tbuckley/cabot-search huggingface dataset:
A Novel Role for 15-Lipoxygenase Metabolites in Aspirin Exacerbated Respiratory Disease
Authors: Whitney Stevens, Anna Staudacher, Kathryn Hulse, Roderick Carter, Deborah Winter, Atsushi Kato, Lydia Suh, James Norton, Julia Huang, Anju Peters, Leslie Grammer, David Conley, Stephanie Shintani Smith, Bruce Tan, Kevin Welch, Robert Kern, Robert Schleimer
Journal: Journal of Allergy and Clinical Immunology (2020)
Long-term Consequences of Pelvic Irradiation: Toxicities, Challenges, and Therapeutic Opportunities with Pharmacologic Mitigators
Authors: Jung Wook Huh, Jarred Tanksley, Junzo Chino, Christopher G. Willett, Mark W. Dewhirst
Journal: Clinical Cancer Research (2020)

A percentage of long-term cancer survivors who receive pelvic irradiation will develop treatment-related late effects, collectively termed pelvic radiation disease. Thus, there is a need to prevent or ameliorate treatment-related late effects in these patients. Modern radiotherapy methods can preferentially protect normal tissues from radiation toxicities to permit higher doses to targets. However, concerns about chronic small bowel toxicity, for example, still constrain the prescription dose. This provides strong rationale for considering adding pharmacologic mitigators. Implementation of modern targeted radiotherapy methods enables delivery of focused radiation to target volumes, while minimizing dose to normal tissues. In prostate cancer, these technical advances enabled safe radiation dose escalation and better local tumor control without increasing normal tissue complications. In other pelvic diseases, these new radiotherapy methods have not resulted in the low probability of normal tissue damage achieved with prostate radiotherapy. The persistence of toxicity provides rationale for pharmacologic mitigators. Several new agents could be readily tested in clinical trials because they are being or have been studied in human patients already. Although there are promising preclinical data supporting mitigators, no clinically proven options to treat or prevent pelvic radiation disease currently exist. This review highlights therapeutic options for prevention and/or treatment of pelvic radiation disease, using pharmacologic mitigators. Successful development of mitigators would reduce the number of survivors who suffer from these devastating consequences of pelvic radiotherapy. It is important to note that pharmacologic mitigators to ameliorate pelvic radiation disease may be applicable to other irradiated sites in which chronic toxicity impairs quality of life.
Veterans affairs (VA) prostate cancer treatment (Tx) sequencing (VAPCaTS): A real-world study.
Authors: Stephen J. Freedland, Amanda M. De Hoedt, Maral DerSarkissian, Rose Chang, Ambika Satija, Catherine Nguyen, Suna Park, Aurore Aillaud, Edward Joseph Drea, Mei S. Duh, Thomas J. Polascik, Ted P. Szatrowski
Journal: Journal of Clinical Oncology (2020)

54 Background: Limited real-world data are available on tx sequence for patients (pts) with metastatic hormone-sensitive PC (mHSPC) treated with androgen deprivation therapy (ADT) plus docetaxel (D) or abiraterone (A) who progress to metastatic castrate-resistant prostate cancer (mCRPC). Methods: VA electronic medical records were used to retrospectively analyze 240 men treated for mHSPC with ADT and D (n=208; selected to be overrepresented) from 07/2014-08/2018 or ADT and A (n=32) from 12/2016-09/2018 and receiving at least one tx after progressing to mCRPC. Results: For D and A cohorts respectively, median age at mHSPC diagnosis was 65.2 and 70.8 yrs; 62% and 77% were white; 98% and 100% had bone metastases (mets), 40% and 34% had lymph node mets, 21% and 16% had lung mets, and 20% and 6% had liver mets; median follow-up after ADT start was 2.2 and 1.4 yrs. Pts in D and A cohorts had 56% and 36% low, 33% and 45% intermediate, and 11% and 19% high Halabi risk scores at mCRPC, respectively. Among all pts, max mCRPC tx lines was 6; 106 (44%) had only one line, 71 (30%) had two lines, and 63 (26%) pts had ≥ three lines. Across all mCRPC tx lines, 71 (30%) received a taxane at some point (47 D, 40 cabazitaxel [C]). Txs for first and second line mCRPC are shown in the Table. For D pts who received androgen-receptor targeted agents (ARTA) as first mCRPC tx and received any second mCRPC tx, 70 (62%) were treated with back-to-back ARTA. For A pts, 25 (78%) received back-to-back ARTA as first mCRPC tx. Conclusions: Most pts received ARTA as first mCRPC tx, and a large proportion of pts were treated with back-to-back ARTA. Longer follow-up is needed to assess which sequences are associated with optimal outcomes.[Table: see text]
Expansion of HIV Preexposure Prophylaxis to 35 PEPFAR-Supported Early Program Adopters, October 2016–September 2018
Authors: Gaston Djomand, Trista Bingham, Irene Benech, Mercy Muthui, Helen Savva, Stella Alamo, Chomnad Manopaiboon, Tisha Wheeler, Sasha Mital
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

