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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: Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3 , randomized , controlled , BOLERO-2 trial . Paragraph: Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3 , randomized , controlled , BOLERO-2 trial . The randomized, controlled BOLERO-2 (Breast Cancer Trials of Oral everolimus) trial demonstrated significantly improved progression-free survival with the use of everolimus plus exemestane (EVE + EXE) versus placebo plus exemestane (PBO + EXE) in patients with advanced breast cancer who developed disease progression after treatment with nonsteroidal aromatase inhibitors. This analysis investigated the treatment effects on health-related quality of life (HRQOL). ### methods Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire, HRQOL was assessed at baseline and every 6 weeks thereafter until disease progression and/or treatment discontinuation. The 30 items in 15 subscales of the QLQ-C30 include global health status wherein higher scores (range, 0-100) indicate better HRQOL. This analysis included a protocol-specified time to definitive deterioration (TDD) analysis at a 5% decrease in HRQOL versus baseline, with no subsequent increase above this threshold. The authors report additional sensitivity analyses using 10-point minimal important difference decreases in the global health status score versus baseline. Treatment arms were compared using the stratified log-rank test and Cox proportional hazards model adjusted for trial stratum (visceral metastases, previous hormone sensitivity), age, sex, race, baseline global health status score and Eastern Cooperative Oncology Group performance status, prognostic risk factors, and treatment history. ### results Baseline global health status scores were found to be similar between treatment groups (64.7 vs 65.3). The median TDD in HRQOL was 8.3 months with EVE + EXE versus 5.8 months with PBO + EXE (hazard ratio, 0.74; P = .0084). At the 10-point minimal important difference, the median TDD with EVE + EXE was 11.7 months versus 8.4 months with PBO + EXE (hazard ratio, 0.80; P = .1017). ### conclusions In patients with advanced breast cancer who develop disease progression after treatment with nonsteroidal aromatase inhibitors, EVE + EXE was associated with a longer TDD in global HRQOL versus PBO + EXE. ### Assistant: [{"class": "POS", "spans_text": ["everolimus", "exemestane"]}]

### 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 2 study of irinotecan and paclitaxel in patients with recurrent or refractory small cell lung cancer . Paragraph: Phase 2 study of irinotecan and paclitaxel in patients with recurrent or refractory small cell lung cancer . Patients with extensive stage small cell lung cancer (SCLC) who develop disease progression with standard cisplatin-based therapy are reported to have a poor overall prognosis. irinotecan and paclitaxel are active as single agents and exhibit preclinical synergy in SCLC cell lines. A phase 2 study was conducted to evaluate this combination in patients with recurrent or refractory SCLC. ### methods Patients with SCLC who progressed with 1 prior chemotherapy regimen and had measurable disease present; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; and adequate bone marrow, hepatic, and renal function were included in the study. paclitaxel (at a dose of 75 mg/m(2)) and irinotecan (at a dose of 50 mg/m(2)) were administered intravenously on Days 1 and 8 of each 3-week treatment cycle. Therapy was continued until disease progression or unacceptable toxicity. The target response rate of interest was > or =30%. ### results A total of 55 patients were enrolled, 51 of whom received at least 1 dose of therapy. The majority of the patients had an ECOG PS of 0 or 1 (96%). A median of 3 cycles of treatment was administered, and 15 patients received > or =6 cycles. Seventeen patients experienced toxicity of grade 3 or higher (neutropenia in 8 patients and fatigue in 5 patients). The overall response rate was 21%. The median survival was 25.4 weeks, and the 1-year survival rate was 22%. ### conclusions The regimen of irinotecan and paclitaxel was found to be tolerated well in patients with recurrent or refractory SCLC. Although modest anticancer activity was noted, the efficacy failed to meet the primary endpoint of interest. ### Assistant: [{"class": "POS", "spans_text": ["irinotecan", "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: This was a multicenter phase II pilot study of rituximab and modified hyper-fractionated cyclophosphamide , vincristine doxorubicin , dexamethasone ( modified R-hyperCVAD ) administered every 28 days for four to six cycles followed by rituximab maintenance therapy consisting of four weekly doses every 6 months for 2 years . Paragraph: Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network. There is no standard first line treatment for mantle cell lymphoma. ### Patients And Methods This was a multicenter phase II pilot study of rituximab and modified hyper-fractionated cyclophosphamide , vincristine doxorubicin , dexamethasone ( modified R-hyperCVAD ) administered every 28 days for four to six cycles followed by rituximab maintenance therapy consisting of four weekly doses every 6 months for 2 years . Unlike traditional hyperCVAD regimens, no methotrexate or cytarabine was administered. ### results Of 22 patients, the overall response rate was 77% and the complete response rate was 64%. With a median follow-up time of 37 months in surviving patients, the median PFS was 37 months and the median OS was not reached. The achievement of a molecular remission did not correlate with improved outcome. The major toxicity was expected myelosuppression. Two patients died during induction treatment. There were no major adverse effects during maintenance therapy. ### conclusion In a multicenter trial, modified R-hyperCVAD was tolerable and effective induction therapy for untreated MCL. Maintenance rituximab appeared to prolong PFS without increasing toxicity. ### Assistant: [{"class": "POS", "spans_text": ["rituximab", "cyclophosphamide", "vincristine", "doxorubicin", "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: This trial will close to accrual in September 1995 , and analysis of the trial should provide useful information regarding the potential synergy of doxorubicin and paclitaxel , the degree of cross-resistance between the two compounds , and the relationship between steady-state paclitaxel levels and response to therapy . Paragraph: Doxorubicin/paclitaxel combination chemotherapy for metastatic breast cancer: the Eastern Cooperative Oncology Group experience. The addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to the therapeutic armamentarium for breast cancer has resulted in novel opportunities and challenges for the clinician. In a series of trials that began in 1992, the Eastern Cooperative Oncology Group (ECOG) investigated the role of paclitaxel in combination with doxorubicin for the treatment of patients with advanced breast cancer. The design of the first trial, a limited-institution pilot study, involved alternating doxorubicin and paclitaxel as single agents. The alternating schedule was well tolerated and associated with objective responses in seven of 12 patients entered into the trial. In the second trial, a limited-institution phase I trial, bolus doxorubicin was combined with paclitaxel administered over a 24-hour infusion, with administration of the two drugs separated by 4 hours. While no dose-limiting toxicity was seen at doses of 50 and 150 mg/m2 of doxorubicin and paclitaxel, respectively, dose-limiting mucositis occurred at respective doses of 60 and 175 mg/m2. Mucositis was more common when administration of paclitaxel preceded that of doxorubicin than when doxorubicin preceded paclitaxel. Based on these results, the ECOG initiated a phase III trial comparing single-agent paclitaxel, single-agent doxorubicin, and the combination of paclitaxel and doxorubicin. This study, now an Intergroup trial of ECOG, the Southwest Oncology Group, and the North Central Cancer Treatment Group, is designed to accrue 730 patients. This trial will close to accrual in September 1995 , and analysis of the trial should provide useful information regarding the potential synergy of doxorubicin and paclitaxel , the degree of cross-resistance between the two compounds , and the relationship between steady-state paclitaxel levels and response to therapy . In addition, ECOG is currently conducting a trial designed to confirm the striking activity of cisplatin and paclitaxel seen in the British Columbia trials. Future trials by the group will examine means of combining paclitaxel with other active agents. ### Assistant: [{"class": "POS", "spans_text": ["doxorubicin", "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: 26 patients received adjuvant chemotherapy ( carboplatin plus etoposide ) . Paragraph: Outcomes of adult medulloblastoma treated with a multimodality approach: A tertiary cancer center experience. Adult medulloblastoma (AMB) is a rare central nervous system tumor. We aimed to analyze the treatment outcomes of AMB treated at our institute with surgery followed by craniospinal irradiation (CSI) and adjuvant chemotherapy. ### methods We retrospectively evaluated the treatment charts of 31 patients of AMB treated from 2003-2011. The patient demography, treatment details and survival data were collected in a predesigned proforma. Kaplan Meier method was used to analyze disease free survival (DFS) and the impact of prognostic factors was determined by univariate analysis (log rank test). ### results Male: Female ratio was 21:10. Cerebrospinal fluid dissemination was noted in 16% cases. CSI (36 Gray at 1.8 Gray/fraction to entire neuraxis and 20 Gray at 2 Gray/fraction boost to posterior fossa) was used in all cases. 26 patients received adjuvant chemotherapy ( carboplatin plus etoposide ) . Median follows up was 26.85 months (9.47-119.73 months). The estimated 3 and 5 years DFS was found to be 84.9% and 50.7% respectively. On univariate analysis, tumor located laterally had a trend towards better DFS (HR 3.04; 95%CI 0.722 to 12.812; P = 0.07) compared to midline tumors. Other factors like adjuvant chemotherapy, age, gender, surgical extent had no statistically significant impact on survival. ### conclusion The results of our study (largest series from India) show that the regimen of surgery, adjuvant CSI and chemotherapy is feasible and confers descent survival. AMB patients should be treated with a multimodality approach in a tertiary care centre. ### Assistant: [{"class": "POS", "spans_text": ["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: A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified . Paragraph: Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time-variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified . The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400 mg daily QD was estimated to result in a substantial median PFS of 1.8 years (95% confidence interval [CI], 1.7-2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9 years (95% CI, 2.8-5.6). The analysis demonstrates a concentration-dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose. ### Assistant: [{"class": "POS", "spans_text": ["venetoclax", "rituximab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer . Paragraph: Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer . Platinum plays an important role in the treatment of triple-negative breast cancer (TNBC) in neoadjuvant and metastatic settings. However, its role in an adjuvant setting remains unclear. ### methods In this non-inferior randomized phase 2 trial, we randomly assigned 308 chemotherapy-naive patients with histologically confirmed TNBC after primary surgery to receive either six cycles of TP (docetaxel: 75 mg/m ### results At a median follow-up of 66.9 months, the 5-year DFS rate was 85.8% in the EC-T arm, and 84.4% in the TP arm (p non-inferiority = 0.034, p log-rank = 0.712). The 5-year overall survival (OS) rate was 94.4% in the EC-T arm and 93.5% in the TP arm (p = 0.770). Patients in the TP arm showed better compliance and experienced significantly lower frequencies of G3/4 neutrocytopenia and G3/4 alopecia, but higher rates of G1-4 thrombocytopenia than those in the EC-T arm. Patients with PD-L1 expressing tumors showed significantly improved DFS and OS. ### conclusions This study indicates that carboplatin plus taxanes could be a feasible adjuvant chemotherapy for patients with early TNBC who are cannot tolerate intensive chemotherapy with anthracycline. ### Assistant: [{"class": "POS", "spans_text": ["Carboplatin", "taxanes"]}, {"class": "COMB", "spans_text": ["epirubicin", "cyclophosphamide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Comparative study of ceftriaxone monotherapy versus a combination regimen of cefuroxime plus gentamicin for treatment of serious bacterial infections : the efficacy , safety and effect on fecal flora . Paragraph: Comparative study of ceftriaxone monotherapy versus a combination regimen of cefuroxime plus gentamicin for treatment of serious bacterial infections : the efficacy , safety and effect on fecal flora . To assess the efficacy of once daily monotherapy relative to standard combination antibiotic therapy for the initial management of patients suspected of serious bacterial infections, we conducted a randomized trial comparing ceftriaxone (Rocephin) with a combination of cefuroxime plus gentamicin. Of 105 patients, 53 were treated with ceftriaxone alone and 52 with the combination; 13 patients were considered not evaluable. 42 of 53 patients given ceftriaxone and 33 of 52 given cefuroxime plus gentamicin responded to treatment (p = 0.07). Three patients given ceftriaxone and 6 who received gentamicin plus cefuroxime died (p = 0.28). Definite bacterial infections were identified in 67 patients; of the evaluable patients with a definite infection 27 of 29 who received ceftriaxone and 21 of 31 who were treated with the combination were cured (p = 0.01). No difference was found in the number of side effects. However, therapy had to be discontinued due to treatment failure, an adverse effect or death in 1 of 33 patients given ceftriaxone and in 11 of 34 given the combination (p = 0.002). ceftriaxone was found to have an impact on the count of E. coli in intestinal microflora. Changes in normal bacterial composition did not lead to the overgrowth with resistant Enterobacteriaceae or Pseudomonas, however, colonization by yeast was observed. Using ceftriaxone reduced the cost of antimicrobial therapy per patient by 107 pounds (US$ 183). Moreover, the total time save per patient due to decreased nursing and drug administration time per day was 40 min.(ABSTRACT TRUNCATED AT 250 WORDS) ### Assistant: [{"class": "NEG", "spans_text": ["cefuroxime", "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: A phase 1b , dose escalation study was performed to assess maximum tolerated dose , safety/toxicity , clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab . Paragraph: A phase Ib study of entinostat plus lapatinib with or without trastuzumab in patients with HER2-positive metastatic breast cancer that progressed during trastuzumab treatment. Human epidermal growth factor 2 (HER2) is an effective therapeutic target in breast cancer; however, resistance to anti-HER2 agents such as trastuzumab and lapatinib develops. In a preclinical model, an HDAC inhibitor epigenetically reversed the resistance of cancer cells to trastuzumab and showed synergistic efficacy with lapatinib in inhibiting growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer. ### methods A phase 1b , dose escalation study was performed to assess maximum tolerated dose , safety/toxicity , clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab . ### results The combination was safe. The MTD was lapatinib, 1000 mg daily; entinostat, 12 mg every other week; trastuzumab, 8 mg/kg followed by 6 mg/kg every 3 weeks. Adverse events included diarrhoea (89%), neutropenia (31%), and thrombocytopenia (23%). Neutropenia, thrombocytopenia and hypokalaemia were noted. Pharmacodynamic assessment did not yield conclusive results. Among 35 patients with evaluable response, PR was observed in 3 patients and CR in 3 patients, 1 maintained SD for over 6 months. ### discussion This study identified the MTD of the entinostat, lapatinib, and trastuzumab combination that provided acceptable tolerability and anti-tumour activity in heavily pre-treated patients with HER2+ metastatic breast cancer, supporting a confirmatory trial. ### Assistant: [{"class": "POS", "spans_text": ["entinostat", "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: Objective and palliative effect of chemotherapy is marked for weekly doxorubicin , prednisone with mitoxantrone and etoposide associated with platin-salts for prostatic carcinoma with neuroendocrine differentiation . Paragraph: [Study of the hormone-refractory prostate cancer clinical practice in an anti-cancer center]. We have examined 82 patients with hormonoresistant prostate cancer in a retrospective study. Bone and lymph node metastases were observed in 94% and 30% of patients respectively. However, the visceral metastases were frequent: liver (17%), lung (7%), bone marrow (4%), meningitis (4%). PSA is constantly high but 28% of the patients have elevated NSE, which is correlated with lymph node or visceral metastases. ACE is elevated in 27% of cases. Objective and palliative effect of chemotherapy is marked for weekly doxorubicin , prednisone with mitoxantrone and etoposide associated with platin-salts for prostatic carcinoma with neuroendocrine differentiation . This study suggests the presence of different subpopulations of patients with specific evolutive patterns, thus further specific therapy should be evaluated. ### Assistant: [{"class": "COMB", "spans_text": ["doxorubicin", "prednisone", "mitoxantrone", "etoposide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The recommendations derived from the comprehensive assessment of the literature and guidelines are to continue NSAIDs and low dose aspirin , and phosphodiesterase inhibitors ( dipyridamole , cilostazol , Aggrenox ) during interventional techniques . Paragraph: Assessment of bleeding risk of interventional techniques: a best evidence synthesis of practice patterns and perioperative management of anticoagulant and antithrombotic therapy. Interventional pain management is a specialty that utilizes invasive procedures to diagnose and treat chronic pain. Patients undergoing these treatments may be receiving exogenous anticoagulants and antithrombotics. Even though the risk of major bleeding is very small, the consequences can be catastrophic. However, the role of antithrombotic therapy for primary and secondary prevention of cardiovascular disease to decrease the incidence of acute cerebral and cardiovascular events is also crucial. Overall, there is a paucity of literature on the subject of bleeding risk in interventional pain management along with practice patterns and perioperative management of anticoagulant and anti-thrombotic therapy. ### Study Design Best evidence synthesis. ### objective To critically appraise and synthesize the literature with assessment of the bleeding risk of interventional techniques including practice patterns and perioperative management of anticoagulant and antithrombotic therapy. ### methods The available literature on the bleeding risk of interventional techniques and practice patterns and perioperative management of anticoagulant and antithrombotic therapy was reviewed. Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 through December 2012 and manual searches of the bibliographies of known primary and review articles. ### results There is good evidence for the risk of thromboembolic phenomenon in patients who discontinue antithrombotic therapy, spontaneous epidural hematomas occur with or without traumatic injury in patients with or without anticoagulant therapy associated with stressors such as chiropractic manipulation, diving, and anatomic abnormalities such as ankylosing spondylitis, and the lack of necessity of discontinuation of nonsteroidal anti-inflammatory drugs (NSAIDs), including low dose aspirin prior to performing interventional techniques. There is fair evidence that excessive bleeding, including epidural hematoma formation may occur with interventional techniques when antithrombotic therapy is continued, the risk of thromboembolic phenomenon is higher than the risk of epidural hematomas with discontinuation of antiplatelet therapy prior to interventional techniques, to continue phosphodiesterase inhibitors (dipyridamole [Persantine], cilostazol [Pletal], and Aggrenox [aspirin and dipyridamole]), and that anatomic conditions such as spondylosis, ankylosing spondylitis and spinal stenosis, and procedures involving the cervical spine; multiple attempts; and large bore needles increase the risk of epidural hematoma; and rapid assessment and surgical or nonsurgical intervention to manage patients with epidural hematoma can avoid permanent neurological complications. There is limited evidence to discontinue antiplatelet therapy with platelet aggregation inhibitors to avoid bleeding and epidural hematomas and/or to continue antiplatelet therapy clopidogrel (Plavix), ticlopidine (Ticlid), or prasugrel (Effient) during interventional techniques to avoid cerebrovascular and cardiovascular thromboembolic fatalities. There is limited evidence in reference to newer antithrombotic agents dabigatran (Pradaxa) and rivaroxaban (Xarelto) to discontinue to avoid bleeding and epidural hematomas during interventional techniques and to continue to avoid cerebrovascular and cardiovascular thromboembolic events. ### recommendations The recommendations derived from the comprehensive assessment of the literature and guidelines are to continue NSAIDs and low dose aspirin , and phosphodiesterase inhibitors ( dipyridamole , cilostazol , Aggrenox ) during interventional techniques . However, the recommendations for discontinuation of antiplatelet therapy with platelet aggregation inhibitors (clopidogrel, ticlopidine, prasugrel) is variable with clinical judgment to continue or discontinue based on the patient's condition, the planned procedure, risk factors, and desires, and the cardiologist's opinion. Low molecular weight heparin (LMWH) or unfractionated heparin may be discontinued 12 hours prior to performing interventional techniques. warfarin should be discontinued or international normalized ratio (INR) be normalized to 1.4 or less for high risk procedures and 2 or less for low risk procedures based on risk factors. It is also recommended to discontinue Pradaxa for 24 hours for paravertebral interventional techniques in 2 to 4 days for epidural interventions in patients with normal renal function and for longer periods of time in patients with renal impairment, and to discontinue rivaroxaban for 24 hours prior to performing interventional techniques. ### limitations The paucity of the literature. ### conclusion Based on the available literature including guidelines, the recommendations in patients with antithrombotic therapy for therapy prior to interventional techniques are provided. ### Assistant: [{"class": "POS", "spans_text": ["aspirin", "dipyridamole"]}, {"class": "POS", "spans_text": ["aspirin", "cilostazol"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin . Paragraph: Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells. silibinin, the main component of silymarin, is used as a hepatoprotectant and exhibits anticancer effects against various cancer cells. This study evaluated the effects of a combination of silibinin with either gefitinib or sorafenib on hepatocellular carcinoma (HCC) cells. ### methods Several different human HCC cell lines were used to test the growth-inhibiting effects and cell toxicity of silibinin both alone and in combination with either gefitinib or sorafenib. The cell viability and growth inhibition were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and a colony-forming assay. Furthermore, changes in epidermal growth factor receptor (EGFR)-related signals were evaluated by Western blot analysis. ### results gefitinib, sorafenib, and silibinin individually exhibited dose-dependent antiproliferative effects on HCC cells. Combined treatment with silibinin enhanced the gefitinib-induced growth-inhibiting effects in some HCC cell lines. The combination effect of gefitinib and silibinin was synergistic in the SNU761 cell line, but was only additive in the Huh-BAT cell line. The combination effect may be attributable to inhibition of EGFR-dependent Akt signaling. Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin . ### conclusions Combined treatment with silibinin enhanced the growth-inhibiting effects of both gefitinib and sorafenib. Therefore, the combination of silibinin with either sorafenib or gefitinib could be a useful treatment approach for HCC in the future. ### Assistant: [{"class": "POS", "spans_text": ["sorafenib", "silibinin"]}]

