tbuckley/cabot-search huggingface dataset:
Tobacco as a possible prognostic factor in advanced renal cell carcinoma.
Authors: Maria Pilar Solis-Hernandez, Clara Iglesias, Alfonso Revuelta, Carmen Gonzalez Mendez, Lucia Juan Rodriguez, Teresa Quiñones Roces, Sara Gonzalez Lolo, Jorge del Río Fernández, David Gómez, Sena Valcárcel González, Sara Fernandez Arrojo, Carlos Alvarez-Fernandez, Noemí Villanueva, Laura Faez, Esther Uriol, Emilio Esteban
Journal: Journal of Clinical Oncology (2019)

665 Background: It is widely known the causal relationship establised between tobacco use and the development of renal cancer is widely known. Nevertheless, the impact of smoking on the efficacy and safety of anti-angiogenic drugs is unclear. Sunitinib is a tyrosine kinase inhibitor with proven efficacy metastatic renal cell carcinoma (mRCC). Methods: A retrospective analysis was carried out including 194 mRCC patients (pts) who received Sunitinib in a single Institution (Hospital Universitario Central de Asturias) with a high incidence of this disease. The aim of this study is to explore the impact of the smoking habit on treatment response in terms of progression‐free survival (PFS) and overall survival (OS). Results: Most patients presented clear cell histology (92%). Smoking status: 42% (n=82) never‐smoker, and 39% (n=76) former‐smoker and 19% (n=36) current‐smoker. Male predominance 78% (n=145). Median age was 65 (range: 40‐84). Survival analysis favors patients with a history of tobacco use. There was no significant difference in PFS between never‐smoker vs ever-smoker groups: median PFS 8.13 months (95% IC: 4.75‐11.52), vs 12 months (95% IC: 9.97‐14.03) was found respectively (p=0,086). Fewer than 10% developed grade 3 toxicity. A significative improvement in OS in patients ever-smokers: median OS 16.23 months (95% IC: 12.22‐20.25) vs 26.46 months (95% IC: 16.21‐36.73) (p=0.044). The advantage observed in patients with any smoking history became more evident for poor prognosis cases. A median OS 5.03 months (95% IC: 0.84‐9.23) vs 14.03 months (95% IC: 7.81‐20.26). A median PFS 6.4 months (95% IC: 2.53‐10.27) vs 13.33 months (95% IC: 1.14‐26.19) p &gt; 0.05. Conclusions: In this series, tobacco seems to play a role on the efficacy and safety of anti‐angiogenic agents in mRCC. However, additional prospective studies in well‐balanced populations are required to confirm this data.
Bone marrow transplant with post‐transplant cyclophosphamide for recessive dystrophic epidermolysis bullosa expands the related donor pool and permits tolerance of nonhaematopoietic cellular grafts
Authors: C.L. Ebens, J.A. McGrath, K. Tamai, A. Hovnanian, J.E. Wagner, M.J. Riddle, D.R. Keene, T.E. DeFor, R. Tryon, M. Chen, D.T. Woodley, K. Hook, J. Tolar
Journal: British Journal of Dermatology (2019)

