tbuckley/cabot-search huggingface dataset:
Anti-tumor activity, safety and pharmacokinetics (PK) of AGS15E (ASG-15ME) in a phase I dose escalation trial in patients (Pts) with metastatic urothelial cancer (mUC).
Authors: Daniel Peter Petrylak, Elisabeth I. Heath, Guru Sonpavde, Saby George, Alicia Katherine Morgans, Bernhard J. Eigl, Joel Picus, Susanna Y. Cheng, Sebastien J. Hotte, Elaina M. Gartner, Martha Vincent, Rong Chu, Banmeet Anand, Karen Morrison, Lynnae Jackson, Leonard M. Reyno, Evan Y. Yu
Journal: Journal of Clinical Oncology (2016)

4532 Background: SLITRK6 is a cell adhesion molecule highly expressed on several tumors, including mUC. ASG-15ME is an antibody drug conjugate (ADC) that delivers a small molecule microtubule-disrupting agent, monomethyl auristatin E (MMAE), to tumor cells expressing SLITRK6. Methods: mUC pts unselected for SLITRK6 expression (determined by an IHC assay) and previously treated with ≥ 1 prior chemo regimen or unfit for Cisplatin were enrolled using a modified continual reassessment method design. Disease assessments (DA) were performed every 8 weeks (wks) using RECIST v 1.1. ASG-15ME was administered IV weekly for 3 out of every 4 wks until no further benefit. 6 dose levels were studied: 0.1, .25, .5, 0.75, 1, or 1.25 mg/kg. Results: Of analyzed tumor tissues, 85% (n=46) were SLITRK6 positive (56% had H-score ≥150). As of 1/21/16, 43 pts were enrolled. Anti-tumor activity was seen at dose levels ≥ 0.5 mg/kg (n=37 reported here). Median age= 64 y; 100% ECOG PS ≤ 1; 22 pts (56%) had ≥ 2 lines of prior therapy. 1 pt had a confirmed complete response (CR) and 10 pts had partial response (PR) (ORR (PR and CR) =30%) including 3/10 pts (30%) with liver metastases. Median time on study was 14 wks. 37 pts (95%) had adverse events (AEs). The most common AE was fatigue (56%). 20 pts (51%) had Grade 3/4 AEs with 35% considered related. 9 pts (23%) had eye disorders (1 Gr 3). 4 pts (11%) had protocol defined dose limiting toxicities. There were 2 deaths unrelated to study drug. Serum concentrations of ASG-15ME decreased multi-exponentially and exposure was dose-proportional. ASG-15ME half-life is 2.3 days. The median progression free survival is 16 wks (unplanned exploratory analysis). Enrollment is open at active dose levels; updated results will be presented. Conclusions: ASG-15ME targeting SLITRK6 is an ADC in mUC that is well tolerated and active. These results warrant ongoing study of ASG-15ME in mUC pts. Clinical trial information: NCT01963052.Dose (mg/kg) 0.5 0.75 1 1.25 Evaluable pts (n=37) 8 14 10 5 ORR, n (%) 1 (13) 4 (29) 4 (40) 2 (40) Responders (PR/CR) Median Duration on Rx (Wks) 17 24 20 10 DCR (SD/PR/CR) n (%) 3 (38) 10 (71) 8 (80) 4 (80) Evaluable pts = ≥ 1 dose of drug and had ≥ 1 post-baseline DA.
