tbuckley/cabot-search huggingface dataset:
Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer
Authors: A. Poveda, J.M. del Campo, I. Ray-Coquard, J. Alexandre, M. Provansal, E.M. Guerra Alía, A. Casado, A. Gonzalez-Martin, C. Fernández, I. Rodriguez, A. Soto, C. Kahatt, C. Fernández Teruel, C.M. Galmarini, A. Pérez de la Haza, P. Bohan, D. Berton-Rigaud
Journal: Annals of Oncology (2017)

PM01183 is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. PM01183 showed strong antitumor activity in preclinical models of cisplatin-resistant epithelial ovarian cancer.Patients with platinum-resistant/refractory ovarian cancer were included in a two-stage, controlled, randomized (in a second stage), multicenter, phase II study. Primary endpoint was overall response rate (ORR) by RECIST and/or GCIG criteria. The exploratory first stage (n = 22) confirmed the activity of PM01183 as a single agent at 7.0 mg flat dose every 3 weeks (q3wk). The second stage (n = 59) was randomized and controlled with topotecan on days 1-5 q3wk or weekly (every 4 weeks, q4wk).ORR was 23% (95% CI, 13%-37%) for 52 PM01183-treated patients. Median duration of response was 4.6 months (95% CI, 2.5-6.9 months), and 23% (95% CI, 0%-51%) of responses lasted 6 months or more. Ten of the 12 confirmed responses were reported for 33 patients with platinum-resistant disease [ORR = 30% (95% CI, 16%-49%)]; for the 29 patients treated with topotecan in the second stage, no responses were found. Median PFS for all PM01183-treated patients was 4.0 months (95% CI, 2.7-5.6 months), and 5.0 months (95% CI, 2.7-6.9 months) for patients with platinum-resistant disease. Grade 3/4 neutropenia in 85% of patients; febrile neutropenia in 21% and fatigue (grade 3 in 35%) were the principal safety findings for PM01183.PM01183 is an active drug in platinum-resistant/refractory ovarian cancer and warrants further development. The highest activity was observed in platinum-resistant disease. Its safety profile indicates the dose should be adjusted to body surface area (mg/m2).EudraCT 2011-002172-16.
Prognostic value of <i>PIK3CA</i> mutations in HER2-positive early stage breast cancer: A French cohort study.
Authors: Florence Coussy, Jacqueline Lehmann- Che, Alice Sanna, Sylvie Giacchetti, Philippe Bertheau, Caroline Cuvier, Marjorie Lalloum, Brigitte Poirot, Anne de Roquancourt, Fatiha Bouhidel, Matthieu Resche Rigon, Marc Espie, Luis Teixeira, Patricia de Cremoux
Journal: Journal of Clinical Oncology (2015)

e11607 Background: Breast cancer (BC) is a heterogeneous disease with different prognostic according to molecular characteristics. About 15% of breast cancers have erbb2 oncogene (HER2+) overexpression or amplification. Experimental and clinical data suggest that mutational activation of the PIK3 pathway could confer resistance to HER2 targeted therapies. In the adjuvant setting, the prognostic value of PIK3CA mutations is unclear with conflicting results (Loibl, S., et al. J Clin Oncol. 2014,32(29): p. 3212-20; Baselga, J., et al. J Clin Oncol. 2014,32(33): p. 3753-61; Majewski, I.J., et al. J Clin Oncol. 2015; Esteva, F.J., et al. Am J Pathol. 2010,177(4): p. 1647-56; Loi, S., et al. J Natl Cancer Inst. 2013,105(13): p. 960-7.) Our study aims was to determine the impact of mutated PIK3CA gene on HER2+BC outcome treated with adjuvant chemotherapy with or without trastuzumab. Methods: Between 1998 and 2012, we identified 180 patients with HER2+ early breast cancer treated in the adjuvant setting at our center. PIK3CA exon 9 and exon 20 tumor genotyping was retrospectively performed. Patients received adjuvant chemotherapy without trastuzumab before 2005 and with trastuzumab after 2005. The primary end point of our analysis was the disease free survival (DFS). Results: PIK3CA mutations were identified in 18% of tumors (33/180), including mutations in both helical (exon 9) and kinase (exon 20) domains (33% and 67%, respectively). The patients with PIK3CA mutant and wild type tumors had similar characteristics at BC diagnosis: age (50 and 52 years; p = 0.93), ER+/PR+ tumors (42.4 vs 49%; p = 0.57), grade 3 tumor (50 vs 64%; p = 0.16), treatment with trastuzumab (61 vs 64%; p = 0.84). In both treatment groups with or without trastuzumab, 5-years DFS or OS were not statistically different between patients with or without PIK3CA mutation (HR = 1.95; IC95 = 0.76-5; p = 0.16 and HR = 1.39; IC95 = 0.47-4.11; p = 0.55 respectively). Conclusions: PIK3CA mutations were not associated with different outcomes in our series of HER2+ early breast cancer treated with or without trastuzumab in the adjuvant setting.
A Prospective, Multicenter, Randomized Study of Anti-CCR4 Monoclonal Antibody Mogamulizumab Versus Investigator's Choice in the Treatment of Patients with Relapsed/Refractory Adult T-Cell Leukemia-Lymphoma: Overall Response Rate, Progression-Free Survival, and Overall Survival
Authors: Adrienne Phillips, Paul Fields, Olivier Hermine, Juan Carlos Ramos, Brady E Beltran, Juliana Pereira, Carlos Brites, Farooq Ahmad Wandroo, Michael Lill, Tatyana A Feldman, Luis Casanova, Murali Janakiram, Jean-Come Meniane, Ahmed Sawas, Lucy B Cook, Michael R. Kurman, Joyce George, Karen Dwyer, Mollie Leoni, Kevin Conlon, Graham P. Taylor, Jason Gonsky, Steven M. Horwitz
Journal: Blood (2016)
Military health system costs, utilization, and physician prescribing associated with prostate cancer, FY2007-FY2014.
Authors: Diana D Jeffery, Michelle Kloc, Joe Dorris, Harry B Burke
Journal: Journal of Clinical Oncology (2015)