### 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 effects of the Acanthopanax obovatus polysaccharide ( AOPS ) as well as its combination with cyclophosphamide ( CY ) or prednisolone on immune responses were investigated in mice . Paragraph: Immunomodulatory activity of polysaccharide from Acanthopanax obovatus roots. The effects of the Acanthopanax obovatus polysaccharide ( AOPS ) as well as its combination with cyclophosphamide ( CY ) or prednisolone on immune responses were investigated in mice . AOPS (250 mg/kg i.p. x 5) increased the spleen weight and the number of spleen cells, and augmented the phagocytosis of peritoneal macrophages both in normal mice and in immunosuppressed mice. In a haemagglutinin assay AOPS increased the production of specific antibodies and antagonized the suppressive effect of CY. AOPS not only enhanced the degree of in vitro spleen cell-mediated red blood cells (SRBC) hemolysis (quantitative hemolysis of SRBC) but also restored the suppressive effect of CY completely. From these results, AOPS was shown to have an enhancing and a modulating activity on immune responses. ### Assistant: [{"class": "POS", "spans_text": ["Acanthopanax obovatus polysaccharide", "cyclophosphamide"]}, {"class": "POS", "spans_text": ["Acanthopanax obovatus polysaccharide", "prednisolone"]}]

### 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 did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in patients with high-risk smouldering multiple myeloma . Paragraph: Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. The standard of care for smouldering multiple myeloma is observation. We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in patients with high-risk smouldering multiple myeloma . Here we report the long-term follow-up results of the trial. ### methods We did this open-label, randomised, controlled phase 3 study at 19 centres in Spain and three centres in Portugal. Patients aged 18 years or older with high-risk smouldering multiple myeloma were randomly assigned (1:1), via a computerised random number generator, to receive either early treatment with lenalidomide plus dexamethasone or observation, with dynamic balancing to maintain treatment balance within the two groups. Randomisation was stratified by time from diagnosis of smouldering multiple myeloma to study enrolment (≤6 months vs >6 months). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg per day on days 1-21, plus dexamethasone 20 mg per day on days-1-4 and days 12-15), followed by maintenance therapy (lenalidomide 10 mg per day on days 1-21 of each 28-day cycle) up to 2 years. Group allocation was not masked from study investigators or patients. The primary endpoint was time from randomisation to progression to symptomatic myeloma. The primary analysis was based on the per-protocol population, restricted to patients who fulfilled the protocol in terms of eligibility. Safety assessments were based on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00480363. ### findings Between Nov 8, 2007, and June 9, 2010, 125 patients were enrolled and underwent randomisation. 119 patients comprised the per-protocol population and were randomly assigned to receive either lenalidomide plus dexamethasone (n=57) or observation (n=62). The cutoff date for this update was June 30, 2015. Median follow-up for surviving patients was 75 months (IQR 67-85). lenalidomide plus dexamethasone continued to provide a benefit on time to progression compared with observation (median time to progression not reached [95% CI 47 months-not reached] vs 23 months [16-31]; hazard ratio [HR] 0·24 [95% CI 0·14-0·41]; p<0·0001). Progression to multiple myeloma occurred in 53 (86%) of 62 patients in the observation group compared with 22 (39%) of 57 patients in the treatment group. At data cutoff, ten (18%) patients had died in the treatment group and 22 (36%) patients had died in the observation group; median overall survival from the time of study entry had not been reached in either group (95% CI 65 months-not reached vs 53 months-not reached; HR 0·43 [95% CI 0·21-0·92], p=0·024). Survival in patients who had received subsequent treatments at the time of progression to active disease did not differ between groups (HR 1·34 [95% CI 0·54-3·30]; p=0·50). The most frequently reported grade 3 adverse events in patients given lenalidomide plus dexamethasone were infection (four [6%]), asthenia (four [6%]), neutropenia (three [5%]), and skin rash (two [3%]); these events all occurred during induction therapy. No grade 4 adverse events occurred, but one (2%) patient in the lenalidomide plus dexamethasone group died from a respiratory infection during induction therapy The frequency of second primary malignancies was higher in patients in the treatment group than in those in the observation group (six [10%] of 62 patients vs one [2%] of 63 patients), but the cumulative risk of development did not differ significantly between the groups (p=0·070). ### interpretation This study is, to our knowledge, the first randomised trial in which early treatment has been assessed in selected patients with high-risk smouldering multiple myeloma. Positive results from ongoing trials would support the use of early treatment for patients with high-risk disease in the near future. ### funding Pethema (Spanish Program for the Treatment of Hematologic Diseases). ### Assistant: [{"class": "POS", "spans_text": ["lenalidomide", "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: Of the patients , 26 were treated with a chemotherapy regimen known to cause prolonged and sometimes permanent azoospermia ( BEACOPP -- bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisolone ) and 26 with a regimen known to have a much milder effect on gonadal function ( ABVD -- doxorubicin , bleomycin , vincristine , and dacarbazine ) . Paragraph: The impact of systemic chemotherapy on testicular FDG activity in young men with Hodgkin's lymphoma. Based on prior reports suggesting a positive correlation between fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)/CT and total sperm count and concentration, we sought to identify changes in testicular FDG uptake over the course of chemotherapy in young men with Hodgkin's lymphoma. ### methods Fifty-two patients with a mean age of 24.2 years (range 15.5-44.4) at diagnosis monitored with FDG PET/CT to assess treatment response for Hodgkin's lymphoma were selected for this retrospective analysis under an Institutional Review Board waiver. Of the patients , 26 were treated with a chemotherapy regimen known to cause prolonged and sometimes permanent azoospermia ( BEACOPP -- bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisolone ) and 26 with a regimen known to have a much milder effect on gonadal function ( ABVD -- doxorubicin , bleomycin , vincristine , and dacarbazine ) . Each patient underwent one FDG PET/CT before treatment and at least one FDG PET/CT after start of chemotherapy. In all examinations, FDG activity was measured in the testes with different quantification metrics: maximum standardized uptake value (SUVmax), SUVmean, functional volume (FV) and total testicular glycolysis (TTG), and blood pool activity determined (SUVmean). ### results Testicular FDG uptake (SUVmax) was significantly associated with blood pool activity (p < 0.001). Furthermore, testicular FDG uptake metrics incorporating volume (e.g., FV and TTG) were associated with age. There was no significant change in SUVmax, SUVmean, FV, and TTG from the PET/CT at baseline to the PET/CTs over the course of chemotherapy either for patients treated with BEACOPP or for patients treated with ABVD. ### conclusion For patients undergoing chemotherapy for Hodgkin's lymphoma, there is a significant association between testicular FDG uptake and blood pool activity, but no significant changes in FDG uptake over the course of chemotherapy. Therefore, FDG uptake may not be a feasible surrogate marker for fertility monitoring in patients with Hodgkin's lymphoma undergoing chemotherapy. ### Assistant: [{"class": "POS", "spans_text": ["bleomycin", "vincristine", "dacarbazine", "doxorubicin"]}, {"class": "NEG", "spans_text": ["bleomycin", "etoposide", "doxorubicin", "cyclophosphamide", "vincristine", "procarbazine", "prednisolone"]}]

### 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: Tissue from preclinical models and patients ' biopsies were collected pre-treatment and on Cycle ( C ) 1 , Day ( D ) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels . Paragraph: Integrated preclinical and clinical development of S-trans, trans-Farnesylthiosalicylic Acid (FTS, Salirasib) in pancreatic cancer. S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA). ### Patients And Methods In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naïve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients ' biopsies were collected pre-treatment and on Cycle ( C ) 1 , Day ( D ) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels . Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination. ### results salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes. ### conclusion The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA. ### Assistant: [{"class": "POS", "spans_text": ["gemcitabine", "salirasib"]}]

### 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 effect of dasatinib , an inhibitor of Src and Abl kinases , on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts . Paragraph: The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. ### methods A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib , an inhibitor of Src and Abl kinases , on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts . The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. ### results Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. ### conclusion Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. ### Assistant: [{"class": "POS", "spans_text": ["dasatinib", "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 maximum tolerated dose ( MTD ) was 20 mg/m2/day I.V. bolus for 5 days of fludarabine plus 60 mg/m2/day I.V. of paclitaxel given as a continuous infusion over 72 hours . Paragraph: Phase I study of fludarabine and paclitaxel for the treatment of low-grade non-Hodgkin's lymphoma. We conducted a phase I clinical trial of a new combination of fludarabine and paclitaxel in which 19 patients with histologically confirmed recurrent low-grade non-Hodgkin's lymphoma (NHL) were treated at five dose levels. fludarabine was administered intravenously by bolus for 5 days and paclitaxel was given by intravenous (I.V.) continuous infusion for 96 or 72 hours starting day 1. Courses were repeated every 4 weeks. Patients whose disease responded received a maximum of six courses. All 19 patients received at least one course and could be evaluated for toxic effects, and 18 patients could be evaluated for response. The maximum tolerated dose ( MTD ) was 20 mg/m2/day I.V. bolus for 5 days of fludarabine plus 60 mg/m2/day I.V. of paclitaxel given as a continuous infusion over 72 hours . The limiting toxic effect was neutropenic fever, which was observed in five of the seven patients treated at the highest dose level. Grade 3 non-hematologic toxic effects of stomatitis (14%), neuropathy (14%), and hypotension (14%) were also observed at the highest dose level. No grade 4 non-hematologic toxic effects or treatment-related deaths occurred. One patient had herpes zoster infection of the skin 1 year after the completion of therapy. The overall response rate was 50%, with the two patients whose disease completely responded remaining disease free at 22 and 17 months. Patients with no prior exposure to either paclitaxel or fludarabine had 62% response rate. We conclude that the combination of fludarabine and paclitaxel appears to have promising activity for the treatment of recurrent low-grade NHL. ### Assistant: [{"class": "POS", "spans_text": ["fludarabine", "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: Further studies are needed to identify predictors of response and toxicity to this approach , as well as the optimal scheduling of ipilimumab with maintenance nivolumab . Paragraph: Salvage ipilimumab associated with a significant response in sarcomatoid renal cell carcinoma. Metastatic sarcomatoid renal cell carcinoma (sRCC) is an aggressive variant of RCC with generally poor prognosis. Treatment with vascular endothelial growth factor inhibitors or chemotherapy generates only short-lived responses. Recent research has suggested a role for combination checkpoint inhibition as first line treatment for metastatic sRCC. This therapy consists of induction with cytotoxic T-lymphocyte-associated protein 4 inhibitor, ipilimumab, administered with programmed cell death protein 1 (PD-1) inhibitor, nivolumab. After completion of four cycles of combination therapy, single-agent maintenance nivolumab is recommended until progression. Patients who progress on maintenance nivolumab are switched to alternate therapy. Herein, we present a case of a patient with RCC who progressed on maintenance nivolumab who, on retreatment with ipilimumab, demonstrated a significant response In addition, we summarize important findings to support the role of salvage ipilimumab in patients with sRCC. ### Case Presentation A 46-year-old man presented with flank pain and hematuria, the work up of which noted a left kidney mass for which he underwent nephrectomy and was diagnosed with localized sRCC with 60% sarcomatoid differentiation. Within 3 months of nephrectomy, he presented with recurrent flank pain and was diagnosed with recurrence of disease. He was treated with ipilimumab 1 mg/kg and nivolumab 3 mg/kg for four doses and demonstrated a partial response. He was then transitioned to single agent nivolumab maintenance. After 3 months on maintenance therapy, he was noted to have progression of disease. Given prior response to immune check point combination, it was decided to rechallenge the patient with 1 mg/kg ipilimumab. After two doses of ipilimumab and nivolumab combination therapy, the patient was noted to have a partial response. He maintained a response for an additional 9 months and treatment was eventually discontinued due to grade 3 toxicity and progression. ### conclusions This case report demonstrates the utility of retreatment with ipilimumab as a salvage option for patients progressing on maintenance PD-1 inhibitors in metastatic RCC. Further studies are needed to identify predictors of response and toxicity to this approach , as well as the optimal scheduling of ipilimumab with maintenance nivolumab . ### Assistant: [{"class": "POS", "spans_text": ["ipilimumab", "nivolumab"]}]

### 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: Efficacy of palonosetron plus aprepitant in preventing chemoradiotherapy-induced nausea and emesis in patients receiving daily low-dose cisplatin-based concurrent chemoradiotherapy for uterine cervical cancer : a phase II study . Paragraph: Efficacy of palonosetron plus aprepitant in preventing chemoradiotherapy-induced nausea and emesis in patients receiving daily low-dose cisplatin-based concurrent chemoradiotherapy for uterine cervical cancer : a phase II study . Antiemetic recommendations during concurrent chemoradiotherapy (cisplatin-based concurrent chemoradiotherapy (CCRT)) have not been established yet. The aim of this study was to investigate whether the combination of palonosetron plus aprepitant, without routine use of dexamethasone, could alleviate chemoradiotherapy-induced nausea and vomiting (CRINV). ### methods This was a non-randomized, prospective, single-center, open phase II study. Patients with cervical cancer, who were treated with daily low-dose cisplatin (8 mg/m(2)/day) and concurrent radiation (2 Gy/day, 25 fractions, five times a week), were enrolled in this study. All patients received intravenous palonosetron (0.75 mg on day 1 of each week) and oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3 of each week). The primary endpoint was the percentage of patients with a complete response, defined as no emetic episodes and no use of antiemetic rescue medication during the treatment. ### results Twenty-seven patients (median age, 50 years; range, 33-72 years) were enrolled in this study between June 2013 and April 2014. A total of 13 (48 %) patients showed a complete response to the antiemetic regimen, while 8 patients (30 %) had emetic episodes and 6 patients (22 %) used rescue medication without emetic episodes. No severe adverse effects caused by palonosetron plus aprepitant were observed. ### conclusion The combination of palonosetron plus aprepitant was permissive for the prevention of CRINV. This regimen should be considered for patients in whom dexamethasone is contraindicated or not well tolerated. ### Assistant: [{"class": "POS", "spans_text": ["palonosetron", "aprepitant"]}]

### 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: Pre/peri/postmenopausal women with HR+/HER2- MBC were randomized 2:1 to fulvestrant ( 500 mg ) and either palbociclib ( 125 mg/day ; 3 weeks on/1 week off ; n = 347 ) or placebo ( n = 174 ) . Prespecified exploratory analyses compared the efficacy ( data cutoff : October 23 , 2015 ) , safety , and pharmacokinetics ( data cutoff : December 5 , 2014 ) in Japanese women versus the overall population . Paragraph: Palbociclib in combination with fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-3 subgroup analysis of Japanese patients. In the double-blind, phase 3 PALOMA-3 study, palbociclib-fulvestrant significantly prolonged progression-free survival versus placebo-fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) whose disease had progressed on prior endocrine therapy. The present study evaluated the efficacy, safety, and pharmacokinetics of palbociclib plus fulvestrant in Japanese patients enrolled in PALOMA-3. ### methods Pre/peri/postmenopausal women with HR+/HER2- MBC were randomized 2:1 to fulvestrant ( 500 mg ) and either palbociclib ( 125 mg/day ; 3 weeks on/1 week off ; n = 347 ) or placebo ( n = 174 ) . Prespecified exploratory analyses compared the efficacy ( data cutoff : October 23 , 2015 ) , safety , and pharmacokinetics ( data cutoff : December 5 , 2014 ) in Japanese women versus the overall population . ### results A total of 35 Japanese women were randomized to palbociclib-fulvestrant (n = 27) or placebo-fulvestrant (n = 8). Median progression-free survival was 13.6 months (95% CI, 7.5-not estimable) in the Japanese palbociclib-fulvestrant group and 11.2 months (95% CI, 5.6-not estimable) in the placebo-fulvestrant group. The most common adverse event (AE) in Japanese patients was neutropenia (all grades, 93%); no discontinuations were due to an AE. Geometric mean trough concentration values (within-subject mean steady state) for palbociclib were similar for Japanese Asian (excluding Japanese), and non-Asian patients (84.4 ng/mL, 86.3 ng/mL, and 74.8 ng/mL, respectively). ### Conclusion S The results for the overall population and Japanese patients in PALOMA-3 suggest that palbociclib plus fulvestrant was effective and well tolerated in Japanese patients with HR+/HER2‒ MBC whose disease had progressed on prior endocrine therapy (Pfizer; NCT01942135). ### Assistant: [{"class": "POS", "spans_text": ["fulvestrant", "palbociclib"]}]

### 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: was lowest in the propofol + dexmedetomidine group ( all , P < 0.05 ) , and the AUC of pulse oximetry was significantly higher in the propofol + dexmedetomidine and propofol + ketamine groups compared to the other 2 groups ( both , P < 0.05 ) . Paragraph: Efficacy and Tolerability of Sufentanil, Dexmedetomidine, or Ketamine Added to Propofol-based Sedation for Gastrointestinal Endoscopy in Elderly Patients: A Prospective, Randomized, Controlled Trial. To investigate the optimal agent combined with propofol for sedation in elderly patients undergoing gastrointestinal endoscopy. ### methods A total of 120 elderly patients scheduled for gastrointestinal endoscopy under propofol-based sedation were randomly allocated to receive propofol + saline (control group), propofol + sufentanil 0.1 μg/kg, propofol + dexmedetomidine 0.4 μg/kg, or propofol + ketamine 0.4 mg/kg. Mean arterial pressure, heart rate, pulse oximetry, pressure of end-tidal carbon dioxide, respiratory rate, and Ramsay sedation scale score were recorded. Induction time, procedure time, recovery time, propofol dose, and adverse events were also recorded. ### findings During the sedation procedure, the AUC of HR was lowest in the propofol + dexmedetomidine group ( all , P < 0.05 ) , and the AUC of pulse oximetry was significantly higher in the propofol + dexmedetomidine and propofol + ketamine groups compared to the other 2 groups ( both , P < 0.05 ) . The propofol + dexmedetomidine group had the highest prevalences of hypotension and bradycardia, and the control group experienced the largest number of hypoxia episodes (all, P < 0.05). The control group consumed the highest dose of propofol, while the propofol + ketamine group needed the lowest dose (all, P < 0.05). ### implications The combination of propofol + ketamine 0.4 mg/kg maintained hemodynamic and respiratory stability, as evidenced by less hypotension, bradycardia, and hypoxia events, in elderly patients undergoing gastrointestinal endoscopy. China clinical trial registration (chictr.org.cn) ID: ChiCTR-INR-17013710. ### Assistant: [{"class": "POS", "spans_text": ["propofol", "ketamine"]}, {"class": "COMB", "spans_text": ["propofol", "dexmedetomidine", "propofol", "dexmedetomidine"]}]

