bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of germline MET mutation with response to the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Results from a multicenter phase II study (MET111644).
Authors: Srinivasan Ramaprasad , Bottaro Donald P. , Choueiri Toni K. , Vaishampayan Ulka N. , Rosenberg Jonathan E. , Logan Theodore , Harzstark Andrea Lynne , Rini Brian I. , Srinivas Sandy , Adams Laurel M. , Laubscher Kevin , Ottesen Lone Harild , McDermott David F. , Linehan W. Marston 
Published: February 2017

372 Background: Activating mutations and/or amplifications in MET have been described in patients (pts) with papillary renal cell carcinoma (PRC). Foretinib, an oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors, was evaluated in a phase 2 study in pts with PRC. An important objective of this study was to evaluate whether activation of the MET receptor pathway by mutation, amplification, or gain of chromosome 7 was predictive for or correlated with clinical outcomes. Methods: Pts were stratified based on status of MET pathway activation. Blood samples were collected at screening for determination of germline MET mutational status. Archival tumor tissue samples were obtained for the analysis of somatic MET mutation, amplification of the MET locus (7q31), and gain of chromosome 7 using standardized assays. Results: A total of 74 pts were enrolled on the trial (37 each in intermittent and daily dosing arms); overall efficacy and safety data are reported separately at this meeting. Sixty-seven pts were evaluable for both mutation status and response. 5/10 pts (50%) with a germline MET mutation experienced a PR, while 5 pts (50%) had SD as their best response, including 4 pts who demonstrated tumor SLD reductions of > 10%, but did not achieve PR by RECIST 1.0. Responses were also seen in pts without germline MET mutation. However, the presence of a germline MET mutation was highly predictive of a response as only 5/57 pts (9%) without a mutation experienced a PR. Other measures of MET pathway activation did not appear to correlate with activity with only 1/5 pts (20%) with somatic MET mutation having a PR; furthermore, in the absence of a concomitant MET mutation, no responses were seen in patients with MET amplification (n=2) and only 1/18 (5%) pts with a gain of chromosome 7 experienced a PR. Conclusions: The presence of germline MET mutations correlated strongly with activity of the MET inhibitor foretinib in pts with PRC. These data provide early proof of principle that MET may be a valid therapeutic target in a subset of patients with PRC.
Plasma cytokines and angiogenic factors (CAFs) associated with risk of recurrence and tumor dependence in patients (pts) with nonmetastatic renal cell carcinoma (RCC).
Authors: Zurita Amado J. , Khajavi Mehrdad , Wang Xuemei , Wood Christopher G. , Matin Surena F. , Fiorentino Stefania , McKee Kathryn S. , Tran Hai T. , Heymach John , Jonasch Eric 
Published: February 2017