e17771 Background: Cancer is one of the most costly illnesses for health care systems, including the Military Health System (MHS). This study examines the change in health care costs and utilization associated for prostate cancer patients within the MHS from FY07-FY14. Additionally, we assess the impact of physician prescribing patterns on health care costs. Methods: Primary ICD-9 codes for claims paid by TRICARE in fiscal years 2007 – 2014 were obtained from the Military Health System’s Master Data Repository. MHS beneficiaries, ages 18 – 64 and residing within the United States, were included only if they had accessed the healthcare system within the FY. Prostate cancer was identified using the Agency for Healthcare Research and Quality (AHRQ) Clinical Classification Software. Trend analyses were used to examine the overall cost of prostate cancer care and utilization, including variation in costs by ambulatory or inpatient care. Trends in prescribing patterns were assessed through examination of AHFS Pharmaceutical Classifications of prescriptions for prostate cancer patients. Results: Annual sample size of prostate cancer patients was, on average, 15,115. Non-pharmacy costs for prostate cancer patients increased 13% (approximately $12M) between FY07-14, largely related to increasing costs for ambulatory care provided in military settings. Total pharmacy costs (all scripts) increased 45% between FY07 and FY10, then remained stable through FY2014. Trends in physician prescribing patterns will also be presented. Conclusions: Findings may relate to changes in American Urological Association (AUA) guidelines for the management of localized prostate cancer. AUA’s 2007 guidelines recommended a watchful waiting and active monitoring approach for many patients with clinically localized prostate cancer, which may have impacted health care use and associated costs for the MHS. Increased pharmacy costs likely relate to market entry or increased use of chemotherapeutics or ‘targeted’ drugs.
Genetic aberations in PTEN and PIK3CA and prognosis in wild-type <i>EGFR</i> gene mutation patients that received erlotinib.
Authors: Mary J. Fidler, Ekaterina Pestova, Ying Zhang, Jing Du, Philip D. Bonomi, Thomas A. Hensing, Kelly Kaiser Walters, William Barbanera, Lela Buckingham
Journal: Journal of Clinical Oncology (2014)

