bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic profiling and mutation burden of Chinese prostate patients with microsatellite instability.
Authors: Zhang Ning , Hong Baoan , Zhao Xiaochen , Bai Yuezong 
Published: May 2020

e17531 Background: Prostate cancer with microsatellite instability-high (MSI-H) is identified as a distinct genotype that potentially benefit from immune checkpoint inhibitors. But the incidence and genomic profiling of microsatellite instability haven’t been well characterized in Chinese prostate cancer patients. Methods: Tumor tissue and matched blood sample from 241 Chinese prostate cancer patients were analyzed with targeted next-generation sequencing covering whole exon of 381 or 90 genes and 100 microsatellite loci. Tumor mutation burden (TMB), defined by non-silent somatic mutation counts in coding region per megabase (Mb), was calculated in tumors sequenced by 381-gene panel with coding region of 1.12Mb. Results: 7 patients (2.90%) were identified as MSI-H in overall population. Somatic or germline alterations of mismatch repair genes were detected in 5 of the 7 patients, including 2 MSH2 germline mutations, 2 MSH6 somatic mutations, 1 MSH2 somatic mutation, 1 PMS2 somatic mutation and 1 MLH3 somatic mutation. In MSI-H tumors, alterations in KMT2C (6/7), EGFR (5/7), KMT2D (5/7), JAK1 (5/7), PTEN (4/7), TP53 (3/7), ZFHX3 (3/7) and SPOP (3/7) were common. AR ligand binding domain was mutated in 3 of 7 patients, while no AR amplification was detected in MSI-H tumors. In 121 tumors sequenced by 381-gene panel, median TMB was 3.23 mutations/Mb. Median TMB was significantly higher in MSI-H tumors compared with MSS tumors (median TMB, 13.71 mutations/Mb versus 2.93 mutations/Mb, P < 0.001). Median counts of single nucleotide variants (SNVs) and insertion-deletions (Indels) were 13 and 10 in MSI-H tumors that were also higher than that of MSS tumors with median SNVs and Indels of 2 (P = 0.004) and 1 (P < 0.001), respectively. Conclusions: 2.9% patients were identified as MSI-H in Chinese prostate patients. MSI-H was associated with higher TMB, SNVs and Indels. Targeted next-generation sequencing is a practical tool for prostate cancer genotyping and treatment decision-making.
Combined 18F-naf and fluciclovine administration for PET imaging of prostate cancer.
Authors: Huang Franklin W. , Trinh Brian , Wang Sunny , Hope Thomas A. 
Published: May 2020

e17533 Background: 18F-fluciclovine is FDA approved for the detection of recurrent and metastatic prostate cancer. At our institution, 18F-fluciclovine PET had replaced 18F-NaF PET, but fluciclovine has mild to no uptake in dense sclerotic bony lesions. F18-NaF offers increased sensitivity and specificity in detection of osseous metastases and therefore we converted to using a combination of 18F-NaF and 18F-fluciclovine in patients with biochemical recurrence. In this study, we assessed the feasibility of performing a combined F18- fluciclovine and F18-NaF study, and evaluated the biodistribution of the combined radiotracers in patients with prostate cancer. Methods: We retrospectively reviewed 16 consecutive patients over a period of 3 months. 5 mCi of F18-NaF was injected, followed 45 minutes later by a 10 mCi injection of F18-fluciclovine. Patients were asked to hydrate after NaF injection and empty their bladder immediately prior to scanning. A non-diagnostic CT for attenuation correction and an emission PET scan were acquired on a time of flight Discovery 690 PET/CT (GE Healthcare) within 5 minutes of fluciclovine injection. We characterized the extent of soft tissue and osseous disease, as well as assessed the image quality, taking note for F18-NaF excretion in the bladder and the potential scatter artifact limiting evaluation of the prostate bed. Results: On average patients received 5.5 +/- 0.5 mCi of F18-NaF and 10.4 +/- 0.8 mCi of F18-fluciclovine. All 16 patients had diagnostic quality scans. None had limited evaluation of the prostate bed secondary to artifacts from bladder scatter. 10 patients (62.5%) had residual or recurrent prostate cancer within the prostate bed, of which 3 (18.8%) had distant nodal disease in the perirectal, pelvis, retroperitoneal, or periaortic lymph node regions. 7 patients (43.8%) demonstrated osseous metastatic lesions within the clavicle, sternum, iliac wing, vertebra, coccyx, or sacrum. Conclusions: Combined 18F-NaF and 18F-fluciclovine scans in patients with prostate cancer is a feasible method for detecting soft tissue recurrence and osseous disease. Bladder excretion from F18-NaF does not obscure the prostate bed nor degrades the diagnostic quality of the exam. The combined use of 18F-fluciclovine and F18-NaF in one PET/CT acquisition has the potential to increase the sensitivity for detecting prostate cancer and limit the time and radiation dose delivered compared to the conventional, separate acquisitions of the two radiotracers.
An artificial intelligence-enabled analysis of ECG changes after androgen deprivation therapy (ADT) for prostate cancer.
Authors: Breen William , Carter Rickey , Johnson Patrick , Routman David M. , Noseworthy Peter , Herrmann Joerg , Friedman Paul , Lopez-Jimenez Francisco , Attia Zachi Itzhak , Stish Brad J. , Kapa Suraj 
Published: May 2020

