tbuckley/cabot-search huggingface dataset:
Letter to the Editor: Preemptive TIPS Must Be the Treatment of Choice for Child‐Pugh Class C Patients With Variceal Bleeding?
Authors: Gin‐Ho Lo
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: I read with interest the use of preemptive TIPS (transjugular intrahepatic porto‐systemic stent shunt) in patients with high‐risk variceal bleeding.1 Because the mortality of Child‐Pugh class C patients was significantly reduced in patients receiving preemptive TIPS, the authors concluded that preemptive TIPS must be the treatment of choice in Child‐Pugh class C patients with acute variceal bleeding.1 However, this conclusion warrants further clarification. Among the Child‐Pugh class C patients, 387 received drugs and endotherapy, whereas only 47 patients received preemptive TIPS. This study revealed that many Child‐Pugh class C patients with acute variceal bleeding were treated with drugs and endoscopic therapy instead of preemptive TIPS in the real world. Although the baseline data were similar between both treatment groups, the selection bias by clinicians could not be completely excluded. As shown in a similar study from France, patients receiving early TIPS usually had less severe cirrhosis.2 However, up to 31.4% patients in the whole cohort were lost during the 1‐year follow‐up, and a higher proportion of Child‐Pugh class C patients in the TIPS group received orthotropic liver transplantation. The impact of these factors on the mortality in both groups should not be neglected. A previous study showed that active variceal bleeding requiring emergent TIPS, presence of encephalopathy, and serum bilirubin greater than 3 mg/dL were closely correlated with mortality after TIPS.3 A meta‐analysis showed that early TIPS in patients with cirrhosis with acute variceal bleeding did not have a reduced mortality in Child‐Pugh class C patients.4 Apart from the exclusion criteria mentioned in the study, patients with severe encephalopathy or deep jaundice are also not suitable for preemptive TIPS. Moreover, the association of potentially severe complications with TIPS should not be neglected.5 Although preemptive TIPS should be considered in patients with high‐risk variceal bleeding, it appears inappropriate to have a definitive conclusion that preemptive TIPS must be the treatment of choice in Child‐Pugh class C patients with acute variceal bleeding.
Abstract 20553: Minimum Reentrant Path Volume Predicts Arrhythmia Vulnerability in Human Left Ventricle
Authors: Kedar Aras, Brianna Cathey, Igor Efimov
Journal: Circulation (2017)

Introduction: Cardiac wavelength (λ) defines the distance traveled by the propagating wave during the tissue refractory period and is the principle mechanism behind reentry. Reentrant excitation is possible only when λ is less than the reentrant path length. However, the reentrant circuit can also traverse the tissue volume suggesting a need to measure λ in all three dimensions: longitudinal (λL), transverse (λT), and transmural (λM) to accurately represent complexity of the reentrant circuit. We hypothesized that arrhythmia was inducible in the human left ventricle, when the reentrant path volume (VR= λL x λT x λL) was less than or equal to the tissue volume (VT). Methods: Human LV wedges preparations from donor human hearts (N=6) were optically mapped. The study protocol briefly entailed pacing the tissue, first from the epicardium, and then the transmural surface using a steady-state S1S1 restitution protocol until functional refractory period was reached. The tissue was then treated with pinacidil and...
Assessing a drug for an eradicated human disease: US Food and Drug Administration review of tecovirimat for the treatment of smallpox
Authors: Kirk M Chan-Tack, Patrick R Harrington, Su-Young Choi, Laine Myers, Julian O'Rear, Shirley Seo, David McMillan, Hanan Ghantous, Debra Birnkrant, Adam I Sherwat
Journal: The Lancet Infectious Diseases (2019)
Next-Generation Sequencing-Based Assay Shows High Clonal Characterization Success Rate for Plasma Cell Neoplasms, and Concordance with Flow Cytometry in Minimal Residual Disease Detection
Authors: Caleb Ho, Mustafa Syed, Mikhail Roshal, Kseniya Petrova-Drus, Christine Moung, Jin Juan Yao, Wayne Yu, Lidia Maciag, Ryma Benayed, Malin Hultcrantz, Ahmet Dogan, Khedoudja Nafa, Ola Landgren, Maria E Arcila
Journal: Blood (2018)
Perspectives on Directions and Priorities for Future Preclinical Studies in Regenerative Medicine
Authors: Lilian Grigorian Shamagian, Rosalinda Madonna, Doris Taylor, Andreu M. Climent, Felipe Prosper, Luis Bras-Rosario, Antoni Bayes-Genis, Péter Ferdinandy, Francisco Fernández-Avilés, Juan Carlos Izpisua Belmonte, Valentin Fuster, Roberto Bolli
Journal: Circulation Research (2019)

