tbuckley/cabot-search huggingface dataset:
A randomized phase II study of cetuximab (C) every 2 weeks at either 500 or 750 mg/m<sup>2</sup> for patients (Pts) with recurrent or metastatic (R/M) head and neck squamous cell cancer (HNSCC).
Authors: M. G. Fury, E. J. Sherman, D. M. Lisa, N. Agarwal, K. M. Algazy, B. Brockstein, C. J. Langer, D. Lim, R. Mehra, S. K. Rajan, N. Jafri, S. Korte, B. Lipson, F. Yunus, T. Tanvetyanon, S. Smith-Marrone, K. K. Ng, H. Xiao, S. Haque, D. G. Pfister
Journal: Journal of Clinical Oncology (2011)

5563 Background: Conventional dosing of C (400 mg/m2 loading dose, 250 mg/m2 weekly) yields response rate of approximately 13% among pts with R/M HNSCC. Conventional weekly dosing of C may not saturate EGFR adequately (Clin Cancer Res 7:1204), and can be inconvenient for pts. C can safely be administered every 2 weeks (Q2W) at high doses (between 400 and 700 mg/m2) for pts with metastatic colorectal cancer (Ann Oncol 21: 1537). We sought to evaluate high dose C given Q2W patients with R/M HNSCC. Methods: This multicenter prospective phase II study randomized pts (≤2 prior cytotoxic chemotherapy regimens for R/M disease; ECOG PS ≤ 2) to receive C Q2W at either 500 (Group [Gp] A) or 750 mg/m2 (Gp B). The primary endpoint was response rate in each group, assessed by RECIST approximately every 8 weeks. Planned accrual was 35 pts in each group. A 2 stage Simon optimal design was used, in each arm individually, for detection of 25% response rate (power, 88.66%; 12.4% type I error). Results: 61 pts enrolled: 35 Gp A, 26 Gp B. Gp B was closed based on early stopping rule for lack of efficacy. Among all subjects, median age was 60 years (range, 37-84) with 52M, 9F; median PS, 1 (range 0-2); prior chemotherapy, 50 subjects; prior radiotherapy, 57 subjects. Primary sites of disease included oropharynx (n=30), larynx (n=11), hypopharynx (n=6), oral cavity (n=6), paranasal sinus (n=3), and unknown primary/other (n=5). 59 pts were treated. Median number of 4 week cycles administered was 2 (range 0 to 15). Most common C-related AEs (all grades) among treated subjects were rash (Gp A, 77%; Gp B, 79%), fatigue (Gp A, 63%; Gp B 79%), and hypomagnesemia (Gp A, 34%, Gp B, 50%). 5 pts (8%) experienced grade 3/4 hypersensitivity reactions and were removed from study. Partial response rates were 11% for Gp A (4/35) and 11% for Gp B (3/26) by intent to treat analysis. PFS was similar in both groups (Gp A, 65 days; Gp B, 57 days). Median overall survival for the entire population was 8.1 months. Conclusions: Cetuximab 500 mg/m2 Q2W yields similar efficacy and tolerability as conventional dosing for pts with R/M HNSCC. There is no apparent efficacy advantage associated with dose escalation to 750 mg/m2 Q2W.
Risk stratification of local-regional failure in bladder cancer after radical cystectomy.
