tbuckley/cabot-search huggingface dataset:
Comparison of adverse events during capecitabine versus 5-fluorouracil/oxaliplatin adjuvantchemotherapy for stage II/III colon cancer: A population based analysis.
Authors: Aliyah Pabani, Matthew Mazurek, Winson Y. Cheung, Jennifer L. Spratlin, Julie A. Price Hiller, Leah Jean Standeven, Karen E. Mulder, Sunita Ghosh, Maria Yi Ho
Journal: Journal of Clinical Oncology (2015)

e14663 Background: 5-fluorouracil (5FU)/oxaliplatin adjuvant chemotherapy following curative-intent surgery was shown to improve survival for patients who have stage III colon cancer with acceptable toxicity. In addition, data from randomized trials and meta-analyses indicate that 5FU-based chemotherapy may offer benefit in patients with resected high risk stage II disease. Little is known about the rates of oxaliplatin induced toxicities in the real-world population. The objectives of the present study are to 1) examine whether oxaliplatin-containing chemotherapy regimens result in measurable differences in toxicity experienced by patients versus capecitabine in the context of usual care and 2) to determine if oxaliplatin causes additional toxicities versus capecitabine in patients ≥ 75 years. Methods: Patients with stage II and III primary adenocarcinoma of the colon who received 5FU/oxaliplatin or capecitabine adjuvant chemotherapy at the Cross Cancer Institute between 2004 and 2007 were identified from the Alberta Cancer Registry. Hospitalizations, emergency room (ER) visits, and outpatient adverse events (AEs) were captured by chart review from 30 days to 9 months post resection. We conducted multivariate logistic regression analyses to determine the factors for binary outcome variable (5FU/oxaliplatin vs. capecitabine). Results: 280 patients with complete medical records were identified. 51 % (n = 143) were male; median age was 72 (26-92) years. Patients < 75 years were more likely to receive 5FU/oxaliplatin compared to those ≥ 75 years (OR 11.99; P < 0.0001). Hospitalizations, ER visits and AEs were the same in patients who received 5FU/oxaliplatin versus those who received capecitabine alone (see Table). In addition, adverse outcomes were not increased by oxaliplatin for patients ≥ 75 years versus those < 75 years. The 60-day mortality rate was 0% in all subgroups. Conclusions: Adjuvant chemotherapy with 5FU/oxaliplatin did not result in incremental harms compared to capecitabine alone in patients with stage II and III colon cancer. There were no additional adverse outcomes observed in patients ≥ 75 years.
Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib
Authors: A.J. Schoenfeld, K.C. Arbour, H. Rizvi, A.N. Iqbal, S.M. Gadgeel, J. Girshman, M.G. Kris, G.J. Riely, H.A. Yu, M.D. Hellmann
Journal: Annals of Oncology (2019)
A phases II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study.
Authors: John K. Chan, Wei Deng, Robert Higgins, Albert J. Bonebrake, Michael Hicks, Krishnansu Sujata Tewari, Stephanie Gaillard, Pedro T Ramirez, Bradley J. Monk
Journal: Journal of Clinical Oncology (2015)

e16599 Background: Brivanib (BMS582664) is an oral, multi-targeted tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) which are involved in tumor progression of cervical cancers. We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients. Methods: Eligible patients had at least one prior cytotoxic regimen, measurable disease, and GOG performance status of at most 2. Brivanib 800 mg was administered orally every day (one cycle = 28 days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at 6 months and objective tumor response. A 2-stage bivariate design was implemented. The study was designed to determine if the drug had a response rate of at least 15% or PFS at 6 months of 20%. Results: From 2011-2012, 28 patients were enrolled and evaluable (median age: 46.5 years). 23 (82%) were White, 3 (11%) Black, 1 (4%) Asian / Pacific Islander, and 1 (4%) Hispanic. Performance status of 0, 1, and 2 comprised of 19, 8, and 1 patient(s). The majority (68%) had squamous cell carcinoma. 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had two prior chemotherapy regimens. Twelve (43%) had more than 2 cycles of Brivanib with 4 receiving more than 10 cycles (range: 1-20). 5 (18%) patients had PFS ≥ 6 months (90% CI: 7.3%–33.9%). Two (7%) (90% CI: 1.3%–20.8%) patients had partial tumor response with duration of 8 and 17 months. 12 (43%) had stable disease. The median PFS was 3.2 (90% CI: 2.1–4.4) months. The median overall survival was 8.6 (90% CI: 6.1–11.7) months. More common grade 3 adverse events at least possibly related to Brivanib were hypertension (4), anemia (3), hyponatremia (3), hyperglycemia (2), elevated liver enzymes (2), nausea (2), headache (2) and colon hemorrhage (1). Grade 4 adverse events included sepsis (1) and hypertension (1). Conclusions: Based on these early results of this phase II trial, Brivanib was well tolerated and demonstrated sufficient efficacy to proceed to 2nd stage. However, the trial was stopped due to lack of drug availability. Clinical trial information: NCT01267253.
Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial
Authors: Geoffrey A. Block, David P. Rosenbaum, Andrew Yan, Glenn M. Chertow
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Phosphate binders are currently the only medications available to reduce elevated serum phosphate in patients with ESRD receiving hemodialysis. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), acts via a non–phosphate-binding mechanism, reducing paracellular phosphate transport in the intestine. The authors found that tenapanor significantly lowered elevated serum phosphate in patients receiving hemodialysis, resulting in a mean reduction of 1.0–1.2 mg/dl over 8 weeks. Tenapanor also showed a significant benefit over placebo in patients rerandomized to either continue tenapanor treatment or receive a placebo for 4 weeks. Adverse effects were largely limited to softening of stool and more frequent bowel movements. By targeting paracellular phosphate transport’s substantial contribution to net phosphate absorption in the gut, tenapanor has the potential to improve management of mineral bone disorder in CKD. Background Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular phosphate transport. Methods In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg [the latter down-titrated, if needed]) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week ‘withdrawal’ period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group. Results Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg [down-titrated] dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor’s mechanism of action. Conclusions Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.
Abstract 15799: Body Mass Index Modulates Symptomatic Atrial Fibrillation Burden
Authors: Deanna Dickerman, Brandon Chalazan, Ben Shoemaker, Dawood Darbar
Journal: Circulation (2015)

Introduction: Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity and increased mortality. Approximately fifty percent of patients have AF-related symptoms and require rhythm control therapy with antiarrhythmic drugs (AADs) or cathether ablation. Obesity is increasingly recognized as an important risk factor for the development of AF. Hypothesis: We assessed the hypothesis that body mass index (BMI) modulates AF symptom severity. Methods: Cross-sectional data was collected from 1429 patients in the Vanderbilt AF Registry. AF burden was assessed using the Toronto Atrial Fibrillation Severity Scale (AFSS), a validated survey tool measuring the frequency, duration and severity of AF episodes. BMI was categorized according to WHO guidelines, with BMIs of 18.5 kg/m 2 -25 kg/m 2 considered normal, 25 kg/m 2 -30 kg/m 2 overweight, 30 kg/m 2 -35 kg/m 2 obese and &gt;35 kg/m 2 morbidly obese. Patients were grouped according to their current AF treatment regimen; no treatment (n=195), rate control with AV-nodal blocking agents (n=388), rhythm control with AADs (n=678) and prior AF ablation (n=220). Results: Morbidly obese patients had higher AFSS scores than normal and overweight patients in the rate control (43.57 vs 38.21: P=0.0057), AAD (46.61 vs. 41.08: P=0.00016) and ablation (44.01 vs. 39.02: P=0.047) groups. In univariate linear models, BMI was associated with an increase in the AFSS score in the rate control (0.27, 95% CI 0.05-0.5, P=0.0181), AAD (0.38, 95% CI 0.21-0.56, P=2.49 x 10 -5 ) and ablation (0.38, 95% CI 0.03-0.73, P=0.033) groups. The association remained significant in the AAD group after adjusting for age, gender, race, and comorbidities (0.29, 95% CI 0.11-0.49, P=0.0024). Conclusion: In conclusion, our results showed that obesity and increasing BMI were associated with a significant increase in patient-reported measures of AF symptom severity and frequency of AF episodes. The association was most significant in patients on rhythm control therapy with AADs. Further research is needed to determine whether this finding is due to an overlap between subjective obesity-related and AF-related symptoms, or whether obesity may modulate response to rhythm control therapies.
The role of enzalutamide-induced hyperactive Jak2-Stat5 feed-forward signaling loop on enzalutamide-resistant prostate cancer growth and as a therapeutic target for second-line treatment.
