tbuckley/cabot-search huggingface dataset:
The clinical prognostic impact of APOBEC3B protein expression in metastatic urothelial carcinoma.
Authors: Hyunho Kim, In-Ho Kim, Kwangil Yim
Journal: Journal of Clinical Oncology (2020)

544 Background: APOBEC3 enzymes function as a carcinogenic mutagens resulting in substitution of Cytosine to Thymine or Guanine in tCw motif. Mutation signature in urothelial (UC) carcinoma is mediated by APOBEC3 more than smoking which is well known as a risk factor. This study aimed to explore the association of APOBEC3 expression with survival in metastatic UC (mUC). Methods: We examined 94 patients treated with gemcitabine plus platinum chemotherapy for mUC. APOBEC3A and 3B protein expression was measured using immunohistochemistry from archived formalin-fixed paraffin-embedded tissue which was obtained before chemotherapy. Immunohistochemistry results were evaluated by H-score. The cutoff levels of APOBEC3A and 3B expression were calculated with time dependent ROC analysis. Results: APOBEC3B high expression exhibited longer overall survival (OS) and progression-free survival (PFS) than low expression (median OS: 16 months vs 9 months, p=0.032; median PFS: 7 months vs 4 months, p=0.017). APOBEC3A high expression was associated with longer OS (median OS: 13 months vs 9 months, p=0.036; median PFS: 6 months vs 4 months, p=0.405). Disease control (CR/PR/SD) rate (DCR) was higher in APOBEC3B high group than low group (DCR, 79.4% and 57.1%, respectively, p=0.045). Mean H-score of APOBEC3B was higher in disease control group than progressive disease group (mean H-score, 125.3 vs 101.3, p=0.029). APOBEC3A expression was not correlated with chemotherapy response. There was not a significant correlation between APOBEC3A and APOBEC3B (Spearman correlation coefficient=0.111, p=0.319). Conclusions: mUC with APOBEC3B high expression may be associated with better response from gemcitabine plus platinum chemotherapy and longer overall survival. Further functional studies are warranted to clarify the clinical significance of APOBEC3B protein expression in mUC.
PIVOT-10: A phase II study of bempegaldesleukin (NKTR-214) in combination with nivolumab (NIVO) in cisplatin (cis) ineligible patients with previously untreated locally advanced or metastatic urothelial cancer (mUC).
Authors: Robert A. Huddart, Arlene O. Siefker-Radtke, Arjun Vasant Balar, Mehmet Asim Bilen, Thomas Powles, Aristotelis Bamias, Daniel Castellano, Maged F. Khalil, Michiel Simon Van Der Heijden, Vadim S Koshkin, David William Pook, Mustafa Ozguroglu, Linda Santiago, Rabih Saab, Pao-Chen Li, Margit Cecile Tagliaferri, Wei Lin, Mary Ann Tagliaferri, Yohann Loriot
Journal: Journal of Clinical Oncology (2020)

TPS589 Background: Checkpoint inhibitors can achieve durable responses in cis-ineligible 1L mUC. However, use is restricted to patients whose tumors are PD-L1 high. Approximately 70% of cis-ineligible patients have tumors with low PD-L1 expression, leaving a significant proportion of 1L mUC patients in need of new treatment options. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor. NIVO is an anti-PD-1 antibody that is approved for treatment in several types of cancers, including 2L mUC after treatment with a platinum agent. Early BEMPEG plus NIVO data in 1L mUC (cis-eligible and -ineligible) patients found an objective response rate (ORR) of 48% (13/27) in the efficacy evaluable population (defined as having undergone at least one post-baseline scan) and a CR rate of 19%, prompting this further exploration of BEMPEG plus NIVO in a phase 2 study (Siefker-Radke, 2019). Methods: This Phase 2 multi-national trial evaluates BEMPEG plus NIVO in previously untreated patients with cis-ineligible mUC. Eligibility also requires tumor tissue be analyzed by central laboratory to document PD-L1 status. Approximately 205 patients will be enrolled. BEMPEG (0.006 mg/kg) and NIVO (360 mg) are given intravenously (IV) on Day 1 of each 3-week cycle. The primary endpoint is ORR assessed per RECIST 1.1 by blinded independent central review (BICR) in patients with low PD-L1 expression (defined as Combined Positive Score [CPS] &lt; 10). Secondary endpoints include ORR and duration of response in all treated patients, safety, and tolerability. Tumor and blood samples will be collected for biomarker analyses. Enrollment is ongoing. Clinical trial information: NCT03785925.