The myocardium consists of numerous cell types embedded in organized layers of ECM (extracellular matrix) and requires an intricate network of blood and lymphatic vessels and nerves to provide nutrients and electrical coupling to the cells. Although much of the focus has been on cardiomyocytes, these cells make up <40% of cells within a healthy adult heart. Therefore, repairing or regenerating cardiac tissue by merely reconstituting cardiomyocytes is a simplistic and ineffective approach. In fact, when an injury occurs, cardiac tissue organization is disrupted at the level of the cells, the tissue architecture, and the coordinated interaction among the cells. Thus, reconstitution of a functional tissue must reestablish electrical and mechanical communication between cardiomyocytes and restore their surrounding environment. It is also essential to restore distinctive myocardial features, such as vascular patency and pump function. In this article, we review the current status, challenges, and future priorities in cardiac regenerative or reparative medicine. In the first part, we provide an overview of our current understanding of heart repair and comment on the main contributors and mechanisms involved in innate regeneration. A brief section is dedicated to the novel concept of rejuvenation or regeneration, which we think may impact future development in the field. The last section describes regenerative therapies, where the most advanced and disruptive strategies used for myocardial repair are discussed. Our recommendations for priority areas in studies of cardiac regeneration or repair are summarized in Tables 1 and 2 .
Endorsements of Surgeon Punishment and Patient Compensation in Rested and Sleep-Restricted Individuals
Authors: Stacy Nguyen, Abby Corrington, Michelle R. Hebl, Michael K. Scullin
Journal: JAMA Surgery (2019)

This study assesses evidence that healthy adults who are deprived of sleep endorse larger punishments for surgeons who make medical errors and uses this information to conclude that malpractice lawsuits are provoked by patient sleep deprivation.
TIVO-3: A phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC).
Authors: Brian I. Rini, Sumanta K. Pal, Bernard Escudier, Michael B. Atkins, Thomas E. Hutson, Camillo Porta, Elena Verzoni, Michael N. Needle, David F. McDermott
Journal: Journal of Clinical Oncology (2019)

541 Background: Tivozanib (T) is a biochemically potent and highly selective VEGF tyrosine kinase receptor inhibitor in clinical development in RCC. The TIVO-1 trial in treatment naïve or prior cytokine-treated subjects with metastatic (m) RCC showed a median progression free survival (mPFS) of 11.9 months (mos) for T compared to 9.1 mos for sorafenib (S) (p = 0.042, HR = 0.797). However, overall survival (OS) favored sorafenib, likely due to imbalanced crossover to active treatments. TIVO-3 was conducted to confirm the PFS results from TIVO-1. Methods: Subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective was to compare PFS by blinded independent radiological review. 350 subjects were enrolled to yield 244 events with ~88% power to detect a difference of 6 mos vs. 4 mos with a two-sided p-value of 0.05 by the log-rank test. Secondary endpoints were OS, safety, objective response rate (ORR), and duration of response. Results: The two arms were well balanced for demographics and prior cancer history.60% of subjects had 2 prior lines of therapy and 40% had 3 prior lines. 28% had prior treatment with a checkpoint inhibitor. T demonstrated a statistically significant improvement in mPFS compared to S, 5.6 (95% CI 7.3-5.3) v. 3.9 mos (95% CI 5.6-3.7; HR 0.73; p=0.02). PFS rate at 2 years was 18% for T compared to 5% for S. ORR was 18% for T compared to 8% for S. 44% of T treated subjects experienced a grade 3 treatment-related adverse event compared to 55% for S. Subjects on T were less likely to require a dose reduction (24% v. 38%), interruption (48% v. 63%), or discontinuation (21% v. 29%) due to an adverse event than subjects on S. Conclusions: T is superior to S as measured by PFS; 2-year PFS, and ORR in this pre-treated population and is better tolerated than S. OS data will be updated prior to presentation. Clinical trial information: NCT02627963.
KEYNOTE-365 cohort B updated results: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Michael Paul Kolinsky, Gwenaelle Gravis, Loic Mourey, Josep M. Piulats, Srikala S. Sridhar, Emanuela Romano, William R. Berry, Howard Gurney, Margitta Retz, Leonard Joseph Appleman, Martin Boegemann, Johann S. De Bono, Anthony M. Joshua, Urban Emmenegger, Henry Jacob Conter, Brigitte Laguerre, Helen Wu, Charles Schloss, Christian Heinrich Poehlein, Evan Y. Yu
Journal: Journal of Clinical Oncology (2020)