A randomised comparison of two faecal immunochemical tests in population-based colorectal cancer screening
Authors: E J Grobbee, M van der Vlugt, A J van Vuuren, A K Stroobants, M W Mundt, W J Spijker, E J C Bongers, E J Kuipers, I Lansdorp-Vogelaar, P M Bossuyt, E Dekker, M C W Spaander
Journal: Gut (2016)

<h3>Objective</h3> Colorectal cancer screening programmes are implemented worldwide; many are based on faecal immunochemical testing (FIT). The aim of this study was to evaluate two frequently used FITs on participation, usability, positivity rate and diagnostic yield in population-based FIT screening. <h3>Design</h3> Comparison of two FITs was performed in a fourth round population-based FIT-screening cohort. Randomly selected individuals aged 50–74 were invited for FIT screening and were randomly allocated to receive an OC -Sensor (Eiken, Japan) or faecal occult blood (FOB)-Gold (Sentinel, Italy) test (March–December 2014). A cut-off of 10 µg haemoglobin (Hb)/g faeces (ie, 50 ng Hb/mL buffer for OC-Sensor and 59 ng Hb for FOB-Gold) was used for both FITs. <h3>Results</h3> In total, 19 291 eligible invitees were included (median age 61, IQR 57–67; 48% males): 9669 invitees received OC-Sensor and 9622 FOB-Gold; both tests were returned by 63% of invitees (p=0.96). Tests were non-analysable in 0.7% of participants using OC-Sensor vs 2.0% using FOB-Gold (p&lt;0.001). Positivity rate was 7.9% for OC-Sensor, and 6.5% for FOB-Gold (p=0.002). There was no significant difference in diagnostic yield of advanced neoplasia (1.4% for OC-Sensor vs 1.2% for FOB-Gold; p=0.15) or positive predictive value (PPV; 31% vs 32%; p=0.80). When comparing both tests at the same positivity rate instead of cut-off, they yielded similar PPV and detection rates. <h3>Conclusions</h3> The OC-Sensor and FOB-Gold were equally acceptable to a screening population. However, FOB-Gold was prone to more non-analysable tests. Comparison between FIT brands is usually done at the same Hb stool concentration. Our findings imply that for a fair comparison on diagnostic yield between FIT9s positivity rate rather than Hb concentration should be used. <h3>Trial registration number</h3> NTR5385; Results.
Abstract 1652: P16INK4a over-expression sensitizes HPV(-) HNSCC to radiation through down-regulation of USP7
Authors: David Molkentine, Li Wang, Kathleen Bridges, Kathy Mason, Raymond Meyn, Heath D. Skinner
Journal: Cancer Research (2016)

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) tumorigenesis induced by human papillomavirus (HPV) shows a greater clinical response to radiation therapy when compared to HPV negative patients. The underlying mechanism for this more favorable outcome is unknown, but the presumption is that DNA repair response must play a large role. P16INK4a is a known surrogate marker for HPV positivity; however the relationship between radiation sensitivity and P16INK4a has not been completely elucidated in this context. Ubiquitin specific protease 7 (USP7), also known as HAUSP, is a deubiquitylating enzyme that cleaves ubiquitin from substrates to stabilize target proteins. USP7 overexpression is a predictor of poor prognosis in lung carcinomas and correlates with disease progression and lower survival in gliomas. More recent studies have shown USP7 has a role in the stability of DNA damage response proteins such as RNF168, BRCA1 and Chk1; and USP7 knockdown has been shown to radio-sensitize breast cancer cells to radiation. We have investigated the possible role of USP7 in the radio-response of HNSCC cells in the context of HPV status. Methods: Four HPV(+) and four HPV(-) HNSCC were chosen for this study. The radio-response was determined by clonogenic survival assay. P16INK4a overexpression was generated using lentivirus. Western blot analysis was used for visualizing protein expression. The Cancer Genome Atlas was interrogated to examine the relationship between USP7 and clinical outcome. Results: Our data suggest P16INK4a negatively regulates USP7 and leads to the more radiosensitive phenotype associated with HPV(+)HNSCC. Radio-resistant HPV(-) HNSCC cell lines show higher levels of USP7 than HPV(+) lines and over-expression of P16INK4a in HPV(-) HN5 cells leads to down-regulation of USP7 and radio-sensitization. Conversely, P16INK4a siRNA knockdown in HPV(+) UMSCC-47 shows an increase of USP7 protein expression and radio-resistance. P22077, an inhibitor of USP7 activity, was also shown to radiosensitize a HPV(-) cell line. This shows proof of principle that inhibiting USP7 can be a viable approach to sensitizing HPV(-) HNSCC to radiation. USP7 overexpression was also associated with poorer overall survival in HNSCC. Conclusion: These results suggest that USP7 may be a marker of clinical radioresistance in HNSCC and that its inhibition has the potential to improve the treatment outcome of patients with HPV(-) HNSCC when combined with radiotherapy. Citation Format: David Molkentine, Li Wang, Kathleen Bridges, Kathy Mason, Raymond Meyn, Heath D. Skinner. P16INK4a over-expression sensitizes HPV(-) HNSCC to radiation through down-regulation of USP7. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1652.
Heritage: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin.