When taken daily, preexposure prophylaxis (PrEP) reduces the risk of acquiring human immunodeficiency virus (HIV). PrEP is an important tool for preventing HIV among persons at substantial risk for HIV infection, including female sex workers, men who have sex with men, transgender women, and persons who inject drugs.
Regulated differentiation of stem cells into an artificial 3D liver as a transplantable source
Authors: Feng Chen, Hua Wang, Jia Xiao
Journal: Clinical and Molecular Hepatology (2020)

End-stage liver disease is one of the leading causes of death around the world. Since insufficient sources of transplantable liver and possible immune rejection severely hinder the wide application of conventional liver transplantation therapy, artificial three-dimensional (3D) liver culture and assembly from stem cells have become a new hope for patients with end-stage liver diseases, such as cirrhosis and liver cancer. However, the induced differentiation of single-layer or 3D-structured hepatocytes from stem cells cannot physiologically support essential liver functions due to the lack of formation of blood vessels, immune regulation, storage of vitamins, and other vital hepatic activities. Thus, there is emerging evidence showing that 3D organogenesis of artificial vascularized liver tissue from combined hepatic cell types derived from differentiated stem cells is practical for the treatment of end-stage liver diseases. The optimization of novel biomaterials, such as decellularized matrices and natural macromolecules, also strongly supports the organogenesis of 3D tissue with the desired complex structure. This review summarizes new research updates on novel differentiation protocols of stem cell-derived major hepatic cell types and the application of new supportive biomaterials. Future biological and clinical challenges of this concept are also discussed.
Predictors of progression in systemic sclerosis patients with interstitial lung disease
Authors: Oliver Distler, Shervin Assassi, Vincent Cottin, Maurizio Cutolo, Sonye K. Danoff, Christopher P. Denton, Jörg H.W. Distler, Anna-Maria Hoffmann-Vold, Sindhu R. Johnson, Ulf Müller Ladner, Vanessa Smith, Elizabeth R. Volkmann, Toby M. Maher
Journal: European Respiratory Journal (2020)

Systemic sclerosis (SSc) is a systemic autoimmune disease affecting multiple organ systems, including the lungs. Interstitial lung disease (ILD) is the leading cause of death in SSc.There are no valid biomarkers to predict the occurrence of SSc-ILD, although auto-antibodies against anti-topoisomerase I and several inflammatory markers are candidate biomarkers that need further evaluation. Chest auscultation, presence of shortness of breath and pulmonary function testing are important diagnostic tools, but lack sensitivity to detect early ILD. Baseline screening with high-resolution computed tomography (HRCT) is therefore necessary to confirm an SSc-ILD diagnosis. Once diagnosed with SSc-ILD, patients' clinical courses are variable and difficult to predict, although certain patient characteristics and biomarkers are associated with disease progression. It is important to monitor patients with SSc-ILD for signs of disease progression, although there is no consensus about which diagnostic tools to use or how often monitoring should occur. In this article, we review methods used to define and predict disease progression in SSc-ILD.There is no valid definition of SSc-ILD disease progression, but we suggest that either a decline in forced vital capacity (FVC) from baseline of ≥10%, or a decline in FVC of 5-9% in association with a decline in diffusing capacity of the lung for carbon monoxide of ≥15% represents progression. An increase in the radiographic extent of ILD on HRCT imaging would also signify progression. A time period of 1-2 years is generally used for this definition, but a decline over a longer time period may also reflect clinically relevant disease progression.
Disproportionate Emphasis on Proportionate Mitral Regurgitation—Are There Better Measures of Regurgitant Severity?
Authors: Rebecca T. Hahn
Journal: JAMA Cardiology (2020)

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Ultrastructural Characterization of Proteinuric Patients Predicts Clinical Outcomes
Authors: Virginie Royal, Jarcy Zee, Qian Liu, Carmen Avila-Casado, Abigail R. Smith, Gang Liu, Laura H. Mariani, Stephen Hewitt, Lawrence B. Holzman, Brenda W. Gillespie, Jeffrey B. Hodgin, Laura Barisoni
Journal: Journal of the American Society of Nephrology (2020)

