tbuckley/cabot-search huggingface dataset:
Population based testing and treatment characteristics for CML.
Authors: Timothy Styles, Manxia Wu, Reda Wilson, Frances Babcock, David Butterworth, Dee West, Lisa Carolyn Richardson
Journal: Journal of Clinical Oncology (2015)

e17609 Background: National and International Hematology/Oncology Practice guidelines recommend testing for the BCR-ABL mutation for definitive diagnosis of chronic myeloid leukemia (CML) to allow for appropriate treatment with a Tyrosine Kinase Inhibitor (TKI). The purpose of our study is to describe population-based testing and treatment practice characteristics for patients diagnosed with CML. Methods: We analyzed cases of CML using 2011 data from the Centers for Disease Control and Prevention’s (CDC) Comparative Effectiveness Research (CER) Project collected by 10 specialized state central cancer registries in the US. We described completeness of testing for the BCR-ABL gene mutation and availability of outpatient treatment with TKIs and associated characteristics. Results: A total of 717 cases of CML were identified; 380 (53%) had a documented BCR-ABL gene test with 365 (51%) documented as BCR-ABL positive. Another 15 (2%) patients had BCR-ABL gene testing completed but were either negative or had a missing result. Of cases tested for the BCR-ABL gene, TKIs were recorded in 303 (80%) of these cases. One state registry reported a significantly higher percentage of incomplete BCR-ABL gene testing (p < 0.001) and TKI treatment (p < 0.001). Limiting analysis to CML cases reported from the remaining nine specialized registries, 307 (79%) had a documented BCR-ABL gene test; 271 (88%) of those tested had documented treatment with a TKI. Receipt of testing or treatment for these nine states did not vary by sex, race, ethnicity, poverty level, rural/urban residence, or insurance status; BCR-ABL testing was performed less often with increasing age as was treatment with TKIs (p = 0.0001, p = 0.007 respectively). Conclusions: Collection of detailed CML data can vary significantly by states. A majority of the case patients had appropriate testing for the BCR-ABL gene and treatment with tyrosine kinase inhibitors. However, BCRABL testing and TKI treatment decreased with increasing age. Further research is needed to understand CML testing and treatment disparities.
Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: A multicenter randomized phase II trial (OCUU-CRPC study).
Authors: Taro Iguchi, Satoshi Tamada, Minoru Kato, Sayaka Yasuda, Yuichi Machida, Tetsuji Ohmachi, Keiichi Ishii, Hiroyuki Iwata, Shinji Yamamoto, Tomohiro Kanamaru, Kazuya Morimoto, Taro Hase, Koichiro Tashiroro, Koji Harimoto, Takashi Deguhi, Takahisa Adachi, Katsuki Iwamoto, Yoshinori Takegaki, Tatsuya Nakatani
Journal: Journal of Clinical Oncology (2019)