Authors: Hope S. Rugo, Abhijit Barve, Cornelius F. Waller, Miguel Hernandez-Bronchud, Jay Herson, Jinyu Yuan, Alexey Manikhas, Igor Bondarenko, Guzel Mukhametshina, Gia Nemsadze, Joseph D. Parra, Maria Luisa T. Abesamis Tiambeng, Kakhaber Baramidze, Charuwan Akewanlop, Ihor Vynnychenko, Virote Sriuranpong, Gopichand Manillapalli, Sirshendu Ray, Eduardo Patricio Yanez Ruiz, Eduardo J. Pennella
Journal: Journal of Clinical Oncology (2016)

LBA503 Background: Trastuzumab has revolutionized treatment of HER2+ breast cancer. Globally accessible alternatives are a critical need. We evaluated Myl-1401O, a proposed trastuzumab biosimilar, as treatment for HER2+ metastatic breast cancer (MBC), based on physicochemical analyses, nonclinical, pharmacokinetic and pharmacodynamic studies*. Methods: Heritage is a double-blind, randomized clinical trial designed to evaluate comparative efficacy and safety of Myl-1401O vs Herceptin. Eligible patients (pts) had centrally confirmed, measurable HER2+ MBC without prior chemotherapy or trastuzumab for metastatic disease. Pts were randomized to receive either Myl-1401O or Herceptin with docetaxel or paclitaxel for a minimum of 8 cycles. Trastuzumab was continued until progression. The primary endpoint was overall response (ORR) at Week 24 by blinded central evaluation using RECIST 1.1. Secondary endpoints include progression free survival (PFS), overall survival, and safety. A sample size of 456 pts was calculated to demonstrate equivalence in ORR at Week 24 for MYL-1401O vs Herceptin, defined as a 90% confidence interval (CI) for the ratio of best ORR within the equivalence margin (0.81, 1.24). Results: 500 pts were randomized, 458 were evaluable for efficacy. 44% had hormone receptor positive MBC, 84% received docetaxel. Week 24 ORR was 69.6% for Myl-14010 compared to 64% for Herceptin. The ratio of ORR was 1.09; both 90% CI (0.974-1.211) and 95% CI (0.954-1.237) were within the pre-defined equivalence margin. Median PFS is not yet reached (41 events for MYL-1401O vs 48 events for Herceptin). Safety was comparable; serious adverse events (primarily neutropenia related) occurred in 38% (MYL-1401O) vs 36% (Herceptin), with 4 fatal events in each arm. There was no significant change in cardiac function from baseline to Week 24 in either arm. Conclusions: MYL-1401O was equivalent to Herceptin, given in combination with a taxane as first-line therapy for MBC, as measured by 24 week ORR. Safety was comparable. The proposed trastuzumab biosimilar MYL-1401O could be a new treatment option for HER2+ MBC. * Presented at: British Pharmacological Society, Pharmacology Meeting; 2015 Dec 15-17; London, UK. Clinical trial information: 2011-001965-42.
Erratum to: CoMEt: a statistical approach to identify combinations of mutually exclusive alterations in cancer
Authors: Mark D. M. Leiserson, Hsin-Ta Wu, Fabio Vandin, Benjamin J. Raphael
Journal: Genome biology (2016)

Erratum After the publication of this work [1] it has been brought to our attention that the descriptions of the generation of the two simulated datasets were confusing. In the section ‘Benchmarking of methods for individual gene sets’, the first sentence of the second paragraph should specify the number of genes included in the gene set as 100, and it should read: “We compared CoMEt to the other methods on datasets with m = 100 genes and n = 500 samples and with implanted pathways with coverages γ ranging from 0.1 to 1.0.” In the section ‘Benchmarking identification of collections of gene sets’, the first paragraph should specify that genes mutated in fewer than 1% of total samples (that is in fewer than 5 out of 500 samples) were removed from the simulation, and the sixth sentence in this paragraph should read: “Third, we include m = 20,000 genes and remove those genes that are mutated in fewer than 1% of total samples (that is in fewer than 5 out of 500 samples) (Additional file 1: Figure S2).” Additionally, these descriptions are also included in the Additional file 1, section S3, and should read: “We generated two different versions of the simulated datasets, depending on whether we implanted a single or multiple gene sets. We describe the method for generating datasets with multiple implanted gene sets in the main text. For all simulated datasets, we used n = 500, |C| = 5, γC = (0.67, 0.49, 0.29, 0.29, 0.2), and q = 0.0027538462.1 We used μP = (0.5, 0.35, 0.15) for the single pathway simulations.”
Quality of Care and Cost at Safety-Net Hospitals—Is Redistribution of Cases Possible?
Authors: Taylor S. Riall, Purvi Parikh
Journal: JAMA Surgery (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Association of patient age, function and cognition with cancer treatment decisions: A University of Rochester NCORP study.