Authors: Vindhya Udhane, Cristina Maranto, David Hoang, Andrew Erickson, Savita Devi, Kenneth Jacobsohn, Kenneth Iczkowski, William See, Deepak Kilari, Tuomas Mirtti, Marja Nevalainen
Journal: Journal of Clinical Oncology (2019)

221 Background: Androgen targeted therapy remains the mainstay for advanced prostate cancer (PC). Second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ), re-targets persistent AR activity in castrate-resistant (CR) PC tumors, and is approved for CRPC. Despite initial clinical activity, acquired resistance to ENZ arises rapidly and most patients succumb to PC. Mechanisms underlying resistance to ENZ are incompletely understood. Prior work has established Stat5 as a potent inducer of PC growth. Here, we investigated the significance of Jak2-Stat5 signaling in ENZ-resistant growth of PC. Methods: Levels of Jak2 and Stat5 activation in PC cells, tumors and patient samples were evaluated by immunohistochemistry, 3D tumor explant cultures and western blotting. Jak2 and Stat5 were inhibited by lentiviral (expression of) shRNA or pharmacologically. Levels of mRNA were assessed by QPCR and gene expression profiling. Results: ENZ induced a robust increase in Stat5 activation in PC cells in vitro, in xenograft tumors in vivo and in patient-derived PCs during ENZ treatment. Mechanistically, ENZ activation of Stat5 involves a positive feed-forward mechanism where ENZ-liganded AR induces rapid and sustained Jak2 phosphorylation in PC cells through a process involving Jak2-specific phosphatases. This results in a formation of a positive feed-forward loop in PC where activated Stat5 induces Jak2 mRNA and protein levels in PC. We showed that active Stat5 increased viability of PC cells during ENZ treatment and, at the same time, inhibition of Stat5 as a second-line treatment induced excessive death of PC cells surviving ENZ treatment. Importantly, pharmacological Stat5 blockade inhibited CR growth of PC xenograft tumors after ENZ resistance developed. Conclusions: Collectively, this work introduces a novel concept for a pivotal role of Jak2-Stat5 signaling in mediating resistance of PC to ENZ. Pharmacological Jak2-Stat5 inhibition may provide efficacious therapy in advanced PC in combination with ENZ or after ENZ fails.
High Sv2A Expression in Tumor and Peritumoral Tissue in Glioma Patients with Epilepsy Is Associated with High Efficacy of Levetiracetam
Authors: M. de Groot, E Aronica, C.J. Vecht, S.T. Toering, J.J. Heimans, J.C. Reijneveld
Journal: Neuro-Oncology (2010)
Extramedullary relapses after allogeneic stem cell transplantation for leukemia: Clinical characteristics, cumulative incidence and risk factors.
Authors: Hakan Goker, Gursel Gunes, Haluk Demiroglu, Umit Yavuz Malkan, Ibrahim Haznedaroglu, Nilgun Sayinalp, Sezgin Etgul, Eylem Eliacik, Tuncay Aslan, Ayse Isik, Seda Aydin, Suayib Yalcin, Salih Aksu, Osman I. Ozcebe, Yahya Buyukasik
Journal: Journal of Clinical Oncology (2015)

e18005 Background: In acute leukemia (AL) relapse after allogeneic stem cell transplantation (ASCT) is a devastating complication. Although this problem has been well studied in the literature there are limited systematic data on extramedullary (EM) relapse. In this study we aimed to evaluate EM relapse in an AL and CML ASCT cohort including its patterns, cumulative incidence and risk factors. Methods: 131 ASCT patients (57 F, 74 M; median age, range: 35, 17-66; 51 ALL, 61 AML, 12 CML, 7 others) transplanted between June 2001 and September 2014 were analyzed retrospectively. Results: Types of transplantations were reduced intensity conditioning in 105 and myeloablative in 26 patients. The conditioning regimens were Bu/Flu/ATG, Mel/Flu, total body irradiation (TBI) based regimens, Bu/Cy, Bu/Flu and its variants. Relapse was observed in 53 patients. Types of the relapses were bone marrow (BM) in 31, BM and EM in 18 [14 central nervous system (CNS), 2 breast, 2 bone, kidney, and mediastinum 1 each] and isolated EM in 5 patients (2 bone, CNS, skin, testicle 1 each). Significantly more frequent EM relapses were observed in ALL compared to AML or CML, (chi-squared test, p = .02). Only-BM relapse and non-relapse mortality were accepted as competing risks for cumulative extramedullary relapse (CEMR) incidence. EM relapse and non-relapse mortality were considered as competing risks for cumulative only-BM relapse (CBMR) incidence. Estimated CBMR and CEMR incidences [ratio (standard error)] at 60 months were 13.6 (5.3) % and 29.3 (7.5) % in ALL, 26.9 (6) % and 10.8 (4.2) % in AML, and 47.9 (17.1) % and 10.4 (10.6) % in CML (competing risk analyzes by Gray’s test, p = .01 for CBMR incidence and p = .16 for CEMR incidence). Only type of conditioning regimen (p = .06) and GVHD status were found to be related with EM relapse risk. GVHD significantly decreased the EM relapse risk (Cox regression analysis, Exp(B) = 3.46, p = .01). EM relapse risk was lower with TBI-based regimens and significantly higher with Mel/Flu and its variants. Conclusions: EM relapse is quite frequent after ASCT, especially in ALL. GVHD and TBI-based regimens may prevent this devastating complication.