e22043 Background: Loss of PTEN and gain of PIK3CA have been postulated as downstream mechanisms of resistance to anti-EGFR therapy in NSCLC. Clinical data suggests use of EGFR tyroisine kinase inhibitors (EGFR TKIs) is inferior to second line chemotherapy in patients without EGFR sensitizing gene mutations. The purpose of this study was to identify wild type NSCLC patients(pts) with improved outcomes on erlotinib based on PTEN loss and gains in PIK3CA and chromosome 3 (CEP3), on which is located PIK3CA. Methods: Pts treated with erlotinib were included for analysis. Five micron sections of formalin-fixed tumor tissue were assessed by fluorescent in situ hybridization (FISH) using probes for PTEN, PIK3CA and the centromere of CEP3. FISH signals were enumerated by 2 readers, counting 50 cells each. FISH enumeration results were used to determine parameters influencing the overall survival(OS) post therapy. OS time between FISH (+) and FISH (-) pts was compared by COX Proportional Hazard Model and Log-rank test for single FISH parameters or combinations. OS was also graphically presented by Kaplan Meier Curves. Pts with Exon 19 and 21 activating mutations were excluded from the analysis. Results: A total of 116 pts treated with erlotinib were tested, of which 103 pts had no exon 19 or 21 mutations (EGFR wt). 70 pts in this study had adenocarcinoma, majority were females (74) and previous/current smokers (90). Initial data analysis indicated that percent gain of CEP3, as well as a combination of CEP3 percent gain and PTEN percent loss had a statistically significant (p<0.05) predictive value for OS in patients treated with erlotinib (FISH positivity was associated with shorter median survival times, 6 vs 11 months, HR=1.65). Increased percent cells with CEP3 gain was associated with shorter OS in EGFR wt pts (5 vs 8 months, HR = 1.6). There was no prognostic correlation of PIK3CA alterations the variability among readers was high. Conclusions: Downstream measures of cytogenetic alterations in the PTEN/PIK3CA pathway may identify patients with improved prognosis on erlotinib. These results require validation and provide a rationale for combining erlotinib with other targeted agents in this favorable subset.
HIV: Persistence through division
Authors: Lillian B. Cohn, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2017)

A long-lived latent reservoir for HIV-1 persists in CD4+ T cells despite antiretroviral therapy and is the major barrier to cure. In this issue of JEM, Hosmane et al. show that T cell proliferation could explain the long-term persistence of this reservoir.
The R0 resection rate after neoadjuvant bevacizumab (Bev) plus DOF versus DOF in local advanced gastric carcinoma (LAGC) and its association with circulating tumor cell (CTC).
Authors: Nan Du, Junxun Ma, Shan Wang, Xiaosong Li, Junzhong Sun, Huanrong Kang, Yan Fu, Hui Zhao, Yi Hu
Journal: Journal of Clinical Oncology (2014)

4043 Background: Local advanced gastric carcinoma (LAGC) is suggested to be potentially cured by R0 resection, and neoadjuvant chemotherapy can increase the R0 resection rate but not enough. Bevacizumab (Bev), an anti-tumor angiogenesis monoclonal antibody, combined with chemotherapy has been shown effective in advanced GC. In addition, CTC has been suggested as an indicator of the anti-tumor drugs’ efficacy. Therefore, in this study, we plan to evaluate the efficacy and safety of neoadjuvant Bev plus docetaxel/oxaliplatin/5-FU/CF (DOF) versus DOF in mainly gastric antrum LAGC, and to investigate whether CTC is an effectiveness indicator. Methods: 80 patients diagnosed as IIIb-IIIc GC have been enrolled and randomly assigned (1:1) to receive neoadjuvant Bev (5 mg/kg, d1) plus DOF (docetaxel, 75 mg/m2, iv, d1; oxaliplatin, 85 mg/m2, iv, d1; 5-FU, iv infusion 600 mg/m2 and iv injection 400mg/m2, d1-2; CF, 200 mg/m2, d1 and d2) or DOF each 3-week, up to 2-4 cycles preoperation, and another 2-4 cycles postoperation up to total 6 cycles. The primary endpoint is R0 resection rate. CTC was detected every 8 weeks. All patients signed the informed consent. Results: For ORR and R0 resection rate, there were significant differences between the Bev plus DOF and DOF groups (65.0% vs. 42.5% and 77.5% vs. 52.5%; P<0.05). Compared to DOF group, Bev plus DOF group had dramatically more CTC number declined (P<0.05), and had 21 of 24 (87.5%) patients achieving R0 resection [10 of 15 (66.7%) patients with DOF]. The medium survival was 17.6 months (95% CI: 14.153-21.047) with Bev plus DOF versus 16.4 months (95% CI: 12.949-19.851) with DOF; OS of the two groups had no significant statistical difference (p=0.776). Furthermore, both single-variant and multi-variants Cox regression analysis found that neoadjuvant regimen,R0 resection rate and CTC were independent survival prognostic predictors in LAGC (P<0.05). Conclusions: Neoadjuvant Bev plus DOF can reduce TN staging and improve ORR and R0 resection rate in LAGC with controllable adverse effects. CTC number declined may act as an effectiveness and survival predictor in LAGC.
Growth differentiation factor-15 is a predictor of important disease outcomes in patients with COPD
Authors: Gunnar R. Husebø, Rune Grønseth, Lorena Lerner, Jeno Gyuris, Jon A. Hardie, Per S. Bakke, Tomas M. Eagan
Journal: European Respiratory Journal (2017)