The association between allopurinol use and urologic malignancies: A nested case-control study.
Authors: Daniel Keizman, Ido Wolf, Hadas Dresler, David Sarid, Avivit Peer, Keren Rouvinov, Victoria Neiman, Ofer Margalit, Einat Shacham-Shmueli, Ronac Mamtani, Kevin Haynes, Yu-Xiao Yang, Ben Boursi
Journal: Journal of Clinical Oncology (2020)

435 Background: Oxidative stress may be involved in tumorigenesis processes. Uric acid is an important natural antioxidant that may reduce oxidative stress. Allopurinol is a commonly used uric acid lowering agent. There are conflicting data regarding the association between allopurinol use and cancer incidence. In the present nested case control study, we aimed to evaluated the association between allopurinol use and urologic malignancies in a large western population. Methods: conducted a nested case-control study within a population-representative database from the United Kingdom (THIN). Study cases were defined as individuals with any diagnostic code of prostate cancer, bladder cancer, or renal cell carcinoma. For every case, four eligible controls were matched on age, gender, practice site, time of diagnosis, and duration of follow-up. Exposure of interest was any allopurinol use prior to cancer diagnosis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for urologic malignancies were estimated using conditional logistic regression. Adjustment was performed for factors including smoking, BMI, and diabetes. Results: The study population included: for bladder cancer 13440 and 52421 matched controls, prostate cancer 27212 cases and 105940 controls, RCC 1547 cases and 6066 controls. Allopurinol use was associated with a significantly increase of risk for bladder cancer (adjusted OR 1.2, 95%CI 1.09-1.32, p&lt;0.001). prostate cancer (adjusted OR 1.1, 95%CI 1.03-1.,17, p=0.003), RCC (adjusted OR 1.32, 95%CI 1-1..75, p=0.05). In a sensitivity analyses we observed similar associations when alopurinol use was initiated more than two years prior to cancer diagnosis, for bladder cancer (adjusted OR 1.2, 95%CI 1.08-1.33, p=0.001), prostate cancer (adjusted OR 1.09, 95%CI 1.02-1.16, p=0.01), RCC (adjusted OR 1.09, 95%CI 0.78-1.53, p=0.62). Conclusions: Allopurinol use may be associated with an increased risk for urologic malignancies.
Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial
Authors: Hugues Chabriat, Claudio L Bassetti, Ute Marx, Marie-Laure Audoli-Inthavong, Aurore Sors, Estelle Lambert, Marine Wattez, Dirk M Hermann, Katharina ALTHAUS, Sergi AMARO, Hee-Joon BAE, Zbigniew BAK, Leonardo BARBARINI, Pietro BASSI, Rodrigo BAZAN, Daniel BERECZKI, Tomasz BERKOWICZ, Joerg BERROUSCHOT, Dylan BLACQUIERE, Waldemar BROLA, Kenneth BUTCHER, Pere CARDONA, Jae-Kwan CHA, Geoffrey CLOUD, David COHEN, Charlotte CORDONNIER, Attila CSANYI, Anna CZLONKOWSKA, Stephen DAVIS, Jesse DAWSON, Nina DE KLIPPEL, Christian DENIER, Philippe DESFONTAINES, Hans-Christoph DIENER, Peter DIOSZEGHY, Diederik Willem DIPPEL, Laura DORADO, Andras FOLYOVICH, Gabriel Rodriguez FREITAS, Mauricio Andre FRIEDRICH, Waldemar FRYZE, Rubens Jose GAGLIARDI, Marianna GOTTSCHAL, Rohan GRIMLEY, Martin GROND, Klaus GRÖSCHEL, Hassan HOSSEINI, Yangha HWANG, Bernd KALLMUENZER, Usman KHAN, Jong Sung KIM, Tim KLEINIG, Agnes KOVES, Aida LAGO MARTIN, Anetta LASEK-BAL, Giuseppe LEMBO, Robin LEMMENS, Ralf LINDERT, Luiz Carlos PORCELLO MARRONE, Maite MARTINEZ ZABALETA, Jean-Louis MAS, Jaime MASJUAN VALLEJO, Mikael MAZIGHI, Cesar