tbuckley/cabot-search huggingface dataset:
Small cell carcinoma of the prostate: National patterns of care and outcomes.
Authors: Zachary D. Horne, Ryan P Smith, Sushil Beriwal, Ronny Kalash, Ashwin Shinde, Scott Glaser, Russell Fuhrer, Rodney E Wegner
Journal: Journal of Clinical Oncology (2019)

9 Background: Small cell prostate cancer (SCPC) is a rare entity with treatment patterns extrapolated from small cell cancer of the lung. Outcomes have been evaluated in small series but prognostic factors are relatively poorly defined. Methods: We utilized the National Cancer Data Base to analyze men diagnosed with SCPC from 2004-2015. Only men with known clinical TNM staging, treatment modalities, and follow up were included. Overall survival (OS) was analyzed and compared with Kaplan-Meier, log-rank, and Cox proportional hazards ratios. Associations with baseline and tumor properties were performed with Chi-squared, independent t-test, and bivariate regression analyses. Results: 800 men with SCPC were identified. Median PSA was 79.0 ng/dL. 55.6% of men had cM1 disease at diagnosis, 31.4% had cN0M0 disease, and 13.0% were cN1M0. Median follow up was 12.4 months for all patients and 19.3 months for cM0 patients. Median survival for cM1, cN0M0, and cN1M0 patients was 9.8, 28.5, and 17.1 months, respectively (p&lt;0.001). In cM0 patients, 66 (18.7%) underwent radical prostatectomy (RP), 177 (50.1%) received radiation therapy (XRT), and 195 (45.2%) received chemotherapy (CT). Median survival for men undergoing RP was not reached vs those who did not undergo RP (p&lt;0.001). XRT also showed a trend towards improved median OS (25.2 vs. 19.1 months, p=0.139). On multivariable analysis for cM0 men, only age (HR 1.044 [95% CI 1.025-10.64] p&lt;0.001), cN1 (HR 1.378 [95% CI 1.001-1.898] p=0.050, RP (HR 0.429 [95% CI 0.259-0.709] p=0.001), and XRT (HR 0.520 [95% CI 0.384-0.704] p&lt;0.001) were predictive for overall survival. When examining only men who received systemic therapy, XRT was the only additional treatment modality to exhibit a survival benefit (HR 0.623 [95% CI 0.425-0.912] p=0.015). Of men with cM1 disease, 78 (17.5%) underwent definitive local therapy (RP/XRT), but no difference in OS was observed. Conclusions: Small cell prostate cancer is an aggressive disease with the majority of men presenting with metastases. In those with pelvis-confined disease who are fit for systemic therapy, radiation therapy to the primary should be considered.
Recommendations in a new drug application review for dose optimization to potentially improve gastrointestinal tolerability of a tyrosine kinase inhibitor.
Authors: Ruby Leong, Pengfei Song, Qi Liu, Hong Zhao, Gideon Michael Blumenthal, Sean Khozin, Yuzhuo Pan, Ping Zhao, Patricia Keegan, Brian Booth, Nam Atiqur Rahman
Journal: Journal of Clinical Oncology (2015)

2574 Background: On April 29 2014, the U.S. FDA approved ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. At the approved dosing regimen of ceritinib 750 mg once daily taken on an empty stomach, diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients with dose modification in 38% of patients. Anecdotal reports from patients and investigators suggest that gastrointestinal (GI) tolerability may improve when ceritinib is taken with food; however, administration of ceritinib with food increases exposure and may also increase the occurrence of non-GI related toxicities. Methods: Data were obtained from the multicenter, single-arm registration trial in 255 patients with ALK-positive tumors who received ceritinib 750 mg daily under fasted conditions and from a food effect study in healthy subjects. Exposure-response relationships for safety endpoints were evaluated by logistic regression analyses and Kaplan-Meier analyses using average exposure quartiles. Results: Compared to fasting conditions, a high-fat meal and a low fat meal increased ceritinib AUCinf by more than 50%. Higher systemic exposure appeared to be associated with more frequent and earlier safety events including overall Grade 3-4 adverse reactions (ARs), and individual ARs such as ≥ Grade 3 AST/ALT elevation and ≥ Grade 2 hyperglycemia. Higher systemic exposure also appeared to be associated with earlier and more frequent dose reductions or interruptions. A pharmacokinetic / pharmacodynamic analysis showed concentration-dependent QTc interval prolongation. Conclusions: The analyses along with the observed safety data led to an FDA requirement to conduct a postmarketing clinical trial to evaluate a lower dose of ceritinib taken with a meal (providing similar systemic exposure to that of the 750 mg dose taken under a fasted state) that potentially improves GI tolerability.
Integrated analysis of miRNAs expression in breast cancer patients to detect genes deregulation involved in malignant transformation.
Authors: Alejandro Recio Boiles, Devika Prasanna, Ahmad Bassam Shaker, Michaela Oswald, Cathleen Mason, Mary Keogh, Annette Lee, Iuliana Shapira
Journal: Journal of Clinical Oncology (2015)