e17535 Background: Androgen Deprivation Therapy (ADT) is commonly used to treat prostate cancer (PC), but has been associated with cardiac morbidity and mortality. The exact mechanisms of this association are unclear. We sought to use an artificial intelligence (AI) enabled algorithm to identify ECG changes in PC patients who received ADT compared to PC patients who did not receive ADT. Methods: From 1,000,000 ECGs performed on 210,414 patients between 1993 and 2017 at our institution, a convolutional neural network was developed to detect predictive signatures for cardiac pathologies. During this process, the ability to predict “estimated sex” of the patient was developed, with output values ranging from 0 (female) to 1 (male). We applied this algorithm to 8,619 ECGs performed on 1,057 men age 75 or younger treated with radiation for high-risk or recurrent PC at our institution, and compared estimated sex after receiving ADT (n = 1,065) to ADT-naive ECGs (n = 7,554). We correlated ECG-identified estimated sex with serum testosterone levels using Spearman rank correlation. Results: Patients who had received ADT had a mean (SD) estimated sex value of 0.81 (0.26) compared to 0.92 (0.17) for those who did not (p < 0.001). Difference between estimated sex in post-ADT ECGs and ADT-naive ECGs remained significant across age groups (Table). Decreased serum total testosterone correlated with decreased estimated sex values in men receiving ADT (R = .57, p < 0.001). Conclusions: ADT for prostate cancer is associated with changes in AI-identified ECG parameters, including lower estimated male sex after receiving ADT. Lower ECG male sex estimate was associated with decreased serum testosterone. In this study, we provide preliminary proof of concept for a potential non-invasive means of monitoring treatment effect and physiologic change using ECGs. [Table: see text]
Role of nitric oxide-based immunotherapy in augmenting prostate cancer progression by targeting androgen receptor heterogeneity.
Authors: Arora Himanshu , Vedenko Anastasia , Van Booven Derek J. , Narasimman Manish 
Published: May 2020

e17537 Background: A significant proportion of men with Prostate Cancer (PCa) develop castration resistant prostate cancer (CRPC) and do not respond to hormonal agents that decrease androgens. In trying to understand the causes of androgen resistance that develop in CRPC, it is considered most relevant to study the role of Androgen receptor (AR) in the development and progression of PCa from androgen dependent to androgen independent state. Recent studies have highlighted the significance of tumor microenvironment (TME) in regulation of PCa progression in addition to AR. A key molecule in the regulation of TME interactions is nitric oxide (NO). We have shown in our recent study, the critical association of NO with the TME in CRPC. However, the effects of NO to modulate the progression of PCa to CRPC with respect to AR still remains largely unexplored. Methods: 22RV1, LNCaP, LNCaPAPIPC(cells expressing no AR), and LNCaPshAR/pATK (cells expressing low AR), cells were used for the study. Cell proliferation was first assessed by MTT assay. The castrated SCID mice were grafted with 22RV1 cells and were treated with GSNO at the dosage of 10mg/kg/day IP. After treatment, animals were humanely sacrificing. Tumor RNA and proteins were analysed for markers that are important for PCa progression using qPCR, western blot and cytokine antibody array. Animal experiments were carried out in compliance with the IACUC of University of Miami. GraphPad Prism (GraphPad Software) was used for statistical analysis. Results: In addition to reducing the tumor burden, the expression of anti-inflammatory (M2) macrophages (CD206 and Arginase1) is decreased and that of the pro-inflammatory (M1) macrophage (iNOS) is increased in mice which received increased NO levels. Furthermore, to study the effects of NO on progression of PCa from androgen dependent to androgen independent stage, we characterized the LNCAP cell models with differential extent of AR knockdown (LNCaP, LNCaPshAR/pATK and LNCaPAPIPC) for the effects of increased NO levels. Results showed that NO had significant impact on cell proliferation on androgen dependent PCa cells however the effects were negligible in cells expressing low or no AR, suggesting that effects of NO on PCa cell proliferation are AR dependent. Conclusions: Our results suggest that during PCa progression, NO suppresses TAMs to target the TME in an AR dependent manner. Further studies are undergoing to establish the impacts of NO in PCa progression.
Dissecting the immune infiltrate induced by ADT and PD-1 blockade in men with metastatic hormone-sensitive prostate cancer using single-cell RNA-sequencing.
Authors: Hawley Jessica , Obradovic Aleksandar , Guo Xinzheng Victor , Chaimowitz Matthew , Easterlin Clara A , Dallos Matthew , Lim Emerson A. , Drake Charles G. , Stein Mark N. 
Published: May 2020