383 Background: Although recent years have brought great progress into understanding the pathogenesis of RCC and multiple promising biomarkers, no tumor tissue or blood-based test has yet been validated for clinical use. The main objectives of this exploratory analysis were to identify CAFs predictive of recurrence in RCC pts, and to gain insight into tumor dependency of individual factors by comparing CAFs pre- and post-nephrectomy (Nx). Methods: Plasma samples were obtained before and up to 1 year after Nx from pts with sporadic, non-metastatic renal masses suspicious for RCC (n=73). Upon Nx, 52 pts showed dominant clear cell histology and 11 non-clear cell; 10 pts had non-cancerous lesions. RCC pts were categorized by risk of relapse based on pathologic staging (pT1/pT2 as low-risk [LR], n=38; pT3/pT4 as high-risk [HR], n=25). Multiplex bead suspension arrays and ELISA were used to measure concentrations of 58 CAFs including angiogenesis and invasion mediators (VEGF, VEGF-C, soluble CAIX [sCA9], hepatocyte growth factor and transforming growth factor-b1, among others), and multiple inflammatory and/or immunomodulatory chemokines and interleukins (IL). t-test and Wilcoxon signed rank or rank-sum tests were respectively used to assess changes in CAFs between pre- and post-Nx or to compare CAFs between subgroups of pts. Results: Of 58 pre-Nx CAFs available in RCC pts, the concentrations of IL-8, granulocyte-colony stimulating factor, stromal cell-derived factor-1, and osteopontin, among others, were significantly higher in HR vs. LR-RCC (all P<0.01). In pts with clear cell RCC, sCA9 was also higher (P=0.004). A number of CAFs significantly decreased post-Nx, including sCA9, endoglin, and e-selectin, while others increased, such as stem cell factor, IL-12, and vascular cell adhesion molecule-1. The pre-Nx concentrations of e-selectin were lower in pts with eventual disease recurrence (P=0.008). Conclusions: We identified pre-Nx CAFs associated with risk for recurrence, and post-Nx changes related to the presence of the tumor in pts with non-metastatic RCC. If validated in a larger study, these CAFs could be used for risk stratification of RCC pts.
Radium-223 chloride impact on skeletal-related events in patients with castration-resistant prostate cancer (CRPC) with bone metastases: A phase III randomized trial (ALSYMPCA).
Authors: Sartor A. Oliver , Heinrich Daniel , Helle Svein Inge , O'Sullivan Joe M. , Fossa Sophie D. , Chodacki Ales , Demkow Tomasz , Logue John P. , Seke Mihalj , Widmark Anders , Johannessen Dag Clement , Nilsson Sten , Hoskin Peter , Solberg Arne , James Nicholas David , Syndikus Isabel , Vogelzang Nicholas J. , O'Bryan-Tear C. Gillies , Shan Minghua , Parker Chris 
Published: February 2017

9 Background: Radium-223 chloride (Ra-223) is a 1st-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy alpha-particles of short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) vs placebo (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included skeletal-related events (SREs). Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra‐223 (50 kBq/kg IV) q4 wks or matching pbo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. Results: 922 pts (Ra-223, n = 615; pbo, n = 307) were randomized from 6/2008-2/2011. Based on data from a planned interim analysis (n = 809), unblinded June 2011, Ra-223 significantly improved OS in pts with CRPC with bone mets vs pbo (median OS 14.0 vs 11.2 mo, respectively; two-sided P = 0.00185; HR = 0.695; 95% CI, 0.552-0.875). SREs were lower in the Ra-223 vs pbo group, and time to 1st SRE was significantly delayed (median time to SRE 13.6 mo vs 8.4 mo, respectively; P = .00046; HR = .610; 95% CI, .461-.807). Conclusions: Ra-223 significantly delayed time to 1st SRE and SRE components, except surgical intervention. These reductions in SREs, particularly SCC, are noteworthy. Ra-223 is an effective therapy with a highly favorable safety profile and may provide a new standard of care for treatment of CRPC pts with bone mets. [Table: see text]
Is docetaxel-prednisone (DP) feasible in frail elderly (age 75 or older) patients with castration-resistant metastatic prostate cancer (CRMPC)? GERICO10-GETUG P03 trial: A trial from elderly and genitourinary oncology UNICANCER groups.
Authors: Mourey Loic , Sevin Emmanuel , Latorzeff Igor , Houede Nadine , Meunier Jérome , Priou Frank , Gravis Gwenaelle , Carola Elisabeth , Orsini Christine , Filleron Thomas 
Published: February 2017