### 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 aged 15 to 60 years , presenting with newly diagnosed acute myeloid leukemia ( AML ) were randomized to receive either high-dose cytarabine , 3 g/m2 12 hourly on days 1 , 3 , 5 , and 7 for 8 doses , daunorubicin 50 mg/m2 days 1 to 3 , etoposide 75 mg/m2 days 1 to 7 , ( HIDAC-3 - 7 ) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above ( 7 - 3 - 7 ) . Paragraph: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years , presenting with newly diagnosed acute myeloid leukemia ( AML ) were randomized to receive either high-dose cytarabine , 3 g/m2 12 hourly on days 1 , 3 , 5 , and 7 for 8 doses , daunorubicin 50 mg/m2 days 1 to 3 , etoposide 75 mg/m2 days 1 to 7 , ( HIDAC-3 - 7 ) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above ( 7 - 3 - 7 ) . Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5-2-5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC-3-7 and 74% with 7-3-7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3-7 and 12 months with 7-3-7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3-7 and 24% on 7-3-7. Patients in CR tended to survive longer with HIDAC-3-7 but there were no overall survival differences between the two arms. HIDAC-3-7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P < .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7-3-7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3-7 induction (P < .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC-3-7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML. ### Assistant: [{"class": "COMB", "spans_text": ["cytarabine", "daunorubicin", "etoposide"]}, {"class": "COMB", "spans_text": ["cytarabine", "daunorubicin", "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: Therefore , if a combination regimen is necessary to control CMV in a patient , foscarnet and ganciclovir should be used first . Paragraph: Combination antiviral therapy for cytomegalovirus disease in patients with AIDS. Currently, combination therapy with ganciclovir and foscarnet should be reserved for patients with disease progression while receiving monotherapy or for those who are unresponsive to either agent alone. Although cidofovir and ganciclovir were shown to have synergistic activity against human CMV in vitro, there have been no in vivo studies to confirm this activity. Therefore , if a combination regimen is necessary to control CMV in a patient , foscarnet and ganciclovir should be used first . There are several advantages of the combination therapy regimen. For instance, lower doses of the individual agents can be used with superior efficacy to monotherapy and similar toxicities. Also, for neurologic CMV involvement, the combination therapy may be superior to monotherapy because of the variable CSF penetration of either drug alone. In addition, combined therapy may be beneficial in treating and/or preventing drug-resistant strains of CMV. Even though combination therapy has evidence of superior efficacy compared with monotherapy in the treatment of CMV, several issues must be considered. First, combination therapy has longer administration times because of the infusion of multiple drugs, which may be an inconvenience. Also, even though the toxic effects are similar with both combined therapy and monotherapy, the adverse effects associated with combination therapy may be less well tolerated and may negatively affect the patient's quality of life. Finally, combination therapy is more expensive than monotherapy with ganciclovir or foscarnet alone. Patients should be evaluated with these issues in mind before combination therapy is initiated. ### Assistant: [{"class": "POS", "spans_text": ["foscarnet", "ganciclovir"]}]

### 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 Ib/II Study of Afatinib in Combination with Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib . Paragraph: A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib . In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non-small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib. ### Experimental Design In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage. ### results In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7-16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3-5.7 months] and 11.7 months (95% CI, 9.4-14.0 months), respectively. ### conclusions Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety. Clin Cancer Res; 22(9); 2139-45. ©2015 AACR. ### Assistant: [{"class": "POS", "spans_text": ["Afatinib", "Nimotuzumab"]}]

### 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: RESULTS In first-line treatment , compared with sunitinib , improvement of one-year CPFS for the nivolumab plus ipilimumab group after living for 0.5 and 0.75 years were 14 % ( from 53.0 % to 67.0 % ) and 16 % ( from 57.0 % to 73.0 % ) higher than the one-year PFS of 6.5 % ( from 42.9 % to 49.4 % ) , with similar results for one-year COS following first-line treatment . Paragraph: Conditional Survival in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab. BACKGROUND nivolumab is approved for the treatment of advanced renal cell carcinoma (RCC). However, traditional overall survival (OS) or progression-free survival (PFS) do not reflect patient prognosis after initial management. Therefore, this study aimed to evaluate conditional overall survival (COS) and conditional progression-free survival (CPFS) in patients with advanced RCC treated with nivolumab. MATERIAL AND METHODS There were 847 patients with advanced RCC treated with first-line nivolumab plus ipilimumab (n=425) and sunitinib (n=422), and 821 patients were treated with second-line nivolumab (n=410) and everolimus (n=411). Primary endpoints were COS and CPFS. Individual patient data of PFS and OS were digitally reconstructed from two large randomized controlled trials (CheckMate 025 and CheckMate 214). RESULTS In first-line treatment , compared with sunitinib , improvement of one-year CPFS for the nivolumab plus ipilimumab group after living for 0.5 and 0.75 years were 14 % ( from 53.0 % to 67.0 % ) and 16 % ( from 57.0 % to 73.0 % ) higher than the one-year PFS of 6.5 % ( from 42.9 % to 49.4 % ) , with similar results for one-year COS following first-line treatment . For second-line treatment, compared with everolimus, the improvement of one-year CPFS for the nivolumab group after living for 0.5 and 0.75 years were 19% (from 25.0% to 44.0%) and 19% (from 27.0% to 46.0%) and significantly higher than the one-year PFS of 4.5% (from 18.5% to 23.0%). CONCLUSIONS Survival benefit for patients with advanced RCC from nivolumab (plus ipilimumab) compared with sunitinib was more evident from conditional survival (CS) analysis of first-line treatment. ### Assistant: [{"class": "POS", "spans_text": ["nivolumab", "ipilimumab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: This study analysed 126 patients with relapsed , advanced stage follicular lymphoma who received BEAM ( BCNU [ carmustine ] , cytarabine , etoposide , melphalan)-alemtuzumab allogeneic HSCT ( BEAM-allo ) ( n = 44 ) or BEAM-autologous HSCT ( BEAM-auto ) ( n = 82 ) . Paragraph: Outcome of BEAM-autologous and BEAM-alemtuzumab allogeneic transplantation in relapsed advanced stage follicular lymphoma. The role of haematopoietic stem cell transplantation (HSCT) in relapsed follicular lymphoma remains controversial. This study analysed 126 patients with relapsed , advanced stage follicular lymphoma who received BEAM ( BCNU [ carmustine ] , cytarabine , etoposide , melphalan)-alemtuzumab allogeneic HSCT ( BEAM-allo ) ( n = 44 ) or BEAM-autologous HSCT ( BEAM-auto ) ( n = 82 ) . The BEAM-allo group had a younger median age (48 years vs. 56 years, P < 0.001) but received a higher median number of therapies pretransplant (P = 0.015) compared with the BEAM-auto group. There was a higher non-relapse mortality (NRM) in the BEAM-allo group compared with the BEAM-auto group at 1 year (20% vs. 2%, P = 0.001). Older age and heavily pretreated patients were associated with a higher NRM and poorer survival in the BEAM-allo group. There was, however, a significantly lower relapse rate (20% vs. 43%, P = 0.01) at 3 years with BEAM-alemtuzumab, with no relapses after 2 years, compared with a continued pattern of relapse in the autologous group. No difference in overall survival (OS) (P = 0.99) or disease-free survival (DFS) (P = 0.90) was identified at 3 years, whereas a plateau in OS and DFS with crossing of the survival curves in favour of BEAM-allo group was observed. Furthermore, the ability to re-induce remissions with donor leucocytes provides additional benefit in favour of allogeneic HSCT. ### Assistant: [{"class": "COMB", "spans_text": ["carmustine", "cytarabine", "etoposide", "melphalan)-alemtuzumab"]}]

### 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: Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients , most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel . Paragraph: Oral anticoagulants in coronary heart disease (Section IV). Position paper of the ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease. Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients , most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel . Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice. ### Assistant: [{"class": "COMB", "spans_text": ["aspirin", "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: Furthermore , VPA significantly increased chemosensitivity to fludarabine , flavopiridol , bortezomib , thalidomide and lenalidomide . Paragraph: Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis. Epigenetic code modifications by histone deacetylase inhibitors have recently been proposed as potential new therapies for hematological malignancies. Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new treatments. CLL B cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as the bone marrow and lymph nodes. In this study, we analyzed gene expression modifications in CLL B cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. CLL B cells obtained from 14 patients were treated in vitro with a concentration of 1 mM VPA for 4 h. VPA effects on gene expression were thereafter studied using Affymetrix technology, and some identified genes were validated by real-time PCR and western blot. We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. Furthermore , VPA significantly increased chemosensitivity to fludarabine , flavopiridol , bortezomib , thalidomide and lenalidomide . VPA inhibited the proliferation of CpG/IL2-stimulated CLL B cells and modulated many cell cycle messenger RNAs. In conclusion, exposure of CLL B cells to VPA induced apoptosis, potentiated chemotherapeutic agent effects and inhibited proliferation. These data strongly suggest the use of VPA in CLL treatment, particularly in combination with antileukemia agents. ### Assistant: [{"class": "POS", "spans_text": ["VPA", "fludarabine"]}, {"class": "POS", "spans_text": ["VPA", "flavopiridol"]}, {"class": "POS", "spans_text": ["VPA", "bortezomib"]}]

### 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: Use of the tumor-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to combination therapy with pertuzumab , trastuzumab , and docetaxel for advanced HER2-positive breast cancer . Paragraph: Use of the tumor-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to combination therapy with pertuzumab , trastuzumab , and docetaxel for advanced HER2-positive breast cancer . The trastuzumab, pertuzumab, and docetaxel (TPD) regimen is strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER) 2-positive breast cancer. Monitoring the host microenvironments in cancer plays a significant role in predicting prognoses and curative effects. It is important to clarify the role of immune related gene expression in tumor-infiltrating lymphocytes in the tumor microenvironment. In this study, we evaluated the impact of chemotherapy with a TPD regimen, on immune micro environments in HER2-positive breast cancer using immune related proteins as indicators. ### methods The subjects consisted of 30 patients who received the TPD regimen. The expression levels of estrogen receptor, progesterone receptor, Ki67, CD8, forkhead box protein (FOXP) 3, programmed death (PD) 1, programmed death ligand (PD-L) 1, CD163, phosphatase and tensin homolog and lymphocyte activation gene 3 were evaluated in biopsy specimens, by immunostaining. ### results CD8 ### conclusions This study shows with the TPD regimen, a high CFR leads to a high ORR and long PFS in HER2-positive breast cancer. CFR, therefore, may be one of the important prognostic factors for this disease. ### Assistant: [{"class": "POS", "spans_text": ["pertuzumab", "trastuzumab", "docetaxel"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The clinical symptoms were relieved after combination of doxycycline , rifampicin , levofloxacin and amikacin for 6 weeks , only one patient with bone destruction needed orthopedic surgery . Paragraph: [Diagnosis and treatment of seven patients with brucellosis in non-pastoral areas]. To explore how to diagnose and treat brucellosis accurately and timely in patients with fever of unkown origin in non-pastoral areas. The epidemiological history, clinical symptoms, complete blood counts, procalcitonin and treatment efficacy of 7 patients with brucellosis were analyzed retrospectively. Some characteristic manifestations should be differentiated from tuberculosis. The clinical symptoms were relieved after combination of doxycycline , rifampicin , levofloxacin and amikacin for 6 weeks , only one patient with bone destruction needed orthopedic surgery . The overall response rate was 6/7. No relapse occurred during half year follow-up. ### Assistant: [{"class": "POS", "spans_text": ["doxycycline", "rifampicin", "levofloxacin", "amikacin"]}]

### 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: Four years after surgery , she experienced a recurrence of breast cancer in the thoracic wall , and was treated with exemestane , toremifene , and fulvestrant for 1 year and 5 months . Paragraph: [An Elderly Patient with Metastatic Breast Cancer Who Developed Severe Adverse Events such as Stomatitis and Interstitial Pneumonia after Everolimus plus Exemestane Treatment]. An 80-year-old woman was diagnosed with right breast cancer with clinical Stage IIIA 6 years previously. She underwent mastectomy and axillary lymph node dissection. The pathological diagnosis was invasive micropapillary carcinoma with lymph node involvement. Immunohistochemically, the tumor was positive for estrogen receptor and progesterone receptor, and negative for HER2. Postoperatively, the patient was treated with adjuvant chemotherapy consisting of cyclophosphamide, epirubicin, 5-fluorouracil, and paclitaxel, followed by endocrine therapy with letrozole. Four years after surgery , she experienced a recurrence of breast cancer in the thoracic wall , and was treated with exemestane , toremifene , and fulvestrant for 1 year and 5 months . However, she developed carcinomatous pleurisy and was treated with eribulin. This last treatment was ineffective. Subsequently, she received combination therapy with everolimus and exemestane. Although the pleural effusion reduced markedly after 5 weeks, stomatitis, diarrhea, melena, and interstitial pneumonia occurred as adverse events. The symptoms improved after drug discontinuation and steroid therapy. The combination therapy with everolimus and exemestane is a prospective therapy for hormone-resistant recurrent breast cancer, but the management of adverse events is very important. ### Assistant: [{"class": "COMB", "spans_text": ["exemestane", "toremifene", "fulvestrant"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Long-term efficacy of doxazosin plus atenolol in the management of severe and sustained arterial hypertension and reversibility of the cardiac damage induced by chronic cathecolamine excess . Paragraph: Long-term efficacy of doxazosin plus atenolol in the management of severe and sustained arterial hypertension and reversibility of the cardiac damage induced by chronic cathecolamine excess . Herein we report on a young girl with recurrent, functioning paraganglioma of the organ of Zuckerkandl and severe and sustained arterial hypertension (systolic pressure >200, diastolic pressure >120 mmHg); with evidence of cardiac damage induced by chronic cathecolamine excess. She promptly and steadily improved after the institution of doxazosin (6 mg/day) plus atenolol (50 mg bid) treatment. This case demonstrates that a correct therapeutic strategy in the long-term management of patients with inoperable catecholamine-producing neuroendocrine tumors (pheochromocytomas and paragangliomas) can maintain arterial pressure in the normal range and reverse the cardiac damage induced by chronic cathecolamine excess. ### Assistant: [{"class": "POS", "spans_text": ["doxazosin", "atenolol"]}]

### 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 evaluate the use of low-molecular-weight heparin ( LMWH ) in combination with low-dose aspirin ( LDA ) for the treatment of antiphospholipid antibody (APA)-associated recurrent pregnancy loss and to compare the results with the use of unfractionated heparin ( UFH ) plus LDA . Paragraph: Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin. To evaluate the use of low-molecular-weight heparin ( LMWH ) in combination with low-dose aspirin ( LDA ) for the treatment of antiphospholipid antibody (APA)-associated recurrent pregnancy loss and to compare the results with the use of unfractionated heparin ( UFH ) plus LDA . ### design Prospective, controlled, multicenter pilot study. ### setting Two academically based reproductive health centers. ### Patient S Patients with three or more pregnancy losses and positive APA. ### Intervention S Patients were treated with LMWH and LDA (n = 25) or UFH and LDA (n = 25). ### Main Outcome Measure S Fetal outcome and maternal complications from treatments were compared between the two treatment groups. ### Result S Of the 25 patients in the LMWH group, 21 (84%) delivered a viable infant and 4 (16%) miscarried. Of the 25 patients in the UFH group, 20 (80%) delivered a viable infant and 5 (20%) miscarried. These differences were not statistically significant. No major bleeding episodes occurred during pregnancy or at the time of delivery. No cases of deep venous thrombosis, thrombocytopenia, pre-eclampsia, gestational diabetes, or bone fractures were noted in either of the two groups. ### Conclusion S In this pilot study, the use of LDA in combination with LMWH during pregnancy for the prevention of recurrent pregnancy loss in women with antiphospholipid syndrome seems to be as safe as UFH plus LDA. Large, randomized trials will be required to determine differences in outcome with LMWH and LDA compared with treatment with UFH combined with LDA in this group of patients. ### Assistant: [{"class": "POS", "spans_text": ["low-molecular-weight heparin", "aspirin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Therefore , the pain scores were significantly higher in the neostigmine group than the other two groups ( p = 0.02 ) , but no significant difference was found between the two groups that received dexmedetomidine and a combination of dexmedetomidine + neostigmine . Paragraph: Addition of dexmedetomidine and neostigmine to 1.5 % lidocaine and triamcinolone for epidural block to reduce the duration of analgesia in patients suffering from chronic low back pain. Lower back pain is one of the leading causes of disability in the world. The aim of this study was to evaluate the effect of supplementation of dexmedetomidine and neostigmine with lidocaine 1.5% and triamcinolone for epidural block in increasing the duration of analgesia among patients suffering from chronic low back pain. In this double-blind, randomized clinical trial, 33 patients with chronic low back pain were included in three groups of 11 patients for epidural blockage. triamcinolone (40 mg/ml) was added to lidocaine 1.5% solution (2 cc/segment) for all three groups. In group N, neostigmine was used at a dose of 1 mg (mg), followed by group D (dexmedetomidine 35 μg [0.5 μg/kg]), and grou [ND (neostigmine 0.5 mg, and 35 μg dexmedetomidine, all of which were added to the triamcinolone and lidocaine solution in each group. Medications were injected into the epidural space using an interlaminar approach. Subsequently, scores of pain and duration of analgesia were recorded in questionnaires and analysed using SPSS version 23. One month after the injections, pain scores recorded in the N group were 7.6±1.4, followed by 5.88±1.2 in group D and 5.42 ±1.1 in group ND. Therefore , the pain scores were significantly higher in the neostigmine group than the other two groups ( p = 0.02 ) , but no significant difference was found between the two groups that received dexmedetomidine and a combination of dexmedetomidine + neostigmine . Three months after the injections, there was a significant difference in pain scores between the two groups (P = 0.01). Both neostigmine and dexmedetomidine were capable of reducing the pain of patients with chronic low back pain after epidural block. However, neostigmine's impact is lower compared to dexmedetomidine. The combination of the two drugs also reduced the pain scores of the patients after the intervention. ### Assistant: [{"class": "POS", "spans_text": ["dexmedetomidine", "neostigmine"]}]

### 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: [ Two cases of complete response to combination chemotherapy of gemcitabine and docetaxel for recurrent ovarian cancer ] . Paragraph: [ Two cases of complete response to combination chemotherapy of gemcitabine and docetaxel for recurrent ovarian cancer ] . The established standard treatment for advanced ovarian cancer is carboplatin and paclitaxel. However, more than 70% of patients have recurrent disease. The standard therapy for recurrent ovarian cancer has not been confirmed. It was reported that docetaxel had a 30-40% of response rate in patients with recurrent ovarian cancer, and that gemcitabine had a 13-22% response rate. The combination chemotherapy of gemcitabine and docetaxel is also applied to non-small cell lung cancer. We use a regimen of 800 mg/m2 of gemcitabine on day 1 and day 8 in combination with 70 mg/m2 of docetaxel on day 8 with a 3-week interval. We treated 2 patients with recurrent ovarian cancer who responded completely to combination chemotherapy with gemcitabine and docetaxel. ### Assistant: [{"class": "POS", "spans_text": ["gemcitabine", "docetaxel"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Hormonal changes in postmenopausal women with breast cancer treated with trilostane and dexamethasone . Paragraph: Hormonal changes in postmenopausal women with breast cancer treated with trilostane and dexamethasone . Postmenopausal women with metastatic breast cancer were treated with trilostane, initially 240 mg daily increasing after 3 days to 480 mg daily and after a further three days to 960 mg daily. After 3 days at this dose dexamethasone 1 mg daily was added and this combination was continued until disease progression occurred. Partial remission was seen in 26% and stabilization of previously progressive disease in a further 13% of the first twenty-three patients studied. During therapy with trilostane alone significant increases in DHEAS, androstenedione, 17-hydroxypregnenolone, progesterone, testosterone and oestradiol were seen. A significant fall in oestrone concentration occurred at the same time. After dexamethasone was added the elevated steroid concentrations fell back to the baseline while oestrone remained depressed below this and testosterone was also significantly lowered. No change was seen in cortisol or ACTH concentration while patients were on trilostane alone but cortisol levels were undetectable after dexamethasone was added though, in most patients, ACTH remained detectable. There was no change in the ratio of delta 5:delta 4 steroids at any stage of therapy but a highly significant increase in the androstenedione: oestrone ratio was seen. We conclude that in long-term use in vivo it is difficult to demonstrate that trilostane inhibits 3 beta-hydroxysteroid dehydrogenase but it may produce inhibition of aromatase. ### Assistant: [{"class": "COMB", "spans_text": ["trilostane", "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: After surgical insertion of a catheter in the hepatic artery , patients were treated with oxaliplatin 100 mg/m(2 ) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol . Paragraph: Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m(2), FU 400 mg/m(2) IV bolus, FU 600 mg/m(2) 22-hour continuous infusion on days 1 and 2 every 2 weeks). ### Patients And Methods Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery , patients were treated with oxaliplatin 100 mg/m(2 ) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol . Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months. ### results Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively. ### conclusion The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer. ### Assistant: [{"class": "POS", "spans_text": ["oxaliplatin", "leucovorin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Then , doxorubicin with or without flavopiridol was injected . Paragraph: Synergistic anti-tumor efficacy of doxorubicin and flavopiridol in an in vivo hepatocellular carcinoma model. A previous study showed that flavopiridol increased doxorubicin sensitivity in hypoxic hepatocellular carcinoma (HCC) cells by increasing apoptosis through suppressing hypoxia-inducible N-myc downstream-regulated gene-1 (NDRG1) expression. However, this has not been investigated in an in vivo HCC model. Therefore, we aimed to elucidate whether the combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. ### methods An HCC mouse model was established by implanting C3H/He mouse with MH134 cells. Then , doxorubicin with or without flavopiridol was injected . The anti-tumor efficacy was assessed by evaluating tumor volumes, and the underlying mechanism was investigated by quantifying apoptotic cells, the Ki-67 proliferation index, and microvessel densities (MVDs). Immunohistochemistry of NDRG1 was performed to determine the underlying mechanism. ### results Tumor growth was significantly suppressed in the doxorubicin + flavopiridol combination group compared to the other three groups. The percentage of apoptotic cells was significantly higher, and Ki-67-positive proliferating cells were significantly lower in the combination group compared to the other groups; however, MVDs were not significantly different across the groups. Increased apoptosis by flavopiridol occurred by suppressing hypoxia-inducible NDRG1 expression. ### conclusions These results show that a combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. This synergistic effect of combination therapy was attributed to increased apoptosis and decreased proliferation of tumor cells rather than decreased angiogenesis. These findings suggest that flavopiridol might be an effective adjuvant therapy to doxorubicin-resistant HCC cells by inducing apoptosis through suppression of NDRG1 expression. ### Assistant: [{"class": "POS", "spans_text": ["doxorubicin", "flavopiridol"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Subjects were treated in two cycles , 3 months apart , in which they received bicalutamide 150 mg daily days 1 - 28 and tremelimumab on day 29 . Paragraph: Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles , 3 months apart , in which they received bicalutamide 150 mg daily days 1 - 28 and tremelimumab on day 29 . The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression. ### Assistant: [{"class": "COMB", "spans_text": ["bicalutamide", "tremelimumab"]}]