168 Background: In Asia, including Japan, combined androgen blockade (CAB) therapy with bicalutamide is widely administered for metastatic prostate cancer. Alternative anti-androgen therapy (AAT) with flutamide after CAB therapy with bicalutamide was common before the androgen receptor-targeted therapy era. The objective of the OCUU-CRPC study was to compare the efficacy and safety between second-line hormonal therapy of enzalutamide and flutamide as alternative AAT after CAB therapy that included bicalutamide in patients with CRPC. Methods: A total of 104 patients with CRPC with or without distant metastases after disease progression who received CAB therapy with bicalutamide were randomly assigned at a 1:1 ratio according to distant metastases to the enzalutamide (160 mg/day) and flutamide (375 mg/day) groups. The primary endpoint for the drug efficacy was the response rate of prostate-specific antigen (PSA; i.e., declined by ≥50%) at 3 months. Results: Between January 2015 and February 2018, 103 patients were randomly assigned, 52 to enzalutamide and 51 to flutamide. 25 (48%) and 38 (75%) patients, respectively, discontinued their assigned treatment before study end, mainly due to progressive disease. Median follow-up time was 13.4 months (IQR 9.6–23.8) in the enzalutamide group and 17.0 months (9.7–24.4) in the flutamide group. Enzalutamide resulted in significant improvements in the response rate of PSA at 3 months (84.6% vs 31.4%; p&lt; 0.001). Enzalutamide significantly improved in all secondary endpoints: the PSA progression rate at 3 months (HR, 0.17; 95% CI, 0.05 to 0.47; p&lt; 0.01) and at 6 months (HR, 0.22; 95% CI, 0.09 to 0.50; p&lt; 0.01); and PSA response rate at 6 months (75.0% vs 29.4%; p&lt; 0.01); and time to PSA progression (median: not reached vs 6.6 months; HR, 0.29; 95% CI, 0.15 to 0.54; p&lt; 0.01). The observed adverse event profile was consistent with that from phase III enzalutamide trials. Conclusions: Enzalutamide significantly reduced risk of progression compared with flutamide in patients with CRPC after CAB therapy with bicalutamide. This trial is registered with ClinicalTrials.gov, number. Clinical trial information: NCT02346578.
Efficacy and safety of nivolumab in patients with non-clear cell renal cell carcinoma (RCC): Results from the phase IIIb/IV CheckMate 374 study.
Authors: Nicholas J. Vogelzang, Joshua Jemison McFarlane, Mark D. Kochenderfer, Ana M. Molina, Edward Arrowsmith, Todd Michael Bauer, Ralph J. Hauke, Rohit Jain, Bradley G. Somer, Elaine Tat Lam, Gurjyot K. Doshi, Vijay Gunuganti, Joshua Zhang, Huanyu Zhao, Jennifer Johansen, Scott S. Tykodi
Journal: Journal of Clinical Oncology (2019)

562 Background: Initial safety results from the phase 3b/4 CheckMate 374 study showed that flat-dose nivolumab (NIVO) at 240 mg every 2 wk (Q2W) had a consistent safety profile across patients (pts) with clear cell and non-clear cell advanced RCC. We report updated safety and first disclosure of efficacy for pts with non-clear cell RCC (nccRCC) in CheckMate 374. Methods: Eligible pts in this cohort were adults with advanced or metastatic nccRCC who received 0–3 prior systemic therapies. Pts received NIVO 240 mg IV Q2W for ≤24 mo or until confirmed progression, unacceptable toxicity, or withdrawal of consent. Pts who benefited after 24 mo continued treatment according to the standard of care. The primary endpoint was incidence of high-grade immune-mediated adverse events (IMAEs). Exploratory endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR). Results: In CheckMate 374, 44 pts had nccRCC. Histological subtypes included papillary (n = 24), chromophobe (n = 7), unclassified (n = 8), and other (n = 5). Most pts with nccRCC (66%) were treatment-naïve. After a median follow-up of 11.1 mo, median OS was 16.3 mo (95% confidence interval [CI] 9.2–not estimable [NE]). OS was similar regardless of baseline PD-L1 expression. ORR was 13.6% (95% CI 5.2–27.4). One pt had complete response (chromophobe histology) and 5 pts had partial response (2 pts with papillary and 1 pt each with chromophobe, collecting duct, and unclassified histology). Median DOR was 10.2 mo (95% CI 5.6–NE). Median PFS was 2.2 mo (95% CI 1.8–5.4). The 1-year PFS rate was 14% (95% CI 5–27). No new safety concerns were identified. No treatment-related grade 5 AEs or grade 3–4 IMAEs were reported. Conclusions: Clinically meaningful antitumor activity was observed in the first prospective study of NIVO monotherapy in nccRCC. Responses were observed in several histological subtypes. The safety profile of flat-dose NIVO at 240 IV Q2W is consistent with the initial outcomes reported from this study and across the NIVO program. Clinical trial information: NCT02596035.
Collaborative student research efforts provide a solution to research wastage
Authors: Waheed-Ul-Rahman Ahmed, Emily Mills, Rachel A Khaw, Kenneth A McLean, James C Glasbey
Journal: BMJ (2019)

Sharp and Curlewis1 provide a student’s perspective on research waste2 and discuss recognised pressures in UK medical schools to publish research “at all costs.” Research collaborations, such as STARSurg (Student Audit and Research in Surgery), enable students to engage in high quality studies with great impact, while gaining fundamental skills in study design and delivery. …
Challenges in Research on Suicide Prevention—Reply
Authors: Dominic A. Sisti, Steven Joffe
Journal: JAMA (2019)