e17548 Background: Overall survival of men with de novo metastatic, hormone-sensitive prostate cancer (mHSPC) is improved by treatment intensification with docetaxel and hormone therapy compared to androgen deprivation therapy (ADT) alone. However, castration-resistant prostate cancer (CRPC) invariably develops. We and others have shown that ADT induces a robust and complex immune infiltrate in localized prostate cancer, in both animal models and humans. We are conducting a clinical trial (NCT03951831) to test the hypothesis that the ADT-induced immune infiltrate can be further augmented with chemotherapy and an anti-PD-1 inhibitor in men with mHSPC. Here, we present single-cell RNA-sequencing analysis of paired metastatic tumor biopsies at baseline and on-treatment. Methods: In our phase 2, open-label, single-center trial, eligible patients with mHSPC are treated with phased administration of ADT, cemiplimab (anti-PD-1 inhibitor), and docetaxel. All patients undergo baseline metastatic tumor biopsies as well as on-treatment biopsies after either ADT alone or ADT in combination with cemiplimab. Biopsies are dissociated by gentleMACS protocol, and single cells are sequenced using the 10X Chromium platform. Cells are Quality-control filtered to those with over 1000 Unique Molecular Identifiers and less than 25% mitochondrial RNA, then clustered on global gene expression and on inferred protein activity by unsupervised Louvain algorithm with silhouette score selection of optimal clustering resolution. Cell types are assigned by the singleR algorithm and tumor cell identity is verified by inference of Copy Number Variations (InferCNV). Differential gene expression across sub-clusters is performed, and baselines will be compared to their paired on-treatment sample (N = 3). Results: Preliminary results showed a significant increase in the normalized fold-change of CD8+ T cells in on-treatment samples relative to baseline samples (P < 0.001). There was also a dramatic increase in other immune cell subtypes with treatment. In addition, we found a shift in transcriptional state of tumor cells and that tumor cells expressing KLK2/KLK3 significantly dissipate with treatment (normalized fold-change 0.56, P < 0.001). Conclusions: Taken together these show the feasibility of SS-RNA-seq on PC metastatic lesions and provide initial support for the hypothesis that ADT induces complex immunological changes in the tumor microenvironment (TME) in metastatic prostate tumors.
PRINT: Prostate cancer intensive, non-cross reactive therapy for CRPC—Early observations of efficacy.
Authors: Liaw Bobby Chi-Hung , Tsao Che-Kai , Galsky Matt D. , Bakst Richard Lorne , Stewart Robert , Stock Richard , Oh William K. 
Published: May 2020

