tbuckley/cabot-search huggingface dataset:
Cardiac arrhythmia considerations of hormone cancer therapies
Authors: Mary Barber, Lee S Nguyen, Johanna Wassermann, Jean-Philippe Spano, Christian Funck-Brentano, Joe-Elie Salem
Journal: Cardiovascular Research (2019)

Breast and prostate cancers are among the most prevalent cancers worldwide. Oestradiol and progesterone are major drivers for breast cancer proliferation, and androgens for prostate cancer. Endocrine therapies are drugs that interfere with hormone-activated pathways to slow cancer progression. Multiple new breakthrough drugs improving overall survival have recently been developed within this class. As the use of these latter drugs grows, incidence of cardiac arrhythmias has emerged as an unappreciated complication. These changes are not surprising given that sex hormones alter ventricular repolarization. Testosterone shortens action potential duration and QT interval duration, while oestradiol has an opposite effect. In patients with breast cancer, selective oestrogen receptor modulators are associated with more reports for long QT and torsade de pointes (TdP) than aromatase inhibitors, likely through an oestradiol-like effect on the heart. Cyclin-dependent kinase 4/6 inhibitors, a new class of anticancer drugs used in combination with endocrine therapies in hormone receptor positive breast cancer, are also variably associated with drug-induced long QT, particularly with ribociclib. In prostate cancer, androgen deprivation therapy is associated with long QT and TdP, and possibly atrial fibrillation for abiraterone. In this review, we have summarized the clinical and preclinical data focusing on cardiac arrhythmia considerations of hormone cancer therapies.
Abstract 11593: The Impact of Impaired Pancreatic Beta Cell Function on Cardiovascular Prognosis in Heart Failure Patients Without Diabetes Mellitus
Authors: Taro Narumi, Tetsu Watanabe, Harutoshi Tamura, Satoshi Nishiyama, Hiroki Takahashi, Takanori Arimoto, Tetsuro Shishido, Takuya Miyamoto, Isao Kubota
Journal: Circulation (2017)

Introduction: Insulin resistance (homeostasis model assessment ratio; HOMA-R) is associated with latent myocardial damage in apparently healthy subjects in health check. Meanwhile, diabetes mellitu...
Does identity fusion give rise to the group – or the reverse? Politics- versus community-based groups
Authors: Elias L. Khalil
Journal: Behavioral and Brain Sciences (2018)

This comment questions Whitehouse's theory. This comment proffers that people first choose their identity and later employ shared facts from the past to cement it. This is true with respect to two kinds of group identity: politics- and community-based identities. Contrary to Whitehouse, neither shared biology nor shared experience from the past is necessary for the constitution of either kind.
KVD900 as a Single Dose, Rapid, Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema Attacks: Pharmacokinetic and Pharmacodynamic results from a Phase 1 Single Ascending Dose Study
Authors: Sally L. Hampton, Gian Marco De Donatis, Nivetha I. Murugesan, Louise J. Rushbrooke, Lily Li, Edward Duckworth, Michael D. Smith, Rachel M. Morten, Andreas Maetzel, Christopher M. Yea, Edward P. Feener
Journal: Journal of Allergy and Clinical Immunology (2019)
Hematopoietic Stem-Cell Transplantation in Children with Refractory Acute Myeloid Leukemia
Authors: Yasuhiro Okamoto, Kazuko Kudo, Ken Tabuchi, Daisuke Tomizawa, Takashi Taga, Hiroaki Goto, Hiromasa Yabe, Yozo Nakazawa, Katsuyoshi Koh, Kazuhiro Ikegame, Nao Yoshida, Naoyuki Uchida, Kenichiro Watanabe, Yuuki Koga, Masami Inoue, Koji Kato, Yoshiko Atsuta, Hiroyuki Ishida
Journal: Blood (2018)
Trial design for a phase 3 study evaluating pemigatinib (INCB054828) versus gemcitabine plus cisplatin chemotherapy in first-line treatment of patients with cholangiocarcinoma with <i>FGFR2</i> rearrangement.
Authors: Tanios S. Bekaii-Saab, Juan W. Valle, Mitesh J. Borad, Davide Melisi, Arndt Vogel, Luis Féliz, Christine Francis Lihou, Huiling Zhen, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2019)