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Blinded independent validation of the PAM50-based Chemo-Endocrine Sensitivity Predictor (CESP) in hormone receptor (HR)-positive/HER2-negative (HR+/HER2-) breast cancer following neoadjuvant chemotherapy (NAC).
Authors: Aleix Prat, Begona Jimenez Rodriguez, Pedro Sánchez Rovira, Martina Alvarez, Luis Vicioso, Vanessa de Luque, Cristina Fernandez-Sousa, M Rosario Chica Parrado, Angela Santonja, Cesar Ramirez Tortosa, Ana Isabel Lavado Fernandez, Elisabeth Perez Ruiz, Carlos Gonzalez-Hermoso, Wesley Buckingham, Naeem Dowidar, Sean Ferree, Arthur Jeiranian, Carl Schaper, Nuria Ribelles, Emilio Alba
Journal: Journal of Clinical Oncology (2015)

569 Background: Pathological complete response following NAC is associated with improved survival. CESP is a novel algorithm derived from the GEICAM 2006-03 clinical trial which is based on the association of treatment response with correlation to each PAM50 subtype centroid. CESP has been validated in two datasets consisting of patients with HR+/HER2- disease treated with either NAC or neoadjuvant endocrine therapy (unpublished data). Here, we examined whether CESP score is associated with chemosensitivity in another independent dataset. Methods: 216 pre-/post-menopausal patients from a multi-center Spanish cohort, with banked and centrally-confirmed FFPE HR+/HER2- pre-treatment breast tumor samples, were re-consented. All patients were treated with anthracycline/taxane-based NAC between years 2003-2014. The Prosigna assay was performed on the NanoString nCounter Dx Analysis System at Hospital Universitario Virgen de la Victoria de Málaga and CESP score and cutoffs were determined from those results at Hospital Clínic of Barcelona (blinded from clinical data). Univariate and multivariable analyses were used to evaluate the association of CESP score with centrally determined Residual Cancer Burden (RCB). Results: 207 core-needle pre-treatment biopsy samples yielded passing results (95.8%) of which 180 had clinical data including an RCB classification. The overall proportion of RCB-0/I in this patient population was 18.9%. In univariate and multivariate (adjusted for tumor size, age at diagnosis and grade) analyses, CESP as a continuous variable was significantly associated with response (p < 0.001 and p = 0.003). The rates of response in CESP-high, -med and -low groups were 10.3%, 15.2% and 30.4%, respectively (p = 0.006). The odds ratio of the CESP-low group for achieving a RCB-0/I was 3.80 (95% Confidence Interval 1.57-9.18) compared with the CESP-high group. Similar results were obtained after excluding PAM50 non-Luminal disease (n = 23). Conclusions: CESP is a strong and independent predictor of pathological response in patients with HR+/HER2- disease treated with NAC.
Corrigendum to “Targeting cancer stem cells and their niche: Perspectives for future therapeutic targets and strategies” [Semin. Cancer Biol. (2018) (August) pii: S1044-579X(18)30045-2, 139–155]
Authors: Yue Zhao, Qiongzhu Dong, Jiahui Li, Kaili Zhang, Jie Qin, Jiangang Zhao, Qiye Sun, Zhefang Wang, Thomas Wartmann, Karl Walter Jauch, Peter J. Nelson, LunXiu Qin, Christiane Bruns
Journal: Seminars in Cancer Biology (2019)
Hypertension Hot Potato — Anatomy of the Angiotensin-Receptor Blocker Recalls
Authors: J. Brian Byrd, Glenn M. Chertow, Vivek Bhalla
Journal: New England Journal of Medicine (2019)

Hypertension Hot Potato A spate of recalls of angiotensin-receptor blockers highlights several issues related to the readiness of our health systems to respond to drug recalls, trust between patients and providers, uncertain drug-dose equivalences, and the regulation of drug manufacturing in the global marketplace.
Immunogenomic landscape of neuroendocrine prostate cancer (NEPC).
Authors: Alison Ferguson, Bhavneet Bhinder, Vincenza Conteduca, Michael Sigouros, Andrea Sboner, David M. Nanus, Scott T. Tagawa, David Rickman, Olivier Elemento, Himisha Beltran
Journal: Journal of Clinical Oncology (2019)