e12560 Background: Outcomes of breast cancer patients depend on a number of phenotypic and molecular markers present in the malignancy. MicroRNAs dysregulation, often inhibiting gene expression, are present in cancerous tissue. miRNA expression, affected mRNA and resulting pathways can advert in pathologic breast tissue. We aim to detect miRNA differences profiles between benign and malignant breast tissue. Methods: Between 2010-2014, patients' breast samples, 41 cancer and 24 control, were processed by Taqman OpenArray miRNAs analysis. Mean statistical comparison by two-sample t-test and ANOVA followed by Benjamin-Hochberg was used at the < 5% level. TargetScan context+scores identified mRNAs regulated by overexpressed miRs. Reactome constructed deregulated pathways. Results: MiR-16, miR-19a, miR-20a, miR-21, miR-191, and miR-720 are 2-14 folds significantly higher in breast cancer relative to benign breast tissue. Target scan showed mRNA of GATAD2B; YOD1; BMPR2; SKI; GLIS2; IL12A; PLAG1; GRAMD3; SCML2; ZNF367; FAM13A; VCL to be decreased the most by our identified miRs. Reactome pathway analysis revealed deregulated pathways to be: 1) HDAC1/2 deacetylase complexes 2) Signaling by TGF-beta receptor complex (loss of function of SMAD4, SMAD2, TGFBR1, TGFRB2) SMAD4 MH2 domain mutants in cancer 3) Decrease in protein folding CCT/3C substrate proteins with unknown chaperones 4) Muscle contraction with calcium bound myosin actin complex 5) Signaling by RhoGTPase mainly downregulation of GAP proteins 6) Signaling by BMP SMAD 7) Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer involved in degradation of SKI/SKIL. Conclusions: Deregulation of TGF-beta signaling, abnormal protein folding, downregulation of GAP proteins and lack of degradation of SKI/SKIL appear to be common pathways for malignant transformation in breast cancer. miRNA regulated mRNA destabilization have detectable biological function with marginal influence on protein output. Each miR downregulates protein output by less than 30% without observable phenotypic consequences; however combined miRs have a robust functional repression in breast cancer cells leading to malignant process.
Comprehensive genomic profiling (CGP) of gynecologic malignancies in Israeli population to reveal potentially clinically relevant genomic alterations and opportunities for targeted therapies.
Authors: Tamar Safra, Ora Rosengarten, Jacob Korach, Claude Koren, Nava Siegelmann-Danieli, Noa Ben Baruch, Rotem Merose, Shulim Shpigel, Mario Beiner, Julia Greenberg, Juliann Chmielecki, Zachary Chalmers, Julia Andrea Elvin, Phil Stephens, Addie Dvir, Vincent A. Miller, Jeffrey S. Ross, Lior Soussan-Gutman, Siraj Mahamed Ali
Journal: Journal of Clinical Oncology (2015)