e17575 Background: Optimal sequencing of therapeutic agents in mCRPC remains debated, but the standard approach is to treat with one agent until resistance is met before switching. PRINT explores the efficacy of treating mCRPC with a rapidly-cycling, non-cross reactive regimen as a way to more effectively treat intrinsic heterogeneity, delay or prevent drug resistance, and minimize treatment toxicity. Methods: Patients received treatment with 3 consecutive treatment modules, each lasting 12 weeks: 1. abiraterone acetate 1000 mg PO daily + prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV + carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily + radium-223 50 kBq/kg IV q4 weeks (in those with bone metastases). Upon completion of the 9-month regimen, patients are followed on ADT alone. Primary endpoint for the study is PSA or radiographic time to progression (TTP). Results: From 3/2017 to 1/2020, 38 of 40 planned men with mCRPC were enrolled, 28 patients have completed the 9-month study regimen and evaluable for TTP analysis. With median follow up of 54+ weeks, median time to PSA progression after therapy completion is 14.7+ weeks (95%CI; 5.5-23.9+ weeks). PSA response rates showed successive improvements with each sequential treatment module (Table). Eight patients (21.1%) continue on post-study surveillance with ADT alone, two of which have remained off any mCRPC agents for over a year (82+ weeks, 79+ weeks). In patients needing to restart therapy, experience with efficacy and tolerability of each agent while on the study, has helped inform subsequent mCRPC drug selection. The study regimen is well-tolerated, with few grade 3/4 AE’s: hyperglycemia (15.8%), diarrhea (5.3%), anemia (2.6%), fatigue (2.6%), neutropenia (2.6%), and thrombocytopenia (2.6%). Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross reactive regimen demonstrates significant antitumor benefits, with potential for long-term suppression of disease. Further longitudinal follow up will determine if PRINT delays progression compared with standard approaches. Clinical trial information: NCT02903160 . [Table: see text]
The prognostic biomarkers of the patients treated with platinum-based chemotherapy in treatment emergent or related neuroendocrine prostate cancer.
Authors: Kosaka Takeo , Hongo Hiroshi , Yasumizu Yota , Matshumoto Kazuhiro , Mizuno Ryuichi , Oya Mototsugu 
Published: May 2020

e17576 Background: Treatment emergent or related neuroendocrine prostate cancer (tNEPC) is an aggressive subtype of prostate cancer in patients previously treated with androgen receptor pathway inhibitor (ARPI) as a mechanism of resistance. These patients are typically treated platinum-based chemotherapy using small cell lung cancer (SCLC). The clinical features of tNEPC are poorly defined. The aim of the present study was to investigate the prognostic biomarkers of the patients treated with platinum-based chemotherapy in tNEPC. Methods: We reviewed baseline, treatment and outcome data of 41 patients with tNEPC. Clinicopathological factors and laboratory data before administering the first cycle of platinum-based chemotherapy were collected to assess the prognostic factors for overall survival (OS). Definition of tNEPC were based on NEPC morphology on the basis of any current or prior tissue sample, development of liver metastases in the absent of PSA progression, or elevated serum neuron specific enolase (NSE). Results: Median PSA and NSE were 119.8 ng/ml and 18.2 ng/ml, respectively. Twenty-four patients had pathologic features of NEPC. NSE were elevated above the 32 patients. The median OS from the start of platinum-based chemotherapy treatment was 10 months. Univariate analysis revealed that LDH (p = 0.003), absolute monocyte count < 280 (p = 0.022), visceral metastasis (p = 0.014) prior to platinum-based chemotherapy were significantly associated with shorter OS. Multivariate analysis revealed that LDH (p = 0.047), absolute monocyte count < 280, (p = 0.012), visceral metastasis (p = 0.005) prior to platinum-based chemotherapy treatment were independent prognostic indicators for OS. Based on the relative risk of death, NEPC patients before platinum-based chemotherapy were divided into 3 risk groups: low, intermediate and high ( p< 0.001). Conclusions: Our findings provide new insights into the practical implication of NEPC. Our results might be to tailor the management of NEPC treated with platinum-based chemotherapy.
Phase 1b study of BXCL701, a novel small molecule inhibitor of dipeptidyl peptidases (DPP), combined with pembrolizumab (pembro), in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Aggarwal Rahul Raj , Costin Dan , O'Neill Vincent J. , Corsi-Travali Stefani , Adurthi Sreenivas , Adedoyin Adedayo , Healey Diane I. , De Bono Johann S. , Monk Paul , Zhang Jingsong , Small Eric Jay 
Published: May 2020

