tbuckley/cabot-search huggingface dataset:
Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer
Authors: Gabriel N. Hortobagyi, Salomon M. Stemmer, Howard A. Burris, Yoon-Sim Yap, Gabe S. Sonke, Shani Paluch-Shimon, Mario Campone, Kimberly L. Blackwell, Fabrice André, Eric P. Winer, Wolfgang Janni, Sunil Verma, Pierfranco Conte, Carlos L. Arteaga, David A. Cameron, Katarina Petrakova, Lowell L. Hart, Cristian Villanueva, Arlene Chan, Erik Jakobsen, Arnd Nusch, Olga Burdaeva, Eva-Maria Grischke, Emilio Alba, Erik Wist, Norbert Marschner, Anne M. Favret, Denise Yardley, Thomas Bachelot, Ling-Ming Tseng, Sibel Blau, Fengjuan Xuan, Farida Souami, Michelle Miller, Caroline Germa, Samit Hirawat, Joyce O’Shaughnessy
Journal: New England Journal of Medicine (2016)

The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2).In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10-5.The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively.Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).
Identification Of Actionable Genomic Alterations In Hematologic Malignancies By a Clinical Next Generation Sequencing-Based Assay
Authors: Doron Lipson, Michelle K Nahas, Geoff A. Otto, Roman Yelensky, Omar Abdel-Wahab, Kai Wang, Jie He, Andrew M. Intlekofer, Raajit K. Rampal, Timothy A Brennan, Kristina M. Knapp, Kristina W Brennan, Geneva Young, Amy L Donahue, Eric M Sanford, Joel R Greenbowe, Garrett M Frampton, Alex Fichtenholtz, Lauren E Young, Rachel L Erlich, Alex Parker, David Klimstra, Ahmet Dogan, Jeffrey S Ross, Scott A. Armstrong, Philip J. Stephens, Marcel R. M. van den Brink, Vincent A. Miller, Ross L. Levine
Journal: Blood (2013)
Treatment of advanced seminoma with 3 cycles of etoposide-cisplatin chemotherapy (EP120): A single-centre retrospective cohort study.
Authors: Ankit Rohit Rao, Stephen Kihara, Paul Hutton, Michael H. Cullen, Emilio Porfiri
Journal: Journal of Clinical Oncology (2016)

e16046 Background: More than 95% of patients diagnosed with advanced seminoma are cured with chemotherapy - either 3 cycles of bleomycin (B), etoposide (E) and cisplatin (P) or 4 cycles of E-P. Radiotherapy can also be used for low-volume (Stage IIA-B) metastatic disease but may be associated with a higher risk of secondary malignancy. There is increasing emphasis on minimising late treatment toxicity in chemo-curable cancers. The optimal regimen to achieve long-term survival with minimal toxicity in advanced seminoma remains uncertain, in particular the value of bleomycin. Methods: Patients with advanced (Stage IIA and above) pure seminoma treated with etoposide 120mg/m2 days 1,2 and 3 and cisplatin 50mg/m2 day 1 and 2 (EP120) every 3 weeks for 3 cycles between the years 2000 and 2015 were retrospectively identified. Demographics, stage, clinical response, time of relapse, subsequent treatments and overall survival were recorded. Results: 117 patients were identified with a median age of 41years, and 15% were over 50 years. 96% had a testicular primary and 88% had de-novo metastatic disease. 32% had AJCC Stage IIC-IIIC disease. Two patients were in the IGCCC intermediate-risk category with hepatic and intra-gastric metastases. Just over one-third (38%) of patients had an elevated serum β-HCG level. All except one patient achieved a complete biochemical response and all patients had at least a partial radiologic response. At median follow up of 6 years, 96% (112/117) patients have been continuously relapse-free. 1 patient with hepatic metastases was chemo-refractory and died of progressive disease. 4 patients relapsed – all are alive and disease-free at 20, 53, 135 and 68 months from diagnosis. Two relapsing patients received TIP (paclitaxel, ifosphamide, cisplatin) chemotherapy, 1 para-aortic radiotherapy and one had both radiotherapy and TIP. 2 patients died of unrelated causes whilst in complete remission. Conclusions: 3 cycles of EP120 chemotherapy is well-tolerated, feasible and efficacious in advanced seminoma and merits further consideration as standard-of-care in particular in patients with good-risk disease.
Regulating Stem Cell Secretome Using Injectable Hydrogels with In Situ Network Formation
Authors: Lei Cai, Ruby E. Dewi, Andrew B. Goldstone, Jeffrey E. Cohen, Amanda N. Steele, Y. Joseph Woo, Sarah C. Heilshorn
Journal: Advanced Healthcare Materials (2016)