224 Background: Prostate cancer (PCa) shows limited clinical benefit from current immunotherapy strategies. NEPC is a histologic subtype of advanced PCa that most often arises clonally from castrate resistant prostate adenocarcinoma (CRPC) as a mechanism of resistance, but shares pathologic, clinical, and molecular features with small cell lung carcinoma (SCLC). We investigated the immune landscape of NEPC in relation to other PCa subtypes and SCLC to identify potential immunological targets. Methods: We evaluated RNA-seq from 190 patients comprising benign prostate (n = 29; 25 PCa matched), localized PCa (n = 68), hormone-naïve metastatic prostate adenocarcinoma (mPCa; n = 11), CRPC (n = 54), NEPC (n = 25) with follow-up data, and SCLC (n = 28) (Rudin et al., Nat Gen 2012). Additionally, 290 patients had WES data available for tumor mutational burden (TMB). Unsupervised clustering of FPKMs was performed to identify an immune rich cluster of 232 genes, which was used to categorize immune status and prioritize validation of select targets by IHC. Results: Median TMB of NEPC was similar to CRPC (38.0 vs 37.0 p= 0.44) but significantly lower than SCLC (38.0 vs 142.5, p&lt; 0.001). Unsupervised assessment of T-cell related gene expression identified a predominantly cold immune status across subtypes, with hot (n = 8) tumors associated with metastatic tumors of the LN and bone. Worse overall survival was seen with intermediate vs cold T-cell immune status (66.5 mo vs 101.5 mo; p &lt; 0.001). Further analysis of NEPC showed lower expression of cytokines ( p&lt; 0.01) and variation in checkpoint markers. Specifically, NEPC had significantly lower expression of PD1 in relation to CRPC ( p= 0.0001) and SCLC ( p = &lt; 0.0001), higher PDL1 than CRPC ( p= 0.05) but comparable with SCLC ( p= 0.93) and lower PDL2 than PCa and SCLC ( p= 0.03; &lt; 0.001, respectively). Conclusions: NEPC is characterized by a relatively ‘cold’ tumor immune microenvironment similar to other metastatic prostate cancer subtypes but higher PDL1 expression comparable to SCLC. The inverse correlation between survival outcome and immune infiltration, as well as the novel expression changes in cytokines and checkpoint markers support further investigation into the immune landscape and potential targets for NEPC.
Timed-sequential therapy with mibefradil and temozolomide in patients with recurrent high-grade gliomas: A phase I Adult Brain Tumor Consortium study.
Authors: Matthias Holdhoff, Xiaobu Ye, Louis B. Nabors, Arati Suvas Desai, Tom Mikkelsen, Glenn Lesser, William L. Read, Frank S. Lieberman, Jeff Supko, Joy D. Fisher, Serena Desideri, Stuart A. Grossman, David Schiff
Journal: Journal of Clinical Oncology (2015)