Increased levels of growth differentiation factor-15 (GDF15) are associated with cachexia, cardiovascular disease and all-cause mortality. The role of GDF15 in chronic obstructive pulmonary disease (COPD) is unknown.The study included 413 patients with COPD from the Bergen COPD Cohort Study. All patients had a forced expiratory volume in 1 s (FEV1) <80% predicted, a FEV1 to forced vital capacity (FVC) ratio <0.7 and a history of smoking. Spirometry, fat free mass index, blood gases and plasma GDF15 were measured at baseline. Patients were followed for 3 years regarding exacerbations and changes in lung function, and 9 years for mortality. Yearly exacerbation rate, survival and yearly change in FEV1/FVC were evaluated with regression models.Median plasma GDF15 was 0.86 ng·mL-1 (interquartile range 0.64-1.12 ng·mL-1). The distribution was not normal and GDF15 was analysed as a categorical variable. High levels of GDF15 were associated with a higher exacerbation rate (incidence rate ratio 1.39, 95% CI 1.1-1.74, p=0.006, adjusted values). Furthermore, high levels of GDF15 were associated with higher mortality (hazard ratio 2.07, 95% CI 1.4-3.1, p<0.001) and an increased decline in both FEV1 (4.29% versus 3.25%) and FVC (2.63% versus 1.44%) in comparison to low levels (p<0.01 for both).In patients with COPD, high levels of GDF15 were independently associated with a higher yearly rate of exacerbations, higher mortality and increased decline in both FEV1 and FVC.
A phase III, randomized, double-blind study of single-dose intravenous fosaprepitant in preventing chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy.
Authors: Bernardo Leon Rapoport, Cindy Weinstein, Elber S. Camacho, Saleem A. Khanani, Elizabeth Beckford-Brathwaite, Lydia Kevill, Waldimir Vallejos, Li Wen Liang, Stephen Joseph Noga
Journal: Journal of Clinical Oncology (2015)

9629 Background: This is the first study performed to directly evaluate the efficacy and safety of a single dose of intravenous (IV) fosaprepitant (FA), an NK1 receptor antagonist, used with a 5-HT3 antagonist and corticosteroid in subjects receiving moderately emetogenic chemotherapy (MEC). Methods: This was a global, phase 3, randomized, double-blind, parallel-group study in adult subjects naive to MEC and highly emetogenic chemotherapy (HEC) scheduled to receive an IV dose of ≥ 1 MEC agents on treatment day 1. Subjects were randomly assigned 1:1 to a control or FA regimen. Those in the control regimen received 8 mg oral ondansetron, 20 mg dexamethasone, and IV saline as placebo before the first dose of MEC on day 1, and 8 mg oral ondansetron 8 hours after the first dose, followed by 8 mg oral ondansetron every 12 hours on days 2 and 3. Those in the FA regimen received the same dose of oral ondansetron on day 1, along with 12 mg dexamethasone and a single dose of 150 mg IV FA before the first dose of MEC on day 1, with no additional prophylactic antiemetic beyond day 1. Primary outcomes were the proportion of subjects with a complete response (CR: no vomiting and no rescue medication use) during the delayed phase (25 to 120 hours after MEC) and FA safety/tolerability. Results: Baseline characteristics were generally balanced among the 1000 subjects in the primary efficacy population (502 FA, 498 control). The majority were white, ≥ 50 years of age, and female. CR was achieved in 396 (78.9%) subjects in the FA regimen and 341 (68.5%) in the control regimen during the delayed phase (treatment difference of 10.4%, P < 0.001). Safety profiles were comparable between the treatment groups; drug-related adverse events occurred in 8.5% (FA) vs 9.1% (control). There were no cases of severe infusion-site pain, erythema, or induration reported; 3 cases of infusion-site thrombophlebitis were observed in the FA regimen compared with 0 in the control regimen. Conclusions: Single-dose 150-mg IV FA regimen is generally safe and well tolerated and provides superior control of CINV associated with MEC as measured by the proportion of subjects with CR in the delayed phase. Clinical trial information: NCT01594749.
Cardiovascular risk profile and management in patients with head and neck cancer treated with radiotherapy.
Authors: Christian Chinedu Okoye, Jessica Bucher, Guiherme Oliveira, Sahil Parikh, Min Yao, Mitchell Machtay, Jennifer Anne Dorth
Journal: Journal of Clinical Oncology (2015)