MINELLI, Amit MISTRI, Carlos MOLINA, Francisco MONICHE ALVAREZ, Carla Heloisa CABRAL MORO, Wim MULLENERS, Darius NABAVI, Jean-Philippe NEAU, Bill O'BRIEN, Csaba OVARY, Gyula PANCZEL, Man Seok PARK, Thanh PHAN, Suzanne RAGAB, Konrad REJDAK, Gabriel RODRIGUEZ DE FREITAS, Christine ROFFE, Jaume ROQUER GONZALEZ, Luisa ROVER, Gisele SAMPAIO SILVA, Peter SCHELLINGER, Tomas SEGURA MARTIN, Louise SHAW, Igor SIBON, Ondrej SKODA, Didier SMADJA, Piotr SOBOLEWSKI, Hassan SODA, Nikola SPRIGG, Maciej SWIAT, Laszlo SZAPARY, Norbert SZEGEDI, Danilo TONI, Attila VALIKOVICS, Geert VANHOOREN, Laszlo VECSEI, Theodore WEIN, Andrew WONG, Alvaro XIMENEZ CARRILLO
Journal: The Lancet Neurology (2020)
The Nonirritating Skin Test Concentrations for Commonly Used Beta-lactam Containing Antibiotics other than Penicillin
Authors: Alexei Gonzalez-Estrada, Ismael Carrillo-Martin, Ross Renew, Harry Powers, Jared Nelson, Wendelyn Bosch, Kevin Epps, Matthew Rank, Gerald Volcheck, Miguel Park
Journal: Journal of Allergy and Clinical Immunology (2020)
Androgen deprivation therapy and statin therapy in prostate cancer patients.
Authors: Kin Chung Lai, Toiya Turknett, Parminder Singh
Journal: Journal of Clinical Oncology (2020)

205 Background: Metastatic prostate cancer (mPC) is treated with androgen deprivation therapy( ADT). Duration of response to ADT predicts patient’s survival. It has been shown in observational studies that concurrent statin use may prolong response to ADT. Studies in mice have shown negative interactions. We wanted to examine the effect of this interaction in patients being followed at Mayo Clinic Arizona (MCA). Methods: We examined 441 patients with mPC, who received ADT and were treated at MCA from year 2011 to 2017. . Our study evaluated the time to progression (TTP) and overall survival(OS) for patients with mPC on ADT with or without concurrent statin use. Among the patients who were evaluated, there was a subset of 156 patients taking abiraterone (ABI). Characteristics were compared between statin users and nonusers using Chi squared test and Wilcoxon rank-sum tests. The primary outcome was TTP defined as the duration from ADT initiation to disease progression. The association between statin use and TTP was analyzed by multivariable Cox regression to estimate hazard ratios (HRs) and 95% Conference Interval (CI), and adjusted for Gleason score, primary therapy type, prior ADT, metastatic status, and PSA at ADT initiation. Results: There was no significant difference in TTP when comparing patients with statin to those without a statin. The HR for statin use vs no statin use is 1.049 with CI (0.838, 1.314) and p-value is 0.677. There was no significant difference in overall survival when comparing statin vs no statin use. The HR for statin use vs no statin use was 0.928(CI 0.642, 1.342) with p-value at 0.693. In the ABI population, there was no significant difference in TTP for patients with statin vs no statin. HR was 1.00 CI (0.725, 1.377) with p-value at 0.998. For overall survival, there was no significant difference with HR at 0.852 (CI 0.502, 1.446) with p-value at 0.553. Conclusions: Despite retrospective studies showing benefit of use of statin in men with prostate cancer, our study observed no difference in long term outcomes. Possible explanations could be smaller sample size, inability to verify data as medication intake was not verified directly. Also, patient’s compliance with medications could be a confounding variable.
