverse events were observed with ondansetron or granisetron. Headache, the most reported drug-related adverse event for all three treatment groups, occurred in 9% of all patients. In summary, no significant difference was observed between any of the treatment groups with respect to emesis, nausea or drug-related adverse events. ### Assistant: [{"class": "POS", "spans_text": ["cisplatin", "ondansetron"]}, {"class": "POS", "spans_text": ["cisplatin", "granisetron"]}]