Authors: B. C. Baumann, T. J. Guzzo, J. He, S. M. Keefe, K. Tucker, L. Magerfleisch, W. Hwang, D. J. Vaughn, S. B. Malkowicz, J. P. Christodouleas
Journal: Journal of Clinical Oncology (2011)

e15045 Background: Patients with stage ≥T2 transitional cell carcinoma (TCC) of the bladder are typically treated with radical cystectomy (RC) + pelvic node dissection (PND) +/- chemotherapy. Adjuvant radiation therapy (RT) has no clearly defined role, although local-regional failure (LF) following RC remains a significant problem. Adjuvant RT could potentially reduce LF, but the morbidity reported in the past for such RT discouraged its use. Modern RT techniques with improved normal tissue sparing have rekindled interest in adjuvant RT. Identifying subgroups with differing LF risk could facilitate patient selection for adjuvant RT protocols. Methods: From 1990 - 2008, 442 patients with TCC of the bladder were followed after RC + PND +/- chemotherapy at the Hospital of the University of Pennsylvania. 132 (30%) received neoadjuvant or adjuvant chemotherapy. LF was scored as any failure within the pelvis before or within 3 months of distant failure. Univariate, multivariate Cox regression, and recursive partitioning analyses (RPA) were performed to identify subgroups with differing LF risk. Results: On univariate analysis, stage ≥pT3, nodes removed (<10 vs. ≥10), positive margins, positive nodes (pN+), node density, hydronephrosis, lymphovascular invasion, mixed histology disease and type of surgical diversion were significant predictors of LF, while chemotherapy, gender, race and BMI were not. Age at surgery was a marginal predictor of LF. On multivariate analysis, stage ≥pT3, nodes removed (<10 vs. ≥10), positive margins, pN+ and age were significant independent predictors of LF with hazard ratios of 3.36, 2.98, 2.08, 1.84, 1.04(per yr), respectively (p <0.05 for all variables). Different cut points and definitions were explored for pT stage, pN status, number of nodes removed and chemotherapy status, but none improved the regression models. RPA identified 3 patient subgroups with significantly different LF risk (logrank/p<0.01): low (<pT3), intermediate (≥pT3 + >10 nodes), and high (≥pT3 + <10 nodes) with 5 yr LF rates of 11%, 31% and 73%. Conclusions: The risk of LF after RC varies significantly among different subgroups of TCC patients. This risk stratification model could facilitate patient selection in future trials.
Implementation of an integrative wellness program for pediatric cancer survivors at risk for cardiac late-effects.
Authors: Theresa C DiSipio, Frances Zappalla, Joanne Quillen
Journal: Journal of Clinical Oncology (2016)

168 Background: Many adult childhood cancer survivors are at risk of developing adverse health outcomes as a result of their previous diagnosis and treatments. Cardiac events are the most common cause of non-malignant mortality among pediatric cancer survivors; one in eight will develop severe cardiac disease (Lipshultz et al, 2012). The use of integrative therapies in the survivorship setting has the potential to reduce risk of developing late effects and assist with positive coping mechanisms (Kelly, 2009). Early exposure to anti-inflammatory nutrition, yoga and relaxation techniques in combination with thorough cardiac monitoring has the potential to reduce feelings of anxiety and fear of recurrence while catalyzing positive lifestyle modifications and improving overall wellness. Methods: In partnership with the Department of Cardiology at AIDHC, childhood cancer survivors at moderate-to-high risk were identified and referred for integrative cardiology consults (ICC) with a goal of providing an introduction to integrative medicine approaches, and a long-term emphasis on decreasing the incidence of future adverse cardiac events. Patients were approached during their routine post-therapy follow-up appointments. Cardiology consult orders were placed by the oncology provider through the electronic medical record (EPIC) via smart phrasing. Results: A total of 15 patients and families were approached. All 15 complied to ICC in conjunction with their routine ECHO/EKG testing. 47% of the referred patients were exposed to both anthracycline chemotherapy and radiation. 17% presented with significant cardiac related family medical history and 40% had existing comorbidities or lifestyles that may affect future cardiac health. Conclusions: Implementing an ICC standard for childhood cancer survivors at moderate-to-high risk for cardiac late-effects has been successful for AIDHC’s Cancer Survivorship Clinic and shows promise as a preventative intervention. Efficacy will be assessed by measuring patient and family knowledge pre and post ICC in the future.
Evaluation of overall survival (OS) in patients (pts) with metastatic breast cancer (MBC) according to phosphathidylinositol-3-kinase (PI3K) pathway status.