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe systemic genodermatosis lacking therapies beyond supportive care for its extensive, life‐limiting manifestations. To report the safety and preliminary responses of 10 patients with RDEB to bone marrow transplant (BMT) with post‐transplant cyclophosphamide (PTCy BMT) after reduced‐intensity conditioning with infusions of immunomodulatory donor‐derived mesenchymal stromal cells (median follow‐up 16 months). BMT toxicities, donor blood and skin engraftment, skin biopsies, photographic and dynamic assessments of RDEB disease activity were obtained at intervals from pre‐BMT to 1 year post‐BMT. Related donors varied from haploidentical (n = 6) to human leucocyte antigen (HLA)‐matched (n = 3), with one HLA‐matched unrelated donor. Transplant complications included graft failure (n = 3; two pursued a second PTCy BMT), veno‐occlusive disease (n = 2), posterior reversible encephalopathy (n = 1) and chronic graft‐versus‐host disease (n = 1; this patient died). In the nine ultimately engrafted patients, median donor chimerism at 180 days after transplant was 100% in peripheral blood and 27% in skin. Skin biopsies showed stable (n = 7) to improved (n = 2) type VII collagen protein expression by immunofluorescence and gain of anchoring fibril components (n = 3) by transmission electron microscopy. Early signs of clinical response include trends toward reduced body surface area of blisters/erosions from a median of 49·5% to 27·5% at 100 days after BMT (P = 0·05), with parental measures indicating stable quality of life. PTCy BMT in RDEB provides a means of attaining immunotolerance for future donor‐derived cellular grafts (ClinicalTrials.gov identifier NCT02582775). What's already known about this topic? Severe, generalized recessive dystrophic epidermolysis bullosa (RDEB) is marked by great morbidity and early death. No cure currently exists for RDEB. Bone marrow transplant (BMT) is the only described systemic therapy for RDEB. What does this study add? The first description of post‐transplant cyclophosphamide (PTCy) BMT for RDEB. PTCy was well tolerated and provided excellent graft‐versus‐host disease prophylaxis, replacing long courses of calcineurin inhibitors in patients receiving human leucocyte antigen‐matched sibling BMT. What is the translational message? The PTCy BMT platform permits identification of a suitable related donor for most patients and for subsequent adoptive transfer of donor nonhaematopoietic cells after establishment of immunological tolerance.
Carbenoxolone Decreases the Microenvironment-Induced Chemoresistance of Acute Myeloid Leukemia Cells
Authors: Farah Kouzi, Frederic Picou, Jerome Bourgeais, Nathalie Gallay, Fabrice Gouilleux, Florence Rouleux-Bonnin, Frederic Mazurier, Emmanuel Gyan, Jorge Domenech, Kazem Zibara, Olivier Herault
Journal: Blood (2018)
Analysis of real-world PD-L1 testing in patients with urothelial carcinoma.
Authors: Gabriel S Krigsfeld, Emily Prince, Kim Zerba, Vladislav Chizhevsky, Josette William Ragheb, James Novotny, James William White
Journal: Journal of Clinical Oncology (2019)

447 Background: Programmed death-1/programmed death ligand 1 (PD-1/PD-L1) inhibitors are FDA-approved for urothelial carcinoma (UC) among other tumor types. PD-L1 immunohistochemistry (IHC) testing for UC has evolved with several diagnostic approvals. As of August 2018, the Dako PD-L1 IHC 22C3 pharmDx is a companion diagnostic, while the Dako PD-L1 IHC 28-8 pharmDx and the Ventana PD-L1 (SP263) assays are complementary diagnostics. The Ventana PD-L1 (SP142) assay has complementary status for platinum-treated patients with UC but gained companion status in July 2018 for cisplatin-ineligible patients with PD-L1-expressing UC. Here, we assess PD-L1 testing with the 22C3, 28-8, and SP142 assays on real-world UC samples. Methods: Analyses on 55,652 tumor samples from Symphony Health Solutions were performed between October 2015 and March 2018. PD-L1 results were linked to clinical characteristics using unique identifiers. PD-L1 testing on UC samples was performed at NeoGenomics Laboratories, Inc. based on the manufacturer’s protocols at the time. Results from the Dako assays were reported as % of tumor cells with PD-L1 expression. Test failure (TF) was defined as the absence of adequate sample with measurable PD-L1. Turnaround time (TAT) was defined as the time from sample receipt by the laboratory to test-report delivery. Paired 28-8 and 22C3 testing was performed on 13 samples. Results: 251 confirmed PD-L1 IHC tests (0.4% of tests conducted for the entire dataset) were performed on 223 UC samples, 98.2% of which had quantifiable PD-L1 expression. Mean TAT was 3.0 (1.0–4.2) days and the TF rate was 2.0% for all tests. The 22C3, 28-8, and SP142 assays were used in 52.2%, 9.6%, and 38.3% of tests, respectively. Paired testing with the 22C3 and 28-8 assays was highly correlated (Spearman’s r = 0.94; n = 13). Further analyses of UC PD-L1 prevalence will be presented. Conclusions: Based on the total tests conducted by this US national reference laboratory, PD-L1 testing was not commonly requested for UC during the analysis period. However, PD-L1 tests that were conducted displayed high success rates and reasonable TAT. This is the first comparison of the 22C3 and 28-8 assays on real-world UC samples, adding to the literature on PD-L1 testing concordance.
Relationship between abiraterone plasma concentration and PSA response in metastatic castration resistant prostate cancer patients.
Authors: Edith Carton, Gaelle Noe, Olivier Huillard, Julie Giroux, Anatole Cessot, Michael Peyromaure, Marc Zerbib, Celine Narjoz, Audrey Thomas-Schoemann, Michel Vidal, Francois Goldwasser, Benoit Blanchet, Jérôme Alexandre
Journal: Journal of Clinical Oncology (2015)