TPS462 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR genetic alterations is implicated in many cancers, including cholangiocarcinoma (CCA). FGFR2 translocations with fusion partners occur in ≈10% to 20% of intrahepatic CCA tumors. Pemigatinib is a selective oral inhibitor of FGFR-1, 2, 3. Preliminary data from the ongoing phase 2 study show efficacy and tolerable safety in patients (pts) with CCA with FGFR2 translocations. We present the design for a phase 3, open-label, randomized trial investigating pemigatinib monotherapy versus gemcitabine plus cisplatin chemotherapy in the first-line treatment of pts with advanced/metastatic or unresectable CCA with FGFR2 rearrangement. Methods: Eligible pts (target, N = 432) are ≥ 18 years (≥ 20 years for Japanese pts) and have ECOG performance status ≤ 1 and histologically confirmed advanced (locally advanced, metastatic, or recurrent) CCA with a documented FGFR2 rearrangement. Key exclusion criteria include prior systemic therapy, excluding adjuvant/neoadjuvant treatment completed ≥ 6 months before enrollment; current evidence of clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues; and known, untreated CNS metastases or history of uncontrolled seizures. Pts are randomized 1:1 and stratified by geographic region and tumor burden into 2 treatment groups: pemigatinib starting dose 13.5 mg once daily continuously on a 3-week cycle; or gemcitabine (1000 mg/m 2 ) and cisplatin (25 mg/m 2 ) administered intravenously on days 1 and 8 of every 3-week cycle for up to 8 cycles until disease progression or unacceptable toxicity. Crossover to pemigatinib may be allowed once progressive disease is confirmed. The primary endpoint is progression-free survival (based on independent central review using RECIST v1.1). Secondary endpoints include overall response rate, overall survival, duration of response, disease control rate, safety and tolerability, and impact on quality of life. Clinical trial information: NCT03656536.
The Association Between Hysterectomy and Ovarian Cancer Risk: A Population-Based Record-Linkage Study
Authors: Suzanne C Dixon-Suen, Penelope M Webb, Louise F Wilson, Karen Tuesley, Louise M Stewart, Susan J Jordan
Journal: JNCI Journal of the National Cancer Institute (2019)

Recent studies have called into question the long-held belief that hysterectomy without oophorectomy protects against ovarian cancer. This population-based longitudinal record-linkage study aimed to explore this relationship, overall and by age at hysterectomy, time period, surgery type, and indication for hysterectomy.We followed the female adult Western Australian population (837 942 women) across a 27-year period using linked electoral, hospital, births, deaths, and cancer records. Surgery dates were determined from hospital records, and ovarian cancer diagnoses (n = 1640) were ascertained from cancer registry records. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between hysterectomy and ovarian cancer incidence.Hysterectomy without oophorectomy (n = 78 594) was not associated with risk of invasive ovarian cancer overall (HR = 0.98, 95% CI = 0.85 to 1.11) or with the most common serous subtype (HR = 1.05, 95% CI = 0.89 to 1.23). Estimates did not vary statistically significantly by age at procedure, time period, or surgical approach. However, among women with endometriosis (5.8%) or with fibroids (5.7%), hysterectomy was associated with substantially decreased ovarian cancer risk overall (HR = 0.17, 95% CI = 0.12 to 0.24, and HR = 0.27, 95% CI = 0.20 to 0.36, respectively) and across all subtypes.Our results suggest that for most women, having a hysterectomy with ovarian conservation is not likely to substantially alter their risk of developing ovarian cancer. However, our results, if confirmed, suggest that ovarian cancer risk reduction could be considered as a possible benefit of hysterectomy when making decisions about surgical management of endometriosis or fibroids.
People with chronic obstructive pulmonary disease exacerbations prefer early discharge, then treatment at home
Authors: Rob Cook, Vaughan Thomas, Rosie Martin
Journal: BMJ (2019)

The study Home treatment of COPD exacerbation selected by DECAF score: a non-inferiority, randomised controlled trial and economic evaluation Echevarria C, Gray J, Hartley T, Miller J, Simpson AJ, Gibson GJ, Bourke SC Published on 24 April 2018 Thorax 2018;73:713-22 This project was funded by the National Institute for Health Research—Research for Patient Benefit Programme (project number PB-PG-0213-30105). To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000691/hospital-at-home-treatment-for-copd-flare-ups
Downstaging and survival after neoadjuvant approaches to gastroesophageal junction adenocarcinoma.
Authors: Michael H. Xiang, Daniel Tandel Chang, Gregory M. Heestand, Erqi L. Pollom
Journal: Journal of Clinical Oncology (2019)