Authors: L. De Mattos-Arruda, M. Oliveira, G. Sánchez-Ollé, D. Moreno-Fernandez, B. Graña, J. Cortes, M. Bellet, S. Di Cosimo, P. Gomez Pardo, J. Rodon Ahnert, J. M. Perez-Garcia, M. Vidal, E. Muñoz-Couselo, J. Hernandez-Losa, A. Vivancos, L. Prudkin, C. Aura, J. Baselga, J. Tabernero, C. Saura
Journal: Journal of Clinical Oncology (2011)

e21130 Background: In breast cancer (BC), PI3K pathway activation is frequently identified and is a potential target for therapies currently in development. Nowadays, the role of PIK3CA mutation as a prognostic marker is controversial. The aim of this study is to determine the prognostic implications of PI3K pathway in MBC and to correlate it with BC subtypes. Methods: We analyzed 148 MBC pts. DNA was extracted from paraffin-embedded tumor tissue with EZ1 DNA Tissue Kit and was analyzed with DxS PI3K Mutation Test Kit or Sequenom MALDI-TOF MassARRAY technology. PTEN status was determined by immunohistochemistry and PTEN loss was defined as H-score ≤50. All pts signed informed consent. SPSS v.15 software was used for statistical analysis. Results: PIK3CA status was tested in 119 pts and mutations were found in 44 (37%): 26 (59%) in exon 20 [H1047R] and 18 in exon 9 [11 E545K, 5 Q546K and 2 E542K]. PIK3CA mutations were present in 35% of hormonal receptor positive BC group (HR+), 21% of HER2 positive (HER2+) and 25% of triple negative BC (TNBC). In HR+, the frequency of mutations in exon 9 was higher (52%) than in HER2+ (14%) and TNBC (25%) (p=0.057). PTEN H-score was determined in 142 pts; loss of function was present in 40 pts (28%): 23 (57%) of HR+ tumors, 10 (25%) of TNBC and 7 (18%) of HER2 +. There is no significant difference in PTEN expression between BC subtypes. PIK3CA mutation and PTEN loss of function were not mutually exclusive as 9 pts had both alterations assessed. In pts with PIK3CA mutation and/or PTEN loss OS was shorter compared to wild-type cases (p=0.009). Among those with a PI3K pathway alteration, TNBC was associated with shorter OS, but not HR+ and/or HER2+ (p=0.015). No differences were found in disease free survival among different BC subtypes. Overall, 17 pts were enrolled in a PI3K-pathway inhibitor phase 1 clinical trial. Conclusions: In our BC population, the prevalence of the different PIK3CA mutations and PTEN loss rates correlates with previous published data. A higher frequency of exon 9 mutations was found in HR+ compared with HER2+ and TNBC. In our database, PI3K pathway alteration is associated with lower OS, especially among TNBC pts.
Pharmacogenetic dosing by UGT1A1 genotype as first-line therapy for advanced small-bowel adenocarcinoma: A North Central Cancer Treatment Group (NCCTG) trial.