Authors: Kah Poh Loh, Allison Magnuson, William Dale, Carla Velarde, Chintan Pandya, Charles E. Heckler, Arti Hurria, Karen Michelle Mustian, Judith O. Hopkins, Jijun Liu, David M. King, Srihari Peri, Gary R. Morrow, Supriya Gupta Mohile
Journal: Journal of Clinical Oncology (2016)

10038 Background: Geriatric assessment (GA), a validated mechanism to assess health status, has been advocated as a way to assist with decision-making for cancer treatment. This study’s aim was to examine whether providing oncologists with GA information influences treatment decisions. Methods: Community oncologists were surveyed as part of a multisite geriatric oncology clinical trial. Eight vignettes of varying combinations of age (72/82), impaired function (yes/no), and impaired cognition (yes/no) were created to describe patients with advanced pancreatic cancer considering first line chemotherapy. Other patient characteristics were the same: sex (F), comorbidities (well-controlled), fatigue (moderate), and ECOG performance status (1). Each physician received a single vignette chosen randomly, and provided a treatment recommendation (combination vs single agent vs no chemotherapy). Logistic regression models were used to identify associations between oncologist and patient characteristics with decisions. Results: Physician response rate was 55% (n = 234). 19% reported using GA in practice. The table shows the proportion of physicians who recommended treatment for each vignette. Oncologists’ demographics were not associated with decisions. Each varied patient characteristic was independently associated with the decision to not treat: older age (Odds Ratio, 95% CI 4.8, 2.4-9.6), impaired function (3.1, 1.6-6.2), and impaired cognition (7.2, 3.6-14.5). Age and cognition were also associated with prescribing single-agent over combination (older age: 2.7, 1.1-6.9; impaired cognition: 4.6, 1.6-13.2). Conclusions: Few community oncologists use GA in practice. However, GA information, when provided, influences community oncologists’ treatment decisions. Cognitive impairment had the strongest association with treatment decisions. This study provides evidence that GA influences cancer treatment decisions. Age Impaired function: Instrumental Activity of Daily Living assistance & falls Impaired cognition: Mini-Mental State Examination score = 15 Chemotherapy recommended (%) 72 No No 100 82 No No 75 72 Yes No 76 82 Yes No 48 72 No Yes 52 82 No Yes 33 72 Yes Yes 50 82 Yes Yes 12
Abstract 3559: The rare BCL-2 isoform BCL-2β is associated with melanoma survival and the apoptotic response to UV and cisplatin
Authors: Chloe Warren, Ricardo E. Vilain, Katie A. Ashton, Juhura G. Almazi, Stephen Braye, Pablo Moscato, Nikola A. Bowden
Journal: Cancer Research (2016)

Abstract There are two isoforms of the anti-apoptotic protein BCL-2. BCL-2α (wild-type) is well characterised and is known predominantly for its role in apoptosis, BCL-2β lacks the C-terminal transmembrane (TM) domain and its function has not yet been characterised. The aim of this study was to quantify and determine the biological role of the BCL-2β isoform in melanoma. BCL-2α and BCL-2β isoforms were quantified at the mRNA and protein level in a cohort of 141 FFPE melanoma tumours using qPCR and multiple reaction monitoring (MRM) tandem mass spectrometry and compared to clinical parameters including age at diagnosis, gender, solar elastosis, BRAF/NRAS mutation, Breslow thickness, disease free survival and overall survival. The role of the BCL-2α and BCL-2β isoforms in apoptosis were investigated by quantifying transcript expression and apoptosis before and up to 72 hours after UVB irradiation (650J/m2) and cisplatin treatment (10ug/mL). siRNA knockdown targeted to each individual isoform transcript was used to verify the apoptotic response. Expression of the BCL-2β isoform in tumours was significantly associated with increased overall survival (686.4 weeks, 95% CI 462.5-910.3). BCL-2α response to UVB and cisplatin (i.e. downregulation prior to apoptosis) was the same in melanocyte and melanoma cell lines. However, BCL-2β response was varied across the melanoma cell lines, but was similar to that of BCL-2α in melanocytes. siRNA knock-down of BCL-2α resulted in increased apoptosis and cell death in melanoma cell lines, but knock-down of BCL-2β delayed onset of apoptosis, suggesting the BCL-2β is pro-apoptotic. Our current understanding of the role of BCL-2β is based on the concept that it lack the C-terminal transmembrane domain, and is incapable of localising to target organelles. It is currently thought that the isoform is of null function. However, these observations are based on studies of non-representative synthetic versions of BCL-2β. This is the first time the naturally transcribed version of the rare isoform has been studied. We have demonstrated herein that BCL-2β performs an apoptotic role, and that its regulation in melanoma may be a biomarker of better overall survival. Citation Format: Chloe Warren, Ricardo E. Vilain, Katie A. Ashton, Juhura G. Almazi, Stephen Braye, Pablo Moscato, Nikola A. Bowden. The rare BCL-2 isoform BCL-2β is associated with melanoma survival and the apoptotic response to UV and cisplatin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3559.
