tbuckley/cabot-search huggingface dataset:
Phase I study of entinostat in combination with enzalutamide for treatment of patients with castration-resistant prostate cancer.
Authors: Jianqing Lin, Jacob Matt Elkon, Brittany Ricart, Brooke Burgess, Erica Palmer, Robert S. Siegel, Yan Ma, Alejandro Villagra
Journal: Journal of Clinical Oncology (2021)

96 Background: Entinostat (SNDX-275, MS-275) is an oral histone deacetylase (HDAC) inhibitor with selectivity towards class I and IV HDACs. Entinostat inhibits prostate cancer (PCa) growth and suppresses Treg cell function in vitro and in vivo. The primary objective of this study was to determine the safe dose of Entinostat in combination with Enzalutamide in prostate cancer patients (PCa). Methods: Phase I, 2 cohorts "3+3", dose-escalation study to explore the safety and preliminary efficacy of Entinostat in combination with Enzalutamide in castration-resistant PCa (CRPC). The planned dose level of Entinostat was 3 and 5 mg orally per week. CRPC Patients progressed on Enzalutamide or eligible for Enzalutamide, able to tolerate 160 mg daily dose (in the initial run-in phase if Enzalutamide naïve), ECOG 0-1, and acceptable organ functions were enrolled in the study. The safety profile of the combination therapy, PSA, pharmacokinetics of Enzalutamide post-Entinostat administration, and peripheral T cell subtype (including Treg), mononuclear cell (PBMC) histone 3 acetylation were analyzed. Results: Total 6 mCRPC patients were enrolled. There was no dose limiting toxicity related to Entinostat in these patients. No obvious increased fatigue related to Entinostat. Toxicities possibly or probably related to Entinostat or the combination therapy included G3 anemia 1/6 (17%), G2 WBC decrease 1/6 (17%), All other toxicities were grade 1 only (Nausea 2/6, anorexia 1/6, emesis 1/6, constipation 1/6, headache 1/6, platelet count decrease 1/6, hypokalemia 1/6, hypoalbuminemia 1/6, hypermagnesemia 1/6). The median duration of treatment with Entinostat was 18 weeks. For patients already progressed on Enzalutamide there was no PSA response after Entinostat was added. Entinostat did not affect the steady plasma concentration of Enzalutamide. Increased PBMC H3 acetylation was observed (up to 3.6 fold from baseline) in the tested samples. No evident T cell subtype, including Treg, changes from these sample analysis. Phase II part of the trial was terminated because of sponsor withdrawal. Conclusions: Entinostat at the selected dose levels in combination with standard dose of enzalutamide showed promising safety profile in this small phase I study. Clinical trial information: NCT03829930.
TALAPRO-1: Phase II study of talazoparib (TALA) in patients (pts) with DNA damage repair alterations (DDRm) and metastatic castration-resistant prostate cancer (mCRPC).
Authors: Johann S. De Bono, Niven Mehra, Celestia S. Higano, Fred Saad, Consuelo Buttigliero, Inge M. van Oort, Marielena Mata, Hsiang-Chun Chen, Cynthia G. Healy, Akos Czibere, Karim Fizazi
Journal: Journal of Clinical Oncology (2021)