e16578 Background: Treatment options for relapsed and refractory metastatic gynecologic malignancies have limited success. Given the scant availability of mechanism-based clinical trials in Israel, we queried whether the use of a comprehensive genomic profiling (CGP), could open new routes to available targeted therapies and improve clinical outcomes. Methods: DNA was extracted from 40 microns of FFPE sections from advanced gynecologic malignancies. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of > 698x of 236 cancer-related genes. All classes of genomic alterations (GA) were evaluated. Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: 36 Stage IV, m age 60 (19-76)y patients were evaluated. There were 20 (53%) ovarian, 7 (21%) endometrial, 7 (19%) cervical carcinomas and 1 (3%) case of each leiomyosarcoma, yolk sacand granulosa cell tumor. CGP revealed 86% (32/37) with at least 1 CRGA, and 97% with at least 1 GA with an average of 4.1 GA/case. The most frequent CRGA were in PIK3CA 44% (12/37), PTEN 22% (6/37), MCL1 22% (6/37), BRCA2 19% (5/37), KRAS 15% (4/37) and ERBB2 11% (3/37). Among these patients, 4 received targeted therapy to date based on CGP results. 2 cases responded to therapy: a serous ovarian carcinoma harboring an FGFR1 amplification has an ongoing partial response(PR) to pazopanib for 2 months and a leiomyosarcoma case with an ALK rearrangement and TSC2 truncating splice site alteration showed a PR to combined sirolimus + pazopanib. Conclusions: : In this group of patients with advanced gynecologic malignancies , CGP uncovered a high frequency of CRGA that lead to use of available targeted therapies. Further application of CGP as a route to precision treatment appears warranted and will benefit from more widespread availability of targeted agents or combinations in clinical trials.
Non-HLA agonistic anti-angiotensin II type 1 receptor antibodies induce a distinctive phenotype of antibody-mediated rejection in kidney transplant recipients
Authors: Carmen Lefaucheur, Denis Viglietti, Yassine Bouatou, Aurélie Philippe, Daniele Pievani, Olivier Aubert, Jean-Paul Duong Van Huyen, Jean-Luc Taupin, Denis Glotz, Christophe Legendre, Alexandre Loupy, Philip F Halloran, Duska Dragun
Journal: Kidney International (2019)
Abstract P008: Pulse Pressure Following a Brief Patient Rest Period: Age and Gender Variations
Authors: Landai Nguyen, Sarina Sachdev, Hassan Tahir, Bassam Omar, Farnoosh Rahimi, Christopher Malozzi, G. Mustafa Awan
Journal: Circulation (2019)

Background: Increased pulse pressure (PP) is an independent determinant of cardiovascular disease. The effect of rest period on office-based systolic blood pressure has been previously reported, but not on PP in particular. Whether such rest period impacts the measured pulse pressure, and the variability of such response with age and gender remains unknown. Methods: Patient charts reviewed in University-based cardiology clinic identified 170 encounters which contained blood pressure (BP) re-measurement data due to elevated initial BP of &gt; 130/80 mmHg. BP was measured initially by the nurse, with the patient in a sitting position and the arm resting at the level of the heart. If BP was &gt; 130/80 mmHg, it was repeated by the physician after resting the patient for 15 minutes. There were 112 (66%) elderly patients ≥ 60 years of age and 58 (34%) younger patients &lt; 60 years of age. Among the elderly patients, there were 51 males (46%) and 61 females (54%). Results: Among all encounters, after a brief rest period, initial pulse pressure (PP) of 67 ± 2 mmHg decreased to 62 ± 1 mmHg (5 mmHg; P &lt; 0.01). PP decreased by 8 mmHg in the elderly (72 ± 2 to 64 ± 2 mmHg; P &lt; 0.01) but did not significantly change in the young (56 ± 3 to 58 ± 3 mmHg; P = NS). PP decrease among the elderly was more pronounced in females (11 mmHg; 76 ± 4 to 65 ± 2 mmHg; P &lt; 0.01) compared with males (4 mmHg; 68 ± 3 to 64 ± 2 mmHg; P = 0.03). Conclusion: Hypertension is a challenging public health problem. The new ACC/AHA High Blood Pressure Guidelines have decreased the range for Stage 1 hypertension to systolic blood pressure of 130-139 mmHg, and diastolic blood pressure of 80-89 mmHg, with normal blood pressure as less than 120/80 mmHg. Blood pressure guidelines recommend that prior to BP measurement, persons should be seated quietly for at least 5 minutes in a chair, with feet on the floor, and arm supported at heart level; which resulted in significant decrease in pulse pressure in our patients. We show that while a decrease in pulse pressure was confined to the elderly, elderly females had a more pronounced PP decrease compared to males; both, however, fell to the same level. White coat hypertension may explain this observation, since it is more frequent in elderly females. The implication of this observation is that physicians should take extra care in re-measuring the blood pressure and pulse pressure, especially in elderly females, in whom a more pronounced drop in pressure may be observed after a brief rest period, and thereby, result in reclassifying their risk and need for treatment.
Impact of testosterone replacement therapy after radiation therapy on prostate cancer outcomes.
Authors: Reith Sarkar, J Kellogg Parsons, John Paul Einck, Arno James Mundt, A. Karim Kader, Christopher J. Kane, Paul Riviere, Rana R. McKay, James Don Murphy, Brent Shane Rose
Journal: Journal of Clinical Oncology (2019)