103 Background: KEYNOTE-365 (NCT02861573) is a phase 1b/2 study to evaluate pembro in combination with other agents in mCRPC. Here we report updated results from cohort B (pembro + docetaxel and prednisone). Methods: Cohort B enrolled pts who failed or were intolerant to ≥4 wk of abi or enza in the prechemotherapy mCRPC state and whose disease progressed within 6 mo of screening as determined by PSA progression or radiologic bone/soft tissue progression. Pts received pembro 200 mg IV + docetaxel 75 mg/m 2 IV Q3W and prednisone 5 mg orally twice daily. Primary end points were safety, PSA response rate (confirmed PSA decrease &gt;50%), and ORR per blinded independent central review (BICR). Results: Of 104 treated pts, 72 discontinued, primarily due to progression (55%). Median age was 68 y (range 50-86), 24% were PD-L1 + , 25% had visceral disease, and 50% had measurable disease. Median follow-up was 13 mo for all pts (n=104) and 19 mo for pts who had ≥27 wk of follow up (n=72). See table for efficacy outcomes. Treatment-related AEs occurred in 100 pts (96%); most frequent (≥30%) were alopecia, diarrhea, and fatigue (39% each). Grade 3-5 treatment-related AEs occurred in 42 pts (40%). Five pts died of AEs; 2 deaths were from treatment-related AEs (pneumonitis). Conclusions: With additional follow-up, pembro + docetaxel and prednisone continued to show activity in pts with mCRPC who failed previous antihormonal therapy. Safety of the combination was consistent with the known profiles of the individual agents and will be further evaluated in a phase 3 study (KEYNOTE-921). Clinical trial information: NCT02861573. [Table: see text]
Plasma citrulline levels as a biomarker for bowel toxicity in prostate stereotactic radiotherapy with or without pelvic nodal radiation.
Authors: Ciaran Fairmichael, Kelly M. Redmond, Ciara Lyons, Sarah R. Stevenson, Sarah O. Osman, Conor K. McGarry, Denise M. Irvine, Darren M. Mitchell, Raymond B. King, Alan R. Hounsell, Joe M. O'Sullivan, David J. Waugh, Suneil Jain
Journal: Journal of Clinical Oncology (2019)

73 Background: Plasma levels of citrulline, an amino acid, are derived mainly from small bowel enterocytes. Decreased levels occur in a range of bowel conditions and citrulline has been proposed as a biomarker of bowel toxicity in pelvic radiotherapy. In a prospective study, we identify no correlation between plasma citrulline and toxicity in men receiving prostate stereotactic radiotherapy randomized to receive either pelvic nodal irradiation or not. Furthermore, citrulline levels were not significantly different between these two groups. Methods: As part of an approved clinical trial, men with intermediate to high risk prostate cancer were randomised 1:1 to prostate only or prostate + pelvic nodal radiotherapy, delivered with a rectal spacer gel in situ. The prostate and proximal seminal vesicles received 40 Gy in 5 fractions. Those randomised to the pelvic nodal arm also received 25 Gy in 5 fractions to pelvic nodes. Citrulline was measured at 10 points during treatment – consent, before fraction 1, 1 and 24 hours following fraction 1, prior to each fraction 2 – 5 and at 6 weeks’ and 3 months’ follow up. Bowel toxicity was measured by EPIC patient reported scores. Results: 16 men with follow up of at least 3 months (median 9, maximum 18 months) were analysed. Reported toxicity was significantly higher in the prostate and pelvis arm: 5 of 9 men showed a decrease in EPIC bowel domain summary score of 10 points or more compared to 0 of 7 in the prostate-only arm (p = 0.0337, two tailed Fisher’s exact test). No significant correlation between toxicity and citrulline levels was seen, nor did citrulline vary significantly between arms or fall as treatment progressed. Data analysis for a further 8 men already recruited to the study is ongoing. Conclusions: Toxicity was more commonly reported by men randomised to receive pelvic radiotherapy, suggesting that the small bowel irradiated in pelvic fields plays a role in bowel toxicity experienced during stereotactic radiotherapy. Citrulline levels showed no significant correlation with toxicity or radiation dose to small bowel. We propose that citrulline is not a useful biomarker of small bowel toxicity in this setting. Clinical trial information: NCT03253978.
SWI/SNF-Compromised Cancers Are Susceptible to Bromodomain Inhibitors
Authors: Tatiana Shorstova, Maud Marques, Jie Su, Jake Johnston, Claudia L. Kleinman, Nancy Hamel, Sidong Huang, Moulay A. Alaoui-Jamali, William D. Foulkes, Michael Witcher
Journal: Cancer Research (2019)