2033 Background: Mibefradil (MIB) is a selective T-type calcium channel blocker that had previously been approved for treatment of hypertension. MIB has shown significant preclinical activity in many cancers, including high-grade gliomas (HGG). MIB was found to impact cell cycle activity with arrest at G1/S in tumor cells, suggesting a possible chemo-sensitizing effect of the drug if given prior to cytotoxic therapy. This was a multi-center open label phase I study to determine the maximum tolerated dose (MTD) of MIB followed by temozolomide (TMZ) in recurrent HGG and to assess the safety and tolerability of MIB, particularly its myelosuppressive effects, in a timed-sequential combination with TMZ. Methods: Adult patients with recurrent HGG (WHO grade III and IV) who were selected to likely have a benefit from repeat treatment with TMZ (no progression ≥ 3 months from their last dose of TMZ) were eligible. MIB was given in 4 daily doses (QID) for 7 days followed 24 hours later by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. Dose escalation of MIB was done using a modified 3+3 design, followed by an extension cohort of 10 patients at the MTD. Results: 27 eligible patients with recurrent HGG participated (at time of enrollment, 21 with WHO grade IV, 6 with grade III; median age 50y; median KPS 90). The MTD of MIB was determined as 87.5 mg po QID. Most common side effects (grade 1 and 2) were fatigue, nausea, constipation and anorexia. Grade 3 elevation of ALT/AST was observed in one patient. Dose limiting toxicities were elevation of ALT/AST and sinus bradycardia. 5 partial and 1 complete responses were observed based on review by the sites (response rate 22%; 95% CI:9-42%). Plasma concentrations of MIB achieved a steady-state after 4 days of dosing with a mean peak concentration of approximately 1,700 ng/mL and a peak-to-trough ratio of 1.1 at the MTD. Conclusions: MIB followed by TMZ was well tolerated in patients with recurrent HGG. The MTD for MIB in this setting was determined as 87.5 mg po QID. The lack of toxicity, including extensive myelosuppression, and the presence of responses in this selected patient population suggests that this regimen deserves further investigation. Clinical trial information: NCT01480050.
Abstract 18582: Self-reported Health Status and 30-Day Hospital Readmission in Cardiovascular Disease
Authors: Hanzhang Xu, Matthew E Dupre, Bradi B Granger, Erik Churchill, Lesley H Curtis, Eric D Peterson
Journal: Circulation (2017)

Introduction: Self-rated health status is often assessed yet whether these data are predictive of future risk for rehospitalization following cardiovascular admissions not been evaluated. Methods: ...
A phase Ib study of BBI608 in combination with FOLFIRI with and without bevacizumab in patients (pts) with advanced colorectal cancer (CRC).
Authors: Joleen Marie Hubbard, Derek J. Jonker, Bert H. O'Neil, Thorvardur Ragnar Halfdanarson, Axel Grothey, Youzhi Li, Laura Borodyansky, Chiang Li
Journal: Journal of Clinical Oncology (2015)

3616 Background: BBI608 is an oral first-in-class cancer stemness inhibitor of Stat3. Potent anti-tumor activity was observed in vitro and in vivo,in mono- and combination therapy. In a phase I study, BBI608 monotherapy was generally well tolerated at 500 mg BID with encouraging signs of anti-tumor activity. Methods: A phase Ib open label, multi-center study in pts with advanced CRC was performed to determine RP2D, safety, tolerability, and preliminary anti-cancer activity of BBI608 in combination with FOLFIRI with or without bevacizumab. BBI608 was administered at 240 mg BID in combination with FOLFIRI (5-FU 400 mg/m2 bolus with 2400 mg/m2, irinotecan 180 mg/m2, and leucovorin 400 mg/m2infusion) with or without bevacizumab 5 mg/kg, administered bi-weekly until progression of disease, unacceptable toxicity, or other discontinuation criterion was met. Results: 9 pts were enrolled with 4 pts receiving FOLFIRI and 5 pts receiving FOLFIRI with bevacizumab in combination with BBI608. All pts were pretreated with ≥ 1 line and 67% (6/9) of pts with ≥ 4 prior lines of therapy. Combination treatment was well tolerated with no dose-limiting toxicity and safety profile similar to that of each regimen individually, with no difference in safety observed with addition of bevacizumab. Most common adverse events included grade 1 and 2 diarrhea, abdominal cramps, nausea, vomiting and anorexia. Grade 3 diarrhea was observed in 2 pts, and resolved with a brief BBI608 dose holiday or dose reduction to 160 mg BID and anti-diarrheal medications, respectively. Additionally, self-resolving grade 3 fatigue lasting 4-8 days was observed in 2 pts. No significant pharmacokinetic interactions were observed. Disease control (PR+SD) was observed in 9 of 9 evaluable pts (100%) with 1 PR (44% regression) and 8 SD with tumor size reduction (25%, 23%, 17%, 16%, 14%, 14%, 4% and 2%, respectively). The median progression free survival was 23.7 weeks with SD of ≥ 6 months in (33.3%) 3/9 pts. Conclusions: This phase Ib study demonstrated that BBI608 at 240 mg BID can be safely combined with FOLFIRI with and without bevacizumab. Encouraging anti-tumor activity was observed in pts with advanced and heavily pretreated CRC. Clinical trial information: NCT02024607.