PU.1 haploinsufficiency arrests pro-B cell development
Authors: Carole Le Coz, Brian Nolan, Piyush Pillarisetti, Caroline Khanna, David Nguyen, Titus Boggon, Sarah Nicholas, James Verbsky, Joud Hajjar, Gregory Poon, Ivan Chinn, Alexander Marson, Neil Romberg
Journal: Journal of Allergy and Clinical Immunology (2020)
Treatment of high-grade non-muscle invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: Results of the phase III clinical trial (NIMBUS).
Authors: Marc-Oliver Grimm, Toine van der Heijden, Marc Colombel, Luis Martinez Pineiro, Tim Muilwijk, Marek Babjuk, Levent N. Turkeri, Joan Palou-Redorta, Anup Patel, Anders Bjartell, Christien Caris, Raymond Schipper, Wim Witjes
Journal: Journal of Clinical Oncology (2020)

436 Background: Intravesical instillation of BCG is an accepted strategy to prevent recurrence of non muscle invasive bladder cancer (NMIBC). However, the optimal number of instillations is unknown. NIMBUS assessed whether a reduced number/standard dose BCG instillations is not inferior to standard number and dose BCG in patients with high-grade (HG) NMIBC. The primary endpoint was time to first recurrence. Methods: The aim was to enroll 824 BCG naïve patients with HG Ta-T1 NMIBC +/- CIS. NIMBUS was an international randomized not blinded trial to establish therapeutic equivalence defined as the lower part of the Confidence Interval (CI) (using one-sided 2.5% level of significance) being higher than a HR (hazard experimental/hazard standard) of 0.75 for recurrence. The treatment arms were: Standard: Induction cycle BCG weekly wks 1-6; maintenance cycles at months 3,6,12 (wks 1,2,3) and Reduced: Induction cycle at wks 1,2,6; maintenance cycles at months 3,6,12 (wks 1,3). Safety was evaluated at yearly intervals by the IDMC and in case inferiority was shown, defined as the upper part of the CI (one-sided 2.5% level) lower than a HR of 0.75, an advice to stop the trial would be given. Results: Available data at July 1, 2019 were analyzed for the IDMC meeting. A total of 345 patients were recruited from Germany (149), the Netherlands (109), France (64), Belgium (22) and Spain (1). Prognostic factors at initial resection were Ta/T1: 46/54%; primary/recurrent disease: 92/8%; single/multiple lesions: 57/43% and concomitant CIS/no CIS: 27/73%. The intention to treat analysis showed a clear difference in time to and number of recurrences between treatment arms: 27% in the reduced arm versus 12% in the standard arm. Known prognostic factors were evenly distributed between arms. Additional safety analyses were performed showing a HR of 0.40 [95% CI: 0.24-0.67]. Conclusions: Safety analysis showed that the reduced frequency schedule of BCG was inferior to the standard frequency schedule for time to first recurrence according to the previously defined stop criterion. Recruitment of patients was stopped immediately. Clinical trial information: NTR4011.
Fatty acid–binding protein 4 downregulation drives calcification in the development of kidney stone disease
Authors: Kazumi Taguchi, Ling Chen, Manint Usawachintachit, Shuzo Hamamoto, Misun Kang, Teruaki Sugino, Rei Unno, David T. Tzou, Benjamin A. Sherer, Atsushi Okada, Takahiro Yasui, Sunita P. Ho, Marshall L. Stoller, Thomas Chi
Journal: Kidney International (2020)
A multicenter, randomized, controlled phase II study: Efficacy and safety of PSMA-targeted radioligand therapy I-131-1095 (1095) plus enzalutamide (enza) in 18F-DCFPyL PSMA scan avid, metastatic castration-resistant prostate cancer (mCRPC) patients post-abiraterone (abi) progression (ARROW).
