tbuckley/cabot-search huggingface dataset:
Renin–Angiotensin System Inhibitors to Mitigate Cancer Treatment–Related Adverse Events
Authors: Matthias Pinter, Wilhelmus J. Kwanten, Rakesh K. Jain
Journal: Clinical Cancer Research (2018)

Abstract Treatment-related side effects are a major clinical problem in cancer treatment. They lead to reduced compliance to therapy as well as increased morbidity and mortality. Well-known are the sequelae of chemotherapy on the heart, especially in childhood cancer survivors. Therefore, measures to mitigate the adverse events of cancer therapy may improve health and quality of life in patients with cancer, both in the short and long term. The renin–angiotensin system (RAS) affects all hallmarks of cancer, and blockage of the RAS is associated with an improved outcome in several cancer types. There is also increasing evidence that inhibition of the RAS might be able to alleviate or even prevent certain types of cancer treatment–related adverse effects. In this review, we summarize the potential of RAS inhibitors to mitigate cancer treatment–related adverse events, with a special emphasis on chemotherapy-induced cardiotoxicity, radiation injury, and arterial hypertension. Clin Cancer Res; 24(16); 3803–12. ©2018 AACR.
Updated Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation
Authors: A Pieter Kappetein, Stuart J Head, Philippe Généreux, Nicolo Piazza, Nicolas M van Mieghem, Eugene H Blackstone, Thomas G Brott, David J Cohen, Donald E Cutlip, Gerrit-Anne van Es, Rebecca T Hahn, Ajay J Kirtane, Mitchell W Krucoff, Susheel Kodali, Michael J Mack, Roxana Mehran, Josep Rodés-Cabau, Pascal Vranckx, John G Webb, Stephan Windecker, Patrick W Serruys, Martin B Leon
Journal: Journal of the American College of Cardiology (2012)
Expression, regulation and targeting of receptor tyrosine kinases in esophageal squamous cell carcinoma
Authors: Manoj Kumar Kashyap, Omar Abdel-Rahman
Journal: Molecular Cancer (2018)

Esophageal cancer is one of the most common types of cancer, which is a leading cause of cancer-related death worldwide. Based on histological behavior, it is mainly of two types (i) Esophageal squamous cell carcinoma (ESCC), and (ii) esophageal adenocarcinoma (EAD or EAC). In astronomically immense majority of malignancies, receptor tyrosine kinases (RTKs) have been kenned to play a consequential role in cellular proliferation, migration, and metastasis of the cells. The post-translational modifications (PTMs) including phosphorylation of tyrosine (pY) residue of the tyrosine kinase (TK) domain have been exploited for treatment in different malignancies. Lung cancer where pY residues of EGFR have been exploited for treatment purpose in lung adenocarcinoma patients, but we do not have such kind of felicitously studied and catalogued data in ESCC patients. Thus, the goal of this review is to summarize the studies carried out on ESCC to explore the role of RTKs, tyrosine kinase inhibitors, and their pertinence and consequentiality for the treatment of ESCC patients.
Incorrect Conclusions of a Secondary Analysis—Reply
Authors: David L. Brown, Samuel W. Reinhardt, Chien-Jung Lin
Journal: JAMA Internal Medicine (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Abstract 13736: Mast Cell Activation During Aortic Repair Requiring Circulatory Arrest is Associated With Hemodynamic Instability and Indications of End-Organ Injury
Authors: Sreekanth Cheruku, Miklos D Kertai, Wenjing Qi, Yi-Ju Li, G. C Hughes, Joseph P Mathew, Joern Karhausen
Journal: Circulation (2015)