### 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 examines a novel regimen utilizing the combination of epidurally infused ropivacaine - hydromorphone and scheduled ketorolac . Paragraph: Peri-operative pain management in children with cerebral palsy: comparative efficacy of epidural vs systemic analgesia protocols. Selective Dorsal Rhizotomy (SDR) is the only surgical intervention with class I evidence supporting permanent reduction in spasticity for children with cerebral palsy (Paediatr Anaesth, 12, 2002, 296; Neurosurg Focus, 21, 2006, e2). Postoperatively, adequate analgesia can be difficult to achieve (J Neurosurg, 105, 2006, 8; Childs Nerv Syst, 17, 2001, 556; Pediatr Neurosurg, 43, 2007, 107; Anesth Analg, 79, 1994, 340; Reg Anesth Pain Med, 24, 1999, 438; Pediatr Anesth, 19, 2009, 1213). This study examines a novel regimen utilizing the combination of epidurally infused ropivacaine - hydromorphone and scheduled ketorolac . This regimen was compared to a protocol utilizing systemic fentanyl and diazepam. ### methods Following IRB approval, 31 patients receiving epidural analgesia were compared with 41 patients who received systemic analgesia. All surgeries were performed by one surgeon with standardized anesthetic and nursing care. Studied outcomes included: pain scores; episodes of severe pain; nausea, itching; oxygen desaturation; and ICU admission. Data were analyzed using Mann-Whitney U-test, CHI square, and Fisher exact test where indicated with P < 0.05 considered significant. ### results Studied groups had similar demographics, biometrics and disease burdens. Patients in the epidural group had statistically and clinically significant reductions in peak recorded pain scores for each 4-h period in the first 24 postoperative hours. Severe pain (score >5) was markedly reduced in the epidural group with 9% of epidural patients vs. 68% of systemic patients experiencing at least one episode. Fewer epidural patients experienced oxygen desaturation during the first two postoperative days (6.5% vs. 41%, 6.5% vs. 39%). ### conclusion Epidural analgesia resulted in substantial improvements in pain control and safety. The data supports the superiority of a multimodal analgesia approach centered on epidural analgesia. A similar protocol should be considered following simple laminectomies or procedures associated with lower-extremity muscle spasm. ### Assistant: [{"class": "POS", "spans_text": ["ropivacaine", "hydromorphone", "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: Patients in the HXP arm also received trastuzumab ( 8 mg/kg intravenous infusion on Day 1 ) , concurrently with capecitabine . Paragraph: Pharmacokinetic analysis of capecitabine and cisplatin in combination with trastuzumab in Japanese patients with advanced HER2-positive gastric cancer. To evaluate the pharmacokinetics (PK) of capecitabine and cisplatin, administered in combination with or without trastuzumab, in Japanese patients with HER2-positive advanced gastric cancer (AGC). ### methods Patients eligible for this PK study (study JP19959), which was carried out during treatment Cycle 1 of the ToGA study, received either capecitabine and cisplatin (XP arm) or trastuzumab plus capecitabine and cisplatin (HXP arm). All patients received capecitabine (1,000 mg/m(2) orally, twice daily for 14 days) and cisplatin (80 mg/m(2) intravenous infusion on Day 1). Patients in the HXP arm also received trastuzumab ( 8 mg/kg intravenous infusion on Day 1 ) , concurrently with capecitabine . No further study medication was administered during study JP19959. Serial plasma samples for PK analysis were obtained at intervals before and after the administration of capecitabine and cisplatin on Day 1. ### results Twenty-two patients were enrolled in this PK study: eight in the HXP arm and 14 in the XP arm. All blood samples were available for PK analysis. Co-administration of trastuzumab resulted in no statistically or clinically significant changes in the PK profiles of capecitabine or its metabolites, or of cisplatin (total or unbound platinum). ### conclusions Variability in the AUC(last) and C (max) values for the capecitabine was consistent with the known PK profile of capecitabine and fell within established limits. Concurrent trastuzumab therapy is unlikely to alter the PK or safety profile of capecitabine or cisplatin in Japanese patients with HER2-positive AGC. ### Assistant: [{"class": "COMB", "spans_text": ["trastuzumab", "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: Among targeted therapies , lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine . Paragraph: Chemotherapy and biological treatment options in breast cancer patients with brain metastasis: an update. Breast cancer (BC) is the second most common cause of CNS metastasis. Ten to 20% of all, and 38% of human epidermal growth factor-2(+), metastatic BC patients experience brain metastasis (BM). Prolonged survival with better control of systemic disease and limited penetration of drugs to CNS increased the probability of CNS metastasis as a sanctuary site of relapse. Treatment of CNS disease has become an important component of overall disease control and quality of life. ### Areas Covered Current standard therapy for BM is whole-brain radiotherapy, surgery, stereotactic body radiation therapy for selected cases, corticosteroids and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of BM in patients with BC. Nevertheless, new treatment choices have emerged. In this review, we aimed to update current and future treatment options in systemic treatment for BM of BC. ### Expert Opinion Cornerstone local treatment options for BM of BC are radiotherapy and surgery in selected cases. Efficacy of cytotoxic chemotherapeutics is limited. Among targeted therapies , lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine . Novel agents are currently investigated. ### Assistant: [{"class": "POS", "spans_text": ["lapatinib", "capecitabine"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: An in vitro assessment of azithromycin in combination with gentamicin demonstrated inhibition of growth and suggests that clinical trials may be warranted to assess the utility of this combination in treating gonorrhea infections . Paragraph: In vitro assessment of dual drug combinations to inhibit growth of Neisseria gonorrhoeae. The development of resistance to first-line antimicrobial therapies has led to recommendations for combination therapies for the treatment of gonorrhea infection. Recent studies have shown the success of combination therapies in treating patients, but few have reported on the in vitro activities of these drug combinations. An in vitro assessment of azithromycin in combination with gentamicin demonstrated inhibition of growth and suggests that clinical trials may be warranted to assess the utility of this combination in treating gonorrhea infections . ### Assistant: [{"class": "POS", "spans_text": ["azithromycin", "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: Clinical efficacy of immunochemotherapy with rituximab , fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial ( AGMT-NHL9 ) . Paragraph: Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response. Treatment of follicular lymphoma with rituximab is currently recommended at a dose of 375 mg/m(2). We aimed to provide a rationale for optimal dosing and scheduling of this anti-CD20 antibody based on pharmacokinetics. ### Design And Methods Clinical efficacy of immunochemotherapy with rituximab , fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial ( AGMT-NHL9 ) . Pharmacokinetic analysis was assessed in 17 patients. ### results Induction treatment resulted in high clinical response rates (complete remission 66%; ORR 100%). Significantly higher complete remission rates were observed in female patients (86 vs. 47%; Odds Ratio 6.8, 95% CI: 1.12; 41.82; P=0.05). rituximab pharmacokinetic analysis showed a high variability ranging over almost 1 order of magnitude at maintenance cycle 1 (area under the curve 1,540-12,025 g/L*days). Median area under the curve was lower in men (81%) and in patients with initial bone marrow infiltration (76%). Higher rituximab serum concentrations before next therapy (C(trough)) were associated with female sex (P=0.04) as well as with absence of initial bone marrow infiltration (P=0.001). C(trough) correlated with remission quality (complete vs. partial remission; P=0.005) and progression-free survival (P=0.03). A decline in rituximab C(trough) below 25,000 ng/mL was observed 9.5 to 62 months before clinical relapse (P=0.008). ### conclusions The results of this pilot trial suggest that more differentiated dosing schedules based on gender and bone marrow infiltration should be explored for rituximab therapy for lymphoma. This study was registered in ClinicalTrials.gov (Identifier: NCT01560117). ### Assistant: [{"class": "POS", "spans_text": ["rituximab", "fludarabine", "mitoxantrone"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Palliative chemotherapy with carboplatin and etoposide produced a minimal response . Paragraph: Merkel cell carcinoma: A case of palliative upper limb amputation in a patient with refractory in-transit metastases. We report an unusual case of Merkel cell carcinoma in a 70-year-old woman with the rapid development of left upper limb in-transit and hepatic metastases. The patient had a preceding history of left-sided breast cancer. Palliative chemotherapy with carboplatin and etoposide produced a minimal response . The in-transit metastases rapidly progressed and were refractory to chemotherapy and a single fraction of palliative radiotherapy, leading to a marked impact on her quality of life, secondary to sepsis and bleeding. After lengthy discussion, she consented to an above-elbow amputation resulting in a marked improvement in her well-being. In this case, we believe that palliative amputation of the involved arm was justified and beneficial to the patient. ### Assistant: [{"class": "NEG", "spans_text": ["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 vitro susceptibilities of ocular Bacillus cereus isolates to clindamycin , gentamicin , and vancomycin alone or in combination . Paragraph: In vitro susceptibilities of ocular Bacillus cereus isolates to clindamycin , gentamicin , and vancomycin alone or in combination . A broth dilution assay was used to determine the in vitro susceptibilities of 10 ocular isolates of Bacillus cereus to clindamycin, gentamicin, and vancomycin both alone and in combination. The checkerboard technique was used to determine fractional inhibitory and bactericidal concentration indices for combinations of clindamycin-gentamicin and vancomycin-gentamicin. ### Assistant: [{"class": "COMB", "spans_text": ["clindamycin", "gentamicin", "vancomycin"]}]

### 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: Most ( ≥ 75 % ) patients received ESHAP ( etoposide , methylprednisolone , cytarabine , cisplatin ) or DHAP ( cisplatin , cytosine arabinoside , dexamethasone ) as salvage chemotherapy . Paragraph: Treatment response and overall outcome of patients with relapsed and refractory peripheral T-cell lymphoma compared to diffuse large B-cell lymphoma. The purpose of the study was to assess treatment response and overall outcome in a cohort of patients with relapsed and refractory peripheral T-cell lymphoma and to compare the results with those for patients with diffuse large B-cell lymphoma treated in a similar manner. We retrospectively analyzed data of 40 consecutive adult patients with relapsed and refractory peripheral T-cell lymphoma referred to our institution for consideration of second-line chemotherapy aiming for autologous stem cell transplant between January 1999 and December 2006. A cohort of 126 patients with diffuse large B-cell lymphoma managed similarly served as a comparison group. Most ( ≥ 75 % ) patients received ESHAP ( etoposide , methylprednisolone , cytarabine , cisplatin ) or DHAP ( cisplatin , cytosine arabinoside , dexamethasone ) as salvage chemotherapy . From first relapse/progression, overall survival at 2 years was 54% (95% confidence interval [CI]: 38-76) for the peripheral T-cell lymphoma cohort and 49% (95% CI: 39-60) for the diffuse large B-cell lymphoma cohort (p = 0.098). Overall response rate to salvage chemotherapy was similar between both groups (63% vs. 52%). Post-autologous stem cell transplant, 1-year progression-free survival was 20% (95% CI: 9-48) for patients with peripheral T-cell lymphoma and 47% (95% CI: 36-61) for patients with diffuse large B-cell lymphoma. Two-year overall survival post-autologous stem cell transplant was 43% (95% CI: 26-71) and 54% (95% CI: 43-68), respectively. Patients with relapsed and refractory peripheral T-cell lymphoma and diffuse large B-cell lymphoma showed a similar response to salvage chemotherapy and overall survival. Likely due to imbalances in risk factors at relapse, progression-free survival post-autologous stem cell transplant was inferior in the peripheral T-cell lymphoma group. Strategies aiming to maintain response duration post-autologous stem cell transplant could improve the outcome of patients with peripheral T-cell lymphoma. ### Assistant: [{"class": "COMB", "spans_text": ["etoposide", "methylprednisolone", "cytarabine", "cisplatin"]}, {"class": "COMB", "spans_text": ["cisplatin", "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: Patients treated on CCG-3881 ( n = 116 ) received four-drug chemotherapy for 9 months ( cisplatin , cyclophosphamide , doxorubicin , and etoposide ) , with surgery and local radiation to residual disease . Paragraph: Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study. A prospective Children's Cancer Group study, CCG-3881, has been completed to determine if a more accurate prediction of prognosis by biologic features can identify subgroups of infants with stage IV neuroblastoma (NBL) who require differing intensities of treatment. ### Patients And Methods One hundred thirty-four infants were registered from June 1989 to August 1995, with a median follow-up of 47.1 months (range, 0 to 88 months). The biologic factors examined were tumor MYCN copy number, Shimada histopathologic classification, serum ferritin, and bone marrow immunocytology (sensitivity, one tumor cell per 10(5) bone marrow cells). Patients treated on CCG-3881 ( n = 116 ) received four-drug chemotherapy for 9 months ( cisplatin , cyclophosphamide , doxorubicin , and etoposide ) , with surgery and local radiation to residual disease . After January 1991, all subsequent infants with tumor MYCN amplification (n = 18) were transferred after one cycle of therapy to the high-risk CCG-3891 protocol (open January 1991 to April 1996) for more intensive treatment. ### results The 3-year event-free survival (EFS) and overall survival (mean +/- SD) for the 134 infants were 63% +/- 5% and 71% +/- 5%, respectively. Patients whose tumors were without MYCN amplification had a 93% +/- 4% 3-year EFS, whereas those with amplified MYCN had a 10% +/- 7% 3-year EFS (P <. 0001). Each of the other biologic features studied had prognostic significance in univariate analysis but not after stratifying by MYCN copy number. ### conclusion Infants less than 1 year of age at diagnosis with stage IV NBL have a much improved outcome compared with children >/= 1 year of age. Nonamplified MYCN tumors identify a group of infants with a 93% +/- 4% EFS, whereas amplified MYCN copy number clearly identifies patients who are unlikely to survive despite intensive chemotherapy. ### Assistant: [{"class": "POS", "spans_text": ["cisplatin", "cyclophosphamide", "doxorubicin", "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: These data suggest that weekly docetaxel plus carboplatin may be an important therapeutic second-line treatment option for patients with DRPC . Paragraph: Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer. There is no proven, effective, standard second-line chemotherapy for castration- and docetaxel-resistant prostate cancer (DRPC). Recent data suggest that carboplatin may be effective in combination with docetaxel in this setting; however, the optimal docetaxel/carboplatin-based regimen is still unclear. ### Aim Of The Study We identified 43 consecutive patients with DRPC treated with carboplatin (AUC5 d1) and docetaxel (35 mg/m(2) d1, 8, 15 q4w i.v.) as a second-line or subsequent salvage chemotherapy until discontinuation of therapy due to disease progression or unacceptable toxicity. ### results Decreased prostate-specific antigen (> or =50% PSA) was observed in 22/43 (51.2%, 95% CI, 35.5, 66.7%) patients, with > or =90% reduction in 12/43 patients (27.9%). At the time of analysis, the median follow-up time for all patients was 10.4 months. Median progression-free survival (PFS) for all patients was 6.5 months (95% CI 4.1, 8.9), and median overall survival (OS) was 15.8 months (95% CI 12.1, 18.5). In PSA responders, PFS was 9.5 (95% CI 8.2, 19.0) months versus 3.3 (95% CI 2.6, 4.0) months in PSA non-responders (P < 0.0001; hazard ratio (HR) 0.108) and OS was 24.4 months (95% CI 19.5, 29.4) versus 7.8 (95% CI 5.2, 10.3) months (P = 0.001; HR 0.232). Established prognostic factors were associated with survival. This regimen was reasonably well tolerated, with leukopenia/neutropenia as the most common reversible grade 3/4 toxicity (41.9/39.5%). ### conclusion These data suggest that weekly docetaxel plus carboplatin may be an important therapeutic second-line treatment option for patients with DRPC . ### Assistant: [{"class": "POS", "spans_text": ["docetaxel", "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 recommended phase II dose is bortezomib 1.0 mg/m on days 1 , 4 , 8 , and 11 plus docetaxel 75 mg/m on day 1 , cycled every 21 days . Paragraph: Bortezomib plus docetaxel in advanced non-small cell lung cancer and other solid tumors: a phase I California Cancer Consortium trial. This phase I study was performed to determine the dose-limiting toxicity and maximum tolerated dose (MTD) of docetaxel in combination with bortezomib in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors. ### methods Patients were enrolled in cohorts of three over six dose levels. Each treatment cycle was 3 weeks long and consisted of one docetaxel infusion (day 1) and four bortezomib injections (days 1, 4, 8, and 11). Dose escalation and MTD determination were based on the occurrence of dose-limiting toxicities in cycle 1 only. ### results A total of 36 patients were enrolled, 26 of whom had NSCLC. All patients received at least one dose of study drug at one of five dose levels. The MTD of the combined regimen was determined to be 1.0/75 mg/m bortezomib/docetaxel. The combination was generally well tolerated. Toxicities were manageable, and no additive toxicities were observed. The most common adverse events were fatigue (67% of patients), nausea (50%), diarrhea (39%), and neutropenia (39%). Two patients with NSCLC achieved a partial response, and seven (19%) patients achieved stable disease (including six patients with NSCLC). ### conclusion The combination of bortezomib and docetaxel was feasible and well tolerated in patients with advanced NSCLC or other solid tumors. The recommended phase II dose is bortezomib 1.0 mg/m on days 1 , 4 , 8 , and 11 plus docetaxel 75 mg/m on day 1 , cycled every 21 days . Therapeutic doses of docetaxel and bortezomib are achievable for this combination. ### Assistant: [{"class": "POS", "spans_text": ["bortezomib", "docetaxel"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Budesonide/formoterol pMDI affords equivalent formoterol-related bronchodilatory effects versus formoterol DPI at formoterol doses of 4.5 , 9 , and 18 microg , indicating that practitioners can expect and patients will experience similar bronchodilation from the same dose of formoterol whether it is delivered as monotherapy via a DPI or as combination therapy with budesonide via one pMDI . Paragraph: Bronchodilation of formoterol administered with budesonide: device and formulation effects. Previous single-dose crossover studies have established therapeutic equivalence of formoterol when administered at the same nominal dose via a dry powder inhaler (DPI) or pressurized hydrofluoroalkane (HFA) metered-dose inhaler (pMDI). Demonstration of equivalent bronchodilation for formoterol administered as formoterol DPI or combined with budesonide in one pMDI (budesonide/formoterol pMDI) would indicate that the greater clinical efficacy of the budesonide/formoterol pMDI combination is due to the budesonide contribution and not to differences in formoterol formulation or delivery device. ### objective To determine whether the formoterol-related bronchodilatory effects of formoterol DPI and budesonide/formoterol pMDI are similar, despite formoterol formulation and delivery device differences. ### methods This was a multicenter, open-label, five-period crossover study conducted in 201 adult patients with stable asthma. The study included a screening visit, a 7- to 14-day run-in period, during which patients were treated with budesonide pMDI (80 microg per inhalation, two inhalations twice daily), and a randomized treatment period that included five single-day treatment periods, during which patients received single-dose crossover treatments, each of which was separated by a 3- to 14-day washout period. Patients were randomized to five of seven single-dose treatments (one, two, or four inhalations of budesonide/formoterol pMDI 80/4.5 microg; four inhalations of budesonide pMDI 80 microg plus one, two, or four inhalations of formoterol DPI 4.5 microg; or four inhalations of budesonide pMDI 80 microg alone). At clinic visits, the budesonide pMDI dose was coordinated with the budesonide dose delivered via the budesonide/formoterol pMDI such that all patients received a 320-microg dose of budesonide. The primary variable was average forced expiratory volume in 1 s (FEV1) from the area under the curve divided by time from 12-h serial spirometry. ### results Average 12-h FEV1 values were similar, regardless of delivery device, among treatments with the same nominal formoterol doses and dose-ordered within each device; mean FEV1 values were significantly higher for treatments containing formoterol versus budesonide alone. The formoterol dose potency ratio for budesonide/formoterol pMDI:formoterol DPI (0.97; 95% confidence interval, 0.73-1.27) demonstrated clinical equivalence in bronchodilation at the same formoterol dose. ### conclusion Budesonide/formoterol pMDI affords equivalent formoterol-related bronchodilatory effects versus formoterol DPI at formoterol doses of 4.5 , 9 , and 18 microg , indicating that practitioners can expect and patients will experience similar bronchodilation from the same dose of formoterol whether it is delivered as monotherapy via a DPI or as combination therapy with budesonide via one pMDI . ### Assistant: [{"class": "COMB", "spans_text": ["formoterol", "budesonide"]}]