99 Background: Currently there is little data to guide the use of testosterone replacement therapy in prostate cancer patients who have received radiation therapy (RT). We sought to evaluate the impact of post-RT testosterone replacement on prostate cancer outcomes in a large national cohort. Methods: We conducted a population-based cohort study using the Veterans Affairs Informatics and Computing Infrastructure. We identified node-negative and non-metastatic prostate cancer patients diagnosed between 2001-2015 treated with RT. We excluded patients for missing covariate and follow-up data. Receipt of testosterone was coded as a time-dependent covariate. Other covariates included: age, Charlson Comorbidity index, diagnosis year, body mass index, race, PSA, clinical T/N/M stage, Gleason score, and receipt of hormone therapy. We evaluated prostate cancer-specific survival, overall survival, and biochemical recurrence free survival using multivariable Cox regression. Results: Our cohort included 41,544 patients, of whom 544 (1.3%) received testosterone replacement after RT. There were no differences in Charlson comorbidity, clinical T stage, median pre-treatment PSA or Gleason score between treatment groups. Testosterone patients were more likely to be of younger age, non-black, have a lower median post-treatment PSA nadir (0.1 vs. 0.2; p &lt; 0.001), have higher BMI, and have used hormone therapy (46.7% vs 40.3%; p = 0.003). Median duration of ADT usage was equivalent between treatment groups (testosterone: 185 days vs. non-testosterone: 186 days, p = 0.77). The median time from RT to TRT was 3.52 years. After controlling for differences in covariates between treatment groups, we found no difference in prostate cancer specific mortality (HR 1.02; 95% CI 0.62-1.67; p = 0.95), overall survival (HR 1.02; 95% CI 0.84-1.24; p = 0.86), non-cancer mortality (HR 1.02; 95% CI 0.82-1.27; p = 0.86) biochemical recurrence free survival (HR 1.07; 95% CI 0.90-1.28; p = 0.45). Conclusions: Our results suggest that testosterone replacement is safe in prostate cancer patients who have received RT. Prospective data are required to confirm the safety of post-RT testosterone replacement.
Reduction in PD-L1 expression by STAT3 inhibition with GPA500 in enzalutamide-resistant prosate cancer.
Authors: Jennifer L Bishop, Daksh L Thaper, Sepideh Vaheid, Martin Hans Johansson, Amina Zoubeidi
Journal: Journal of Clinical Oncology (2015)

e16075 Background: Treatment benefits of the anti-androgen Enzalutamide (ENZ) in patients with castration-resistant prostate cancer (CRPC) are limited, underscoring the need for alternative therapies. Mechanisms of resistance to androgen targeted therapies like ENZ are varied, but include hyperactivation of oncogenic signaling pathways, such as STAT3, as well as potential immune suppression by expression of the T cell inhibitory checkpoint molecule PD-L1. In immune cells and other cancer types STAT3 regulates PD-L1 expression, and STAT3 signaling is important for CRPC progression, but whether STAT3 regulates PD-L1 expression in CRPC remains unknown. Based on our observations that STAT3 is hyperactivated and PD-L1 is uniquely expressed in our pre-clinical model of ENZ resistance compared to CRPC, we hypothesized that STAT3 is required for ENZR cell growth and expression of PD-L1 and that targeting STAT3 can reverse immune suppresive mechanisms. Methods: Dose dependent effects of the small molecule STAT3 inhibitor GPA500 were tested on ENZR and CRPC cells. STAT3 activation was assessed at baseline and after treatment by western blot for pSTAT3 and RT-PCR for STAT3 target genes (c-Myc, MCL1, BCL-XL). Cell viability and proliferation after treatment was assessed by crystal violet, MTT, cell cycle and PARP cleavage assays. Expression of PD-L1 and PD-L2 were assessed by flow cytometry. Results: ENZR cell lines that express PD-L1 displayed increased pSTAT3Y705 compared to CRPC cells. These ENZR cell lines were more sensitive to reduced viability and proliferation after treatment with GPA500 than CRPC control. Reduction in growth of treated ENZR cells was independent of PARP cleavage and associated with decreased frequency of cells in S phase. Flow cytometry showed that inhibition of STAT3 in ENZR cells with GPA500 reduced expression of PD-L1 and PD-L2. Inhibition of STAT3 activity was confirmed by WB as well as qRT-PCR analysis of STAT3 regulated genes like c-Myc, MCL1, BCL-XL. Conclusions: Our results suggest thathyperactivation of the STAT3 pathway, leading to cellular proliferation and the expression of the immune checkpoint molecule PD-L1, is a mechanism of resistance that can be targeted with STAT3 inhibitors.
Safety and tolerability results from a phase I study of MEDI4736, a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib in patients (pts) with non-small-cell lung cancer (NSCLC).
Authors: Ben C. Creelan, Laura Q. Chow, Dong-Wan Kim, Sang-We Kim, Tammie Yeh, Joyson Joseph Karakunnel, Don Lynn Gibbons
Journal: Journal of Clinical Oncology (2015)