The analysis and reporting of glomerular features ascertained by electron microscopy are limited to few parameters with minimal predictive value, despite some contributions to disease diagnoses.We investigated the prognostic value of 12 electron microscopy histologic and ultrastructural changes (descriptors) from the Nephrotic Syndrome Study Network (NEPTUNE) Digital Pathology Scoring System. Study pathologists scored 12 descriptors in NEPTUNE renal biopsies from 242 patients with minimal change disease or FSGS, with duplicate readings to evaluate reproducibility. We performed consensus clustering of patients to identify unique electron microscopy profiles. For both individual descriptors and clusters, we used Cox regression models to assess associations with time from biopsy to proteinuria remission and time to a composite progression outcome (≥40% decline in eGFR, with eGFR<60 ml/min per 1.73 m2, or ESKD), and linear mixed models for longitudinal eGFR measures.Intrarater and interrater reproducibility was >0.60 for 12 out of 12 and seven out of 12 descriptors, respectively. Individual podocyte descriptors such as effacement and microvillous transformation were associated with complete remission, whereas endothelial cell and glomerular basement membrane abnormalities were associated with progression. We identified six descriptor-based clusters with distinct electron microscopy profiles and clinical outcomes. Patients in a cluster with more prominent foot process effacement and microvillous transformation had the highest rates of complete proteinuria remission, whereas patients in clusters with extensive loss of primary processes and endothelial cell damage had the highest rates of the composite progression outcome.Systematic analysis of electron microscopic findings reveals clusters of findings associated with either proteinuria remission or disease progression.
Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study
Authors: Suzanne Lentzsch, Galina G. Lagos, Raymond L. Comenzo, Jeffrey A. Zonder, Keren Osman, Samuel Pan, Divaya Bhutani, Silva Pregja, Vaishali Sanchorawala, Heather Landau
Journal: Journal of Clinical Oncology (2020)

No established treatments exist for relapsed/refractory systemic light-chain (AL) amyloidosis. Bendamustine has shown potential in the treatment of multiple myeloma. We conducted a phase II, multicenter trial to assess the efficacy and safety of bendamustine with dexamethasone (ben-dex) in patients with persistent or progressive AL amyloidosis after ≥ 1 prior therapy.The trial enrolled 31 patients who received bendamustine on days 1 and 2 (100 mg/m2 intravenously) with 40 mg of weekly dexamethasone in 28-day cycles until disease progression or up to 6 cycles after complete hematologic response. The primary objective was the rate of partial hematologic response (PR) or better.Patients received a median of 4 cycles (range, 2-12 cycles) with 57% of patients achieving a PR or better (11% complete response, 18% very good PR). The overall organ response was 29% among the 24 patients who had measurable organ involvement. Treatment was well tolerated with no grade 5 treatment-related adverse events (AEs). Sixty-five percent of patients had a therapy-related grade 3-4 AE. The most common AEs included myelosuppression, fatigue, and nausea/vomiting. The median overall survival was 18.2 months (95% CI, 11.3 to 43.8 months), and hematologic response was associated with prolonged survival (P = .0291). The median progression-free survival was 11.3 months (95% CI, 5.0 to 15.4 months).Overall, ben-dex is a viable treatment option with substantial efficacy and limited toxicity for patients with pretreated AL amyloidosis who have limited therapeutic options. This trial was registered at (ClinicalTrials.gov identifier: NCT01222260).
Comprehensive genomic profiling (CGP) of histologic subtypes of urethral carcinomas (UrthCa).
Authors: Petros Grivas, Joseph M Jacob, Oleg Shapiro, Andrea Necchi, Ethan Sokol, Jonathan Keith Killian, Douglas I. Lin, Shakti H. Ramkissoon, Eric Allan Severson, Richard Huang, Brian Michael Alexander, Jeffrey Venstrom, Venkataprasanth P. Reddy, Kimberly McGregor, Julia Andrea Elvin, Alexa Betzig Schrock, Natalie Danziger, Jeffrey S. Ross, Gennady Bratslavsky
Journal: Journal of Clinical Oncology (2020)