### 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 29-year-old white man with recurrent Hodgkin 's disease received doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) chemotherapy once every two weeks for 12 cycles . Paragraph: Ototoxicity associated with vinblastine. To describe a patient with ototoxicity associated with vinblastine chemotherapy. ### Case Summary A 29-year-old white man with recurrent Hodgkin 's disease received doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) chemotherapy once every two weeks for 12 cycles . He reported tinnitus after each treatment, with an onset of about six hours and a duration of seven to 10 days. This interfered with reading, watching television, and general concentration. Symptoms returned to baseline prior to the beginning of each subsequent cycle. Audiograms performed before and after several cycles showed mild sensorineural hearing loss in the high-decibel range, but no loss of speech recognition. ### discussion No reported cases of ototoxicity or tinnitus from ABVD were found. All concomitant medications were eliminated as possible causes either due to lack of temporal association with the symptoms or no reports of ototoxicity in the literature. vincristine, a more commonly used vinca alkaloid very similar to vinblastine, was noted to have caused several cases of sensorineural hearing loss. ### conclusions This case suggests that vinblastine may cause ototoxicity. ### Assistant: [{"class": "COMB", "spans_text": ["doxorubicin", "bleomycin", "vinblastine", "dacarbazine"]}]

### 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 review focuses on the activity and toxicity of the time-limited combination of venetoclax plus rituximab for the treatment of relapsed or refractory CLL , presenting clinical trial results and data from correlative studies , with the aim of highlighting the strengths of this treatment approach and discuss weaknesses and possible areas of improvement . Paragraph: The combination of venetoclax and rituximab for the treatment of patients with recurrent chronic lymphocytic leukemia. In patients with recurrent chronic lymphocytic leukemia (CLL), treatment with targeted agents such as Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax is rapidly replacing chemo-immunotherapy regimens. venetoclax has demonstrated efficacy as monotherapy in patients with previously treated CLL and has been evaluated in combination with the anti-CD20 monoclonal antibody rituximab. ### Areas Covered This review focuses on the activity and toxicity of the time-limited combination of venetoclax plus rituximab for the treatment of relapsed or refractory CLL , presenting clinical trial results and data from correlative studies , with the aim of highlighting the strengths of this treatment approach and discuss weaknesses and possible areas of improvement . Data from PubMed indexed papers as well as from abstracts presented at major international conferences are included. ### Expert Opinion Deep responses with venetoclax-based regimens have been shown to allow time-limited treatment and prolonged remission off-therapy in patients with CLL. The clinical benefit of venetoclax and rituximab over chemo-immunotherapy has been demonstrated in recurrent CLL. Potential advantages of time-limited treatment approaches include avoidance of long-term toxicities, high drug costs, and the selection of resistant subclones. ### Assistant: [{"class": "POS", "spans_text": ["venetoclax", "rituximab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Advanced male breast cancer treatment with the LH-RH analogue buserelin alone or in combination with the antiandrogen flutamide . Paragraph: Advanced male breast cancer treatment with the LH-RH analogue buserelin alone or in combination with the antiandrogen flutamide . Ten men with advanced breast cancer were evaluated for response to treatment with the luteinizing hormone-releasing hormone (LH-RH) analogue, buserelin, alone or in combination with the antiandrogen, flutamide. One of five patients receiving buserelin as a single agent had a partial remission lasting 12 months, and with the addition of flutamide, this lasted over 24 additional months. Three patients had stable disease with a median duration of 6 months (range, two to 14). One patient had progressive disease. Of five patients receiving the combination of buserelin and flutamide from the beginning of therapy, four patients had a partial remission with a median duration of over 15 months (range, over five to 16). One patient's disease remained stable for 12 months. Major side effects were hot flushes, loss of libido, and impotence. buserelin initiates a castration-like endocrine response and has potential in the treatment of men with disseminated breast cancer when used either alone or in combination with flutamide. ### Assistant: [{"class": "COMB", "spans_text": ["buserelin", "flutamide"]}]

### 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 an effort to improve its efficacy , mitoxantrone was tested for synergistic activity with cidofovir . Paragraph: Inhibition of cowpox virus and monkeypox virus infection by mitoxantrone. mitoxantrone, an FDA-approved therapeutic for the treatment of cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against vaccinia virus. To determine whether this activity extends to other orthopoxviruses, mitoxantrone was tested against cowpox and monkeypox. mitoxantrone demonstrated an EC(50) of 0.25 μM against cowpox and 0.8 μM against monkeypox. Intraperitoneal treatment of cowpox virus-challenged C57Bl/6 mice with 0.5 mg/kg mitoxantrone resulted in 25% survival and a significant increase in survival time. In an effort to improve its efficacy , mitoxantrone was tested for synergistic activity with cidofovir . In vitro tests demonstrated significant synergy between the two drugs against cowpox; however, no synergistic effect on animal survival or median time-to-death was seen in intranasally-infected BALB/c mice. Significantly fewer animals survived when treated with a combination of 0.5 mg/kg mitoxantrone and 100 mg/kg cidofovir than with 100 mg/kg cidofovir alone. This is, to our knowledge, the first report of limited anti-orthopoxvirus activity by mitoxantrone in an animal model. ### Assistant: [{"class": "POS", "spans_text": ["mitoxantrone", "cidofovir"]}]

### 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 current study , we investigated the hypothesis that targeting of P-gp by diltiazem can enhance the cytotoxicity of gemcitabine and 5-FU against human pancreatic cancer cells . Paragraph: Diltiazem potentiates the cytotoxicity of gemcitabine and 5-fluorouracil in PANC-1 human pancreatic cancer cells through inhibition of P-glycoprotein. Pancreatic cancer (PC) is one of the most aggressive tumors with dismal survival and a high death rate due to chemotherapeutic failure. P-glycoprotein (P-gp) plays a pivotal role in PC response to gemcitabine and 5-fluorouracil (5-FU). diltiazem, a calcium channel blocker, is a P-gp inhibitor. In the current study , we investigated the hypothesis that targeting of P-gp by diltiazem can enhance the cytotoxicity of gemcitabine and 5-FU against human pancreatic cancer cells . ### Main Methods The cytotoxic effect of diltiazem, gemcitabine, and 5-FU in single and combined forms against PANC-1 and AsPC-1 cells were assayed by MTT. Flow cytometric analysis was used for the determination of cell cycle, apoptosis, and stemness markers in PC cells. Besides, immunoblotting was used for assessment of Bax, caspase 3, cyclin D1, and P-gp expressions. ### Key Findings diltiazem co-treatment, either with gemcitabine or 5-FU, synergistically reduced cell viability, induced apoptosis, and caused cell cycle arrest. In addition, diltiazem co-treatment decreased the expressions of stem cell markers CD24 and CD44, increased the expressions of Bax and cleaved caspase 3, enhanced DNA fragmentation, and attenuated cyclin D1 and P-gp expressions as compared to cells treated with either gemcitabine or 5-FU alone. ### significance Our findings suggest that diltiazem may be potential neoadjuvant therapy to enhance the response of PC to gemcitabine or 5-FU treatment. ### Assistant: [{"class": "POS", "spans_text": ["diltiazem", "gemcitabine"]}, {"class": "POS", "spans_text": ["diltiazem", "5-FU"]}]

### 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 all , 171 patients with histologically verified non-small cell lung carcinoma were treated with ifosfamide 2.0 g/m2 on days 1 - 5 in combination with ( 91 patients ) etoposide 120 mg/m2 on day 1 . Paragraph: Experience with ifosfamide combinations (etoposide or DDP) in non-small cell lung cancer. In all , 171 patients with histologically verified non-small cell lung carcinoma were treated with ifosfamide 2.0 g/m2 on days 1 - 5 in combination with ( 91 patients ) etoposide 120 mg/m2 on day 1 . Therapeutic regimens were repeated after 4 weeks. Supportive treatment with mesna (20% of the ifosfamide doses at 0, 4, and 8 h) was performed. cisplatin treatment was supported by mannitol-induced diuretic hydration. The overall response rate of ifosfamide/etoposide was calculated to be 27%, with 1 complete and 24 partial remissions. The median survival time for all patients was 8.5 months, for responders 14 months (P less than 0.05), for patients with no change 9.5 months, and for patients with tumor progression 4 months. With ifosfamide/cisplatin, there were 4 complete and 21 partial remissions (response rate 35%). The median survival time for all patients was 8.3 months, for responders 11.5 months, and for patients with tumor progression 4 months. Age, sex, and histological tumor type had no significant effect on survival. Patients with better performance stage and limited disease lived significantly longer. The main side-effects of the cisplatin combination were vomiting, bone marrow depression, and neuropathy. The etoposide combination was tolerated better. Urotoxicity was not significant, as a consequence of treatment with mesna. The results show that the combination ifosfamide/etoposide or ifosfamide/cisplatin are effective in the treatment of non-small cell lung cancer, being comparable to other combinations of etoposide/cisplatin and vindesine/cisplatin. Because of the better tolerability, the combination ifosfamide/etoposide is superior to cisplatin combinations. ### Assistant: [{"class": "POS", "spans_text": ["ifosfamide", "etoposide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In the large-scale trials carried out in Tanganyika and described in this paper , such a combination , containing amodiaquine for schizontocidal effect and primaquine as a gametocytocide , was administered to three distinct population groups of more than 5000 at differing intervals of time , in order to determine the ability of this combination to interfere with transmission in the absence of other malaria control measures . Paragraph: Mass administration of an antimalarial drug combining 4-aminoquinoline and 8-aminoquinoline in Tanganyika. For the eradication of malaria from hyperendemic regions of tropical Africa it is apparent that use may have to be made of antimalarial drugs, administered individually on a census basis, in addition to measures directed against the mosquito. The suppressive activity of existing compounds among individuals having different degrees of immunity is well established, and trials among large groups of people have been conducted with single drugs and with combination of drugs. In the large-scale trials carried out in Tanganyika and described in this paper , such a combination , containing amodiaquine for schizontocidal effect and primaquine as a gametocytocide , was administered to three distinct population groups of more than 5000 at differing intervals of time , in order to determine the ability of this combination to interfere with transmission in the absence of other malaria control measures . It was found that treatment of 93% of the population at intervals of one or two weeks resulted in a reduction of the malaria indices to a very low level but such success was not obtained when the combination of drugs was administered every four weeks, although in the area concerned population coverage was less satisfactory owing to migration. ### Assistant: [{"class": "COMB", "spans_text": ["amodiaquine", "primaquine"]}]

### 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 transplant eligible patients , induction therapy consists of bortezomib , lenalidomide , dexamethasone ( VRd ) given for approximately 3 - 4 cycles followed by autologous stem cell transplantation ( ASCT ) . Paragraph: Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Multiple myeloma accounts for approximately 10% of hematologic malignancies. ### diagnosis The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE) namely CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging (MRI). ### Risk Stratification The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma. ### Risk Adapted Initial Therapy In transplant eligible patients , induction therapy consists of bortezomib , lenalidomide , dexamethasone ( VRd ) given for approximately 3 - 4 cycles followed by autologous stem cell transplantation ( ASCT ) . In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard risk patients can get additional cycles of induction, and delay transplant until first relapse. Patients not candidates for transplant are typically treated with VRd for approximately 8-12 cycles followed by lenalidomide; alternatively these patients can be treated with daratumumab, lenalidomide, dexamethasone (DRd). ### Maintenance Therapy After ASCT, standard risk patients need lenalidomide maintenance, while bortezomib-based maintenance is needed for patients with high-risk myeloma. ### Management Of Refractory Disease Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse. ### Assistant: [{"class": "POS", "spans_text": ["bortezomib", "lenalidomide", "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: Genistein combined polysaccharide enhances activity of docetaxel , bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines . Paragraph: Genistein combined polysaccharide enhances activity of docetaxel , bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines . To determine the benefit of genistein combined polysaccharide (GCP) in combination with the androgen receptor antagonist bicalutamide, the antimicrotubule taxane docetaxel, and the Src kinase inhibitor pp2 as part of a treatment regimen for advanced prostate cancer (CaP). ### Materials And Methods The growth inhibitory and apoptotic effects of GCP in combination with bicalutamide, docetaxel and pp2 were evaluated in both the androgen-dependent LNCaP line, and three androgen-independent lines: CWR22Rv1, PC-3, and LNCaP-R273H. The LNCaP-R273H model is an LNCaP variant expressing a p53(GOF) allele; like CWR22Rv1 and PC-3, it is able to grow in a minimal androgen environment. The effects of GCP treatment in combination with the aforementioned drugs were measured using an MTT assay, Western blotting, flow cytometric analysis, and caspase activation assay. Altered schedules of drug administration were explored using combinations of GCP and docetaxel. ### results GCP potentiated the activity of docetaxel in all four cell lines, resulting in growth inhibition and increased apoptosis. The combination of GCP and bicalutamide had enhanced activity in both the LNCaP and LNCaP-R273H lines, which may better represent patient tumour cells after progression to androgen independence. Administration of docetaxel followed by GCP resulted in a synergistic interaction in LNCaP cells, with increased apoptosis. By contrast, GCP administered first showed subadditivity, probably resulting from GCP-mediated induction of G1 arrest interfering with docetaxel activity. ### conclusion These data suggest that GCP, an isoflavone-enriched compound with minimal side-effects and far superior intestinal absorption rate of genistein, has significant clinical potential in combination with docetaxel, bicalutamide or targeted agents for the treatment of advanced CaP. ### Assistant: [{"class": "POS", "spans_text": ["Genistein", "docetaxel"]}, {"class": "POS", "spans_text": ["Genistein", "bicalutamide"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Combination therapy with bosentan and sildenafil was effective for this case of refractory PAH associated with fibrotic lung in systemic sclerosis . Paragraph: [Efficacy of combination therapy with bosentan and sildenafil for refractory pulmonary arterial hypertension associated with fibrotic lung in systemic sclerosis]. A 54-year-old woman with a 20-year history of Raynaud phenomenon was admitted to our hospital complaining of progressive dyspnea on exertion since 5 years previously. Interstitial lung disease was diagnosed, accompanied by pulmonary arterial hypertension (PAH) associated with systemic sclerosis. After oxygen therapy and treatment with sildenafil, her clinical condition and PAH gradually improved. However, she was readmitted due to deterioration of Raynaud phenomenon and progressive dyspnea in March 2009. Right heart catheterization findings demonstrated that her mean pulmonary arterial pressure (PAP) was elevated, at 48 mmHg. bosentan was therefore added to an increased dose of sildenafil. Consequently, her dyspnea, 6-min walking distance, serum brain natriuretic peptide level, and PAP improved. Combination therapy with bosentan and sildenafil was effective for this case of refractory PAH associated with fibrotic lung in systemic sclerosis . ### Assistant: [{"class": "POS", "spans_text": ["bosentan", "sildenafil"]}]

### 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: Analysis of 52 eyes with high-risk retinoblastoma managed with postenucleation adjuvant chemotherapy using vincristine sulfate , etoposide phosphate , and carboplatin showed no evidence of systemic metastasis in any case during a mean ( range ) follow-up of 66 ( 12 - 202 ) months . Paragraph: Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma. Analysis of 52 eyes with high-risk retinoblastoma managed with postenucleation adjuvant chemotherapy using vincristine sulfate , etoposide phosphate , and carboplatin showed no evidence of systemic metastasis in any case during a mean ( range ) follow-up of 66 ( 12 - 202 ) months . ### purpose To determine the efficacy of postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin in the prevention of metastasis for patients with high-risk retinoblastoma. ### methods Retrospective, nonrandomized, interventional case series of 52 eyes in 51 patients with high-risk retinoblastoma consisting of tumor invasion into the anterior segment, posterior uvea 3 mm or greater, postlaminar optic nerve, or any combination of posterior uvea and optic nerve involvement. ### results Of 51 consecutive patients with high-risk retinoblastoma, there were 30 males (59%) and 21 females (41%), with a median age of 28 months at diagnosis. All 52 eyes were classified as group E. The main histopathologic risk factors included anterior segment invasion (7 [13%]), isolated massive posterior uveal invasion of 3 mm or greater (6 [12%]), isolated postlaminar optic nerve invasion (15 [29%]), or any posterior uveal invasion with any optic nerve involvement (24 [46%]). There was additional invasion into the sclera (3 [6%]) and extrascleral structures, including the orbit (1 [2%]). A single histopathologic high-risk factor was present in 32 eyes (62%), whereas 20 eyes (38%) manifested 2 or more high-risk characteristics. Based on previously published series, untreated high-risk retinoblastoma carries at least a 24% risk for metastatic disease. In the present series, using vincristine, etoposide, and carboplatin in all cases, there was no metastasis during a mean follow-up of 66 months (median [range], 55 [12-202] months). ### conclusions Retinoblastoma with invasion into the postlaminar optic nerve and/or posterior uvea is at high risk for metastasis and death. In this study, postenucleation chemotherapy using vincristine, etoposide, and carboplatin was effective in preventing metastasis in every case (100%). ### Assistant: [{"class": "POS", "spans_text": ["vincristine", "etoposide", "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: Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer : systematic review and economic evaluation . Paragraph: Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer : systematic review and economic evaluation . To evaluate the clinical and cost-effectiveness of capecitabine and tegafur with uracil (UFT/LV) as first-line treatments for patients with metastatic colorectal cancer, as compared with 5-fluorouracil/folinic acid (5-FU/FA) regimens. ### Data Sources Electronic databases, reference lists of relevant articles and sponsor submissions were also consulted. ### Review Methods Systematic searches, selection against criteria and quality assessment were performed to obtain data from relevant studies. Costs were estimated through resource-use data taken from the published trials and the unpublished sponsor submissions. Unit costs were taken from published sources, where available. An economic evaluation was undertaken to compare the cost-effectiveness of capecitabine and UFT/LV with three intravenous 5-FU/LV regimens widely used in the UK: the Mayo, the modified de Gramont regimen and the inpatient de Gramont regimens. ### results The evidence suggests that treatment with capecitabine improves overall response rates and has an improved adverse effect profile in comparison with 5-FU/LV treatment with the Mayo regimen, with the exception of hand-foot syndrome. Time to disease progression or death after treatment with UFT/LV in one study appears to be shorter than after treatment with 5-FU/LV with the Mayo regimen, although it also had an improved adverse effect profile. Neither capecitabine nor UFT/LV appeared to improve health-related quality of life. Little information on patient preference was available for UFT/LV, but there was indicated a strong preference for this over 5-FU/LV. The total cost of capecitabine and UFT/LV treatments were estimated at 2111 pounds and 3375 pounds, respectively, compared with the total treatment cost for the Mayo regimen of 3579 pounds. Cost estimates were also presented for the modified de Gramont and inpatient de Gramont regimens. These were 3684 pounds and 6155 pounds, respectively. No survival advantage was shown in the RCTs of the oral drugs against the Mayo regimen. Cost savings of capecitabine and UFT/LV over the Mayo regimen were estimated to be 1461 pounds and 209 pounds, respectively. Drug acquisition costs were higher for the oral therapies than for the Mayo regimen, but were offset by lower administration costs. Adverse event treatment costs were similar across the three regimens. It was inferred that there was no survival difference between the oral drugs and the de Gramont regimens. Cost savings of capecitabine and UFT/LV over the modified de Gramont regimen were estimated to be 1353 pounds and 101 pounds, respectively, and over the inpatient de Gramont regimen were estimated to be 4123 pounds and 2870 pounds, respectively. ### conclusions The results show that there are cost savings associated with the use of oral therapies. No survival difference has been proven between the oral drugs and the Mayo regimen. In addition, no evidence of a survival difference between the Mayo regimen and the de Gramont regimens has been identified. However, improved progression-free survival and an improved adverse event profile have been shown for the de Gramont regimen over the Mayo regimen. Further research is recommended into the following areas: quality of life data should be included in trials of colorectal cancer treatments; the place of effective oral treatments in the treatment of colorectal cancer, the safety mechanisms needed to ensure compliance and the monitoring of adverse effects; the optimum duration of treatment; the measurement of patient preference; and a phase III comparative trial of capecitabine and UFT/LV versus modified de Gramont treatment to determine whether there was any survival advantage and to collate the necessary economic data. ### Assistant: [{"class": "COMB", "spans_text": ["capecitabine", "tegafur"]}]