A family of shear-thinning hydrogels for injectable encapsulation and long-term delivery (SHIELD) has been designed and synthesized with controlled in situ stiffening properties to regulate the stem cell secretome. The authors demonstrate that SHIELD with an intermediate stiffness (200–400 Pa) could significantly promote the angiogenic potential of human adipose-derived stem cells. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Prophylactic Cranial Irradiation for Patients with Surgically Resected Small Cell Lung Cancer
Authors: Jianlin Xu, Haitang Yang, Xiaolong Fu, Bo Jin, Yuqing Lou, Yanwei Zhang, Xueyan Zhang, Hua Zhong, Huimin Wang, Dan Wu, Baohui Han
Journal: Journal of Thoracic Oncology (2016)
Epidermal growth factor receptor (EGFR) as a predictive and prognostic marker in patients with advanced colorectal cancer (aCRC): The MRC COIN trial experience.
Authors: R. A. Adams, M. D. James, C. G. Smith, R. H. Wilson, D. Fisher, S. L. Kenny, R. S. Kaplan, S. Stoerkel, T. S. Maughan, B. Jasani
Journal: Journal of Clinical Oncology (2011)

359 Background: KRAS mutation has been shown to be a more effective (though negative) biomarker for selection of patients for EGFR targeted therapy in aCRC. However, positive EGFR immunohistochemistry (IHC) remains a license requirement and was an inclusion criterion in most trials to date. The MRC COIN trial recruited 2445 pts into 3 arms of oxaliplatin + fluoropyrimidine +/- cetuximab without prior EGFR assessment. This trial provides a unique opportunity to definitively examine the role of EGFR IHC as prognostic and predictive marker and potentially the evidence required to remove this assessment from the license for this drug. Methods: Formalin-fixed paraffin embedded (FFPE) tissue was stained retrospectively for EGFR using Dako kit in a national reference lab. Results were assessed by 3 reviewers (BJ, SS, RA) using digital imaging software in a blinded fashion, then by BJ/SS providing consensus for discrepancies. EGFR scoring was assessed as a prognostic variable in association with selected patient, tumor and biochemical data. Cut off points examined for +ve vs -ve tumours, in terms of total tumour cells demonstrating membrane staining, were: 0% vs &gt;0%; &lt;10% vs ≥10%; &lt;20% vs ≥20%. Results: EGFR IHC was adequately assessed for 1621 pts (66% of randomised), 22% were negative (0%) and 78% positive (&gt;0%), balanced across arms. EGFR was not prognostic for PFS within KRAS wt pts at the standardized cut off point 0% vs &gt;0% HR=1.11 95% CI 0.91-1.36 p=0.31 but was at &lt;10% vs ≥10% (HR=1.27 95% CI 1.07-1.52 p=0.008) this was robust to other prognostic variables. No effect was seen for overall response or survival. There was no prognostic effect for the KRAS mutant group. In the 1065 assessable pts randomised to +/- cetuximab, no evidence of EGFR IHC as a predictive marker for response or survival outcomes was observed for the addition of cetuximab to chemotherapy (OS HR=1.11 95% CI 0.70-1.75 p=0.66; PFS HR=0.95 95% CI 0.64-1.43 p=0.82). Conclusions: Extensive assessment of samples from this trial suggest a role for EGFR IHC as a prognostic marker in KRAS wt aCRC but refute the predictive value embedded within the licence for cetuximab used in combination with chemo in first-line therapy. [Table: see text]
Correlation of cyclin D1, A870G, polymorphism, and clinical outcome in patients with HER2-positive, metastatic breast cancer treated with lapatinib plus capecitabine.
Authors: M. J. Labonte, D. Yang, W. Zhang, P. M. Wilson, R. D. Ladner, T. Winder, P. O. Bohanes, Y. Ning, H. Lenz
Journal: Journal of Clinical Oncology (2010)