e17581 Background: BXCL701 (talabostat previously PT100) is an oral small molecule inhibitor of DPP4, DPP8 and DPP9, which trigger macrophage cell death via pyroptosis resulting in proinflammatory stimulation of the innate immunity pathway. Expression of PD-L1 correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor responses were observed when BXCL701 was used with checkpoint inhibition. In a prior clinical study, BXCL701 at a total daily dose of 0.6mg (as 0.3mg BID) demonstrated single agent activity in 2 pts with Stage IV melanoma (unpublished). Methods: In this multi-center study, eligible patients (pts) had progressing mCRPC (PCWG3), at least 1 line of systemic therapy and ≤ 2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anti-cancer therapy, and an ECOG PS of ≤ 2. Pts received fixed dose pembro (200mg IV q21 days) with escalating doses of BXCL701 (0.4mg and 0.6mg PO QD days 1-14 of 21-day cycles) using a 3X3 design. The key endpoints were safety and identification of the recommended phase 2 dose (RP2D) for the combination. Composite response (RECIST, PSA, CTC), plasma drug concentration and change in relevant immune effector cytokines were also evaluated. Results: Six pts were treated at 2 BXCL701 dose levels of 0.4mg qd (n = 3) and 0.6mg qd (n = 3), with 5 pts having adeno, 1 pt having mixed adeno and SC-NEPC. Prior tx included ADT (n = 6), 2nd generation androgen signaling inhibitors (n = 4), chemo (n = 4), RT (n = 5). Among 3 pts at the BXCL701 dose level of 0.6mg, 1 pt had a DLT of Grade 3 syncope (C1D6) and 1 pt had fatal acidosis (C3D8). A dose-dependent increase in pts with low-grade on-target clinical effects was observed. In the 0.4mg qd cohort 1 pt had lower extremity (LE) edema. Whereas in the 0.6mg qd cohort, all pts had events consistent with cytokine release: 3 had hypotension and 2 pts each had dizziness and LE edema. The 0.6mg/day dose level was expanded using a split dose strategy to improve tolerability while maintaining the daily dose previously associated with objective responses. BXCL701 was quantifiable in plasma. Conclusions: BXCL701 0.4 mg QD on days 1 to 14 of 21-day cycle plus pembrolizumab 200 mg IV on day 1 every 21 days was well tolerated in pts with mCRPC. A dose-dependent increase in on-target clinical effects expected with cytokine upregulation was seen. The final dose expansion using the split dose for the RP2D, plasma drug concentrations and relevant biomarkers will be presented. Clinical trial information: NCT03910660 .
Phase II study of pembrolizumab in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer (mCRPC): Updated follow-up of cohorts (C) one to three from KEYNOTE-199.
Authors: Goh Jeffrey C. , Piulats Rodriguez Jose Maria M. , Gross-Goupil Marine , Vaishampayan Ulka N. , De Wit Ronald , Alanko Tuomo , Fukasawa Satoshi , Tabata Kenichi , Feyerabend Susan , Berger Raanan , Wu Haiyan , Kim Jeri , Schloss Charles , De Bono Johann S. , Antonarakis Emmanuel S. 
Published: May 2020

e17584 Background: Pembrolizumab monotherapy has shown antitumor activity and acceptable safety in patients with mCRPC previously treated with a next-generation hormone agent (NHA) and docetaxel. Presented herein are updated results from KEYNOTE-199 (NCT02787005), a multicohort phase 2 study, in patients with RECIST-measurable PD-L1+ disease (C1), RECIST-measurable, PD-L1− disease (C2), and bone-predominant disease, irrespective of PD-L1 (C3). Methods: Patients who previously received ≥1 NHA and 1 or 2 chemotherapies, including docetaxel, received pembrolizumab 200 mg Q3W for 35 cycles or until progression/toxicity. The primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR). Key secondary end points were DCR, PSA response rate (≥50% decrease from baseline), time to PSA progression, rPFS, OS, DOR, and safety. rPFS and OS were evaluated using the Kaplan-Meier method. Results: Of 258 treated patients (C1, 133; C2, 67; C3, 58), 6 completed therapy (C1, 4; C3, 2) and 252 discontinued (C1, 129; C2, 67; C3, 56), primarily due to progression (C1, 106; C2, 61; C3, 45). Median (range) time from enrollment to data cutoff was 31.3 mo (26.7-34.7) in C1, 30.6 mo (28.0-34.1) in C2, and 32.6 mo (27.4-34.4) in C3. Efficacy results are displayed in the table. ORR (95% CI) for patients with measurable disease was 6% (2.6-11.5) in C1 and 3% (0.4-10.4) in C2. Of 10 responders, 6 had a DOR ≥18 mo. Median time to PSA progression was 4 mo across cohorts. Any grade treatment-related AEs (TRAEs) occurred in 57-60% of patients across C1-3. Grade ≥3 TRAEs occurred in 16% of patients in C1, 15% in C2, and 17% in C3; 1 patient in each cohort died of a TRAE (C1, sepsis; C2, unknown; C3, immune-related pneumonitis). Conclusions: Pembrolizumab monotherapy was well tolerated and showed durable, antitumor activity and disease control with survival up to 24 mo in 3 cohorts of docetaxel and NHA-pretreated patients with RECIST-measurable or bone-predominant mCRPC. Clinical trial information: NCT02787005 . [Table: see text]