### 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: Cost-effectiveness of cetuximab , cetuximab plus irinotecan , and panitumumab for third and further lines of treatment for KRAS wild-type patients with metastatic colorectal cancer . Paragraph: Cost-effectiveness of cetuximab , cetuximab plus irinotecan , and panitumumab for third and further lines of treatment for KRAS wild-type patients with metastatic colorectal cancer . To estimate the cost-effectiveness of cetuximab monotherapy, cetuximab plus irinotecan, and panitumumab monotherapy compared with best supportive care (BSC) for the third and subsequent lines of treatment of patients with Kirsten rat sarcoma wild-type metastatic colorectal cancer from the perspective of the UK National Health Service. ### methods An "an area under the curve" cost-effectiveness model was developed. The clinical effectiveness evidence for both cetuximab and panitumumab was taken from a single randomized controlled trial (RCT) in each case and for cetuximab plus irinotecan from several sources. ### results Patients are predicted to survive for approximately 6 months on BSC, 8.5 months on panitumumab, 10 months on cetuximab, and 16.5 months on cetuximab plus irinotecan. panitumumab is dominated, and cetuximab is extended dominated. An incremental cost-effectiveness ratio (ICER) of £95,000 per quality-adjusted life-year (QALY) was estimated for cetuximab versus BSC and is likely to be relatively accurate, because the relevant clinical evidence is taken from a high-quality RCT. The estimated ICER for panitumumab versus BSC, at £187,000 per QALY, is less certain due to assumptions in the adjustment for the substantial crossing-over of patients in the RCT. The ICER for cetuximab plus irinotecan versus BSC, at £88,000 per QALY, is least certain due to substantial uncertainty about progression-free survival, treatment duration, and overall survival. Nonetheless, when key parameters are varied within plausible ranges, all three treatments always remain poor value for money. ### conclusions All three treatments are highly unlikely to be considered cost-effective in this patient population in the United Kingdom. We explain how the reader can adapt the model for other countries. ### 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: This multicenter pilot study assessed the feasibility and efficacy of a time-intensified bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ( BEACOPP ) regimen given in 14-day intervals ( BEACOPP-14 ) with granulocyte colony-stimulating factor ( G-CSF ) support in advanced Hodgkin 's lymphoma . Paragraph: 14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin's lymphoma: results of a pilot study of the German Hodgkin's Lymphoma Study Group. This multicenter pilot study assessed the feasibility and efficacy of a time-intensified bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ( BEACOPP ) regimen given in 14-day intervals ( BEACOPP-14 ) with granulocyte colony-stimulating factor ( G-CSF ) support in advanced Hodgkin 's lymphoma . ### Patients And Methods From July 1997 until March 2000, 94 patients with Hodgkin's lymphoma stage IIB, III, and IV were scheduled to receive eight cycles of BEACOPP-14. Consolidation radiotherapy was administered to regions with initial bulky disease or residual tumor after chemotherapy. ### results All patients were assessable for toxicity and treatment outcome. Eighty-six patients received the planned eight cycles of BEACOPP-14. Consolidation radiotherapy was given in 66 patients. Chemotherapy could generally be administered on schedule. Dose reductions varied among drugs but were generally low. Acute toxicity was moderate, with World Health Organization grade 3/4 leukopenia in 75%, thrombocytopenia in 23%, anemia in 65%, and infection in 12% of patients. A total of 88 patients (94%) achieved a complete remission. Four patients had progressive disease. At a median observation time of 34 months, five patients have relapsed, one patient developed a secondary non-Hodgkin's lymphoma, and three deaths were documented. The overall survival and freedom from treatment failure rates at 34 months were 97% (95% confidence interval [CI], 93% to 100%) and 90% (95% CI, 84% to 97%), respectively. ### conclusion Acceleration of the BEACOPP baseline regimen by shortening cycle duration with G-CSF support is feasible and effective with moderate acute toxicity. On the basis of these results, the German Hodgkin's Lymphoma Study Group will compare the BEACOPP-14 regimen with BEACOPP-21 escalated in a prospective multicenter randomized trial. ### Assistant: [{"class": "POS", "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: Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus-infected patients with renal impairment . Paragraph: Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus-infected patients with renal impairment . Hepatitis C virus (HCV) infection is a risk factor for end-stage renal disease, renal graft failure, and hemodialysis patient mortality. However, the efficacy of direct-acting antiviral therapy for HCV-infected patients with renal impairment is unclear. Additionally, the promising NS5B inhibitor sofosbuvir has not been recommended for patients with severe renal impairment. In this prospective, multicenter study, we evaluated the efficacy and safety of daclatasvir and asunaprevir combination therapy, with a focus on patients with renal impairment. ### methods The study included 322 genotype 1 HCV-infected patients who received daclatasvir and asunaprevir combination therapy. The safety and sustained virological response was examined at 12 weeks after the end of treatment and safety was evaluated according to renal function. ### results Of 322 patients, 5% (16/322) and 2.5% (8/322) had chronic kidney disease stage G3b (estimated glomerular filtration rate [eGFR], 30-44 mL/min/1.73 m ### conclusion daclatasvir and asunaprevir combination therapy for patients with renal dysfunction was highly effective and safe. ### Assistant: [{"class": "POS", "spans_text": ["daclatasvir", "asunaprevir"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We report the results of replacement of steroids by azathioprine ( AZA ) in 25 primary cadaveric renal transplant recipients initially treated with CsA and methylprednisolone ( MP ) . Paragraph: Complete replacement of methylprednisolone by azathioprine in cyclosporine-treated primary cadaveric renal transplant recipients. In cyclosporine (CsA)-treated renal transplant recipients complete corticosteroid withdrawal followed by CsA monotherapy has been associated with severe rejection episodes in a significant proportion of patients. We report the results of replacement of steroids by azathioprine ( AZA ) in 25 primary cadaveric renal transplant recipients initially treated with CsA and methylprednisolone ( MP ) . MP taper was started 8.8 +/- 5.6 months posttransplant when the MP dose was either 10 mg/day or 20 mg every other day. MP was tapered off over a 5-month period. At the initiation of MP taper, AZA was added at 1 mg/kg/day and increased to 1.5 mg/kg/day after two months. The CsA dose was adjusted to maintain trough serum levels as measured by radioimmunoassay (RIA) of 50-75 ng/ml, during and after MP withdrawal. Seventeen patients have remained continuously off MP for 14.6 +/- 5.0 months with stable renal function. Reinstitution of MP at 10 mg/day was required in 8 patients, 6 for rejection (1.8 +/- 0.7 months after MP withdrawal), 1 for AZA-induced leukopenia, and 1 for de novo glomerulopathy. Renal function returned to baseline in all 6 patients with rejection after reinstitution of MP. Two of these patients have again been successfully retapered off MP. In the patients withdrawn from MP, body weight and mean arterial blood pressure had decreased by 2.1 +/- 1.3 kg (P less than .05) and 11 +/- 7 mmHg (P less than .05), respectively, at the time of the most recent follow-up compared with values at the initiation of steroid withdrawal. The number of blood pressure medications per patient decreased by 38% (P less than .05) and 6 patients were able to discontinue all antihypertensive drugs after cessation of steroids. Discontinuation of MP also resulted in a decrease in serum cholesterol concentration from 248 +/- 50 to 217 +/- 55 mg/dl (P less than .05). We conclude that steroids can be replaced by AZA in the majority of CsA-treated primary cadaveric renal transplant recipients by the end of the first posttransplant year without an adverse effect on graft survival. This protocol resulted in significant reductions in serum cholesterol, mean arterial blood pressure, and body weight, and may avoid the long-term side effects of steroid therapy. ### Assistant: [{"class": "POS", "spans_text": ["azathioprine", "CsA"]}]

### 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: One group of patients was treated with oral mefloquine ( 750 mg ) and artemether ( 600 mg by injection , 200 mg initially and 100 mg every 12 h ) . Paragraph: The effect of mefloquine-artemether compared with quinine on patients with complicated falciparum malaria. 30 pairs of patients with complicated Plasmodium falciparum malaria (with anaemia, hyperpyrexia, jaundice or more than 5% of erythrocytes parasitized) were studied. Patients with cerebral signs and symptoms were excluded. One group of patients was treated with oral mefloquine ( 750 mg ) and artemether ( 600 mg by injection , 200 mg initially and 100 mg every 12 h ) . The second group of patients was treated with quinine (10 mg/kg orally every 8 h for 7 d). All patients were admitted to hospital for 7 d and examined subsequently on days 14, 21 and 28. All those treated with mefloquine plus artemether survived and their parasite clearance time and fever clearance time were significantly shorter than those of patients receiving quinine. 2 patients treated with quinine died. There was no recrudescence in any patient of either group. ### Assistant: [{"class": "POS", "spans_text": ["mefloquine", "artemether"]}]

### 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 role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer . Paragraph: The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer . Colorectal carcinoma is one of the most common malignancies in the western world, and although fluorouracil (5-FU) has been used in its treatment for almost 40 years, new agents with significant activity have been introduced recently. irinotecan (CPT-11, Camptosar), a topoisomerase I inhibitor, administered at 300 to 350 mg/m2 every 3 weeks is significantly more active than continuous-infusion 5-FU in patients who have experienced disease progression after conventional therapy with 5-FU. In comparison to best supportive care, irinotecan improves survival and preserves quality of life despite treatment-related toxicity. Moreover, the combination of irinotecan and 5-FU has been explored in a number of different schedules. In previously untreated patients, overall response rates are high. irinotecan can also be combined with mitomycin (mitomycin-C [Mutamycin]), oxaliplatin, or raltitrexed (Tomudex). oxaliplatin is a new-generation platinum compound that has demonstrated activity against colorectal carcinoma in preclinical trials. It has been evaluated as a single agent against advanced colorectal carcinoma in the salvage setting and also in combination with 5-FU as initial therapy for metastatic disease (where it shows significant activity). The toxicity profile of oxaliplatin (chiefly characterized by neurotoxicity) differs from that of irinotecan (primarily producing diarrhea) and the potential, therefore, exists for combining these agents or for exploiting their possible synergy with 5-FU. The introduction of these two new active agents of different pharmacologic classes promises to enable significant improvements in the treatment of patients with colorectal carcinoma. ### Assistant: [{"class": "POS", "spans_text": ["irinotecan", "oxaliplatin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In both cases , chemotherapy comprising rituximab + dose-adjusted EPOCH regimen ( etoposide , prednisone , vincristine , cyclophosphamide and doxorubicin ) was administered . Paragraph: Successful Treatment of Gastrosplenic Fistula Arising from Diffuse Large B-Cell Lymphoma with Chemotherapy: Two Case Reports. Gastrosplenic fistula (GSF) is a rare condition arising from gastric or splenic lymphomas. Surgical resection is the most common treatment, as described in previous reports. We report two cases of GSF in diffuse large B-cell lymphoma (DLBCL) patients that were successfully treated with chemotherapy and irradiation without surgical resection. Case 1 was of a 63-year-old man who had primary gastric DLBCL with a large lesion outside the stomach wall, leading to a spontaneous fistula in the spleen. Case 2 was of a 59-year-old man who had primary splenic DLBCL, which proliferated and infiltrated directly into the stomach. In both cases , chemotherapy comprising rituximab + dose-adjusted EPOCH regimen ( etoposide , prednisone , vincristine , cyclophosphamide and doxorubicin ) was administered . Case 1 had significant bleeding from the lesion of the stomach during the treatment cycle; however, endoscopic hemostasis was achieved. Case 2 developed a fistula between the stomach and the spleen following therapeutic chemotherapy; however, no complications related to the fistula were observed thereafter. In both cases, irradiation was administered, and complete remission was achieved. ### Assistant: [{"class": "POS", "spans_text": ["rituximab", "etoposide", "prednisone", "vincristine", "cyclophosphamide", "doxorubicin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Bleeding prophylaxis included combinations of plasma-derived factor ( VWD ) or recombinant factor ( haemophilia A and haemophilia B ) , desmopressin and/or tranexamic acid . Paragraph: Low endoscopy bleeding risk in patients with congenital bleeding disorders. Haemophilia A and haemophilia B, von Willebrand disease (VWD), factor VII deficiency and factor XI deficiency are congenital bleeding disorders predisposing to bleeding during invasive procedures. The ageing population of people with congenital bleeding disorders will likely increasingly require gastrointestinal endoscopy. The bleeding risk postgastrointestinal endoscopy and optimal prophylactic treatment regimens are not well described. ### methods We performed a retrospective chart review at the McGill University Health Centre. Adult patients with haemophilia A or B, VWD, FVII deficiency and FXI deficiency who underwent gastrointestinal endoscopic procedures were included. Bleeding prophylaxis included combinations of plasma-derived factor ( VWD ) or recombinant factor ( haemophilia A and haemophilia B ) , desmopressin and/or tranexamic acid . Our primary outcome was the 72-hour postendoscopy bleeding rate. ### results One hundred and four endoscopies were performed in 48 patients. Haemophilia A (45.3% of endoscopies) was the most common bleeding disorder, followed by VWD (38.5%), FXI deficiency (8.7%), haemophilia B (4.8%) and FVII deficiency (2.9%). All patients were reviewed by the Haemophilia Treatment Center with peri-procedure treatment protocols put in place as required. The overall 72-hour bleeding rate was 0.96%, confidence interval (CI) 95% (0.17%-5.25%). The colonoscopic postpolypectomy bleeding rate was 1/21 (4.8%, CI 95% (0.9%-22.7%)) in comparison with the general population rate of 0.3%-10% for high-risk endoscopy (including colonoscopic polypectomy). ### conclusion To the best of our knowledge, this is the largest study describing patients with inherited bleeding disorders undergoing gastrointestinal endoscopy. The bleeding risk is not significantly higher to the general population when haemostatically managed by a team experienced in bleeding disorders. ### Assistant: [{"class": "POS", "spans_text": ["desmopressin", "tranexamic"]}]

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

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The combination of ixabepilone and bevacizumab was well tolerated , with modest activity in second - or later-line mRCC , but it is not recommended as a therapy without further clinical development . Paragraph: A Phase II Multi-Center Study of Bevacizumab in Combination with Ixabepilone in Subjects with Advanced Renal Cell Carcinoma. Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development. ### background Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule-stabilizing agent approved for the treatment of breast cancer, is active in taxane-sensitive and -resistant cells. In this single-arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC. ### methods We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)-approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m ### results The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2-54). The median follow-up was 36.4 months (range 23.5-96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9-10.6) and the median OS was 15.0 months (95% CI, 11.3-28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%). ### conclusion The combination of ixabepilone and bevacizumab was well tolerated , with modest activity in second - or later-line mRCC , but it is not recommended as a therapy without further clinical development . Alternative combinations with these agents could be explored in future studies. ### Assistant: [{"class": "COMB", "spans_text": ["ixabepilone", "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: Eligible patients with unresectable MPM , without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression , stratified by number of cycles ( < 6 or 6 ) , cis- or carboplatin containing regimen , and histology . Paragraph: Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB 30901. The role of maintenance therapy for malignant pleural mesothelioma (MPM) is unknown. We performed a randomized phase II trial to determine if continuation of pemetrexed after first-line pemetrexed and platinum would improve progression-free survival (PFS). ### Patients And Methods Eligible patients with unresectable MPM , without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression , stratified by number of cycles ( < 6 or 6 ) , cis- or carboplatin containing regimen , and histology . Study size was calculated based on the assumption that observation would produce a median PFS of 3 months and pemetrexed would yield median PFS of 6 months. ### results A total of 72 patients were registered from December 2010 to June 2016. The study closed early after 53 patients were randomized; 49 eligible (22 on the observation arm and 27 on the pemetrexed arm) were included in the analysis. The median PFS was 3 months (95% confidence interval [CI], 2.6-11.9 months) on observation and 3.4 months (95% CI, 2.8-9.8 months) on pemetrexed (hazard ratio [HR], 0.99; 95% CI, 0.51-1.90; P = .9733). The median overall survival (OS) was 11.8 months (95% CI, 9.3-28.7 months) for observation, and 16.3 months (95% CI, 10.5-26.0 months) for pemetrexed (HR, 0.86; 95% CI, 0.44-1.71; P = .6737). Grade 3 or 4 toxicities on the pemetrexed arm included anemia (8%), lymphopenia (8%), neutropenia (4%), and fatigue (4%). A higher baseline level of soluble mesothelin-related peptide was associated with worse PFS (HR, 1.86; 95% CI, 1.00-3.46; P = .049). ### conclusion Maintenance pemetrexed following initial pemetrexed and platinum chemotherapy does not improve PFS in patients with MPM. ### Assistant: [{"class": "COMB", "spans_text": ["pemetrexed", "platinum"]}]