1015 Background: The clinical trial EGF100151 (NCT00078572) demonstrated that the addition of the dual EGFR/HER2 TKI lapatinib (lap) to capecitabine (cap) significantly improved time-to-tumor progression versus cap alone in HER2-positive metastatic breast cancer (MBC) patients (pts) (median 6.2 vs. 4.3 mo; HR: 0.57; p<0.001). Response rates (RR) were 23.7% (lap+cap) vs. 13.9% (cap alone) (p=0.017). Currently no biomarkers are available that identify pts who benefit from the lap+cap combination, therefore we aimed to identify germline single nucleotide polymorphisms (SNPs) in genes involved in 5-FU metabolism and HER signaling to assist in selecting patients likely to benefit from this regimen. Methods: DNA was extracted from whole blood in 240 of 399 enrolled pts. SNPs evaluated included TYMS, MTHFR, EGF, EGFR, HER2, VEGF, IL8, COX2, and CCND1 and were analyzed using PCR based protocols. The associations between SNPs and RR and progression-free survival (PFS) were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, and likelihood ratio test within logistic or Cox regression model as appropriate. Results: SNPs were successfully genotyped in 234 pts of whom 125 received cap and 109 lap+cap. There were significant interactions between CCND1 functional A870G SNP and treatment on RR and PFS (p=0.022 and 0.024, respectively). Pts carrying CCND1 AA or AG were more likely to benefit (RR and PFS) from lap+cap vs. cap alone compared to pts harboring GG. The RR was significantly higher when treated with lap+cap (35%) compared with cap alone (11%) in patients with AA or AG (p=0.001), but not between treatment groups in pts with GG (RR=24% and 32%, respectively; p=0.85). PFS was also significantly longer in lap+cap compared with cap alone in pts with CCND1 AA or AG (median PFS=7.9 and 3.4 mo, respectively; p<0.001), but not in pts with GG (median PFS=6.1 and 4.5 mo; p=0.92). No significant interactions between treatment and other SNPs were observed. Conclusions: Although exploratory, our findings suggest that CCND1 A870G SNP may be useful in predicting clinical outcome in HER2-positive MBC pts treated with lap+cap. Prospective trials based on these correlative studies are warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
P0602 : Serologic profile and reactivation of hepatitis B in rheumatic and inflammatory bowel disease patients treated with TNF inhibitors bowel disease
Authors: S. Vítor, L Meireles, V.C. Romão, C. Freitas, S. Fernandes, M.J. Gonçalves, M.J. Saavedra, H. Canhão, J.E. Fonseca, J.A. Pereira da Silva, R.T. Marinho, J. Velosa
Journal: Journal of Hepatology (2015)
Response to Targeted Therapy in<i>BRAF</i>Mutant Anaplastic Thyroid Cancer
Authors: Rishi Agarwal, Jiang Wang, Keith Wilson, William Barrett, John C. Morris
Journal: Journal of the National Comprehensive Cancer Network (2016)