5087 Background: UrthCa is an uncommon GU malignancy that can progress to advanced metastatic disease. Methods: 127 metastatic UrthCa underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 49 (39%) urothelial (UrthUC), 31 (24%) squamous (UrthSCC), 34 (19%) adenocarcinomas (UrthAC) and 13 (9%) clear cell (UrthCC) were evaluated along with a control cohort of 2,130 bladderUC cases. UrthUC and UrthSCC were more common in men; UrthAC and UrthCC more common in women. Age was similar in all 4 groups. GA in PIK3CA were the most frequent potentially targetable GA; MTOR pathway GA in PTEN also identified. GA in other potentially targetable genes were also identified including ERBB2(6% in UrthUC, 3% in UrthSCC and 12% in UrthAC), FGFR1-3 (3% in UrthSCC), BRAF (3% in UrthAC), PTCH1 (8% in UrthCC) and MET (8% in UrthCC). Higher TMB was seen in UrthUC and UrthCC compared to UrthAC and UrthSCC, possibly reflecting their higher GA/tumor status and suggesting potential for immunotherapy benefit. MSI high status was absent throughout. The bladderUC cases had similar genomic pattern as UrthUC with significantly lower frequency of HPV16/18 positive cases. Conclusions: CGP reveals GA that may be predictive of both targeted and immunotherapy benefit in patients with advanced UrthCa and that could potentially be used in future adjuvant, neoadjuvant and metastatic disease trials. [Table: see text]
Prospective trial of adjuvant therapy after radical cystectomy for locally advanced bladder cancer: Analysis of the squamous cell carcinoma subgroup.
Authors: Mohamed S. Zaghloul, John Paul Christodouleas, Tarek Zaghloul, Ahmed Abdalla, Hany William, Hussein Mustafa Khaled, Wei-Ting Hwang, Brian Christopher Baumann
Journal: Journal of Clinical Oncology (2020)

524 Background: The role of adjuvant therapy after radical cystectomy (RC) is not well-defined for squamous cell carcinoma (SqCC) of the bladder. Several studies suggest limited efficacy for chemo while adjuvant RT improved disease-free survival (DFS) vs. observation in a previous trial. In this study, we report a post-hoc subgroup analysis of SqCC to compare adjuvant therapies. We hypothesized that adjuvant RT would improve DFS vs. chemo for locally advanced bladder cancer (LABC) (≥pT3N0-N+). Methods: A randomized phase III trial was opened to compare adjuvant RT vs. sandwich chemo+RT after RC for LABC at the NCI in Cairo. A 3rd arm, adjuvant chemo, was added later. Bladder cancer patients ≤70 y/o with ≥1 of the following (pT3b/pT4a, grade 3, or pN+) with negative margins after RC were eligible. RT was delivered to the pelvis with 3D conformal RT (45Gy in 1.5Gy BID). Chemo+RT included 2 cycles of gemcitabine/cisplatin before &amp; after RT. Chemo alone included gem/cis x 4. Primary &amp; secondary endpoints were DFS and overall survival (OS). Results: 198 patients were enrolled. 82 (41%) had SqCC &amp; 77 had ≥pT3N0-N+ disease and were analyzed (34 RT, 27 chemo+RT, &amp; 16 chemo). Median age was 53. Median F/U was 20 months (1-127 months). The RT vs chemo arms were well-balanced except for number of nodes removed (mean 12 vs. 9, p=0.05). On univariable analysis, RT was not significantly associated with DFS [HR 0.56 (95%CI 0.26-1.21), p=0.14]. On multivariable analysis, only pN+ was significant. 2-yr DFS was 60% for RT &amp; 43% for chemo (log-rank p=0.13). OS was improved with RT (2-yr OS 71% vs. 43%, p=0.04). There was one death during treatment (chemo-related). There was no significant difference in DFS or OS for RT vs. chemo+RT with 2-yr DFS of 59% &amp; 55% (p=0.65) &amp; 2-yr OS of 67% &amp; 74% (p=0.16). Conclusions: On post-hoc analysis, RT for locally advanced bladder SqCC was associated with significantly improved OS vs. adjuvant chemo. We hypothesize that the inferior OS with chemo was due to increased toxicity &amp; limited efficacy. There was no difference in outcomes for RT vs. chemo+RT. Adjuvant RT should be a standard option for ≥pT3 SqCC of the bladder after RC. Alternative chemo agents for SqCC should be explored. Clinical trial information: NCT01734798.
Pathogenic variants in PTEN to predict for increased risk of relapse and death in patients with limited stage small cell bladder cancer.
Authors: Earle Frederick Burgess, Nury Steuerwald, James Thomas Symanowski, Chad Livasy, Carol J. Farhangfar, Zoran Gatalica, David Arguello, Jason Zhu, Claud Grigg, Peter E. Clark, Derek Raghavan
Journal: Journal of Clinical Oncology (2020)