93 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) show antitumor activity in mCRPC/DDRm pts treated with novel hormonal therapy (NHT). TALAPRO-1 is an open-label study evaluating TALA (a potent PARP inhibitor/trapper) in men with mCRPC/DDRm. We report a planned interim analysis (IA; Dec 2019). Updated results at a Sep 4 2020 cut-off, available in November 2020, will be presented at the meeting. Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) for metastatic disease and progressed on ≥1 NHT (enzalutamide/abiraterone acetate) given for mCRPC. DDRm are defined as known/likely pathogenic variants or homozygous deletions. Pts receive oral TALA 1 mg/day (moderate renal impairment 0.75 mg/day) until radiographic progression, unacceptable toxicity, consent withdrawal, or death. Primary endpoint is objective response rate (ORR). Secondary endpoints: time to objective response; response duration; prostate-specific antigen (PSA) decrease ≥50%; circulating tumor cell (CTC) count conversion (to CTC = 0 and &lt;5 per 7.5 mL blood); time to PSA progression; radiographic progression-free survival (rPFS); overall survival; safety. A planned efficacy/safety IA was done when 60 pts with DDRm and measurable disease completed ≥6 months of TALA/no longer followed. Radiographic responses are based on investigator assessments. Results: 113 pts received TALA (cut-off Dec 12 2019); 75 pts were evaluable for IA, with DDRm, had measurable disease, received ≥16 weeks’ treatment, and were assessed for ORR (54.7% BRCA1/2, 4.0% PALB2, 22.7% ATM; 18.7% other DDRm).All pts evaluable for IA had prior docetaxel; 45.3% cabazitaxel. Confirmed ORR, rPFS, and composite response (investigator-assessed) in pts who received TALA for ≥16 weeks are in the table. Most common treatment-emergent adverse events: anemia (42.5%); nausea (32.7%). Conclusions: TALA monotherapy has encouraging antitumor activity in docetaxel-pretreated mCRPC pts with BRCA1/2 alterations and was generally well tolerated. Funding: Pfizer Inc. Clinical trial information: NCT03148795. [Table: see text]
Abstract 10792: Mitochondrial Fusion Promoter Effectively Alleviates Mitochondrial Dysfunction And Improves Cardiac Function In Diabetic Rats
Authors: Mingge Ding, Ke Zeng, Mingzhe Yu, Feng Fu
Journal: Circulation (2019)

Introduction: Increased mitochondrial fission and decreased mitochondrial fusion have been associated with increased mitochondrial oxidative stress and cardiac dysfunction in diabetic hearts. Mitoc...
Abstract PO013: Blood-brain barrier dysfunction leads to neuronal loss in glioma pathology
Authors: Pablo Mata-Martínez, Berta Segura-Collar, Maria Garranzo-Asensio, Juan M. Sepúlveda-Sánchez, Aurelio Hernández-Lain, Pilar Sánchez-Gómez, Ricardo Gargini
Journal: Cancer Research (2021)

Abstract The blood-brain barrier (BBB) defines the physiological function of the brain. Its disruption is common in multiple neuropathological diseases. Accumulating evidence suggest that BBB alterations occur in early stages of neurodegenerative diseases, being associated with neuronal loss processes. The vascular abnormalities and BBB leakage characterize the progression of gliomas, however it is unclear their correlation with the neurodegeneration observed in such tumors. Methods: To establish the different gene signatures we have performed an in-silico analysis using glioma data sets and we have validated the results in a cohort of 26 gliomas (high and low grade) and 7 controls from non-tumor donors. We have also used patient-derived xenografts (PDXs) to correlate the degree of BBB disruption (measured by IgG extravasation immunofluorescence staining) with the neuronal loss (evaluated by NeuN immunofluorescence staining) and with the motor impairment (assessed by a rotarod test). Results: We measured the expression of a series of signatures associated with different biological processes, relevant for glioma development. The “Synapse” and the “BBB dysfunction” signatures were inversely correlated during glioma development. Thus, the most aggressive tumors were associated with BBB breakdown and neuronal dysfunction. These phenotypes correlate with the mesenchymal subtype of gliomas and with a shorter survival. The vascular normalization induced by the isocitrate dehydrogenase 1 (IDH1) mutations rescued the neuronal loss, reducing the motor impairment and increasing the overall survival of PDX-bearing mice. Conclusions: Our data demonstrate that vascular normalization can revert the neuronal loss and the aggressiveness in those tumors, which is linked to the appearance of motor dysfunction symptoms. Overall, we propose that disruption of the BBB is associated with neurodegeneration in glioma patients. These results could help us to understand the progression of this pathology as well as other neurodegenerative diseases and therefore to improve their therapeutic approaches. Citation Format: Pablo Mata-Martínez, Berta Segura-Collar, Maria Garranzo-Asensio, Juan M. Sepúlveda-Sánchez, Aurelio Hernández-Lain, Pilar Sánchez-Gómez, Ricardo Gargini. Blood-brain barrier dysfunction leads to neuronal loss in glioma pathology [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO013.
Fluoroquinolones and Aortic Disease—Reply
Authors: Yaa-Hui Dong, Jiun-Ling Wang, Jou-Wei Lin
Journal: JAMA Internal Medicine (2021)