Anaplastic thyroid cancer (ATC) is an aggressive uncommon malignancy with limited treatment. Traditional antineoplastic chemotherapy has not been successful in the management of metastatic ATC. As a result, the focus has shifted to the development of novel therapies for this disease. The availability of economical comprehensive genomic profiling (CGP) platforms with rapid turn-around to identify molecular aberrations in tumors that are potential therapeutic targets has increasingly changed the face of cancer therapy. Identification of targetable aberrations may help identify novel treatment options for ATC. Herein, we report our experience with a 47-year-old patient with metastatic ATC who experienced recurrent, progressive disease and rapid clinical deterioration despite surgery, radiation therapy, and treatment with 2 different chemotherapy regimens. She was found to have a BRAF V600E mutation on CGP, and was started on targeted therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. After 2 months of treatment, she showed a clinical and radiologic response. The patient remained on this combination for 9 months until evidence of disease progression. Discontinuation of these drugs was associated with rapid tumor growth. Through this case we want to emphasize the importance of early molecular sequencing and identification of genetic aberrations in patients with ATC, and using that information to develop therapies for ATC, an aggressive malignancy with limited therapy and a poor outcome.
Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate
Authors: R. M. Witteles, M. L. Telli, G. A. Fisher, S. Srinivas
Journal: Journal of Clinical Oncology (2008)

9597 Background: In the pivotal phase III metastatic renal cell carcinoma trial, updated data indicates that 21% of sunitinib-treated patients experienced a decline in left ventricular ejection fraction to below normal. This cardiac dysfunction was previously reported to be reversible and not associated with clinical sequelae. We conducted a retrospective analysis of our institutional experience of cardiotoxicity with sunitinib after observing a higher than expected incidence of symptomatic heart failure. Methods: Patients receiving sunitinib at the Stanford University Cancer Center for either renal cell carcinoma or gastrointestinal stromal tumor from July 1, 2004 to July 1, 2007 were identified. Medical records were reviewed and those patients experiencing symptomatic Grade 3/4 left ventricular systolic dysfunction according to the Common Terminology Criteria for Adverse Events, Version 3.0 during treatment were identified. Potential cardiac risk factors were analyzed. Results: Forty-eight patients treated with sunitinib were assessable. Eighty-five percent had a diagnosis of renal cell carcinoma. Seven patients experienced symptomatic Grade 3/4 left ventricular dysfunction 22 - 435 days after initiation of sunitinib. Mean age of patients experiencing cardiotoxicity was 67 years. Three out of five patients with subsequent cardiac evaluations had persistent left ventricular dysfunction after discontinuation of sunitinib and initiation of standard heart failure therapy. A history of congestive heart failure (p = 0.002), coronary artery disease (p = 0.05) and lower body mass index (p = 0.03) were factors associated with increased risk. A non-significant trend was observed between female gender and increased risk of cardiotoxicity (p = 0.11). Conclusions: Among patients treated with sunitinib at our institution, 15% (95% CI 6.1% to 27.8%) developed symptomatic Grade 3/4 heart failure. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer
Increased Activity of the Chondrocyte Translational Apparatus Accompanies Osteoarthritic Changes in Human and Rodent Knee Cartilage
Authors: Olga Katsara, Mukundan Attur, Rachel Ruoff, Steven B. Abramson, Victoria Kolupaeva
Journal: Arthritis & Rheumatology (2016)