93 Background: Standard treatment of CRMPC is DP 75 mg/m² every 3 weeks since a symptomatic and overall survival benefit was demonstrated. Little is known about feasibility of DP in unselected elderly patients (day to day practice). Methods: Randomized phase II study evaluating prospectively the feasibility of DP administered every 3 weeks (60 mg / m² C1 then 70 mg / m² for subsequent cycles) or weekly (35mg/m² D1D8 with Day 1 = Day 21) in patients ≥75 years old, evaluated by comprehensive geriatric assessment, belonging to group 2 “vulnerable” or to group 3 “frail” of the classification proposed by the International Society of Geriatric Oncology (SIOG). Feasibility is defined as the possibility for a patient to receive 6 cycles of chemotherapy without fulfilling the criteria for withdrawal from study defined “a priori” by GERICO group: - stop or delay chemotherapy > 2 weeks - necessity to reduce chemotherapy dose > 25% - febrile neutropenia or NCI CTC grade III non-haematological toxicity (except alopecia) - loss of autonomy ( Activity of Daily Living (ADL) decrease≥2 points) →geriatric criterion It is a double randomized phase II based on a Simon’s optimum two stage design for each strata defined according to the SIOG criteria (α = 5%, 1-β = 90 %, p0 = 0.70 and p1 = 0.90). A pharmacokinetic / pharmacodynamic study (method of population pharmacokinetics) and pharmacogenetic study of PXR (pregnane X receptor) CYP3A4 and CYP3A5) are planed. Results: 25 centers participate to the study (23 opened). 10 centers have included 22 patients (16 “vulnerable” and 6 “frail”) from December 2010 until now. Conclusions: The results of this study will support the prescription of chemotherapy and its modalities, in patients aged 75 and over, classified as “vulnerable” or “frail” according to SIOG criteria, after comprehensive geriatric assessment.
Role of Troponins I and T and N-Terminal Prohormone of Brain Natriuretic Peptide in Monitoring Cardiac Safety of Patients With Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Receiving Trastuzumab: A Herceptin Adjuvant Study Cardiac Marker Substudy
Authors: Zardavas Dimitrios , Suter Thomas M. , Van Veldhuisen Dirk J. , Steinseifer Jutta , Noe Johannes , Lauer Sabine , Al-Sakaff Nedal , Piccart-Gebhart Martine J. , de Azambuja Evandro 
Published: February 2017

Purpose Women receiving trastuzumab with chemotherapy are at risk for trastuzumab-related cardiac dysfunction (TRCD). We explored the prognostic value of cardiac markers (troponins I and T, N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) to predict baseline susceptibility to develop TRCD. We examined whether development of cardiac end points or significant left ventricular ejection fraction (LVEF) drop was associated with markers’ increases. Patients and Methods Cardiac marker assessments were coupled with LVEF measurements at different time points for 533 patients from the Herceptin Adjuvant (HERA) study who agreed to participate in this study. Patients with missing marker assessments were excluded, resulting in 452 evaluable patients. A primary cardiac end point was defined as symptomatic congestive heart failure of New York Heart Association class III or IV, confirmed by a cardiologist, and a significant LVEF drop, or death of definite or probable cardiac causes. A secondary cardiac end point was defined as a confirmed significant asymptomatic or mildly symptomatic LVEF drop. Results Elevated baseline troponin I (> 40 ng/L) and T (> 14 ng/L), occurring in 56 of 412 (13.6%) and 101 of 407 (24.8%) patients, respectively, were associated with an increased significant LVEF drop risk (univariate analysis: hazard ratio, 4.52; P < .001 and hazard ratio, 3.57; P < .001, respectively). Few patients had their first elevated troponin value recorded during the study (six patients for troponin I and 25 patients for troponin T). Two patients developed a primary and 31 patients a secondary cardiac end point (recovery rate of 74%, 23 of 31). For NT-proBNP, higher increases from baseline were seen in patients with significant LVEF drop. Conclusion Elevated troponin I or T before trastuzumab is associated with increased risk for TRCD. A similar conclusion for NT-proBNP could not be drawn because of the lack of a well-established elevation threshold; however, higher increases from baseline were seen in patients with TRCD compared with patients without.
Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia WithNPM1Mutation: A Study by the Acute Leukemia French Association Group
Authors: Balsat Marie , Renneville Aline , Thomas Xavier , de Botton Stéphane , Caillot Denis , Marceau Alice , Lemasle Emilie , Marolleau Jean-Pierre , Nibourel Olivier , Berthon Céline , Raffoux Emmanuel , Pigneux Arnaud , Rodriguez Céline , Vey Norbert , Cayuela Jean-Michel , Hayette Sandrine , Braun Thorsten , Coudé Marie Magdeleine , Terre Christine , Celli-Lebras Karine , Dombret Hervé , Preudhomme Claude , Boissel Nicolas 
Published: February 2017