Authors: Robert R. McWilliams, Michelle R. Mahoney, Benjamin T. Marchello, Aminah Jatoi, Keith D. Krewer, Matthew M. Ames, Daniel Jay Schneider, Grant R. Seeger, Rex B. Mowat, Steven R. Alberts, Matthew P. Goetz
Journal: Journal of Clinical Oncology (2012)

314 Background: Small bowel adenocarcinoma (SB-ACA) is rare, having little prospective data guiding management. A prior phase I study evaluated UGT1A1 genotype specific dosing of oxaliplatin, irinotecan, and capecitabine. Our prospective, multicenter clinical trial assessing tumor response in pts having metastatic SB-ACA, used a similar dosing strategy. Methods: Genotypes were determined via central lab. Previously untreated pts were dosed by UGT1A1*28 genotypes 6/6, 6/7, and 7/7 receiving 100/85/85 mg/m 2 oxaliplatin d1, 150/150/75 mg/m 2 irinotecan d1, and 1600/400/200 mg/m 2 capecitabine (BID) d2-15 of 21 days. The study design was such that 1 confirmed response in 16 pts expanded enrollment to 33 pts, with 7 required for demonstrating efficacy. Results: 28 pts (13-6/6, 10-6/7, 5-7/7) have been enrolled [75% male, mean age 62.5 (range 41-77)]. Location of primary included: duodenum (63%), jejunum (26%), and ileum (7%), with pts having &gt;1 metastatic site (abdominal-41%, bone-7%, liver-56%, lung-30%, nodal-52%, subcutaneous-4%, other-19%). Gr 3+ treatment related toxicity was not significantly different by genotype (50%-6/6, 44%-6/7, 20%-7/7, p=0.48) and included (pts): diarrhea(5), vomiting(5), leukopenia(5), neutropenia(7), and nausea(6). 57% (13 of 23) pts achieved responses during therapy, with a confirmed response rate of 39% (95% CI 0-58%). 18 have died, with a median follow-up of 8.3 mos (range 0-43). Conclusions: UGT1A1 genotype directed dosing with oxaliplatin, irinotecan, and capecitabine appears to result in prolonged response in this population. Larger studies are needed to determine comparability to CapeOx alone or if response/toxicity differs among genotypes. Supported by NIH Grant CA25224, Sanofi-Aventis, and Pfizer. [Table: see text]
Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal malignancies.
Authors: Tian Zhang, Rengasamy Boominathan, Brad Foulk, Mark Carle Connelly, Chandra Rao, Gabor Kemeny, Herbert Hurwitz, Mariano A. Garcia-Blanco, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2015)

84 Background: Multiple GI malignancies including gastric, pancreatic, and colorectal cancers harbor genetic alterations in the MET oncogene. MET amplification is associated with poor prognosis, and c-MET targeted therapies are in development. We aimed to capture and identify c-MET CTCs using a non-invasive, rapid test. Methods: We modified the CELLSEARCH platform by using nanomagnetic particles conjugated to antibodies against the extracellular domain of c-MET to capture c-MET-expressing CTCs. The method was validated by spiking MET-amplified gastric cancer cells, c-MET-overexpressing, nonamplified cancer cells, and MET-negative cancer cells into peripheral blood from healthy volunteers. Peripheral blood samples were obtained from patients (pts) with refractory metastatic gastric, pancreatic, and colorectal cancers, prepared in duplicate, and characterized by immunofluorescence staining for intracellular c-MET-PE, DAPI, and pan-CK-FITC. CD45 + cells were excluded. CTC enumeration with c-MET capture was compared to EpCAM capture. After CTC isolation, MET DNA FISH was performed. Results: The novel c-MET CTC assay was found to be 80% sensitive for MET-amplified cells, 40-80% sensitive for c-MET-overexpressed cells, and 100% specific for c-MET negative cells and in 10 healthy volunteers. In 7/7 pts with metastatic pancreatic and 8/8 pts with metastatic colorectal cancers, we did not capture c-MET CTCs. Of 3 gastric cancer pts tested thus far, one pt had a significant number of c-MET + CTCs, with 52 CTCs and 90 CTCs in each of the duplicate samples, compared to 20 CTCs with EpCAM capture. CTC FISH demonstrated polysomy 7 and METamplification. This pt had HER2 amplification in primary tumor tissue and had progressed on FOLFOX and trastuzumab at the time of enrollment. Conclusions: We have developed a sensitive and specific c-MET CTC assay. c-MET-expressing CTCs can be detected in gastric cancer but not controls or other GI cancers to date. While not detectable in many pts, high levels in one pt support the importance of MET amplification as a resistance mechanism to HER2 therapy, and suggest that this approach may be useful to identify and follow patients who may be candidates for c-MET directed therapies.