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The effect of antibiotic use within 30 days of initiation of immune checkpoint inhibitor (ICI) efficacy in patients with metastatic urothelial carcinoma (mUC) in real-world setting.
Authors: Shilpa Gupta, Mohammad Siddique Khan, Nathan Radakovich, Wei Wei, Moshe Chaim Ornstein, Timothy D. Gilligan, Omar Y. Mian, Scott Dawsey
Journal: Journal of Clinical Oncology (2021)

417 Background: There is emerging evidence that patients (pts) treated with immune-checkpoint inhibitors (ICIs) may have a poorer response in the setting of antibiotic use (ABx), possibly due to negative impact on gut microbiota. Our group previously demonstrated that Abx use 60 days before or 60 days in mUC pts after initiation of ICI therapy did not have a significant impact on overall survival (OS) in real-world setting. We now studied the effect of Abx use within 30 days of initiation of ICI on OS in the same cohort of mUC patients. Methods: We performed a retrospective analysis of adult pts with mUC treated at the Cleveland Clinic between 2015 and 2020. Pts included in the study received at least 2 cycles of ICI therapy with either atezolizumab or pembrolizumab. Statistical analysis included study of OS in weeks using the Kaplan Meier method and rank log test, Fischer’s exact test, and Kruskal-Wallis test. Results: A total of 115 pts that received ICI therapy were included. 57 pts received atezolizumab and 58 pts received pembrolizumab. 38 pts (33%) received antibiotics and 77pts (67%) did not. The most commonly used Abx used were Cephalosporins (27%), Penicillins/Carbapenems (25%), Flouroquinolones (23%), and Bactrim (11%). 18 pts received Abx within 30 days before initiation of ICI, 13 pts received Abx within 30 days after initiation of ICI, and 7 pts received Abx before and after initiation of ICI. There was no statistical difference in OS in the group of pts that received Abx 30 days prior to initiation of ICI with median OS of 5.95 months (95% CI 3.22-13.67, p=0.0695) compared to 12.39 months (95% CI 10.09 – 18.6) in those who did not receive Abx. Similarly, there was no statistical difference in OS in the group of pts that received Abx 30 days after initiation of ICI with median OS of 5.09 months (95% CI 2.53-22.57, p=0.2339) compared to 12.02 months (95% CI 8.6`-17.02 Table). Conclusions: In our single institution study of mUC patients receiving ICI treatment, the use of Abx did not affect the OS. Although there was a trend for better OS seen in pts who did not receive Abx, it was not statistically significant (Table). Due to the limitations of a retrospective analysis and small sample size, further studies are warranted taking into account other factors that may affect gut microbiota in mUC pts. [Table: see text]
Hepatitis B–Induced IL8 Promotes Hepatocellular Carcinoma Venous Metastasis and Intrahepatic Treg Accumulation
Authors: Changlu Zhang, Yanan Gao, Chengzhi Du, Geoffrey J. Markowitz, Jing Fu, Zhenxing Zhang, Chunliang Liu, Wenhao Qin, Hongyang Wang, Fan Wang, Pengyuan Yang
Journal: Cancer Research (2021)