Background: Systemic inflammatory responses after cardiac surgery are associated with hemodynamic instability and an increased risk of end-organ injury. We recently identified mast cell activation as a critical mechanism of tissue injury, local and systemic inflammation in a rat model of circulatory arrest (CA). To test the clinical relevance of these findings, we now examined mast cell activation in patients undergoing cardiopulmonary bypass (CPB) and CA. Methods: After institutional review board approval, 31 patients with elective aortic arch surgery employing CPB and CA were prospectively enrolled from June 2013 until April 2015. Arterial blood samples were obtained at induction of anesthesia, on CPB when reaching target temperature, 10 minutes after CA, and after weaning from CPB. Plasma mast cell specific chymase, IL-6, TNFa, and IL-8 were measured by ELISA. Patient demographics and clinical parameters were retrieved from the electronic charting system. Statistical analysis was performed using SAS software. Results: Chymase levels increased with institution of CPB (delta baseline chymase: 5.59±6.29* at target temperature, 5.46±6.14* after CA, and 9.66±7.82* at end of CPB; * pg/mg plasma protein, p≤0.05). We observed no changes in TNFα at any time-point and significant changes of IL-6 and IL-8 only after end of CPB (delta baseline: 1.4±2.6pg/mg plasma protein and 10.8±6.3pg/mg plasma protein, p≤0.05). Time and area under the curve of a mean arterial pressure below 60 were significantly increased in patients with above-median chymase level vs. patients with below-median chymase levels at the end of CPB (p=0.0097 and p=0.014 respectively by 2-sample t test). Also, in these patients there was a consistent trend towards increased intraoperative phenylephrine, vasopressin, and epinephrine dose, increased postoperative lactate levels and a higher incidence of postoperative renal injury. Analysis of surgical factors revealed an association of chymase levels with higher target temperatures during CA, but not with duration of CPB or CA. Conclusions: We provide first evidence that significant and rapid mast cell activation occurs during cardiac surgery and is associated with a complicated intraoperative and early postoperative clinical course.
Assessing the prognostic impact of intermediate outcomes on survival time in relapsed/refractory multiple myeloma (RRMM) patients (pts) via a robust and clinically interpretable quantitative procedure.
Authors: Rajeev Ayyagari, Wendy Y Cheng, Xiaopeng Cai, Casey Jones, Esprit Ma, Vijayveer Bonthapally, Yanyan Zhu, Patrick Lefebvre, L J Wei, Mei Sheng Duh
Journal: Journal of Clinical Oncology (2015)

e17743 Background: Assessing the impact of intermediate outcomes on overall survival (OS) is crucial in RRMM. The conventional approach, using the hazard ratio (HR), is difficult to interpret clinically as hazard is not a risk measure. When the proportional hazards assumption is violated, the HR lacks clinical meaning as a contrast measure between two groups. An attractive alternative is to use the mean survival time at study end (restricted mean survival time [RMST]). The difference and ratio of two RMSTs can be used to quantify the prognostic impact of intermediate outcomes on OS by landmark (LM) analysis. This procedure is robust (model-free) and yields a clinically meaningful interpretation. Methods: 669 RRMM pts randomized to bortezomib or dexamethasone in the phase III APEX trial (NCT00048230) were considered for inclusion. Pts alive at a pre-specified LM time (0.5 yrs from randomization) were assessed for OS until trial end (N = 568). Quality of response (QOR, best response by LM), was categorized as complete response (CR), partial response (PR), minimal response (MR), stable disease (SD), progressive disease (PD), and combinations of these categories. The RMST difference and ratio were used to assess the prognostic impact of QOR on OS at LM (2-yr follow-up). Cox regressions were also performed. Results: Compared to pts with SD/PD, pts with CR at the 0.5-yr LM lived on average 144.2 days (1.31 times) longer from LM (p < .001), while pts with CR/PR or CR/PR/MR lived on average 130.6 days (1.28 times; p < .001) and 99.1 days (1.21 times; p < .001) longer. Compared to pts with SD/PD, pts with CR had a 58% lower hazard of death (HR 0.42; p = 0.038); HR in pts with CR/PR or CR/PR/MR were 0.45 (p < .001) and 0.55 (p < .001), respectively. Conclusions: By RMST analysis, achievement of CR was significantly associated with longer OS. When combined with lesser responses, RMST decreased relative to that for CR alone, suggesting that higher QOR may be associated with improved OS. Unlike conventional HR analysis, the RMST method demonstrated a difference in survival at study end, directly quantifying the effect of intermediate outcomes on OS.
Consanguineous Marriage and the Psychopathology of Progeny
Authors: Aideen Maguire, Foteini Tseliou, Dermot O’Reilly
Journal: JAMA Psychiatry (2018)