5041 Background: Abiraterone (ABI) is a standard treatment in metastatic castration-resistant prostate cancer (mCRPC). However, the large interindividual variability in ABI pharmacokinetics could contribute to the lack of PSA regression observed in some patients. We aimed to explore the pharmacokinetic/pharmacodynamic (PK/PD) relationship of ABI in progressive mCRPC patients (pts). Methods: We prospectively included mCRPC pts receiving ABI, pre-treated or not with docetaxel. ABI was administrated once daily at 1000 mg, in a fasted state, with 10 mg of prednisone. Trough ABI plasma concentration (Cmin) was assayed using liquid chromatography at month 1, 2 and 3 after treatment initiation, and PSA level was measured at baseline and after 3 months (ms) of treatment. The individual average Cmin during the first 3 ms of treatment was used for the statistical analysis. Pts who had a PSA decline of at least 50% after 3 ms were defined as responders, according to Prostate Cancer Working Group 2 (PCWG2). All pts gave their informed consent. Results: From December 2012 to October 2014, 57 pts were included. Forty-one pts (76%) were docetaxel-naïve. ABI Cmin was available in 48 pts. The median average ABI Cmin was 11.2 ng/mL (IQR 7.2 - 16.2 ng/mL). No intraindividual variability in ABI Cmin was identified (CV = 23.5%, p = 0.79). The interindividual variability in ABI Cmin was large (CV = 70%), but was not influenced by age, body mass index, albumin level, hepatic or renal function. Among 45 pts available for PK/PD assessment, 29 pts (64%, IC95% [50-78]) were responders at 3 ms. The average plasma ABI Cmin was significantly higher in the responder group (median 13.1 [IC 95% 10.6 - 15.6] vs 8.5 [5.6-15.7] ng/mL, p < 0.01, respectively). Pts were classified into two groups based on ABI plasma Cmin: low (quartile 1 [Q1]) and high (Q2-Q4). In 11 pts exhibiting average ABI Cmin below 8.5ng/mL (Q1), 18% were responders. In contrast, 80% of pts in Q2-Q4 were responders (Fisher test, p < 0.001). Conclusions: In addition to molecular profiling, plasma monitoring of ABI Cmin could help optimizing its efficacy. We propose 8.5 ng/mL as the threshold ABI Cmin to explore the benefit of PK-guided dosing strategy in clinical practice.
Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation
Authors: Renato D. Lopes, Gretchen Heizer, Ronald Aronson, Amit N. Vora, Tyler Massaro, Roxana Mehran, Shaun G. Goodman, Stephan Windecker, Harald Darius, Jia Li, Oleg Averkov, M. Cecilia Bahit, Otavio Berwanger, Andrzej Budaj, Ziad Hijazi, Alexander Parkhomenko, Peter Sinnaeve, Robert F. Storey, Holger Thiele, Dragos Vinereanu, Christopher B. Granger, John H. Alexander
Journal: New England Journal of Medicine (2019)

Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear.
Ferumoxytol-Enhanced CMR for Vasodilator Stress Testing: A Feasibility Study
Authors: Kim-Lien Nguyen, Jiaxin Shao, Vahid K. Ghodrati, Olujimi A. Ajijola, Rohan Dharmakumar, J. Paul Finn, Peng Hu
Journal: JACC. Cardiovascular imaging (2019)
A multigene expression score for predicting response to anti-PD-1/PD-L1 therapy for clear cell renal cell cancer patients.
Authors: Yukti Choudhury, Kai Wei Tan, Hui Shan Tan, Jian Cheng Hong, Miah Hiang Tay, Min-Han Tan, Puay Hoon Tan, Wan Ling Tan, Quan Sing Ng, Chee Keong Toh, Ravindran Kanesvaran
Journal: Journal of Clinical Oncology (2019)

656 Background: Anti-PD-1 inhibitor nivolumab and combination checkpoint inhibition (nivolumab and ipilimumab) are approved for advanced clear cell renal cell cancer (ccRCC), with objective response rates between 25% to 40%. PD-L1 expression is a poor predictor of anti-PD-1/PD-L1 therapy response in ccRCC. Better predictive biomarkers are required. The CLEAR score (CS) is a multigene prognostic expression score for ccRCC (Eur Urol 2015) previously associated with TKI outcomes. Given association of prognosis and clinical benefit, CS was explored as a biomarker for response to anti-PD-1/PD-L1 therapy in this study. Methods: CS is derived from the expression of 8 genes in ccRCC tumor tissue and intervening stroma and includes components of chemokine signaling. Based on this, immunohistochemistry of ccRCC tumor tissue (n = 24; matched CS also derived from same tissue), was done for tumor-infiltrating lymphocytes (CD8+) and PD-L1. Staining intensity was also correlated to CS. In another set of RCC patients who received nivolumab or pembrolizumab after progression on anti-angiogenic therapy (n = 12), correlation of their tumor CS and response outcome to anti-PD-1 therapy was done. Results: CS was significantly higher for ccRCC tumors with higher intratumor and/or stromal CD8+ cell infiltration (p &lt; 0.001). A similar correlation with PD-L1 staining was not observed. Among RCC patients receiving anti-PD-1 therapy, clinical benefit (stable disease or partial response) was characterized by higher CS, regardless of treatment line. When analysis was limited to ccRCC histology, CS were significantly higher (p &lt; 0.05) for responders (n = 2) compared to non-responders (n = 4) to nivolumab treatment. Conclusions: This is the first study reporting the correlation of a multi-gene score (CS) with immune phenotypes in ccRCC. CS correlates well with intratumor/stromal CD8+ cell infiltration, and is a potential biomarker for response to anti-PD-1 therapy. Consistent with clinical trial data, high CS (associated with poor prognostic tumors) correlated with better responses. Studies with a larger cohort of patients are underway to establish the utility of CS in predicting response to anti-PD-1/PD-L1 therapy.
Experience with sipuleucel-T in metastatic castration-resistant prostate cancer (mCRPC) with visceral spread from PROCEED.
Authors: Nicholas J. Vogelzang, Philip W. Kantoff, Mark C. Scholz, Jeffrey L. Vacirca, Shaker R. Dakhil, Sanjay Goel, Matthew Harmon, Hong Tang, Bruce Brown, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2019)