Abstract Hepatitis B–associated hepatocellular carcinoma (HCC) is often accompanied by severe vascular invasion and portal vein tumor thrombus, leading to a poor prognosis. However, the underlying mechanism of this disease remains obscure. In this study, we demonstrate that the hepatitis B virus (HBV)–encoded gene HBx induces high IL8 production through MEK–ERK signal activation, leading to enhanced endothelial permeability to facilitate tumor vascular invasion. In a vascular metastatic model using a tail vein injection in a transgenic mouse with selective expression of human CXCR1 in the endothelium, activation of the IL8–CXCR1 cascade by overexpression of IL8 in tumor cells dramatically enhanced liver metastasis. Mechanistically, IL8 selectively induced GARP-latent-TGFβ in liver sinusoidal endothelial cells and subsequently provoked preferential regulatory T-cell polarization to suppress antitumor immunity. Collectively, these findings reveal a hepatitis B–associated IL8–CXCR1 signaling axis that mediates vascular invasion and local microenvironmental immune escape of HCC to induce intrahepatic metastasis, which may serve as potential therapeutic targets for HBV-associated HCC. Significance: This study identifies a hepatitis B–induced IL8/CXCR1/TGFβ signaling cascade that suppresses antitumor immunity and enhances metastasis in hepatocellular carcinoma, providing new potential targets for therapeutic intervention.
日本人男性におけるグルコース異常状態および前冠動脈疾患による冠動脈疾患のリスク【JST・京大機械翻訳】
Authors: Kitazawa Masaru, Fujihara Kazuya, Osawa Taeko, Yamamoto Masahiko, Yamada Mayuko Harada, Kaneko Masanori, Matsubayashi Yasuhiro, Yamada Takaho, Yamanaka Nauta, Seida Hiroyasu, Sone Hirohito
Journal: Metabolism (2019)
Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma
Authors: Nathan H. Fowler, Felipe Samaniego, Wojciech Jurczak, Nilanjan Ghosh, Enrico Derenzini, James A. Reeves, Wanda Knopińska-Posłuszny, Chan Y. Cheah, Tycel Phillips, Ewa Lech-Maranda, Bruce D. Cheson, Paolo F. Caimi, Sebastian Grosicki, Lori A. Leslie, Julio C. Chavez, Gustavo Fonseca, Sunil Babu, Daniel J. Hodson, Spencer H. Shao, John M. Burke, Jeff P. Sharman, Jennie Y. Law, John M. Pagel, Hari P. Miskin, Peter Sportelli, Owen A. O'Connor, Michael S. Weiss, Pier Luigi Zinzani
Journal: Journal of Clinical Oncology (2021)

Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL.In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20-based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety.The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients.Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event-related discontinuations.
Abstract 17052: Insoluble Iron-Ceroid Complex From Apoptotic Siderophage-Derived Foam Cells Promotes Perpetual Macrophage Ingress and Expansion of “Death Zone” in Hemorrhagic Myocardial Infarctions
Authors: Ivan Cokic, Kolja Wawrowsky, Hsin-Jung Yang, Richard L Tang, Rohan Dharmakumar
Journal: Circulation (2017)

Introduction: Upon phagocytosis of oxidized red blood cells, iron-laden macrophages (siderophages) tend to oxidize surrounding LDL, accumulate cholesterol, produce iron-containing ceroid (CR) and t...
Clinical significance of the sonazoid-enhanced ultrasound for prostate cancer.
Authors: Jun Akatsuka, Go Kimura, Yuka Toyama, Hiroya Hasegawa, Hikaru Mikami, Yuki Endo, Hayato Takeda, Tatsuro Hayashi, Yukihiro Kondo
Journal: Journal of Clinical Oncology (2021)