Authors: Evan Y. Yu, David Laidley, Frederic Pouliot, Stephan Probst, Fred Saad, Robert Sabbagh, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2020)

TPS260 Background: PSMA is a transmembrane glycoprotein expressed in normal human prostate epithelium at low levels, but highly upregulated in metastatic prostate cancer (PC). 18 F-DCFPyL is a novel PSMA-targeted PET imaging agent that has shown highly promising diagnostic performance for detection of metastatic disease, with potential to identify disease amenable to theranostic targeting. 1095 is a novel PSMA-targeted small molecule that binds to the extracellular domain of PSMA selectively with high affinity. The complex is internalized, allowing the beta emitter, I-131, to kill PC cells. Methods: ARROW is an open-label, randomized (2:1) trial of enza plus 1095 or enza alone in pts with progressive mCRPC who previously received abi. ~120 pts (80: 1095 + enza; 40: enza alone) will be treated at ~40 sites in the US and Canada. Eligible male pts must be at least 18 yo with metastatic disease documented by bone scan or soft tissue lesions measurable per RECIST 1.1 on CT/MRI, be PSMA-avid as determined by 18 F-DCFPyL PET/CT, have evidence of biochemical or radiographic progression on abi, and be ineligible for or refuse to receive chemotherapy. Pts will receive enza (prescribed per approved labeling) with or without 1095 (100 mCi dose, followed by up to 3 additional dose(s) administered at least 8 weeks apart, as determined by dosimetry evaluation and occurrence of dose-limiting events). The primary objective is to determine the efficacy of 1095 plus enza compared to enza alone, based on PSA response (confirmed PSA decline ≥50%) rate according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Additional objectives include objective response rate based on PCWG3-modified RECIST 1.1, progression-free survival (PFS) defined as the first occurrence of radiographic progression (PCWG3-modified RECIST 1.1), unequivocal clinical progression, or death from any cause, duration of response, overall survival, and the safety and tolerability of 1095 radioligand therapy. Clinical trial information: NCT03939689.
Impact of upstream use of novel hormonal therapy on progression of patients (pts) to metastatic castration-resistant prostate cancer (mCRPC) in the United States (US).
Authors: Howard I. Scher, Fred Saad, Maneesha Mehra, Sandhya Nair, Lindsay Dearden, Ravi C. Potluri
Journal: Journal of Clinical Oncology (2020)

92 Background: Novel hormonal therapies (nHTs) provide significant delay in disease progression in metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic (nm)CRPC. The impact of earlier use of these agents on the epidemiological burden of PC in the US was assessed. Methods: A disease stage transition model capturing pt flow through eight clinical states and tracking pt treatment history was used, with each nHT being used once. Progression-free survival (PFS) and overall survival (OS) data for each drug/regimen were derived from published sources where available. We analyzed scenarios 1) no nHTs and 2) with nHTs: (abiraterone acetate + prednisone [AAP], apalutamide [APA] and enzalutamide [ENZA] in high-risk mCSPC, and APA and ENZA in low-risk mCSPC and in high-risk nmCRPC). Resultant state progression parameters were compared, evaluating the impact of nHTs. The assumed nHT utilization was 17.2% in high-risk mCSPC, 7.1% in low-risk mCSPC, and 60.0% in high-risk nmCRPC. Results: For 2018, the model resulted in PC incidence of 240,150 and prevalence of 2,445,173; 49,450 pts progressed to mCRPC, 42% from PSA biochemical recurrence, 31% from mCSPC, and 27% from nmCRPC states. Longer PFS and OS afforded by novel treatments extended the mean time spent from 4.4 to 4.7 yrs in mCSPC and from 2.4 to 3.0 yrs in nmCRPC. This further resulted in reduction in inflow to mCRPC over 2019 – 2025 (table). Conclusions: Novel hormonal therapies are currently used earlier in PC, a trend anticipated to intensify. The disease model shows this change in the treatment paradigm to result in delaying progression to mCRPC and increasing OS in PC.[Table: see text]
A prospective study evaluating oral-only hormonal therapy with radiation for intermediate or high-risk prostate cancer in men age ≥ 70 years or with moderate comorbidity.