Beyond MYD88: Implications of TNFAIP3 Loss on MYD88 Driven Lymphomas
Authors: Kerstin Wenzl, Michelle Manske, Anna Muse, Yan W Asmann, Matthew J Maurer, Thomas E Witzig, Susan L Slager, Stephen M Ansell, James R. Cerhan, Anne J Novak
Journal: Blood (2017)
Non-invasive ventilation versus high-flow nasal cannula oxygen therapy with apnoeic oxygenation for preoxygenation before intubation of patients with acute hypoxaemic respiratory failure: a randomised, multicentre, open-label trial
Authors: Jean-Pierre Frat, Jean-Damien Ricard, Jean-Pierre Quenot, Nicolas Pichon, Alexandre Demoule, Jean-Marie Forel, Jean-Paul Mira, Rémi Coudroy, Guillaume Berquier, Benoit Voisin, Gwenhaël Colin, Bertrand Pons, Pierre Eric Danin, Jérome Devaquet, Gwenael Prat, Raphaël Clere-Jehl, Franck Petitpas, Emmanuel Vivier, Keyvan Razazi, Mai-Anh Nay, Vincent Souday, Jean Dellamonica, Laurent Argaud, Stephan Ehrmann, Aude Gibelin, Christophe Girault, Pascal Andreu, Philippe Vignon, Laurence Dangers, Stéphanie Ragot, Arnaud W Thille, Delphine Chatellier, Florence Boissier, Anne Veinstein, René Robert, Céline Deletage-Métreau, Morgane Olivry, Claire Dahyot-Fizelier, Auguste Dargent, Audrey Large, Emmanuelle Begot, Claire Mancia, Maxence Decavele, Martin Dres, Samuel Lehingue, Laurent Papazian, Marine Paul, Nathalie Marin, Matthieu Le Meur, Mohammed Laissy, Anaita Rouzé, Saad Nseir, Matthieu Henry-Lagarrigue, Aihem Yehia, Frédéric Martino, Charles Cerf, Pierre Bailly, Julie Helms, Jean Baptiste Putegnat, Armand Mekontso-Dessap, Thierry Boulain, Pierre Asfar, Séverin Cabasson, Florent Wallet, Kada Klouche, Frédéric Bellec, Delphine Chatellier, Florence Boissier, Anne Veinstein, René Robert, Céline Deletage-Métreau, Morgane Olivry, Maxence Decavele, Martin Dres, Samuel Lehingue, Laurent Papazian, Matthieu Le Meur, Mohammed Laissy, Anaita Rouzé, Saad Nseir, Matthieu Henry-Lagarrigue, Aihem Yehia, Charles Cerf, Armand Mekontso-Dessap, Thierry Boulain, Pierre Asfar
Journal: The Lancet Respiratory Medicine (2019)
Randomized phase III trial of adjuvant sequential chemotherapy plus radiotherapy versus adjuvant radiotherapy alone for locally advanced bladder cancer after radical cystectomy: Urothelial carcinoma subgroup analysis.