174 Background: Trials of approved agents in mCRPC have reported shorter overall survival (OS) in men with visceral metastases (mets). The phase 3 IMPACT trial evaluated sipuleucel-T, an autologous cellular immunotherapy, in mCRPC but excluded visceral mets. PROCEED, a registry of mCRPC patients receiving sipuleucel-T, offers the first description of sipuleucel-T in patients with visceral mets. Methods: PROCEED enrolled men with mCRPC treated with sipuleucel-T biweekly x 3. Dose adjustment for organ dysfunction was unnecessary. Men were followed until death, study withdrawal, or a minimum of 3 years. OS is reported in this post-hoc subgroup analysis. Results: 1902 men received ≥1 sipuleucel-T infusion between 2011-2014. Visceral mets (n = 90) included liver (n=21), lung (n=61), and brain (n=2) involvement. Compared to patients without visceral mets (Table), men with visceral mets had poorer performance status (PS) and higher baseline prostate-specific antigen (PSA). Median OS was 20.5 and 31.2 mo in those with and without visceral mets. Patients with liver and lung mets had a median OS of 16.3 and 21.0 mo, respectively. Activation of antigen-presenting cells, a measure of immune activation and product potency, was similar in those with and without visceral mets. Conclusions: Initial observations suggest that patients with mCRPC and visceral spread can activate their immune cells to produce sipuleucel-T, but have a shorter OS than those with bone and/or lymph node spread. (NCT01306890). Clinical trial information: NCT00065442. [Table: see text]
Choosing Wisely India: ten low-value or harmful practices that should be avoided in cancer care
Authors: C S Pramesh, Harit Chaturvedi, Vijay Anand Reddy, Tapan Saikia, Sushmita Ghoshal, Mrinalini Pandit, K Govind Babu, K V Ganpathy, Dhairyasheel Savant, Gunita Mitera, Richard Sullivan, Christopher M Booth
Journal: The Lancet Oncology (2019)
Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency
Authors: Mohammed F. Alosaimi, Manfred Hoenig, Faris Jaber, Craig D. Platt, Jennifer Jones, Jacqueline Wallace, Klaus-Michael Debatin, Ansgar Schulz, Eva Jacobsen, Peter Möller, Hanan E. Shamseldin, Ferdous Abdulwahab, Niema Ibrahim, Hosam Alardati, Faisal Almuhizi, Ibraheem F. Abosoudah, Talal A. Basha, Janet Chou, Fowzan S. Alkuraya, Raif S. Geha
Journal: Journal of Allergy and Clinical Immunology (2019)
The validation of the 2014 International Society of Urological Pathology (ISUP) grading system for patients with high-risk prostate cancer: A single-center retrospective study.
Authors: Jiandong Liu
Journal: Journal of Clinical Oncology (2019)

128 Background: Since the new 2014 grading system was recommended by the International Society of Urological Pathology (ISUP), it has been validated in patients with localized prostate cancer (PCa) and has shown excellent prognostic value. However, its predictive power in high-risk PCa remained unclear. Methods: Overall, 420 patients with high-risk PCa who underwent radical prostatectomy (RP) were included. Biochemical recurrence-free survival (BRFS) was set as the endpoint. Results: Biochemical recurrence occurred in 84/420 (20.0%) patients at the end of follow-up. Compared to the three-tier grouping system, the five-tier grouping system could more effectively distinguish the BRFS of patients with higher predictive accuracy (C-index: 0.599 vs 0.646). The BRFS of patients with grade group (GG) 1 and GG 2 was similar (p = 0.593). Also, the prognosis between those in the GG 2 and GG 3 could be clearly distinguished (p = 0.001). Whereas the discrimination capacity between patients with GG 3 and GG 4 was limited (p = 0.681). The high proportion of tertiary Gleason pattern 5 (TGP5) among patients with GG 3 might be an important confounder leading to the overlap of survival between GG 4 and GG 3. Conclusions: This study is the first one to validate the new 2014 ISUP grading system in patients with high-risk PCa who underwent RP. The 2014 system could effectively separate patients into five groups with high predictive accuracy. Notably, the existence of TGP5 needs to be routinely reported in clinical practice, which could help to support the predictive ability of the new grading system.
Design of phase Ib/II study of oral VERU-111, an α and β-tubulin inhibitor, for the treatment of metastatic castration- and androgen-blocking-agent-resistant prostate cancer.
Authors: Mark Christopher Markowski, Mario A. Eisenberger, Emmanuel S. Antonarakis, Evan Y. Yu, Gary Barnette, Domingo Rodriguez, Robert H. Getzenberg, Mitchell S. Steiner
Journal: Journal of Clinical Oncology (2019)