Approximately 1 in 10 children worldwide are born to consanguineous parents. The literature on consanguinity and mental health of progeny is scarce despite the fact that many of the factors associated with consanguineous unions are also associated with mental health.To investigate if children of consanguineous parents are at increased risk of common mood disorders or psychoses.This investigation was a retrospective population-wide cohort study of all individuals born in Northern Ireland between January 1, 1971, and December 31, 1986, derived from the Child Health System data set and linked to nationwide administrative data sources on prescription medication and death records. Data from the Child Health System data set identified all 447 452 births delivered to mothers residing in Northern Ireland between 1971 and 1986. The final data set comprised 363 960 individuals, alive and residing in Northern Ireland in 2014, with full data on all variables. The dates of analysis were June 1 to October 31, 2017.Degree of parental consanguinity was assessed from questions asked of the parents during routine health visitor house calls within 2 weeks of the child's birth. Potential mental ill health was estimated by receipt of psychotropic medication in 2010 to 2014. Ever or never use was used for the main analysis, with sensitivity analyses using a cutoff of at least 3 months' prescriptions. Receipt of antidepressant or anxiolytic medications was used as a proxy for common mood disorders, whereas receipt of antipsychotic medications was used as a proxy indicator of psychoses.Of the 363 960 individuals (52.5% [191 102] male), 609 (0.2%) were born to consanguineous parents. After full adjustment for factors known to be associated with poor mental health, multilevel logistic regression models found that children of first-cousin consanguineous parents were more than 3 times as likely to be in receipt of antidepressant or anxiolytic medications (odds ratio, 3.01; 95% CI, 1.24-7.31) and more than twice as likely to be in receipt of antipsychotic medication (odds ratio, 2.13; 95% CI, 1.29-3.51) compared with children of nonrelated parents.A child of consanguineous parents is at increased risk of common mood disorders and psychoses.
Phase II open-label, single-center study evaluating safety and efficacy of pembrolizumab following induction with the hypomethylating agent azacitidine in patients with advanced pancreatic cancer after failure of first-line therapy.
Authors: Rachael A Safyan, Tamas Gonda, Benjamin Tycko, John A. Chabot, Gulam Abbas Manji, Gary K. Schwartz, Paul Eliezer Oberstein
Journal: Journal of Clinical Oncology (2018)

TPS534 Background: First-line cytotoxic chemotherapy improves survival for patients with metastatic pancreatic adenocarcinoma (PDA) but the majority will progress after a median of 5-7 months. CD8 T-cells are thought to be the major anti-tumor effector cells and their density in resected pancreatic tumors correlates with survival. Our published pre-clinical data in the KPC-Brca1 mouse model shows that treatment with a hypomethylating agent inhibits tumor growth (Shakya, Gonda et al., Cancer Res, 2013) and, in recent data (B.T. and T.G. in preparation), combining a hypomethylating agent with an immune checkpoint inhibitor leads to slowing of tumor growth and increased survival in KPC mice. We propose a novel approach to improve response rates with immune checkpoint blockade in pancreatic cancer by utilizing a hypomethylating agent to prime the tumor and its microenvironment, thereby increasing the number of intratumoral effector T cells, decreasing the immunosuppressive cell population, and influencing stromal-tumor cell interactions. Methods: Thirty-one evaluable subjects with advanced pancreatic cancer will be enrolled in this phase II study to evaluate the efficacy and safety of pembrolizumab following induction with azacitidine in the second-line setting. All subjects will have received a single line of chemotherapy for locally advanced or metastatic PDA prior to study enrollment. Subjects must have available baseline biopsy or archival tissue for analysis. Low-dose azacitidine (50 mg/m2 subcutaneous) will be given daily for 5 days every 4 weeks, and pembrolizumab 200 mg IV will be administered starting on day 15 and then continued every 3 weeks. Subjects will undergo an on-treatment biopsy during week 8. The primary efficacy endpoint will be PFS according to RECIST v1.1 criteria. There will be an accelerated phase Ib dose determination component with an initial 6 subjects. Secondary endpoints will include safety/tolerability, ORR, DOR, and OS. Multiple correlative analyses utilizing tissue and serum samples will be performed. Clinical trial information: NCT03264404.
Treatment and survival rates of stage IV pancreatic cancer at VA hospitals: A nationwide study.
Authors: Ibrahim Azar, Gurjiwan Virk, Saghi Esfandiarifard, Ali Wazir, Tariq Khreis, Syed Mehdi
Journal: Journal of Clinical Oncology (2018)