PurposeThis study assessed the prognostic impact of postinduction NPM1-mutated ( NPM1m) minimal residual disease (MRD) in young adult patients (age, 18 to 60 years) with acute myeloid leukemia, and addressed the question of whether NPM1m MRD may be used as a predictive factor of allogeneic stem cell transplantation (ASCT) benefit.Patients and MethodsAmong 229 patients with NPM1m who were treated in the Acute Leukemia French Association 0702 (ALFA-0702) trial, MRD evaluation was available in 152 patients in first remission. Patients with nonfavorable AML according to the European LeukemiaNet (ELN) classification were eligible for ASCT in first remission.ResultsAfter induction therapy, patients who did not achieve a 4-log reduction in NPM1m peripheral blood-MRD (PB-MRD) had a higher cumulative incidence of relapse (subhazard ratio [SHR], 5.83; P < .001) and a shorter overall survival (OS; hazard ratio [HR], 10.99; P < .001). In multivariable analysis, an abnormal karyotype, the presence of FLT3-internal tandem duplication (ITD), and a < 4-log reduction in PB-MRD were significantly associated with a higher relapse incidence and shorter OS. In the subset of patients with FLT3-ITD, only age, white blood cell count, and < 4-log reduction in PB-MRD, but not FLT3-ITD allelic ratio, remained of significant prognostic value. In these patients with nonfavorable AML according to European LeukemiaNet, disease-free survival and OS were significantly improved by ASCT in those with a < 4-log reduction in PB-MRD. This benefit was not observed in those with a > 4-log reduction in PB-MRD, with a significant interaction between ASCT effect and PB-MRD response ( P = .024 and .027 for disease-free survival and OS, respectively).ConclusionOur study supports the strong prognostic significance of early NPM1m PB-MRD, independent of the cytogenetic and molecular context. Moreover, NPM1m PB-MRD may be used as a predictive factor for ASCT indication.
Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months
Authors: Leijen Suzanne , van Geel Robin M.J.M. , Sonke Gabe S. , de Jong Daphne , Rosenberg Efraim H. , Marchetti Serena , Pluim Dick , van Werkhoven Erik , Rose Shelonitda , Lee Mark A. , Freshwater Tomoko , Beijnen Jos H. , Schellens Jan H.M. 
Published: February 2017

Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)–mutated ovarian cancer refractory or resistant (< 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies. Patients and Methods Patients were treated with carboplatin (area under the curve, 5 mg/mL⋅min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression. Results AZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff. Conclusion To our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (< 3 months) to first-line therapy warrants further development.
Association Between Out-Of-Pocket Costs, Race/Ethnicity, and Adjuvant Endocrine Therapy Adherence Among Medicare Patients With Breast Cancer
Authors: Farias Albert J. , Du Xianglin L. 
Published: February 2017

Purpose Previous studies suggest that adherence to adjuvant endocrine therapy (AET) for patients with breast cancer is suboptimal, especially among minorities, and is associated with out-of-pocket medication costs. This study aimed to determine whether there are racial/ethnic differences in 1-year adherence to AET and whether out-of-pocket costs explain the racial/ethnic disparities in adherence. Methods This retrospective cohort study used the SEER-Medicare linked database to identify patients ≥ 65 years of age with hormone receptor–positive breast cancer who were enrolled in Medicare Part D from 2007 to 2009. The cohort included non-Hispanic whites, blacks, Hispanics, and Asians. Out-of-pocket costs for AET medications were standardized for a 30-day supply. Adherence to tamoxifen, aromatase inhibitors (AIs), and overall AET (tamoxifen or AIs) was assessed using the medication possession ratio (≥ 80%) during the 12-month period. Results Of 8,688 patients, 3,197 (36.8%) were nonadherent to AET. Out-of-pocket costs for AET medication were associated with lower adjusted odds of adherence for all four cost categories compared with the lowest category of ≤ $2.65 ( P < .01). In the univariable analysis, Hispanics had higher odds of adherence to any AET at initiation (OR, 1.30; 95% CI, 1.07 to 1.57), and blacks had higher odds of adherence to AIs at initiation (OR, 1.27; 95% CI, 1.04 to 1.54) compared with non-Hispanic whites. After adjusting for copayments, poverty status, and comorbidities, the association was no longer significant for Hispanics (OR, 0.95; 95% CI, 0.78 to 1.17) or blacks (OR, 0.96; 95% CI, 0.77 to 1.19). Blacks had significantly lower adjusted odds of adherence than non-Hispanic whites when they initiated AET therapy with tamoxifen (OR, 0.54; 95% CI, 0.31 to 0.93) after adjusting for socioeconomic, clinic, and prognostic factors. Conclusion Racial/ethnic disparities in AET adherence were largely explained by women's differences in socioeconomic status and out-of-pocket medication costs.
Obesity and Other Cancers
Authors: Yang Lin , Drake Bettina F. , Colditz Graham A. 
Published: February 2017