3047 Background: MEDI4736 is a human IgG1 monoclonal antibody which blocks PD-L1 binding to PD-1 and CD-80 with high affinity and selectivity. A Phase I open-label multicenter study was initiated to evaluate MEDI4736 combined with the EGFR tyrosine kinase inhibitor (TKI) gefitinib in NSCLC (NCT02088112). Dose escalation phase data are reported. Methods: Key eligibility criteria included: locally advanced/metastatic NSCLC of any EGFR mutation status, relapsed/refractory/intolerant of standard treatment; ≤ 4 prior therapies. Cohort A received MEDI4736 3 mg/kg (starting dose) every 2 weeks plus gefitinib 250 mg once-daily (QD). If no dose-limiting toxicities were observed, Cohort B received MEDI4736 at a higher dose of 10 mg/kg every two weeks plus gefitinib 250 mg QD. Primary endpoint: safety/tolerability and recommended dose of the MEDI4736 plus gefitinib combination. Secondary endpoints included: tumor response (RECIST 1.1); pharmacokinetics (PK); immunogenicity. Results: Of 10 pts (Cohort A = 3; Cohort B = 7): 4 male; 4 Asian; median age 58.5 years. Maximum tolerated dose was not reached, and no dose limiting toxicities were observed. Adverse events (AEs) were observed in all pts; treatment-related CTC Grade 3-4 AEs in 3 pts led to study discontinuation: dyspnea/hypoxia (Cohort A; 1 pt), myalgia/fatigue and elevated ALT (Cohort B; 1 pt each). These AEs resolved upon discontinuation and standard management guidelines. Two unrelated deaths occurred in Cohort B. No PK interactions were observed nor anti-drug antibodies detected with the drug combination. Of 7 pts with ≥ 1 8-week tumor assessment; 3 pts had reduction in tumor size (Cohort A = 2; Cohort B = 1). Conclusions: MEDI4736 (3 and 10 mg/kg) plus gefitinib was generally well tolerated in pts with NSCLC in the escalation phase, with early clinical activity observed in these heavily pre-treated pts. Preliminary data support continued evaluation of MEDI4736 10 mg/kg with gefitinib 250 mg as the recommended expansion phase dose in pts with EGFR sensitized mutation-positive/TKI naïve NSCLC. Sponsored by MedImmune, global biologics R&D arm of AstraZeneca Clinical trial information: NCT02088112.
MRI-based prostate specific antigen density predicts Gleason score upgrade in an active surveillance cohort.
Authors: Samuel L. Washington, Avi Lefridge Baskin, Niloufar Ameli, Hao Gia Nguyen, Antonio C. Westphalen, Katsuto Shinohara, Peter Carroll
Journal: Journal of Clinical Oncology (2019)

107 Background: Elevated prostate specific antigen density (PSAD) based on transrectal ultrasound (TRUS) measurements has been shown to be strongly associated with clinically significant disease and to predict progression on active surveillance for men with low stage/grade disease. We hypothesize that elevated MRI PSAD is similarly associated with increased risk of progression on subsequent biopsy. Methods: Patients with Gleason grade 3+3 on diagnostic transrectal ultrasound-guided biopsy who were managed with active surveillance and underwent at least one additional biopsy were included. Patients who underwent MRI greater than 6 months after diagnosis were excluded. Summary statistics were generated for demographic and clinical characteristics. MRI PSAD was calculated using prostate volume on MRI and PSA temporally closest to the MRI. Multivariable logistics regression models were used to evaluate the association between MRI PSAD and predictors of upgrade on serial biopsy. Results: 166 patients were included in the study. Of these patients, 74 of them were upgraded to Gleason grade ≥7 on follow up biopsy. TRUS volume was noted be strongly correlated with MRI prostate volume (Pearson’s r=0.82, p&lt;0.01). MRI PSAD 0.15-0.225 ng/ccl and ≥0.0225 ng/cc were significantly associated with upgrade to Gleason grade 7 compared to MRI PSAD &lt;0.075 ng/ml/ml after controlling for age and time since diagnosis. MRI PSAD less than 0.15 was not associated with upgrade on follow up biopsy (in any patient, if so, state that no one with a PSAD &lt; 0.15 upgraded). Conclusions: MRI PSAD is significantly associated with Gleason upgrading on follow up biopsy for men initially diagnosed with Gleason grade 3+3 disease. This finding is important because surveillance MRI is increasingly being used to monitor men on active surveillance.