92 Background: Outcomes after neoadjuvant chemoradiation (NACRT) versus chemotherapy alone (NAC) in gastroesophageal junction (GEJ) adenocarcinoma are unclear, as such tumors can be treated with equipoise using either approach. Methods: We included patients in the National Cancer Database with non-metastatic T2-4 or N1-3 GEJ adenocarcinoma who underwent definitive surgery within 6 months of diagnosis and NAC or NACRT. Overall survival (OS) was compared using the Kaplan-Meier method and logrank test. Multivariable logistic and Cox regressions were used to obtain odds and hazard ratios (OR, HR) adjusted for age, comorbidity, and other patient and tumor characteristics. Results: We identified 2,362 patients treated with NACRT and 658 patients treated with NAC. Median follow-up was 3.9 years. OS modestly favored NAC compared to NACRT (54% vs 51% at 3 years, P = 0.05; adjusted HR 0.86, P = 0.01). Further analysis stratified by the extent of pathological downstaging revealed large separations in the survival curves for both NAC and NACRT according to pathological response (complete, partial/mixed, or none; see table). Patients with no response did equally poorly after either preoperative regimen. NAC was significantly less likely to produce any response than NACRT (adjusted OR 0.62, P &lt; 0.0001). Since NACRT had increased downstaging but not survival, we analyzed use of adjuvant chemotherapy (AC). AC was used significantly less after NACRT than after NAC ( P &lt; 0.0001) (see table). In patients with residual disease in both tumor and lymph nodes, AC was associated with increased OS (47% vs 39% at 3 years, P = 0.05; adjusted HR 0.81, P = 0.07) after NACRT, but not after NAC. Conclusions: NACRT had superior pathological downstaging compared to NAC, but was not associated with increased OS. Adjuvant chemotherapy is relatively underused after NACRT and warrants further study as a risk-adapted means to improve survival, especially in patients with larger burden of residual disease. [Table: see text]
Significance of monitoring plasma vascular endothelial growth factor signals during treatment of colorectal cancer patients.
Authors: Nao Kakizawa, Koichi Suzuki, Hideki Ishikawa, Fumiaki Watanabe, Fumi Hasegawa, Rina Kikugawa, Shingo Tsujinaka, Kazushige Futsuhara, Yasuyuki Miyakura, Toshiki Rikiyama
Journal: Journal of Clinical Oncology (2019)

577 Background: Vascular endothelial growth factor (VEGF) signals may change during colorectal cancer (CRC) treatment, but monitoring real time changes has not been conducted. Methods: Blood monitoring was carried out to track changes in the status of VEGF ligands (A, C, and D) in CRC patients. Expression was determined by ELISA. Results: VEGF-A monitoring was performed in 148 CRC patients preoperatively and VEGF-C and -D monitoring was performed in 52 metastatic CRC patients. Patients with high VEGF-A had significantly shorter recurrence free survival (p = 0.00438). Univariate analysis associating with recurrence detected high VEGF-A, high pathological stage, and with lymph node metastasis were risk factors, and high VEGF-A was identified as an independent risk factor of recurrence by multivariate analysis. There was no significant difference in prognosis between metastatic CRC patients with high and low VEGF-D in early-line treatment, however, in late line patients with high VEGF-D had significantly worse prognosis than those with low VEGF-D (p = 0.0121). When they had treatment with bevacizumab, same result was seen in late line (p = 0.0416). VEGF-C showed no significant correlation with prognosis. Conclusions: Preoperative high VEGF-A is an important risk factor of recurrence and VEGF targeting drugs might be useful as an adjuvant chemotherapy for the patients with high VEGF-A. In late line chemotherapy, patients with high VEGF-D had poor prognosis in regardless of bevacizumab, therefore, they will be candidates of other anti-VEGF drugs than bevacizumab in late line chemotherapy. Measurement of plasma VEGF level can have benefit for the treatment of CRC patients to predict their recurrence and prognosis. It would be helpful for VEGF targeting drug selection and provide useful information for better treatment strategy.
Cell-Free DNA Screening During Pregnancy—Reply
Authors: Megan Allyse, Myra Wick
Journal: JAMA (2019)