Quality-of-life assessment in a randomized, double-blind study of sipuleucel-T in men with androgen-dependent prostate cancer.
Authors: T. M. Beer, P. F. Schellhammer, J. M. Corman, L. M. Glode, S. Hall, Y. Xu, M. W. Frohlich, D. F. Penson
Journal: Journal of Clinical Oncology (2011)

4648 Background: Sipuleucel-T is an autologous cellular immunotherapy designed to stimulate an immune response to prostate cancer. P-11 is a phase III study in men with prostate specific antigen (PSA) progression after radical prostatectomy. Following 3 to 4 months of androgen deprivation therapy (ADT), men were randomized 2:1 to treatment with sipuleucel-T or control. Methods: Quality of life (QoL) was assessed at baseline (following ADT and prior to randomization) and at Wks 13 and 26 after treatment. The global rating of change evaluated overall QoL (about the same, worse, or better) compared to baseline. The brief fatigue inventory (BFI) scored fatigue level (now, usual, and worst in last 24 hours) and fatigue interference with general activity for 6 activities. Fatigue scores ranged from 0 (none) to 10 (worst). The linear analogue scale (LAS) was based on self-assessment of state of health (0 to 100, with 100= “perfect health”). Missing data were not imputed. Results: 176 patients were randomized to sipuleucel-T (n=117) or control (n=59). 98% of subjects had a baseline QoL assessment, and 92% of subjects had at least 1 post-treatment assessment. As expected with ADT, in the 3 months prior to sipuleucel-T, QoL measures declined and were comparable in both arms. Following initiation of study treatment, no significant differences in QoL were observed between treatment groups (Table). Conclusions: Sipuleucel-T can be administered without negative effects on QoL in this patient population. Baseline Week 13 Week 26 Sipuleucel-T Control Sipuleucel-T Control Sipuleucel-T Control N 116 57 103-105 58-59 91-92 52-53 Global QOL Change Better NA NA 18.4% 13.8% 15.2% 11.3% Same NA NA 73.8% 82.8% 77.2% 81.1% Worse NA NA 7.8% 3.4% 7.6% 7.5% Fatigue (0-10) Worst severity Mean (SE) 2.0 (0.24) 2.2 (0.37) 1.8 (0.23) 2.2 (0.38) 1.6 (0.26) 1.6 (0.35) Average interference Mean (SE) 1.1 (0.17) 1.1 (0.24) 1.0 (0.16) 0.9 (0.20) 0.9 (0.19) 0.9 (0.21) LAS (0-100%) Mean (SE) 83.5% (1.22) 82.1% (1.62) 83.4% (1.25) 81.7% (1.71) 83.2% (1.18) 80.8% (1.91)
Regional acidosis locally inhibits but remotely stimulates Ca2+ waves in ventricular myocytes
Authors: Kerrie L. Ford, Emma L. Moorhouse, Mario Bortolozzi, Mark A. Richards, Pawel Swietach, Richard D. Vaughan-Jones
Journal: Cardiovascular Research (2017)

Spontaneous Ca2+ waves in cardiomyocytes are potentially arrhythmogenic. A powerful controller of Ca2+ waves is the cytoplasmic H+ concentration ([H+]i), which fluctuates spatially and temporally in conditions such as myocardial ischaemia/reperfusion. H+-control of Ca2+ waves is poorly understood. We have therefore investigated how [H+]i co-ordinates their initiation and frequency.Spontaneous Ca2+ waves were imaged (fluo-3) in rat isolated ventricular myocytes, subjected to modest Ca2+-overload. Whole-cell intracellular acidosis (induced by acetate-superfusion) stimulated wave frequency. Pharmacologically blocking sarcolemmal Na+/H+ exchange (NHE1) prevented this stimulation, unveiling inhibition by H+. Acidosis also increased Ca2+ wave velocity. Restricting acidosis to one end of a myocyte, using a microfluidic device, inhibited Ca2+ waves in the acidic zone (consistent with ryanodine receptor inhibition), but stimulated wave emergence elsewhere in the cell. This remote stimulation was absent when NHE1 was selectively inhibited in the acidic zone. Remote stimulation depended on a locally evoked, NHE1-driven rise of [Na+]i that spread rapidly downstream.Acidosis influences Ca2+ waves via inhibitory Hi+ and stimulatory Nai+ signals (the latter facilitating intracellular Ca2+-loading through modulation of sarcolemmal Na+/Ca2+ exchange activity). During spatial [H+]i-heterogeneity, Hi+-inhibition dominates in acidic regions, while rapid Nai+ diffusion stimulates waves in downstream, non-acidic regions. Local acidosis thus simultaneously inhibits and stimulates arrhythmogenic Ca2+-signalling in the same myocyte. If the principle of remote H+-stimulation of Ca2+ waves also applies in multicellular myocardium, it raises the possibility of electrical disturbances being driven remotely by adjacent ischaemic areas, which are known to be intensely acidic.