### 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 II trial reported a median OS duration of 8.6 months for patients receiving cetuximab plus irinotecan , plus a median time to progression of 4.1 months , a tumour response rate of 22.9 % and suggested that treatment with cetuximab in combination with irinotecan is associated with significantly more adverse events ( any grade 3 or grade 4 adverse event ) than cetuximab monotherapy . Paragraph: Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. To assess the clinical effectiveness and cost-effectiveness of bevacizumab and cetuximab in the treatment of individuals with metastatic colorectal cancer (CRC). ### Data Sources Searches of main electronic databases were conducted in April and May 2005. ### Review Methods For the assessment of bevacizumab, trials were included if they recruited participants with untreated metastatic CRC for first-line treatment. Only trials comparing bevacizumab in combination with irinotecan and/or established fluorouracil (5-FU)-containing or releasing regimens given as first-line therapy were included. For the assessment of cetuximab, trials were included if they recruited participants with epidermal growth-factor receptor-expressing metastatic CRC who had previously failed irinotecan-including therapy. Independent cost-effectiveness models of bevacizumab and cetuximab were developed using survival modelling methods. ### results Adding bevacizumab to irinotecan in combination with 5-FU/folic acid (FA) plus irinotecan resulted in a statistically significant increase in median overall survival (OS) of 4.7 months. Adding bevacizumab to 5-FU/FA resulted in a non-significant increase in median OS of 3.7 months within one study and 7.7 months in another. Adding bevacizumab to irinotecan, fluorouracil and leucovorin (IFL) resulted in a statistically significant increase in median progression-free survival (PFS) of 4.4 months. Adding bevacizumab to 5-FU/FA resulted in a statistically significant increase in median PFS of 3.7 months, and a statistically significant increase in time to disease progression of 3.8 months compared to FU/FA alone. An overall tumour response rate of 44.8% was reported for bevacizumab plus IFL compared to 34.8% for IFL plus placebo. This addition was statistically significant. The addition of bevacizumab to 5-FU/FA resulted in a significant difference in tumour response rate within one study, but not another. bevacizumab in combination with IFL or 5-FU/FA was observed to result in an increase of grade 3/4 adverse events. The independent health economic assessment suggests that the cost-effectiveness of bevacizumab plus IFL is unlikely to be better than pound 46,853 per life-year gained (LYG); the cost-utility of bevacizumab plus IFL is unlikely to be better than pound 62,857 per quality-adjusted life-year (QALY) gained. The cost-effectiveness of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 84,607 per LYG; the cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. A Phase II trial reported a median OS duration of 8.6 months for patients receiving cetuximab plus irinotecan , plus a median time to progression of 4.1 months , a tumour response rate of 22.9 % and suggested that treatment with cetuximab in combination with irinotecan is associated with significantly more adverse events ( any grade 3 or grade 4 adverse event ) than cetuximab monotherapy . The single arm study of cetuximab plus irinotecan reported a median OS duration of 8.4 months, a median time to progression of 2.9 months and a tumour response rate of 15.2%. The cost-effectiveness model suggested that the expected survival duration of patients receiving cetuximab plus irinotecan is 0.79 years (9.5 months) when the proposed continuation rule is applied. In order for cetuximab plus irinotecan to achieve a cost-utility ratio of pound 30,000 per QALY gained, treatment with cetuximab plus irinotecan must provide an additional 0.65 life years (7.8 months) over treatment with active/best supportive care, implying that survival in the active/best supportive care group must be 0.14 life years (1.7 months) or less. ### conclusions The trials indicate that bevacizumab in combination with 5-FU/FA, and bevacizumab in combination with IFL, is clinically effective in comparison to standard chemotherapy options for the first-line treatment of metastatic CRC. The health economic analysis suggests that the marginal cost-utility of bevacizumab plus IFL versus IFL is unlikely to be better than pound 62,857 per QALY gained, and the marginal cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. There is no direct evidence to demonstrate whether cetuximab in combination with irinotecan improves health-related quality of life or OS in comparison to active/best supportive care or oxaliplatin plus 5-FU/FA, although the evidence on tumour response rates suggests that cetuximab plus irinotecan has some clinical activity. While it is difficult to suggest whether cetuximab represents value for money, indirect comparisons suggest that the incremental cost-utility of cetuximab plus irinotecan is unlikely to be better than pound 30,000 per QALY gained. This review highlights a number of areas for further research, including clarifying the true impact of first-line bevacizumab in combination with irinotecan and/or infusional 5-FU/FA, without subsequent bevacizumab treatment following disease progression, on OS in patients with metastatic CRC who are representative of the typical population of CRC patients in England and Wales. Further research concerning the impact of therapies on health-related quality of life is essential. ### Assistant: [{"class": "COMB", "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: Our results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane , with about 27 % of patients having an objective response and 40 % of patients achieving durable disease control . Paragraph: T-DM1 Efficacy in Patients With HER2-positive Metastatic Breast Cancer Progressing After a Taxane Plus Pertuzumab and Trastuzumab: An Italian Multicenter Observational Study. T-DM1 improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic human epidermal growth factor receptor 2-positive (HER2 ### Patients And Methods Eligible patients were identified within the Gruppo Italiano Mammella (GIM) 14/BIOMETA study, a retrospective/prospective multicenter study on treatment patterns and outcomes of patients with metastatic breast cancer (ClinicalTrials.gov Identifier: NCT02284581). We searched for patients who received second-line T-DM1 after taxane plus trastuzumab and pertuzumab between November 15, 2013 and May 31, 2018. We calculated median PFS, median time to treatment failure (TTF), prolonged duration of therapy (PDT), objective response rate (ORR), and 1-year OS. ### results Of 445 patients with HER2 ### conclusions Our results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane , with about 27 % of patients having an objective response and 40 % of patients achieving durable disease control . ### Assistant: [{"class": "POS", "spans_text": ["pertuzumab", "trastuzumab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Dapagliflozin seemed to play a role in accelerating the patient 's urinary sodium excretion as well as reducing gross fluid retention despite the fact that her nephrotic condition was resistant to furosemide . Paragraph: Management of Diabetes Associated with Nephrotic Syndrome: Therapeutic Potential of Dapagliflozin for Protracted Volume Retention. A 48-year-old female was admitted to our hospital presenting with a chief complaint of progressive swelling because of diabetic nephrotic syndrome. Dapagliflozin seemed to play a role in accelerating the patient 's urinary sodium excretion as well as reducing gross fluid retention despite the fact that her nephrotic condition was resistant to furosemide . Our experience emphasizes a potential novel approach to overcoming loop diuretic resistance using this agent among some subsets of type 2 diabetic subjects complicated with severe volume accumulation. We believe that combination treatment consisting of dapagliflozin and furosemide may produce diuretic synergy via sequential nephron blockade. The accumulation of more experience with additional cases similar to ours requires continuous and careful attention. ### Assistant: [{"class": "POS", "spans_text": ["Dapagliflozin", "furosemide"]}]

### 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: PA combination of goserelin and tamoxifen in patients with relapsed ovarian cancer can not be recommended as standard therapy , but may result in long-term survival in individual patients . Paragraph: Combined treatment with goserelin and tamoxifen in patients with advanced chemotherapy resistant ovarian cancer. The purpose of this study was to determine the response in patients with recurrent, chemotherapy-resistant ovarian cancer to a combination of the LHRH-analog goserelin and tamoxifen. ### Patients And Methods Twenty-five patients with recurrent, chemotherapy resistant ovarian cancer received a combination of goserelin and tamoxifen until clinical or serological evidence of progression as measured by serum CA-125 levels. Suppression of LH, FSH and prolactin levels in this group were compared with a second group of ten patients treated with decapeptyl for the same indication. ### results The combination was well tolerated. The median progression free survival amounted to five (range 2-96+) months and overall survival to eight (range 3-96+) months. One of the responding patients is still alive without progression at 8 years. With this combination the median levels of LH and FSH were markedly suppressed, to respectively 2.6% and 3.7% of baseline values. With decapeptyl the LH levels were also suppressed, but the resulting FSH levels were significantly higher. PA combination of goserelin and tamoxifen in patients with relapsed ovarian cancer can not be recommended as standard therapy , but may result in long-term survival in individual patients . ### Assistant: [{"class": "COMB", "spans_text": ["goserelin", "tamoxifen"]}]

### 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 previous analyses of the MURANO study , fixed-duration venetoclax plus rituximab ( VenR ) resulted in improved progression-free survival ( PFS ) compared with bendamustine plus rituximab ( BR ) in patients with relapsed or refractory chronic lymphocytic leukemia ( CLL ) . Paragraph: Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. In previous analyses of the MURANO study , fixed-duration venetoclax plus rituximab ( VenR ) resulted in improved progression-free survival ( PFS ) compared with bendamustine plus rituximab ( BR ) in patients with relapsed or refractory chronic lymphocytic leukemia ( CLL ) . At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics. ### Patients And Methods Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed. ### results Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC ( ### conclusion Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS. ### Assistant: [{"class": "POS", "spans_text": ["venetoclax", "rituximab"]}, {"class": "COMB", "spans_text": ["bendamustine", "rituximab"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The aim of the present study was to determine whether a combination of atorvastatin and amlodipine causes sympathoinhibition via reduction of oxidative stress in the RVLM and improves cognitive dysfunction of hypertensive rats . Paragraph: Combination therapy of atorvastatin and amlodipine inhibits sympathetic nervous system activation and improves cognitive function in hypertensive rats. A previous study has demonstrated that orally administered atorvastatin reduces sympathetic nervous system (SNS) activation via an anti-oxidant in the rostral ventrolateral medulla (RVLM) of hypertensive rats, whereas amlodipine did not. Furthermore, several previous reports have suggested that atorvastatin or amlodipine improves cognitive dysfunction during hypertension. The aim of the present study was to determine whether a combination of atorvastatin and amlodipine causes sympathoinhibition via reduction of oxidative stress in the RVLM and improves cognitive dysfunction of hypertensive rats . ### Methods And Results Stroke-prone spontaneously hypertensive rats (SHRSPs), as a hypertensive model with sympathoexcitation, were divided into 4 groups; a combination of atorvastatin and amlodipine-treated (COM), atorvastatin-treated (ATR), amlodipine-treated (AML), hydralazine-treated (HYD), and vehicle-treated SHRSPs (VEH). After treatment for 28 days, the mean blood pressure did not change in ATR rats, and was reduced to the similar levels in COM, AML, and HYD rats. However, SNS activation and oxidative stress in the RVLM were significantly lower only in COM than in ATR, AML, HYD, and VEH rats. Cognitive performance and manganese-superoxide dismutase activity in the hippocampus were significantly higher, and oxidative stress in the hippocampus was significantly lower in COM than in VEH, AML, and HYD rats to a greater extent than in ATR rats. ### conclusions A combination of atorvastatin and amlodipine causes sympathoinhibition via an anti-oxidant in the RVLM and improves cognitive dysfunction via an anti-oxidant in the hippocampus in hypertensive rats, independent of the blood pressure-lowering effect. ### Assistant: [{"class": "POS", "spans_text": ["atorvastatin", "amlodipine"]}]

### 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: Active treatment consisted of hydrochlorothiazide ( 25 - 50 mg/day ) plus triamterene ( 50 - 100 mg/day ) with the addition of alpha-methyldopa ( 0.5 - 2.0 g/day ) in one-third of the patients . Paragraph: Is a high serum cholesterol level associated with longer survival in elderly hypertensives? The relationship between serum total cholesterol, measured at randomization, and mortality was investigated in 822 patients, who were followed for an average of 3.1 years in a double-blind trial, conducted by the European Working Party on High Blood Pressure in the Elderly. Serum cholesterol, measured at randomization, was 0.54 mmol/l higher in women than in men, and declined with increasing age in both men (0.028 mmol/l per year) and women (0.036 mmol/l per year). During follow-up on randomized treatment, cholesterol fell by a similar amount with placebo (0.11 mmol/l per year) and with active treatment (0.14 mmol/l per year). Active treatment consisted of hydrochlorothiazide ( 25 - 50 mg/day ) plus triamterene ( 50 - 100 mg/day ) with the addition of alpha-methyldopa ( 0.5 - 2.0 g/day ) in one-third of the patients . Serum total cholesterol, measured at randomization, was independently and inversely correlated with total (P = 0.03), non-cardiovascular (P = 0.03) and cancer (P = 0.04) mortality during follow-up on double-blind treatment. Total and non-cardiovascular mortality were also negatively correlated with haemoglobin and body weight at randomization. ### Assistant: [{"class": "POS", "spans_text": ["hydrochlorothiazide", "triamterene", "alpha-methyldopa"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: It is predicted that patients suffering from both VL and cardiac disorders ( atrial fibrillation ) may benefit if they are treated with warfarin in conjunction with first-line antileishmanial therapies such as miltefosine and AmBisome . Paragraph: Analysis of sequence, structure of GAPDH of Leishmania donovani and its interactions. Drug resistance acquired by Leishmania donovani (Ldv) is a major problem in the treatment and control of visceral leishmaniasis (VL). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a major glycolytic enzyme has been targeted as is found in other protozoan which cause diseases like sleeping sickness. GAPDH gene of Ldv (AG83 strain) was amplified, sequenced, and modeled on the basis of crystal structure of Leishmania mexicana. The model of the Ldv GAPDH exhibited NAD-binding domain with Rossmann folding. Virtual screening of different experimentally proved compounds with the crystal and the modeled structures of GAPDH of Leishmania strains revealed diverse binding affinities of different compounds. Comparison of binding affinities (based on different programs) of compounds revealed that discovery studio v2.5 (Ligandfit) was able to predict the most hit compounds, the best hit compounds against GAPDH of Leishmania strains are hydrazine, vetrazine, and benzyl carbazate. It is predicted that patients suffering from both VL and cardiac disorders ( atrial fibrillation ) may benefit if they are treated with warfarin in conjunction with first-line antileishmanial therapies such as miltefosine and AmBisome . ### Assistant: [{"class": "COMB", "spans_text": ["warfarin", "miltefosine"]}]

### 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: If concomitant therapy is absolutely necessary , the dose of digoxin should be halved prior to initiating dronedarone . Paragraph: Chronic Digoxin Toxicity Precipitated by Dronedarone. To report the case of a patient who presented with chronic symptoms attributable to dronedarone-induced digoxin toxicity. A review of the literature is also provided. ### Case Summary This case report details a case of a 77-year-old male patient who presented to the hospital with multiple ambiguous symptoms that lasted several weeks. The patient was later hospitalized for symptoms of chronic digoxin toxicity, including prolonged nausea, diarrhea, weakness, and lack of appetite. The patient had a long history of digoxin use for control of his atrial fibrillation but experienced signs and symptoms of toxicity only after the addition of dronedarone. ### discussion Both the Naranjo and Drug Interaction Probability Scales indicated a "probable" relationship between the development of digoxin toxicity and dronedarone. Due to a p-glycoprotein-mediated interaction, dronedarone is able to decrease the renal clearance of digoxin, thus putting patients at risk for potentially fatal digoxin toxicity. ### conclusion This is the second case report detailing dronedarone-induced digoxin toxicity and the first to focus on chronic digoxin toxicity. The presentation, possible causes, and drug-drug interactions associated with digoxin toxicity are described. This report aims to increase clinicians' awareness of this possible complication. It is recommended that digoxin be discontinued prior to initiating dronedarone. If concomitant therapy is absolutely necessary , the dose of digoxin should be halved prior to initiating dronedarone . digoxin plasma levels should be monitored closely, with frequent patient evaluation for signs and symptoms of digoxin toxicity. ### Assistant: [{"class": "COMB", "spans_text": ["digoxin", "dronedarone"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: All patients received neoadjuvant chemotherapy with cyclophosphamide , doxorubicin , and fluorouracil , or cyclophosphamide , doxorubicin , vincristine , and prednisone . Paragraph: Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. To determine outcomes in local-regional control, disease-free survival, and overall survival in patients with locally advanced breast cancer (LABC) who present with ipsilateral supraclavicular metastases and who are treated with combined-modality therapy. ### Patients And Methods Seventy patients with regional stage IV LABC, which is defined by our institution as LABC with ipsilateral supraclavicular adenopathy without evidence of distant disease, received treatment on three prospective trials of neoadjuvant chemotherapy. All patients received neoadjuvant chemotherapy with cyclophosphamide , doxorubicin , and fluorouracil , or cyclophosphamide , doxorubicin , vincristine , and prednisone . Patients then received local therapy that consisted of either total mastectomy and axillary lymph node dissection (ALND) or segmental mastectomy and ALND before or after irradiation. Patients with no response to neoadjuvant chemotherapy were treated with surgery and/or radiotherapy. After completion of local therapy, chemotherapy was continued for four to 15 cycles, followed by radiotherapy. Patients older than 50 years who had estrogen receptor-positive tumors received tamoxifen for 5 years. ### results Median follow-up was 11.6 years (range, 4.8 to 22.6 years). Disease-free survival rates at 5 and 10 years were 34% and 32%, respectively. The median disease-free survival was 1.9 years. Overall survival rates at 5 and 10 years were 41% and 31%, respectively. The median overall survival was 3.5 years. The overall response rate (partial and complete responses) to induction chemotherapy was 89%. No treatment-related deaths occurred. ### conclusion Patients with ipsilateral supraclavicular metastases but no other evidence of distant metastases warrant therapy administered with curative intent, ie, combined-modality therapy consisting of chemotherapy, surgery, and radiotherapy. Patients with ipsilateral supraclavicular metastases should be included in the stage IIIB category of the tumor-node-metastasis classification because their clinical course and prognosis are similar to those of patients with stage IIIB LABC. ### Assistant: [{"class": "POS", "spans_text": ["cyclophosphamide", "doxorubicin", "fluorouracil"]}, {"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: We analyzed 129 non-Hodgkin lymphoma patients who underwent AHSCT from 1996 to 2013 using the most common regimens : CBV ( cyclophosphamide , carmustine and etoposide ; n = 16 ) , BEAM ( carmustine , etoposide , cytarabine and melphalan ; n = 36 ) and BEAC ( carmustine , etoposide , cytarabine and cyclophosphamide ; n = 77 ) . Paragraph: Comparison of CBV, BEAM and BEAC high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation in non-Hodgkin lymphoma: Efficacy and toxicity. Limited data are available to guide the choice of conditioning regimen before autologous hematopoietic stem cell transplantation (AHSCT) for patients with lymphoma. ### methods We analyzed 129 non-Hodgkin lymphoma patients who underwent AHSCT from 1996 to 2013 using the most common regimens : CBV ( cyclophosphamide , carmustine and etoposide ; n = 16 ) , BEAM ( carmustine , etoposide , cytarabine and melphalan ; n = 36 ) and BEAC ( carmustine , etoposide , cytarabine and cyclophosphamide ; n = 77 ) . ### results At a median follow-up of 42.5 months, the estimated 5-year overall survival for the CBV, BEAM and BEAC groups was 68.8%, 77.8% and 81.8%, respectively (P = 0.584). The estimated 5-year progression-free survival in the CBV group (43.8%) was relatively inferior to the BEAM (66.7%) and BEAC (67.5%) groups, but the differences were not significant (P = 0.403). Grade 2 or higher mucositis, diarrhea and fever were relatively more common in the BEAM group (P < 0.05). No differences were observed in the time to hematopoietic recovery and the duration of hospitalization. The amount of transfused platelet was significantly less in the CBV. ### conclusion CBV, BEAM and BEAC regimens are all optional high-dose chemotherapy before AHSCT for NHL patients. ### Assistant: [{"class": "POS", "spans_text": ["cyclophosphamide", "carmustine", "etoposide"]}, {"class": "POS", "spans_text": ["carmustine", "etoposide", "cytarabine", "melphalan"]}, {"class": "POS", "spans_text": ["etoposide", "cytarabine", "cyclophosphamide", "carmustine"]}]

### 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: Early Prostate-Specific Antigen ( PSA ) Change at Four Weeks of the First-Line Treatment Using Abiraterone and Enzalutamide Could Predict Early/Primary Resistance in Metastatic Castration-Resistant Prostate Cancer . Paragraph: Early Prostate-Specific Antigen ( PSA ) Change at Four Weeks of the First-Line Treatment Using Abiraterone and Enzalutamide Could Predict Early/Primary Resistance in Metastatic Castration-Resistant Prostate Cancer . The identification of early or primary resistance to androgen signaling inhibitors (ASIs) is of great value for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the predictive value of prostate-specific antigen (PSA) response at dour weeks of first-line ASIs treatment for mCRPC patients. A total of 254 patients treated with ASIs (abiraterone acetate: AA and enzalutamide: Enz) at the first-line treatment are retrospectively analyzed. Patients are stratified according to the achievement of >30% PSA decline at 4 and 12 weeks from the treatment initiation. At four weeks of the treatment, 157 patients (61.8%) achieved >30% PSA decline from the baseline. Thereafter, 177 patients (69.7%) achieved >30% PSA decline at 12 weeks of the treatment. A multivariate analysis exhibits >30% PSA decline at four weeks as an independent predictor for overall survival (OS). We note that 30 of 97 (30.9%) patients who did not achieve >30% PSA decline at four weeks consequently achieved >30% PSA decline at 12 weeks, and had a comparable favorable three years OS rate as the 147 patients achieving >30% PSA decline at both 4 and 12 weeks. To identify the variables that discriminate the patient survival in 97 patients without achieving >30% PSA decline at four weeks, a multivariate analysis is performed. The duration of androgen deprivation therapy before CRPC ≤ 12 months and Eastern Cooperative Oncology Group Performance Status ≥ 1 are identified as independent predictors for shorter OS for those patients. These data offer a concept of early treatment switch after four weeks of first-line ASIs when not observing >30% PSA decline at four weeks-particularly in patients with a modest effect of ADT and poor performance status. ### Assistant: [{"class": "POS", "spans_text": ["Abiraterone", "Enzalutamide"]}]