e17081 Background: Increasingly, deaths among Head and Neck Cancer (HNC) patients are due to non-oncologic causes, including cardiovascular (CV) disease. HNC patients receiving radiotherapy (RT) have an elevated risk of stroke due to both underlying CV risk and RT-enhanced carotid artery injury. The CV risk profile and management has not been well characterized in HNC patients. Methods: Patients with squamous or adenosquamous HNC who underwent RT as part of curative treatment between 2011-2013 at a single institution were retrospectively reviewed. Information regarding CV risk factors and their management was collected. The 10-year risk of CV events was calculated based on both Adult Treatment Panel III (ATP III) and 2013 American Heart Association (AHA) guidelines. Statistical comparisons were made using t-test or chi-square, where appropriate. Results: The 115 included patients were predominantly white (82.6%) males (73.0%) with advanced stage (stage III or IV, 92.2%) oropharyngeal (46.1%), laryngeal (19.1%), or oral cavity (18.3%) HNC. Medical histories included carotid stenosis or stroke in 8.7%, peripheral/coronary artery disease or myocardial infarction in 18.3%, and diabetes in 13.0%. The median follow up after RT completion was 2.0 years. Most patients had intermediate or high CV risk per ATP III (71.3%), with an overall median 10-year CV risk of 6% and 11.5% per ATP III and AHA, respectively. The 10-year AHA CV risk was higher among HPV-negative versus HPV-positive HNC (15.7% v 11.4%, p = 0.048), and for laryngeal versus other primary sites (19.0% v 12.3%, p = 0.01). Despite the use of antihypertensive medication in 49.6% of patients, 30.4% of all patients had baseline blood pressures above recommended cutoffs. Statins were prescribed for 33.9% of patients, while an additional 37.4% had indications for statins per AHA. Among 34 patients with available lipid panels, 23.5% did not have controlled cholesterol levels per ATP III. Conclusions: HNC patients undergoing RT have elevated CV risk profiles but many fail to receive optimal primary prevention. Better application of guideline-directed strategies aimed at CV risk reduction may result in decreased stroke rates and improved survival in this population.
Palliative pelvic radiotherapy for symptomatic incurable prostate cancer.
Authors: Marte Grønlie Cameron, Christian Kersten, Ingvild Vistad, Rene P van Helvoirt, Kjetil Weyde, Eva Skovlund, Sophie D. Fossa, Marianne Grønlie Guren
Journal: Journal of Clinical Oncology (2014)

e16050 Background: External beam radiotherapy is frequently used to treat pelvic symptoms of castration resistant prostate cancer (CRPC). Documentation of palliative effect, toxicity and recommended treatment schedule are lacking. The aims of the study were to evaluate changes in symptom severity and degree of toxicity among patients with CRPC following palliative pelvic radiotherapy (PPRT). Methods: Patients with CRPC and a symptomatic pelvic mass that were prescribed PPRT in 3 Gy fractions to 30-39 Gy were prospectively included. Patient-reported symptoms were assessed before, at the end of, and 6 and 12 wks after PPRT. Results: Of 46 patients included, 39 were evaluable. Median age was 79 yrs (67 – 93). Treatment volume included primary tumor in 45 patients and lymph node metastases in 10. Treatment was given as conformal 3D PPRT in 44 patients. Urinary obstruction, macroscopic hematuria, and pelvic pain were the most common target symptoms (TS) identified by patients. In 69% of evaluable patients, the TS had either resolved or improved 12 wks after PPRT and in an additional 26%, the TS was unchanged. 40 of the 46 included patients (87%) reported complete resolution or improvement at at least 1 of the 3 follow-ups. Hematuria responded most rapidly with 100% improvement, while obstructive symptom response was more variable. Pelvic pain was relieved in 78% of patients. In the same period, opioid use decreased, as did severity of other pelvic symptoms. There was no grade 4 toxicity. Conclusions: In patients with CRPC and a symptomatic pelvic mass, palliative treatment including PPRT with doses in the range of 30-39 Gy relieves macroscopic hematuria, pain and other pelvic symptoms. Findings demonstrate that PPRT contributes to positive outcomes, with little toxicity. Future studies should investigate whether PPRT regimens can be further simplified for the benefit of patients and to conserve resources. Clinical trial information: NCT01023529.TS severity 12 wks after PPRT. Not evaluable (n) Resolved (n) Improved (n) Unchanged (n) Worse (n) Proportion improved or resolved (95% CI) Urinary obstruction n=20 3 4 3 9 1 0.41 (0.18 – 0.64) Macroscopic hematuria n=12 1 8 3 0 0 1.0 Pelvic pain n=9 0 5 2 1 1 0.78 (0.51 – 1.00) Other (edema, rectal obstruction) n=5 3 1 1 0 0 1.0 Total n=46 7 18 9 10 2 0.69 (0.54 – 0.84)