Association of mitochondrial respiratory chain deficiency in older men with muscle mass and physical performance: findings from the Hertfordshire Sarcopenia Study
Authors: Karolina Rygiel, Richard Dodds, Harnish Patel, Holly Syddall, Leo Westbury, Antoneta Granic, Cyrus Cooper, Joshua Cliff, Mariana Rocha, Doug Turnbull, Avan Sayer
Journal: The Lancet (2017)
Clinical activity of lapatinib monotherapy in patients with HER2+ relapsed/refractory inflammatory breast cancer (IBC): Final results of the expanded HER2+ cohort in EGF103009
Authors: B. Kaufman, M. E. Trudeau, S. Johnston, A. Awada, K. L. Blackwell, T. Bachelot, V. Salazar, R. Westlund, M. Desilvio, T. Zaks
Journal: Journal of Clinical Oncology (2008)

636 Background: IBC is an uncommon (∼2–6%) form of breast cancer with a significantly worse prognosis than non-IBC. Lapatinib is a reversible, oral small molecule inhibitor of EGFR and HER-2/neu tyrosine kinases (also known as ERBB1 and ERBB2, respectively). EGF103009 was initially designed as a two stage, Green-Dahlberg study of lapatinib monotherapy in 30 subjects in each of two cohorts, HER2+ and EGFR+/HER2-. Following a 50% response rate in the first 30 HER2+ patients, this cohort was expanded to 120 patients in order to improve the precision of estimated ORR; this represents the only prospective clinical study ever conducted in HER2+ IBC. Methods: Patients with HER2+ (IHC 3+ / FISH Ampified) IBC that was refractory to anthracyclines, taxanes, and trastuzumab (where available) were enrolled. Pretreatment and day 28 fresh biopsies were collected for each subject to assay for relevant biomarkers. Patients received lapatinib daily (1,500 mg/d). Skin lesions were assessed at 4 week intervals and RECIST-measurable disease if present was assessed at 8 week intervals. Results: One hundred twenty-six HER2+ patients were treated continuously with once-daily lapatinib (1,500 mg). Final analysis is currently underway and preliminary data suggest a response rate of approximately 40%; responses were also seen in the ∼50% of patients who were trastuzumab-refractory. Most frequent toxicity was Grade I/II diarrhea and skin rash. Biomarker analyses of pretreatment tumor biopsies confirmed a molecular phenotype consistent with IBC (i.e., RhoC- and E-cadherin-overexpression); co-expression of pHER2 and pHER3 were predictive of lapatinib response. Conclusions: Lapatinib monotherapy is active in the treatment of relapsed / refractory HER2+ IBC where few effective therapies are available, and is well tolerated. Within this group, tumors that have an activated HER2/HER3 pathway appear to be more likely to respond. Final analysis of responses and their durability as well as of biomarkers predictive of responses will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Novartis, Pfizer GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline, Novartis, Roche GlaxoSmithKline