Degeneration of articular cartilage is central to the pathology of osteoarthritis (OA). However, the molecular mechanisms leading to these irreversible changes are still poorly understood. This study was undertaken to investigate how changes in the chondrocyte translational apparatus may contribute to the development and progression of knee OA.Articular cartilage from the knees of normal healthy subjects and patients with OA was used to analyze the activity of different components of the translational machinery. Chondrocytes isolated from lesional and nonlesional areas of the human OA cartilage were used to estimate the relative rate of protein synthesis by metabolic labeling. Experimental OA was induced by transection of the anterior cruciate ligament of rats to investigate changes in the translational apparatus associated with OA. The role of interleukin-1β (IL-1β) signaling was assessed in vitro using rat articular chondrocytes. In human or rodent knee cartilage, messenger RNA expression was analyzed by quantitative polymerase chain reaction, and protein levels were determined by immunohistochemistry and Western blotting.Several novel traits of OA chondrocytes were identified, including up-regulation of the serine/threonine kinases Akt-2 and Akt-3 at the posttranscriptional level and an increased rate of total protein synthesis, likely attributable to inactivation of eukaryotic initiation factor 4E binding protein 1 (4E-BP1), a known repressor of cap-dependent translation. Inactivation of 4E-BP1 was dependent on the activity of mechanistic target of rapamycin and was crucial for the up-regulation of protein synthesis in general and expression of matrix metalloproteinase 13 and ADAMTS-5 in particular. In addition, treatment of articular chondrocytes with IL-1β led to inactivation of 4E-BP1 and up-regulation of protein synthesis.Precise control of protein synthesis is vital for cartilage homeostasis, and its dysregulation contributes to the molecular pathology of OA. The results of this study therefore identify a novel set of potential therapeutic targets to ameliorate the effects of knee OA.
Air Pollution and Deaths among Elderly Residents of São Paulo, Brazil: An Analysis of Mortality Displacement
Authors: Amine Farias Costa, Gerard Hoek, Bert Brunekreef, Antônio C.M. Ponce de Leon
Journal: Environmental Health Perspectives (2016)

Evaluation of short-term mortality displacement is essential to accurately estimate the impact of short-term air pollution exposure on public health.We quantified mortality displacement by estimating single-day lag effects and cumulative effects of air pollutants on mortality using distributed lag models.We performed a daily time series of nonaccidental and cause-specific mortality among elderly residents of São Paulo, Brazil, between 2000 and 2011. Effects of particulate matter smaller than 10 μm (PM10), nitrogen dioxide (NO2) and carbon monoxide (CO) were estimated in Poisson generalized additive models. Single-day lag effects of air pollutant exposure were estimated for 0-, 1- and 2-day lags. Distributed lag models with lags of 0-10, 0-20 and 0-30 days were used to assess mortality displacement and potential cumulative exposure effects.PM10, NO2 and CO were significantly associated with nonaccidental and cause-specific deaths in both single-day lag and cumulative lag models. Cumulative effect estimates for 0-10 days were larger than estimates for single-day lags. Cumulative effect estimates for 0-30 days were essentially zero for nonaccidental and circulatory deaths but remained elevated for respiratory and cancer deaths.We found evidence of mortality displacement within 30 days for nonaccidental and circulatory deaths in elderly residents of São Paulo. We did not find evidence of mortality displacement within 30 days for respiratory or cancer deaths. Citation: Costa AF, Hoek G, Brunekreef B, Ponce de Leon AC. 2017. Air pollution and deaths among elderly residents of São Paulo, Brazil: an analysis of mortality displacement. Environ Health Perspect 125:349-354; http://dx.doi.org/10.1289/EHP98.
The Platelet COUNT at Diagnosis of Essential Thrombocythemia Is a Prognostic Factor for Thrombosis-Free Survival: Retrospective Analysis on 1201 Patients
Authors: Marco Montanaro, Roberto Latagliata, Michele Cedrone, Ambra Di Veroli, Cristina Santoro, Francesca Spirito, Carla Ruscio, Sabrina Leonetti-Crescenzi, Raffaele Porrini, Jonny Di Giandomenico, Nicoletta Villivà, Antonio Spadea, Angela Rago, Cinzia De Gregoris, Paolo Cercola, Barbara Anaclerico, Marianna De Muro, Stefano Felici, Massimo Breccia, Enrico Montefusco, Antonino Bagnato, Giuseppe Cimino, Ignazio Majolino, Maria Gabriella Mazzucconi, Giuliana Alimena, Alessandro Andriani
Journal: Blood (2015)
Bowel function after laparoscopic posterior sutured rectopexy versus ventral mesh rectopexy for rectal prolapse: a double-blind, randomised single-centre study
Authors: Lilli Lundby, Lene H Iversen, Steen Buntzen, Pål Wara, Katrine Høyer, Søren Laurberg
Journal: The Lancet. Gastroenterology & hepatology (2016)