Purpose Evidence on overweight, obesity, and an increased risk of cancer continues to accumulate and was updated in the 2016 handbook on weight control from the International Agency for Research on Cancer (IARC). The underlying primary data, together with dose-response meta-analysis and, finally, pooled analysis of individual participant data, add insight into the relation between obesity and cancer risk and prognosis. We summarize the evidence for mortality from prostate cancer, hematologic malignancies, and kidney cancer. Methods We reviewed pooled analysis of rare end points across cohorts, regardless of primary results reported from the individual studies, further reducing risk of publication bias. Of these cancer sites, only kidney cancer was included in the IARC 2002 report, although mortality from prostate cancer and hematologic malignancies was noted in the American Cancer Society prospective cohort study in 2003. The 2016 update from the IARC added details for prostate and hematologic malignancies, classifying the evidence as sufficient to conclude that avoiding excess body fatness lowers the risk of multiple myeloma but found that the evidence for it lowering the risk of prostate cancer mortality or diffuse large B-cell lymphoma was limited. Results A higher body mass index is associated with an increased risk of advanced prostate cancer and prostate cancer mortality and is associated with worse survival in most subtypes of hematologic malignancies, in a dose-response fashion. Evidence for kidney cancer is built mostly on retrospective data, which supports an obesity paradox in patients with the clear cell variant; however, population-based cohort data indicate that a higher cohort-entry body mass index is associated with worse kidney cancer–specific survival. Conclusion Together, these data add support to the evidence for a growing cancer burden caused by adiposity in both early adult and later adult life, yet leave open the question of the means of weight management after diagnosis as a strategy to improve survival.
Exploring the Relationship Between Patient Age and Cancer-Specific Survival in Papillary Thyroid Cancer: Rethinking Current Staging Systems
Authors: Adam Mohamed Abdelgadir , Thomas Samantha , Hyslop Terry , Scheri Randall P. , Roman Sanziana A. , Sosa Julie A. 
Published: February 2017

Purpose Patient age is considered to play a unique prognostic role in papillary thyroid cancer (PTC), with a distinct staging dichotomization at 45 years of age. This is based on older, limited data demonstrating a marked rise in mortality around the ages of 40 to 50 years. We hypothesized that age is associated with compromised survival from cancer, with no cutoff denoting survival difference. Patients and Methods Patients with PTC who had surgery were identified from the SEER database (1998 to 2012). Multivariable proportional hazards modeling utilizing several flexible smoothing approaches were used to examine the association between age and cancer-specific survival (CSS) and to determine whether there is an age cut point that is associated with CSS decrement. Results A total of 31,802 patients with PTC were included. Median age was 45 years (range, 2 to 105 years). Ten-year CSS according to age was as follows: 2 to 19 years, 99.8%; 20 to 29 years, 99.9%; 30 to 39 years, 99.8%; 40 to 49 years, 99.5%; 50 to 59 years, 98.1%; 60 to 69 years, 94.8%; 70 to 79 years, 91.5%; 80 to 89 years, 79.2%; and ≥ 90 years, 73.9%. After adjustment for patient demographic and clinicopathologic characteristics, increasing age was associated with increasing mortality from the disease in a dose-dependent fashion, without an apparent cut point. Each of the smoothing approaches demonstrated a similar linearity of risk over all ages and provided close measures of goodness of fit to the data. Conclusion Patient age is significantly associated with death from PTC in a linear fashion, without an apparent age cut point demarcating survival difference. These results challenge the appropriateness of a patient age cut point in current staging systems for PTC and argue for considering a revision in how we anticipate prognosis for patients with PTC.