### 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: Dexamethasone , cytarabine , ifosfamide , and cisplatin as salvage therapy in non-Hodgkin lymphoma . Paragraph: Dexamethasone , cytarabine , ifosfamide , and cisplatin as salvage therapy in non-Hodgkin lymphoma . The authors conducted a phase II study to evaluate a new combination of chemotherapeutic drugs that includes dexamethasone, cytarabine, ifosfamide, and cisplatin as salvage therapy in non-Hodgkin lymphoma after prior exposure to both adriamycin and etoposide. All drugs were administered intravenously over 4 consecutive days. The daily dose of dexamethasone was 20 mg twice daily. The maximal daily doses of cytarabine, ifosfamide, and cisplatin were 75 mg/m2, 1,200 mg/m2, and 20 mg/m2, respectively. Cycles were repeated every 3 weeks. A total of 31 patients were entered in the trial. Thirty patients were evaluable for response. A complete response was seen in 11 patients (37%), and a partial response was noted in six patients (20%). A significantly higher complete response rate was seen in patients with relapsing non-Hodgkin lymphoma compared with those who failed to achieve a complete response with the last chemotherapy (10/14 vs. 1/16; p < 0.013). A complete response continues in two patients who received consolidation with high-dose chemotherapy for more than 49 months and more than 60 months for each patient. Median time to treatment failure and median survival were 3.3 months and 7.5 months, respectively, for the entire group and 11 months and 30 months, respectively, for complete responders. Myelosuppression was pronounced but was usually of short duration. Neutropenic fever developed in 13 patients (42%) and in 15 of 96 cycles (16%). Platelet transfusions were required in seven patients (23%). There was one drug-related death associated with myelotoxicity. Nonhematologic toxicity was not dose limiting. The authors conclude that dexamethasone, cytarabine, ifosfamide, and cisplatin is active and a relatively tolerable regime for patients with non-Hodgkin lymphoma previously treated with adriamycin and etoposide. ### Assistant: [{"class": "POS", "spans_text": ["Dexamethasone", "cytarabine", "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: Cost-effectiveness of ribociclib plus letrozole Paragraph: Cost-effectiveness of ribociclib plus letrozole The global burden of breast cancer (BC) is high, especially in advanced stages. CDK 4/6 inhibitors represent a paradigm shift in the treatment of advanced BC HR+/HER2-, given the clinically and statistically significant gain in overall survival associated with this new class of medications. Nevertheless, as an innovation, the incorporation of these drugs impacts healthcare budgets, requiring cost-effectiveness analyses for decision-making. The aim of this study was to evaluate the cost-effectiveness of ribociclib plus letrozole compared with palbociclib plus letrozole or letrozole as monotherapy for first-line treatment of postmenopausal women with HR+/HER2- locally advanced or metastatic BC (aBC) from a Brazilian private healthcare system perspective. ### methods A model including progression-free survival (PFS), progressed disease, and death health states was used to simulate lifetime costs and outcomes. PFS and overall survival were derived from the MONALEESA-2 trial (lifetime horizon). Healthcare costs included drug acquisition and monitoring, subsequent therapies, adverse events, and end-of-life costs. Effectiveness was measured in quality-adjusted life-years (QALYs). Deterministic and probabilistic sensitivity analyses were performed. ### results The total cost of treatment with ribociclib plus letrozole was USD 72,091.82 ### conclusions As demonstrated by the cost-effectiveness dominance over palbociclib, ribociclib results in savings when used as first-line treatment in postmenopausal women with HR+/HER2- aBC, warranting incorporation in the private healthcare system. ### Assistant: [{"class": "POS", "spans_text": ["ribociclib", "letrozole"]}]

### 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 investigated whether lapatinib plus gemcitabine has synergistic or antagonistic effects on the pancreatic cancer cell lines MiaPaca-2 and PANC-1 . Paragraph: In vitro effects of lapatinib with gemcitabine for pancreatic cancer cells. We investigated whether lapatinib plus gemcitabine has synergistic or antagonistic effects on the pancreatic cancer cell lines MiaPaca-2 and PANC-1 . Furthermore, the changes of gemcitabine sensitivity-related genes by lapatinib treatment were examined. ### methodology The effects of lapatinib, gemcitabine, and combined treatment with both agents on cell viability were examined by methyl thiazolyl tetrazolium analysis. Synergy between lapatinib and gemcitabine was assessed by median effect analysis. The mRNA amounts of human equilibrative nucleoside transporter (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit M1 (RRM1) genes were measured by quantitative real-time polymerase chain reaction in cells exposed to lapatinib for 48 h, as compared with untreated cells. ### results No synergistic effects were observed with combined treatment in either cell line. In contrast, antagonistic effects occurred on MiaPaca-2 cells with the two agents. Specific changes in gemcitabine sensitivity-related genes induced by lapatinib were not detected in either MiaPaca-2 or PANC-1. ### conclusions lapatinib may not enhance the anti-tumor effects of gemcitabine for pancreatic cancer. ### Assistant: [{"class": "COMB", "spans_text": ["lapatinib", "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 PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable , but the clinical activity was not sufficient to warrant further testing . Paragraph: Pantoprazole Affecting Docetaxel Resistance Pathways via Autophagy (PANDORA): Phase II Trial of High Dose Pantoprazole (Autophagy Inhibitor) with Docetaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC). Enhancing the effectiveness of docetaxel for men with metastatic castration-resistant prostate cancer (mCRPC) is an unmet clinical need. Preclinical studies demonstrated that high-dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts. ### Materials And Methods Men with chemotherapy-naive mCRPC with a prostate-specific antigen (PSA) >10 ng/mL were eligible for enrolment. Men received intravenous pantoprazole (240 mg) prior to docetaxel (75 mg/m ### results Between November 2012 and March 2015, 21 men with a median age of 70 years (range, 58-81) were treated (median, 6 cycles; range, 2-11). Men had received prior systemic therapies (median, 1; range, 0-3), and 14 had received abiraterone and/or enzalutamide. PSA response rate was 52% (11/21), which did not meet the prespecified criterion (≥13/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow-up of 17 months, 18 (86%) men were deceased (15 castration-resistant prostate cancer, 2 unknown, 1 radiation complication). Of the men with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median overall survival was 15.7 months (95% confidence interval [CI], 9.3-19.6) and median PFS was 5.3 months (95% CI, 2.6-12.9). There were no toxic deaths, and all adverse events were attributed to docetaxel. ### conclusion The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing. ### Implications For Practice To date, no docetaxel combination regimen has reported superior efficacy over docetaxel alone in men with metastatic castration-resistant prostate cancer (mCRPC). The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable , but the clinical activity was not sufficient to warrant further testing . The chemotherapy standard of care for men with mCRPC remains docetaxel with prednisone. Future studies of autophagy inhibitors will need to measure autophagy inhibition accurately and determine the degree of autophagy inhibition required to produce a meaningful clinical response. ### Assistant: [{"class": "COMB", "spans_text": ["pantoprazole", "docetaxel"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir . Paragraph: Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir. To assess the pharmacokinetic interaction of saquinavir and lopinavir/ritonavir. ### design Patients from the Frankfurt HIV cohort with limited reverse transcriptase inhibitor (RTI) options received the protease inhibitor (PI) combination of saquinavir (soft-gel capsules, 1000 mg twice a day) plus lopinavir/ritonavir (400/100 mg twice a day), without RTI (LOPSAQ group). A control group received the same doses of saquinavir and ritonavir plus two to three RTI (RITSAQ group). A steady-state 12 h pharmacokinetic assessment was performed. ### methods Plasma levels of saquinavir, ritonavir and lopinavir were determined by liquid chromatography-tandem mass spectrophotometry. Minimum and maximum plasma concentrations (Cmin and Cmax), the clearance (Cltot) and the area under the concentration time curve (AUC) were calculated. ### results Data were collected from 45 patients (LOPSAQ) and 32 patients (RITSAQ). There was no significant difference between the groups for median saquinavir Cmin, Cmax, Cltot and AUC (LOPSAQ: 543 ng/ml, 2300 ng/ml, 1020 ml/min and 16 977 ng*h/ml; RITSAQ: 427 ng/ml, 2410 ng/ml, 1105 ml/min and 15 130 ng*h/ml). Median ritonavir Cmin, Cmax and AUC were lower, the Cltot was higher in the LOPSAQ group (78 ng/ml, 428 ng/ml and 2972 ng*h/ml, 551 ml/min) compared with RITSAQ (194 ng/ml, 683 ng/ml and 6506 ng*h/ml, 266 ml/min; P < 0.001). lopinavir levels were similar to historical data. ### conclusion Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir . This boosted double PI combination could be an effective option for patients with limited RTI options. ### Assistant: [{"class": "POS", "spans_text": ["saquinavir", "lopinavir"]}]

### 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 recent years several tyrosine kinase inhibitors targeting specific molecular pathways involved in its pathogenesis have been investigated , such as sorafenib , lenvatinib , and sunitinib . Paragraph: Sorafenib and Sunitinib for the Treatment of Metastatic Thyroid Cancer of Follicular Origin: A 7-Year Single-Centre Experience. Radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) is a rare form of DTC which poses a therapeutic challenge due to the scarcity of effective treatment options. In recent years several tyrosine kinase inhibitors targeting specific molecular pathways involved in its pathogenesis have been investigated , such as sorafenib , lenvatinib , and sunitinib . These appear to be associated with improved progression-free survival (PFS). ### objectives We aim to describe our experience with sorafenib and sunitinib in the treatment of RAI-refractory metastatic DTC and to evaluate and compare their efficacy and adverse effect profiles. ### method A total of 28 patients with RAI-refractory metastatic DTC were included - 26 had first-line treatment with sorafenib (8 subsequently switched to sunitinib, most due to disease progression) and 2 with sunitinib. We evaluated PFS and best radiological response achieved with each agent as primary endpoints. The secondary objective was to describe adverse effects and safety profile. ### results Mean PFS was 10.8 months with sorafenib and 6 months with sunitinib as a second-line treatment. Best overall response was partial remission (PR) with either agent - PR rate of 30.7% with sorafenib and 37.5% with second-line sunitinib. All treatment courses had registered adverse effects and 13.9% justified definitive treatment cessation. ### conclusions sorafenib and sunitinib appear to be effective treatment options in delaying disease progression of patients with RAI-refractory metastatic DTC, with an acceptable safety profile. Interestingly, sunitinib appears to show some efficacy even in patients who experience disease progression on sorafenib. ### Assistant: [{"class": "POS", "spans_text": ["sorafenib", "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: The in vitro antibacterial activity of zidovudine alone and in combination with ciprofloxacin was investigated . Paragraph: In vitro activity of zidovudine alone and in combination with ciprofloxacin against Salmonella and Escherichia coli. The in vitro antibacterial activity of zidovudine alone and in combination with ciprofloxacin was investigated . zidovudine showed a good activity against Escherichia coli and Salmonella (MIC range 0.5-8 micrograms/ml and 1.5-62 micrograms/ml respectively) isolated from biological samples of HIV-infected patients. These strains proved to be extremely susceptible to ciprofloxacin alone. The interaction between zidovudine and ciprofloxacin ranged from additive activity to indifference. No antagonism was observed: the FIC index for every combination resulted < or = 1.5. The addition of AZT 1 mg/l (clinically achievable plasma concentration after therapeutic doses of 1200 mg/day) did not affect the bactericidal activity of ciprofloxacin; on the contrary, in some cases we observed an increase of bactericidal effect of the quinolone. These data have to be considered in patients with AIDS who can be treated concomitantly with zidovudine and ciprofloxacin. ### Assistant: [{"class": "POS", "spans_text": ["zidovudine", "ciprofloxacin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: This patient was a case of primary antiphospholipid antibody syndrome in which endothelial cell damage was located exclusively in the capillary lumens and pulse cyclophosphamide therapy in addition to prednisolone and anticoagulant was effective . Paragraph: [A case of primary antiphospholipid antibody syndrome with severe nephrotic syndrome showing remarkable endothelial cell damage in the capillary lumen]. A 25-year-old woman complained of anasarca and was admitted to Sakura National hospital on the presumptive diagnosis of nephrotic syndrome with 10.7 g of 24-hour urinary protein. At first, lupus nephritis with antiphospholipid antibody syndrome was suspected because of prolongation of APTT, existence of lupus anticoagulant and elevation of serum anticardiolipin antibody titer (IgM) in addition to positive ANA, lymphocytopenia and the biologically false positive test for syphilis (BFPTS). On day 28 of hospitalization, renal biopsy findings revealed severe endocapillary cell damage, such as swelling and proliferation of endothelial cells, fragmentation and double contour of the basement membrane walls, which were located only in the capillary lumens with a few thrombi. Immunofluorescent micrography revealed the absence of specific immunoglobulin or complement deposit. Therefore, the diagnosis of lupus nephritis was negated as these findings were suggestive of characteristic glomerulopathy due to primary antiphospholipid antibody syndrome. She was treated initially with oral prednisolone 60 mg and intravenous infusion of heparin 20,000 units daily. Moreover, cyclophosphamide 750 mg was administered intravenously as pulse therapy on day 13 as her serum level of CH50 had fallen suddenly, and hemodialysis was necessary because her renal function had deteriorated and she was suffering from cough and orthopnea with overhydratin. After the combined therapy, BFPTS disappeared and APTT returned to the normal range: dialysis treatment was not required further after the 4th hemodialysis. Thereafter, renal function improved and complete remission of nephrotic syndrome was obtained. This patient was a case of primary antiphospholipid antibody syndrome in which endothelial cell damage was located exclusively in the capillary lumens and pulse cyclophosphamide therapy in addition to prednisolone and anticoagulant was effective . We present this instructive case to promote understanding of the pathogenesis of primary antiphospholipid antibody syndrome. ### Assistant: [{"class": "POS", "spans_text": ["cyclophosphamide", "prednisolone"]}]

### 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: Vancomycin and gentamicin were administered systemically just prior to surgery and streptomycin was added to the irrigating solution . Paragraph: Antibiotic prophylaxis in neurosurgery. A randomized controlled trial. A randomized trial was performed to support the contention that prophylactic antibiotics can reduce the incidence of postoperative neurosurgical wound infections. The regime outlined by Malis was followed. Vancomycin and gentamicin were administered systemically just prior to surgery and streptomycin was added to the irrigating solution . Patients were randomly assigned to two groups: control and treated. The infection rate in the control group was 3.5% and in the treated group 0.5%. ### Assistant: [{"class": "POS", "spans_text": ["Vancomycin", "gentamicin", "streptomycin"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We observed a synergistic cytotoxic effect for the combination of foretinib and lapatinib on the viability and proliferation of the examined melanoma cell lines . Paragraph: Gefitinib or lapatinib with foretinib synergistically induce a cytotoxic effect in melanoma cell lines. Melanoma is an aggressive cancer type with a high mortality rate and an elevated resistance to conventional treatment. Recently, promising new tools for anti-melanoma targeted therapy have emerged including inhibitors directed against frequently overexpressed receptors of growth factors implicated in the progression of this cancer. The ineffectiveness of single-targeted therapy prompted us to study the efficacy of treatment with a combination of foretinib, a MET (hepatocyte growth factor receptor) inhibitor, and gefitinib or lapatinib, EGFR (epidermal growth factor receptor) inhibitors. We observed a synergistic cytotoxic effect for the combination of foretinib and lapatinib on the viability and proliferation of the examined melanoma cell lines . This combination of inhibitors significantly decreased Akt and Erk phosphorylation, while the drugs used independently were insufficient. Additionally, after treatment with pairs of inhibitors, cells became larger, with more pronounced stress fibers and abnormally shaped nuclei. We also noticed the appearance of polyploid cells and massive enrichment in the G2/M phase. Therefore, combination treatment was much more effective against melanoma cells than a single-targeted approach. Based on our results, we conclude that both EGFR and MET receptors might be effective targets in melanoma therapy. However, variation in their levels in patients should be taken into consideration. ### Assistant: [{"class": "POS", "spans_text": ["foretinib", "lapatinib"]}]

### 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 knockdown of ANXA2 in NB cell line SK-N-BE(2 ) using shRNA , we demonstrate enhanced drug sensitivity for doxorubicin ( 2.77-fold ) and etoposide ( 7.87-fold ) compared with control . Paragraph: Annexin A2 could enhance multidrug resistance by regulating NF-κB signaling pathway in pediatric neuroblastoma. Chemotherapy is one of major therapeutic regimens for neuroblastoma (NB) in children. However, recurrence and metastasis associated with poor prognosis caused by acquired multidrug resistance remains a challenge. There is a great need to achieve new insight into the molecular mechanism of drug resistance in NB. The aim of this study is to identify novel drug sensitivity-related biomarkers as well as new therapeutic targets to overcome chemoresistance. ### methods We proteome-wide quantitatively compared protein expression of two NB cell lines with different drug sensitivities, isolated from the same patient prior to and following chemotherapy. Annexin A2 (ANXA2) emerged as a key factor contributing to drug resistance in NB. Then, we assessed the correlation of ANXA2 expression and clinical characteristics using a tissue microarray. Further, the roles of ANXA2 in chemoresistance for NB and the underlying mechanisms were studied by using short hairpin RNA (shRNA) in vitro and vivo. ### results First in total, over 6000 proteins were identified, and there were about 460 significantly regulated proteins which were up- or down-regulated by greater than two folds. We screened out ANXA2 which was upregulated by more than 12-fold in the chemoresistant NB cell line, and it might be involved in the drug resistance of NB. Then, using a tissue chip containing 42 clinical NB samples, we found that strong expression of ANXA2 was closely associated with advanced stage, greater number of chemotherapy cycles, tumor metastasis and poor prognosis. Following knockdown of ANXA2 in NB cell line SK-N-BE(2 ) using shRNA , we demonstrate enhanced drug sensitivity for doxorubicin ( 2.77-fold ) and etoposide ( 7.87-fold ) compared with control . Pro-apoptotic genes such as AIF and cleaved-PARP were upregulated. Inhibiting ANXA2 expression attenuated transcriptional activity of NF-κB via down-regulated nuclear translocation of subunit p50. Finally, simulated chemotherapy in a xenograft NB nude mouse model suggests that ANXA2 knockdown could improve clinical results in vivo. ### conclusion Our profiling data provided a rich source for further study of the molecular mechanisms of acquired drug resistance in NB. Further study may determine the role of ANXA2 as a prognostic biomarker and a potential therapeutic target for patients with multidrug-resistant NB. ### Assistant: [{"class": "POS", "spans_text": ["doxorubicin", "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: Combined therapy with amiodarone and carvedilol provided greatest reduction of sudden arrhythmic and total mortality . Paragraph: [Correction of baroreflex sensitivity impairment and efficacy of prevention of sudden arrhythmic death in patients with postinfarction left ventricular dysfunction]. Baroreflex sensitivity was assessed in 287 patients with history of myocardial infarction and left ventricular ejection fraction < or =40% by phenylephrine test and was found to be depressed (4.44+/-0.38 ms/mm Hg). Repeat study in 3, 6 and 12 months revealed substantial improvement of baroreflex sensitivity in patients treated with perindopril especially when it was combined with amiodarone, metoprolol, bisoprolol and carvedilol but not with atenolol. Combined therapy with amiodarone and carvedilol provided greatest reduction of sudden arrhythmic and total mortality . Superiority of combination of amiodarone with lipophilic beta-adrenoblocker over monotherapy had been anticipate but was not confirmed in any of large prospective studies. ### Assistant: [{"class": "POS", "spans_text": ["amiodarone", "carvedilol"]}]

### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Patients with progressive refractory NSCLC who had previously benefitted from erlotinib ( objective response or stable disease > 8weeks ) were randomized to receive treatment with either erlotinib and sorafenib ( 400 mg orally twice daily ) or sorafenib alone . Paragraph: Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: A randomized phase II study of the Sarah Cannon Research Institute (SCRI). To evaluate the efficacy of erlotinib, continued after tumor progression, plus sorafenib versus sorafenib alone in patients with refractory metastatic non-small cell lung cancer (NSCLC) who previously benefitted from single-agent erlotinib. ### Patients And Methods Patients with progressive refractory NSCLC who had previously benefitted from erlotinib ( objective response or stable disease > 8weeks ) were randomized to receive treatment with either erlotinib and sorafenib ( 400 mg orally twice daily ) or sorafenib alone . Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. ### results Fifty-three patients were randomized (erlotinib/sorafenib, 25; sorafenib, 28) and 52 patients received study treatment. Patients in both groups received a median of 8weeks of treatment. The median PFS was 3.1months for erlotinib/sorafenib versus 1.7months for sorafenib alone; response rates were 8% and 4%, respectively. Both regimens were tolerable, but toxicity was more frequent with erlotinib/sorafenib. ### conclusions These results do not suggest any benefit in continuing erlotinib after tumor progression in patients with refractory metastatic NSCLC. Both regimens tested had limited efficacy, consistent with results from other studies. ClinicalTrials.gov ID:NCT00609804. ### Assistant: [{"class": "NEG", "spans_text": ["erlotinib", "sorafenib"]}]