Abstract The antitumor activity of bromodomain and extraterminal motif protein inhibitors (BETi) has been demonstrated across numerous types of cancer. As such, these inhibitors are currently undergoing widespread clinical evaluation. However, predictive biomarkers allowing the stratification of tumors into responders and nonresponders to BETi are lacking. Here, we showed significant antiproliferative effects of low dosage BETi in vitro and in vivo against aggressive ovarian and lung cancer models lacking SMARCA4 and SMARCA2, key components of SWI/SNF chromatin remodeling complexes. Restoration of SMARCA4 or SMARCA2 promoted resistance to BETi in these models and, conversely, knockdown of SMARCA4 sensitized resistant cells to BETi. Transcriptomic analysis revealed that exposure to BETi potently downregulated a network of genes involved in receptor tyrosine kinase (RTK) signaling in SMARCA4/A2-deficient cells, including the oncogenic RTK HER3. Repression of signaling downstream of HER3 was found to be an important determinant of response to BETi in SMARCA4/A2-deficient cells. Overall, we propose that BETi represent a rational therapeutic strategy in poor-prognosis, SMARCA4/A2-deficient cancers. Significance: These findings address an unmet clinical need by identifying loss of SMARCA4/A2 as biomarkers of hypersensitivity to BETi.
Efficacy of abiraterone and enzalutamide in patients who had disease progression within twelve months of completing docetaxel for metastatic castration sensitive prostate cancer.
Authors: Gang Chen, David James VanderWeele, Fatima Karzai, Marijo Bilusic, Munjid Al Harthy, Philip M. Arlen, Inger L. Rosner, Guinevere Chun, Helen Owens, Anna Couvillon, Amy Hankin, Monique Williams, Lisa M. Cordes, William Douglas Figg, James L. Gulley, William L. Dahut, Ravi Amrit Madan
Journal: Journal of Clinical Oncology (2019)

241 Background: Docetaxel is a standard of care for mCSPC. Enzalutamide and abiraterone have been proven to improve survival in metastatic castration-resistant prostate cancer (mCRPC) patients. Little is known about patients who have been treated with docetaxel for mCSPC and subsequent therapeutic responses. This retrospective analysis is to evaluate the response duration of abiraterone and enzalutamide in patients who previously received docetaxel for mCSPC but developed mCRPC within 12 months. Methods: Clinical Trial NCT02649855 enrolled patients with newly diagnosed mCSPC who were treated with standard androgen deprivation therapy (ADT) and docetaxel (75 mg/m2 every 3 weeks for 6 cycles) sequenced with immunotherapy (PROSTVAC) from February 2016 to present. Patients who had progression (based on consecutive PSA rises or imaging) within 1 year of completing docetaxel and went on to subsequent abiraterone/enzalutamide were evaluated. (Note these are different PSA progression criteria than used in CHAARTED, Sweeney, NEJM, 2015). Results: Of the 46 patients evaluated regardless of immunotherapy sequence, 15 (33%) went on subsequent therapy after progression on docetaxel for mCSPC, with 12 patients starting abiraterone/enzalutamide (6 each with high and low volume disease). The median age was 62 (41-83) years. 7/12 patients (58.3%) initiated enzalutamide and 5/12 patients (41.7%) initiated abiraterone. The median duration of treatment for both was 7.12 (1.53–16.0) months, the median time to prostate-specific antigen (PSA) progression was 5.54 (0–15.83) months; 5/12 (41.7%) of patients did not have PSA response. Of note, patients with low volume disease had a median treatment duration of 5.88 months, 3 of them did not have PSA response. Conclusions: These data from a small cohort suggest that patients who have progression within 12 months of completing docetaxel for mCSPC have limited subsequent benefit from enzalutamide or abiraterone. Additional studies are required to determine optimal timing and treatment sequence for patients with mCSPC who rapidly develop mCRPC. Clinical trial information: NCT02649855.
The impact of histologic variants of urothelial carcinoma on clinical outcomes following trimodal bladder-preserving therapy.
Authors: Yoshiyuki Nagumo, Shuya Kandori, Tomokazu Kimura, Takashi Kawahara, Takahiro Kojima, Koji Kawai, Hitoshi Ishikawa, Hiroyuki Nishiyama
Journal: Journal of Clinical Oncology (2019)