Authors: Mohamed S. Zaghloul, John Paul Christodouleas, Wei-Ting Hwang, Andrew Smith, Ahmed Abdalla, Hany William, Brian Christopher Baumann
Journal: Journal of Clinical Oncology (2019)

351 Background: The role of post-operative chemotherapy after radical cystectomy (RC) is not well-defined. While some retrospective studies have shown a benefit, trials have been under-powered. In a phase III Egyptian trial, we evaluated the benefit of adjuvant chemo in locally advanced bladder cancer (LABC) patients treated with post-operative radiotherapy (PORT). In this study, we report a post-hoc subgroup analysis of patients with urothelial histology. We hypothesized that the addition of adjuvant chemo would improve disease-free survival (DFS) compared to PORT alone for LABC. Methods: A randomized phase III trial was opened to compare PORT vs. sequential chemo+PORT after RC for LABC &amp; accrued from 2002–2008 at the NCI in Cairo. Bladder cancer pts ≤70 with at least one of the following factors (≥pT3b, grade 3, positive nodes) with negative margins after RC plus pelvic node dissection were eligible. RT was delivered using 3-D conformal RT to the pelvis to 45Gy in 1.5Gy BID. Chemo+PORT included 2 cycles of gemcitabine/cisplatin before &amp; after RT. The primary endpoint was DFS. Secondary endpoints included overall survival (OS) &amp; late GI toxicity. Results: 153 pts were enrolled. 53% had urothelial carcinoma (41 chemo+PORT &amp; 40 PORT). In the urothelial cohort, the arms were well-balanced. Median age was 55. Median follow-up was 21 months for chemo+PORT (range 4-127) &amp; 15 months for PORT (range 5-70). There were 2 local failures for PORT &amp; none for chemo+PORT. Two-year DFS for chemo+PORT vs. PORT was 62% (95% CI 53-71%) &amp; 48% (95% CI 39-58%), log-rank p=0.031. Two-year OS was 71% (95% CI 63-80%) &amp; 51% (95% CI 40-61%), log-rank p=0.048. On multivariable analysis, chemo+PORT was a significant predictor of improved DFS (HR 0.42 95% CI 0.21-0.85, p=0.016) and OS (HR 0.45, 95% CI 0.21-0.96, p=0.039). In the entire cohort, late grade ≥3 GI toxicity was observed in 5 chemo+PORT patients (7%) &amp; 6 PORT patients (8%). Conclusions: The addition of adjuvant chemo to PORT improved DFS &amp; OS for LABC after RC with acceptable late GI toxicity. The results suggest a role for adjuvant therapies to address both local &amp; distant disease. Clinical trial information: 01734798.
HERC3-Mediated SMAD7 Ubiquitination Degradation Promotes Autophagy-Induced EMT and Chemoresistance in Glioblastoma
Authors: Hong Li, Junjie Li, Lei Chen, Songtao Qi, Shishi Yu, Zhijian Weng, Ziyou Hu, Qiang Zhou, Zong Xin, Linyong Shi, Liyi Ma, Annie Huang, Yuntao Lu
Journal: Clinical Cancer Research (2019)

Glioblastoma, a common malignant intracranial tumor, has the most dismal prognosis. Autophagy was reported to act as a survival-promoting mechanism in gliomas by inducing epithelial-to-mesenchymal transition (EMT). Here, we determined the critical molecules involved in autophagy-induced EMT and elucidated the possible mechanism of chemoradiotherapy resistance and tumor recurrence.We used isobaric tags for relative and absolute quantitation to identify the critical proteins and pathway mediating EMT via autophagy inducer treatment, and tested the expression of these proteins using tissue microarray of gliomas and clinical glioblastoma samples as well as tissues and cells separated from the core lesion and tumor-peripheral region. Analysis of the Cancer Genome Atlas database and 110 glioblastoma cases revealed the prognostic value of these molecules. The functional role of these critical molecules was further confirmed by in vitro experiments and intracranial xenograft in nude mice.Autophagy inducers significantly upregulated the expression of HERC3, which promotes ubiquitination-mediated degradation of SMAD7 in an autolysosome-dependent manner. The corresponding increase in p-SMAD2/3 level and TGFβ pathway activation finally induced EMT in cell lines and primary glioblastoma cells. Moreover, HERC3 overexpression was observed in pseudo-palisade cells surrounding tumor necrosis and in tumor-adjacent tissue; high HERC3 and low SMAD7 levels predicted poor clinical outcome in glioblastoma; xenograft of nude mice and in vitro experiments confirmed these findings.Together, our findings reveal the indispensable role of HERC3 in regulating canonical SMAD2/3-dependent TGFβ pathway involvement in autophagy-induced EMT, providing insights toward a better understanding of the mechanism of resistance to temozolomide and peripheral recurrence of glioblastoma.