TPS330 Background: VERU-111 is a novel oral small molecule (NCE) that targets α and β-tubulin subunits of microtubules resulting in the inhibition of tubulin polymerization. Agents that target microtubules are among the most effective for the treatment of metastatic cancers. However, these currently available agents target only the β-tubulin subunit and are administered IV. VERU-111 has high oral bioavailability and does not interact with MDR proteins. In nonclinical models, VERU-111 has high activity against many tumor types as well as against prostate cancers that have become resistant to taxanes and novel androgen blocking agents (abiraterone and enzalutamide). In 28-day dog and rat toxicity studies, no neutropenia, myelosuppression, or liver function test changes were observed at oral daily doses in blood concentrations that resulted in antitumor activity in preclinical models. Based on these unique properties, VERU-111 has advanced into a Phase1b/2 clinical trial. Methods: V1011101 is a Phase 1b/2 study, being conducted in at least three sites in the US, evaluating the safety and preliminary efficacy of VERU-111 in men with metastatic castration and androgen blocking agent resistant prostate cancer (mCARPC). The Phase 1b portion of the study consists of 21-day cycles where VERU-111 is taken daily, orally for 7-days followed by a 14-day hiatus (dose cycle). Safety/tolerability of VERU-111 and MTD of VERU-111 will be determined. The Phase 2 will use the selected dose cycle from the Phase 1b and the primary endpoint will be the PSA 50 response rate, defined as a decline in PSA to &gt; 50% of baseline level, confirmed with a second measurement at least 3 weeks apart (PCWG3) and determine the pharmacokinetic profile of VERU-111. The secondary endpoints include determining the safety/tolerability of VERU-111 as defined as incidence of CTCAE v5.0 grade ≥3 toxicities; estimating the median PSA progression-free survival (PCWG3); estimating the median progression-free survival (PCWG3); and estimating the objective response rate. It is anticipated that based upon the Phase 1b/2 clinical findings VERU-111 will also be expanded into other cancer types.
Underuse of Medications and Lifestyle Counseling to Prevent Cardiovascular Disease in Patients With Diabetes
Authors: Jonathan D. Newman, Jeffrey S. Berger, Joseph A. Ladapo
Journal: Diabetes Care (2019)

Cardiovascular disease (CVD) accounts for ≥75% of hospitalizations and >50% of all deaths among patients with diabetes (1,2). Guideline-directed therapies for patients with diabetes aged 50 years and older with an additional cardiovascular risk factor such as hypertension include cardioprotective medications (antiplatelet therapy, statins, and antihypertensives shown to reduce cardiovascular events) and lifestyle counseling for healthy behaviors (weight loss/diet, exercise, and smoking cessation) (1,3). However, data are limited on trends in usage of pharmacotherapies and lifestyle counseling for patients with diabetes at increased CVD risk. Therefore, we used nationally representative data to investigate trends in medication use and lifestyle counseling among U.S. outpatients aged 50 years and over with diabetes and hypertension.

All visits to office-based physicians and hospital-based clinics by adults (aged 50 years and older with hypertension; N = 14,096 visits) from 2006 to 2015 in the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) were included. Data include patient symptoms, comorbidities, and demographics; physician diagnoses; medications ordered or provided; and medical services provided. Diabetes and hypertension were identified using ICD-9-Clinical Modification diagnosis codes. Physician decision making and treatment were evaluated using 1 ) Multum Lexicon drug codes/categories and generic codes for antiplatelet agents (aspirin and clopidogrel), …