421 Background: The current guidelines for muscle-invasive bladder cancer recommend the use of neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. However, a trimodal approach involving the combination of maximal transurethral resection (TUR) and combined chemoradiotherapy is an alternative in selected patients. Clinical outcomes of patients with histologic variants have not well been known. Methods: From 1990 to 2015, 148 patients with cT2-3N0M0 muscle-invasive bladder cancer underwent trimodal bladder-preserving therapy consisting of maximal TUR of the bladder tumor, intra-arterial chemotherapy and radiotherapy at our institution. We compared complete response rate (CRR) of bladder preservation, 5-yr cause-specific survival (CSS), and 5-yr overall survival (OS) for the patients with pure urothelial carcinoma (UC) or variant UC. OS and CSS were analyzed by using the Kaplan-Meier method and log-rank test. Results: The median follow-up was 38.3 months. All patients were T2-T3N0M0 (T2, n = 90; T3, n = 58). There were no significant differences in clinical characteristics between pure and variant UC groups. Eleven (7%) of the 148 patients had variant UC; 7 (64%) had UC with squamous and/or glandular differentiation, and 4 (36%) had other forms, including sarcomatoid (n = 1), plasmacytoid (n = 1), signet ring cell (n = 1), and clear cell variants (n = 1). There was no significant difference between pure UC and variant UC for CRR of bladder preservation (85% vs 82%, p = 0.66), the 5-yr CSS (88% vs 75%, p = 0.86) and the 5-yr OS (81% vs 75%, p = 0.66). Conclusions: Our findings indicate that trimodal bladder-preserving therapy can be an effective treatment option for selected muscle-invasive bladder cancer patients with variant UC.
Patient-Centered Preference Assessment to Improve Satisfaction With Care Among Patients With Localized Prostate Cancer: A Randomized Controlled Trial
Authors: Ravishankar Jayadevappa, Sumedha Chhatre, Joseph J. Gallo, Marsha Wittink, Knashawn H. Morales, David I. Lee, Thomas J. Guzzo, Neha Vapiwala, Yu-Ning Wong, Diane K. Newman, Keith Van Arsdalen, S. Bruce Malkowicz, J. Sanford Schwartz, Alan J. Wein
Journal: Journal of Clinical Oncology (2019)

PURPOSE To study the effectiveness of the Patient Preferences for Prostate Cancer Care (PreProCare) intervention in improving the primary outcome of satisfaction with care and secondary outcomes of satisfaction with decision, decision regret, and treatment choice among patients with localized prostate cancer. METHODS In this multicenter randomized controlled study, we randomly assigned patients with localized prostate cancer to the PreProCare intervention or usual care. Outcomes were satisfaction with care, satisfaction with decision, decision regret, and treatment choice. Assessments were performed at baseline and at 3, 6, 12, and 24 months, and were analyzed using repeated measures. We compared treatment choice across intervention groups by prostate cancer risk categories. RESULTS Between January 2014 and March 2015, 743 patients with localized prostate cancer were recruited and randomly assigned to receive PreProCare (n = 372) or usual care (n = 371). For the general satisfaction subscale, improvement at 24 months from baseline was significantly different between groups ( P &lt; .001). For the intervention group, mean scores at 24 months improved by 0.44 (SE, 0.06; P &lt; .001) from baseline. This improvement was 0.5 standard deviation, which was clinically significant. The proportion reporting satisfaction with decision and no regret increased over time and was higher for the intervention group, compared with the usual care group at 24 months ( P &lt; .05). Among low-risk patients, a higher proportion of the intervention group was receiving active surveillance, compared with the usual care group ( P &lt; .001). CONCLUSION Our patient-centered PreProCare intervention improved satisfaction with care, satisfaction with decision, reduced regrets, and aligned treatment choice with risk category. The majority of our participants had a high income, with implications for generalizability. Additional studies can evaluate the effectiveness of PreProCare as a mechanism for improving clinical and patient-reported outcomes in different settings.