<i>HER2</i> amplification in <i>EGFR</i> mutant NSCLC after acquired resistance (AR) to EGFR-directed therapies.
Authors: Bing Xia, Anna Wurtz, Scott N. Gettinger, Roy S. Herbst, Anne C. Chiang, Mimi Wan, Jeffrey Sklar, Veronique Neumeister, Katerina A Politi, Sarah B. Goldberg
Journal: Journal of Clinical Oncology (2016)

9049 Background: Both first generation EGFR tyrosine kinase inhibitors (TKIs) and second generation agents with dual EGFR/HER2 inhibition have robust activity in EGFR-mutant NSCLC. HER2 amplification (amp) has been proposed as a potential mechanism of AR to first-generation EGFR TKIs. To further understand HER2 alterations as resistance mechanisms to EGFR TKIs, we evaluated HER2 amp in patients (pts) with EGFR-mutant NSCLC before and after AR. Methods: Tissue biopsies from pts with metastatic or recurrent EGFR-mutant lung adenocarcinomas with AR to EGFR TKIs were obtained before initiation of treatment and at the time of AR. HER2/CEP17 ratio and average HER2 copy number were assessed by FISH. HER2 protein expression was determined using IHC. Results were interpreted based on the 2013 ASCO/CAP guidelines. Results: 83 pts with AR to EGFR TKIs have been enrolled. HER2 status was evaluated in 55 samples collected from 49 pts (33 female, 16 male, 27 never-or light smokers). 44 samples were obtained after AR to erlotinib, 9 after resistance to afatinib + cetuximab (AFAT + CET), and 2 after AR to afatinib (AFAT). At AR to erlotinib, 3 cases (6.8%) were found to have HER2 amp. In all 3, low-level HER2 amp was detected pre-treatment and increased in 2 cases at AR. Of the 9 pts treated with AFAT + CET, 2 pts (22.2%) were found to have HER2 amp at time of resistance, in one case exhibiting a 4-fold increase in copy number post-treatment. Neither of the 2 pts treated with AFAT alone had HER2 amp. Results are summarized in the table. Conclusions: We demonstrate that HER2 amp may be a mechanism of resistance to erlotinib and AFAT + CET, as it was detected in 6.8% and 22.2% of cases respectively after AR to these agents. These findings support further investigation into HER2-directed therapies in EGFR mutant tumors that harbor HER2 alterations. Case Treatment Wks on treatment HER2 Copy # HER2:CEP17 ratio HER2 IHC T790M MET 1 Baseline 6.7 2.8 2+ - NA Post Erlotinib 28.7 12.8 8.0 3+ - - 2 Baseline 4.2 2.6 2+ - NA Post Erlotinib 118.3 13.6; 3.6* 6.0; 1.4* 3+ - - 3 Baseline 12.6 3.3 3+ - NA Post Erlotinib 25.7 9.5 2.6 3+ + - 4 Baseline 4.4 1.6 0 - NA Post AFAT + CET 8.0 17.5 6.6 3+ - - 5 Baseline NA NA NA NA NA Post AFAT + CET 33.4 5.3 2.1 NA + - *Two cell populations observed
Sequence-Based Evidence for Antigen Selection in Mantle Cell Lymphoma: Remarkable Immunoglobulin Gene Repertoire Biases, Stereotyped Antigen-Binding Sites and Recurrent Hypermutations in Certain Subsets.
Authors: Anastasia Hadzidimitriou, Andreas Agathagelidis, Fiona Murray, Marie-Helene Delfau-Larue, Nikos Darzentas, Alba Navarro Lopez, Paul Rombout, Kheira Beldjord, Martin H. Dreyling, Theodora Papadaki, Achilles Anagnostopoulos, Andreas Rosenwald, Patricia Groenen, Elias Campo, Richard Rosenquist, Frederic Davi, Christiane Pott, Kostas Stamatopoulos
Journal: Blood (2009)