507 Background: Metastatic Pancreatic Cancer (MPC) is associated with an extremely high mortality. Current NCCN guidelines recommend systemic therapy, as it is superior to best supportive care. Undertreatment of MPC continues to be an issue. Recent treatment and survival data of MPC in Veterans’ Affairs’ (VA) hospitals have not been published. The relationship between treatment and American College of Surgeons’ (ACS) Committee on Cancer (CoC) accreditation has not been studied. Methods: Nationwide data from the National Veterans Affairs Cancer Cube Registry was analyzes. 7,585 patients were diagnosed with MPC between 2000 and 2017. Systemic therapy was only looked at as it is the standard of treatment for MPC. CoC accreditation of each VA hospital was obtained using the ACS website. Local IRB approval was obtained. Results: MPC constitutes 52.44% of pancreatic cancer diagnosed (7,585 out of 14,464 cases). The near totality were men (97.43%). The 60-70 age group constitutes the most common age at diagnosis (38.7%). The anatomic site distribution was: head (38.2%), tail (18.77%) and body (12.25%) with the rest unspecified or overlapping sites. Treatment rate over the years has increased from 32.03% in 2000-2004 to 41.17% in 2010-2014. The use of oxaplatinin and nab-paclitaxel as part of combination drugs has increased over the years as NCCN guidelines changed. This has corresponded with an increase of 1-5 years survival of 7.84% in 2000-2004 to 14.87 % in 2010-2014. Treatment rates in CoC- accredited and non-CoC accredited VA hospitals were similar (38.94% and 38.12%, respectively). Survival rates in CoC- accredited and non-COC accredited VAs were similar with a 1-5years survival rate of 8.89% and 8.57%, respectively. Conclusions: Treatment and survival of MPC have risen significantly in the past decade at VA hospitals. CoC accreditation is not associated with a change in treatment or survival rates. [Table: see text]
What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis
Authors: C.L. Vale, D.J. Fisher, I.R. White, J.R. Carpenter, S. Burdett, N.W. Clarke, K. Fizazi, G. Gravis, N.D. James, M.D. Mason, M.K.B. Parmar, L.H. Rydzewska, C.J. Sweeney, M.R. Spears, M.R. Sydes, J.F. Tierney
Journal: Annals of Oncology (2018)

Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies.Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed.We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability).Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.
Fairness and Desert: A Critique of the Random Selection Criterion in Clinical Trials
Authors: Eisuke Nakazawa, Keiichiro Yamamoto, Akira Akabayashi
Journal: The American Journal of Bioethics (2018)

"Fairness and Desert: A Critique of the Random Selection Criterion in Clinical Trials." The American Journal of Bioethics, 18(4), pp. 81–82
Survival of patients with schistosomiasis-associated pulmonary arterial hypertension in the modern management era
Authors: Caio Julio Cesar Fernandes, Bruna Piloto, Marcela Castro, Francisca Gavilanes Oleas, Jose Leonidas Alves, Luis Felipe Lopes Prada, Carlos Jardim, Rogerio Souza
Journal: European Respiratory Journal (2018)

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by an elevated pulmonary vascular resistance in the absence of left ventricular disease, and increasing pulmonary artery pressure, with consequent right ventricular failure and death [1]. Several aetiologies have been associated with PAH, including connective tissue diseases, congenital heart diseases and chronic infections, such as HIV. Due to its high prevalence in developing countries, one of the most relevant forms of PAH worldwide is the one associated to schistosomiasis [2]. Survival in schistosomiasis associated pulmonary arterial hypertension has improved in recent years with the use of targeted therapies <http://ow.ly/perr30jrhBo>
ROCK inhibition in models of neurodegeneration and its potential for clinical translation
Authors: Jan Christoph Koch, Lars Tatenhorst, Anna-Elisa Roser, Kim-Ann Saal, Lars Tönges, Paul Lingor
Journal: Pharmacology & Therapeutics (2018)

Neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis are affecting a rapidly increasing population worldwide. While common pathomechanisms such as protein aggregation, axonal degeneration, dysfunction of protein clearing and an altered immune response have been characterized, no disease-modifying therapies have been developed so far. Interestingly, a significant involvement of the Rho kinase (ROCK) signaling pathway has been described in all of these mechanisms making it a promising target for new therapeutic approaches. In this article, we first review current knowledge of the involvement of ROCK in neurodegenerative disorders and the utility of its inhibition as a disease-modifying therapy in different neurodegenerative disorders. After a detailed description of the biochemical characteristics of ROCK and its molecular interactors, differences of ROCK-expression under physiological and pathological conditions are compared. Next, different pharmacological and molecular-genetic strategies to inhibit ROCK-function are discussed, focusing on pharmacological ROCK-inhibitors. The role of the ROCK-pathway in cellular processes that are central in neurodegenerative disorders pathology like axonal degeneration, autophagy, synaptic and glial function is explained in detail. Finally, all available data on ROCK-inhibition in different animal models of neurodegenerative disorders is reviewed and first approaches for translation into human patients are discussed. Taken together, there is now extensive evidence from preclinical studies in several neurodegenerative disorders that characterize ROCK as a promising drug target for further translational research in neurodegenerative disorders.