Authors: Benjamin Ernst Onderdonk, Paige L. Dorn, Fauzia Arif, Daniel William Golden, Theodore Karrison, Sean P. Pitroda, Russell Zelig Szmulewitz, Stanley L. Liauw
Journal: Journal of Clinical Oncology (2020)

303 Background: Androgen deprivation therapy (ADT) improves disease control in intermediate (IR) and high risk (HR) prostate cancer (PCa) treated with radiation therapy (RT), but also causes toxicity which may be worse in men of older age or with comorbidity. We hypothesized that dual agent ADT, replacing GnRH agonist for an oral 5-alpha-reductase inhibitor (5AR), would improve hormonal health-related quality of life (HRQOL) without compromising PCa outcomes. Methods: Patients with localized IR or HR PCa, age &gt; 70 years and/or with Charlson comorbidity index (CCI) score &gt; 2 were treated with bicalutamide and finasteride or dutasteride (oADT). A synchronous standard of care (SOC) cohort received bicalutamide and GnRH agonist. Median RT dose was 78 Gy. Dual agent ADT was given for 4 months (mo), while 5AR or GnRH agonist continued for an additional 2 years. The primary endpoint was the Expanded Prostate Cancer Index Composite (EPIC-26) hormonal HRQOL global score at 6 mo, with success defined as &lt; 30% decline, requiring 40 men in the oADT group. Secondary endpoints included a log-rank comparison of freedom from biochemical failure (FFBF), and overall survival (OS). Results: Between 1/2011 and 8/2018, 40 and 30 men were prospectively enrolled in the oADT and SOC cohorts, respectively, with similar CCI scores &gt; 2 (73% vs 66%, p=0.58), and age (mean 71, p=0.99). Median follow-up was 36 mo. Global scores for hormonal HRQOL at baseline, 6 mo, and 2 yr were 89, 88, 84 for the oADT group, and 92, 81, 83 for the SOC group; the declines from baseline to 6 mo (p=0.04) and 2 yr (p=0.05) were smaller in the oADT group. Sexual HRQOL was better preserved at 6 mo (p&lt;0.01) in the oADT group, which maintained higher testosterone at 2 years (452 vs 44, p&lt;0.01). There were no differences in urinary or bowel HRQOL. The 3-year FFBF was 90% vs 96% (p=0.83) and OS was 83 vs 86% (p=0.77) between the oADT and SOC groups, respectively. Conclusions: oADT improves hormonal and sexual HRQOL compared to SOC ADT in men age ≥ 70 or moderate comorbidity treated with RT. These groups could be further evaluated in a randomized comparison; post-ADT RNA expression to evaluate the relative biologic effects will be performed. Clinical trial information: NCT01342367.
Similar Breast Cancer Risk in Women Older Than 65 Years Initiating Glargine, Detemir, and NPH Insulins
Authors: Marie C. Bradley, Yoganand Chillarige, Hana Lee, Xiyuan Wu, Shruti Parulekar, Michael Wernecke, Patricia Bright, Mat Soukup, Thomas E. MaCurdy, Jeffrey A. Kelman, David J. Graham
Journal: Diabetes Care (2020)

OBJECTIVE To assess whether initiation of insulin glargine (glargine), compared with initiation of NPH or insulin detemir (detemir), was associated with an increased risk of breast cancer in women with diabetes. RESEARCH DESIGN AND METHODS This was a retrospective new-user cohort study of female Medicare beneficiaries aged ≥65 years initiating glargine (203,159), detemir (67,012), or NPH (47,388) from September 2006 to September 2015, with follow-up through May 2017. Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for incidence of breast cancer according to ever use, cumulative duration of use, cumulative dose of insulin, length of follow-up time, and a combination of dose and length of follow-up time. RESULTS Ever use of glargine was not associated with an increased risk of breast cancer compared with NPH (HR 0.97; 95% CI 0.88–1.06) or detemir (HR 0.98; 95% CI 0.92–1.05). No increased risk was seen with glargine use compared with either NPH or detemir by duration of insulin use, length of follow-up, or cumulative dose of insulin. No increased risk of breast cancer was observed in medium- or high-dose glargine users compared with low-dose users. CONCLUSIONS Overall, glargine use was not associated with an increased risk of breast cancer compared with NPH or detemir in female Medicare beneficiaries.