526 Background: Small cell bladder cancer (SCBC) is a rare histologic subtype with insufficient genomic characterization. Patients with limited stage (LS) SCBC have a poor prognosis, and no biomarker exists to optimize treatment selection. We sought to identify genomic aberrations in patients with LS-SCBC using a comprehensive next generation sequencing (NGS) platform. Mutations in the PTEN/AKT pathway are important in urothelial tumor biology but have an undefined role in SCBC. Methods: 23 LS-SCBC cases were identified. NGS was performed on diagnostic transurethral bladder tumor resection or cystectomy specimens containing SCBC. Detected variants were filtered by in silico algorithms predicting for a deleterious impact on protein function. Variant allele frequencies (VAF) greater than 2% were permitted in this analysis. Variants in the PTEN gene were assessed for association with relapse-free survival (RFS) and overall survival (OS) using Kaplan-Meier techniques and Cox proportional hazards models. Results: Median follow up for the cohort was 4.02 years. 14/23 (60.9%) patients have died. Six unique deleterious PTEN mutations were observed in 9/23 (39.1%) patients. p.W274C was the most common PTEN variant and was detected in 5 (21.7%) patients. Three variants were detected at &gt; 10% VAF. All 9 patients with a deleterious PTEN variant died. The presence of deleterious PTEN variants [HR = 4.68 [(1.54, 14.27), p = 0.003]] predicted for inferior OS. In the 19 patients with known relapse history, 6/7 (85.7%) with and 3/12 (25%) without any deleterious PTEN mutation relapsed. The presence of deleterious PTEN variants [HR = 9.41 [(2.32, 38.23), p &lt; 0.001]] also predicted for inferior RFS. Conclusions: Pathogenic variants in tumor suppressor PTEN were associated with inferior RFS and OS in this pilot cohort of patients with LS-SCBC, suggesting that disruption of PTEN function may be a critical genomic event underlying the progression of small cell bladder cancer. Our findings also support prior reports that pathogenic gene variants detected at low allele frequencies may be clinically important.
Trends and oncological outcome of testosterone recovery after androgen deprivation therapy in prostate cancer patients who received external beam radiotherapy.
Authors: Akinori Takei, Shinichi Sakamoto, Takaaki Tamura, Ken Wakai, Maihulan Maimaiti, Yusuke Imamura, Akira Komiya, Hiroomi Nakatsu, Koichiro Akakura, Tomohiko Ichikawa
Journal: Journal of Clinical Oncology (2020)

345 Background: Although androgen deprivation therapy (ADT) combined with external beam radiation therapy (EBRT) is standard treatment for high risk prostate cancer (PC) patients, the shift of testosterone (TST) levels after ADT and the optimal duration of ADT is unclear. TST recovery and outcome were studied in PC patients who received EBRT with ADT. Methods: Eighty-two patients who underwent EBRT with ADT for PC were retrospectively analyzed. Serum TST levels after ADT terminations were studied. Cox proportional hazard models and the Kaplan-Meier method were used for statistical analysis. Results: Median age, baseline TST, nadir TST, and duration of ADT were 73 years, 456 ng/dL, 16 ng/dL, and 26 months, respectively. ADT duration of 33 months (HR 0.13; p=0.0018), nadir TST of 20 ng/dL (HR 0.35; p=0.0112), and TST &gt;50 ng/dL at 6 months after ADT termination (HR 0.21; p=0.0075) were significantly associated with TST recovery to normal levels (200 ng/dL) on multivariate analysis. ADT duration of 33 months (HR 0.31; p=0.0023) and nadir TST of 20 ng/dL (HR 0.38; p=0.0012) were significantly associated with TST recovery to supracastrate level (50 ng/dL) on multivariate analysis. In high risk PC patients, ADT≤ 2 year group showed shorter time to TST recovery to supracastrate levels compare to those of ADT&gt;2 year group (HR 4.21; p=0.0022) without affecting biochemical recurrence (p=0.49) and overall survival (p=0.674). Conclusions: ADT duration of 33 months and nadir TST of 20 ng/dL predicted the TST recovery to suparacastrate levels. Less than 2 year of ADT provided better TST recovery without affecting the oncological outcome in high risk patients.[Table: see text]
Single AIEgen for multiple tasks: Imaging of dual organelles and evaluation of cell viability
Authors: Ruoyao Zhang, Guangle Niu, Zhiyang Liu, Joe H.C. Chau, Huifang Su, Michelle M.S. Lee, Yuan Gu, Ryan T.K. Kwok, Jacky W.Y. Lam, Ben Zhong Tang
Journal: Biomaterials (2020)