212 Background: This was a prospective study to evaluate the diagnostic accuracy of the Sonazoid-enhanced ultrasound (SEU) for prostate cancer. The primary end-point was accuracy of SEU to detect prostate cancer. The exploratory end-point was to analyze the prognostic significance of SEU positibity after radical prostatectomy (RP) in patients diagnosed as prostate cancer. Methods: In all cases locations of suspected prostate cancer were examined with SEU, digital rectal examination (DRE), B-mode (B), and power-doppler ultrasound (PDU) before prostate biopsy. We compared the sensitivity, specificity, PPV, NPV, and accuracy of SEU, RE, B, and PD. Among prostate cancer cases, effect of SEU positivity on biochemical recurrence (BCR) after radical prostatectomy was compared with that of DRE, B, and PDU. Results: Of 687 cases 416 cases (60.6%) were prostate cancer. The sensitivity, specificity, PPV, NPV, and accuracy were 52.9%, 63.5%, 69.0%, 46.7%, and 57.1% by DRE, 69.2%, 43.9%, 65.5%, 48.2%, and 59.2% by B, 66.6%, 59.0%, 71.4%, 53.5%, and 63.6% by PDU, and 66.1%, 70.1%, 77.2%, 57.4%, and 67.7% by SEU, respectively. SEU was the highest in specificity, PPV, NPV, and accuracy rate. Eighty three patients underwent radical prostatectomy. The SEU + group (69.3%) had a significantly poor prognosis compared to the SEU− group (88.7%) on the five-year BCR-free survival rate (p &lt; 0.05). Univariate analysis showed SEU+ (HR 3.5; p = 0.02), DRE+ (HR 2.7; p = 0.04), PDU+ (HR2.6; p = 0.09), and B+ (HR 2.0; p = 0.21). SEU was the highest prognostic factor on BCR after radical prostatectomy. Conclusions: Sonazoid was able to visualize even small blood vessels in the prostate. SEU showed the highest accuracy for cancer detection and was the highest prognostic factor on BCR in the univariate analysis. To obtain the maximum benefit of Sonazoid, further examinations are needed.
Prescribing patterns in patients with metastatic castrate-sensitive prostate cancer (mCSPC).
Authors: Nataliya Mar, Michael Forsyth
Journal: Journal of Clinical Oncology (2021)

21 Background: Recent advances and approvals in mCSPC treatment offer improved outcomes. Docetaxel chemotherapy as well as novel hormonal therapies (NHT) including abiraterone, apalutamide and enzalumide are preferred regimens in addition to androgen deprivation therapy (ADT), with category 1 evidence supporting their use. Despite lack of consensus regarding use of first-generation anti-androgens (fgAI) aside from tumor flare prevention, they are still frequently prescribed. This multitude of options may lead to disparities in prescribing patterns. Methods: Retrospective analysis of pharmacy and medical claims data from the IQVIA database was performed. Patients were aged &gt;18 years and had an ICD 9/10 diagnosis of metastatic prostate cancer (PCa) with &gt;1 treatment claim. Patients on active therapy for another primary malignancy as well as those with &lt;12 months of data pre- and &lt;9 months post-first PCa-related event were excluded. Data was collected from 1/1/2015 to 6/30/2020. Treatment categories were classified as NHT, fgAI, chemotherapy, or ADT monotherapy. Results: National (N) and state of California (S) prescribing patterns are provided in Table. Nationally, Medicare reimbursed 16% NHT, 30% fgAI, 2% chemotherapy and 52% ADT, while third-party payers reimbursed 18% NHT, 20% fgAI, 3% chemotherapy and 59% ADT in 2020. State of California 2020 data yielded similar reimbursement patterns. In Southern California, academic centers prescribed 31% NHT, 23% fgAI and 46% ADT, while community-based practices prescribed 7% NHT, 36% fgAI and 57% ADT in 2020. In Southern California, community oncology practices prescribed 12% NHT, 40% fgAI, 2% chemotherapy and 44% ADT, while community urology practices prescribed 2% NHT, 38% fgAI, and 59% ADT in 2020. Data from 2015-2019 was similar. Conclusions: Although NHT utilization is increasing while chemotherapy utilization is declining, only a minority of mCSPC men received these therapies in 2020. Most of mCSPC men still receive ADT monotherapy or fgAI. Type of insurance carrier does not appear to affect prescribing patterns. Dramatic variations across treatment settings and different specialties exist, with academic centers prescribing more NHT than community-based practices and oncology practices prescribing more NHT than urology practices. These disparities should be addressed with provider education to standardize care delivery for mCSPC patients. [Table: see text]
BIOLOGICAL CORRELATES AND CLINICAL IMPLICATION OF ANGIOGRAPHICALLY DETECTED CORONARY ARTERY CALCIFICATION IN PATIENTS WITH END STAGE RENAL DISEASE
Authors: Waqas Aftab, Hammad Khan, Patrick Antoun, Padmini Varadarajan, Shuja Rasool, Ali Motabar, Juliana Gazallo, Michel DeVera, Arputharaj Kore, Ramdas Pai
Journal: Journal of the American College of Cardiology (2012)