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Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8+ T-cell Response against Immunosuppressive Tumors
Authors: Miro Viitala, Reetta Virtakoivu, Sina Tadayon, Jenna Rannikko, Sirpa Jalkanen, Maija Hollmén
Journal: Clinical Cancer Research (2019)

As foremost regulators of cancer-related inflammation and immunotherapeutic resistance, tumor-associated macrophages have garnered major interest as immunotherapeutic drug targets. However, depletory strategies have yielded little benefit in clinical studies to date. An alternative approach is to exploit macrophage plasticity and "reeducate" tumorigenic macrophages toward an immunostimulatory phenotype to activate the host's antitumor immunity.Experimental Design: We investigated the role of the macrophage scavenger receptor common lymphatic endothelial and vascular endothelial receptor-1 (Clever-1) on tumor growth in multiple mouse cancer models with inflammatory and noninflammatory characteristics by using conditional knockouts, bone marrow chimeras, and cell depletion experiments. In addition, the efficacy of immunotherapeutic Clever-1 blockade as monotherapy or in combination with anti-PD-1 was tested.Genetic deficiency of macrophage Clever-1 markedly impaired solid tumor growth. This effect was mediated by macrophages that became immunostimulatory in the absence of Clever-1, skewing the suppressive tumor microenvironment toward inflammation and activating endogenous antitumor CD8+ T cells. Comparable effects were achieved with immunotherapeutic blockade of Clever-1. Notably, these effects were similar to those achieved by PD-1 checkpoint inhibition. Moreover, combining anti-Clever-1 with anti-PD-1 provided synergistic benefit in aggressive, nonresponsive tumors.These findings demonstrate the importance of macrophages in mediating antitumor immune responses and support the clinical evaluation of immunotherapeutic Clever-1 blockade as a novel cancer treatment strategy.See related commentary by Mantovani and Bonecchi, p. 3202.
Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis
Authors: Dorian A. Rosen, Scott M. Seki, Anthony Fernández-Castañeda, Rebecca M. Beiter, Jacob D. Eccles, Judith A. Woodfolk, Alban Gaultier
Journal: Science Translational Medicine (2019)

Sepsis is an often deadly complication of infection in which systemic inflammation damages the vasculature, leading to tissue hypoperfusion and multiple organ failure. Currently, the standard of care for sepsis is predominantly supportive, with few therapeutic options available. Because of increased sepsis incidence worldwide, there is an urgent need for discovery of novel therapeutic targets and development of new treatments. The recently discovered function of the endoplasmic reticulum (ER) in regulation of inflammation offers a potential avenue for sepsis control. Here, we identify the ER-resident protein sigma-1 receptor (S1R) as an essential inhibitor of cytokine production in a preclinical model of septic shock. Mice lacking S1R succumb quickly to hypercytokinemia induced by a sublethal challenge in two models of acute inflammation. Mechanistically, we find that S1R restricts the endonuclease activity of the ER stress sensor IRE1 and cytokine expression but does not inhibit the classical inflammatory signaling pathways. These findings could have substantial clinical implications, as we further find that fluvoxamine, an antidepressant therapeutic with high affinity for S1R, protects mice from lethal septic shock and dampens the inflammatory response in human blood leukocytes. Our data reveal the contribution of S1R to the restraint of the inflammatory response and place S1R as a possible therapeutic target to treat bacterial-derived inflammatory pathology.
Microparticles from vascular endothelial growth factor pathway inhibitor-treated cancer patients mediate endothelial cell injury
Authors: Karla B Neves, Francisco J Rios, Robert Jones, Thomas Ronald Jeffry Evans, Augusto C Montezano, Rhian M Touyz
Journal: Cardiovascular Research (2019)

Vascular endothelial growth factor pathway inhibitors (VEGFi), used as anti-angiogenic drugs to treat cancer are associated with cardiovascular toxicities through unknown molecular mechanisms. Endothelial cell-derived microparticles (ECMPs) are biomarkers of endothelial injury and are also functionally active since they influence downstream target cell signalling and function. We questioned whether microparticle (MP) status is altered in cancer patients treated with VEGFi and whether they influence endothelial cell function associated with vascular dysfunction. Plasma MPs were isolated from cancer patients before and after treatment with VEGFi (pazopanib, sunitinib, or sorafenib). Human aortic endothelial cells (HAECs) were stimulated with isolated MPs (106 MPs/mL). Microparticle characterization was assessed by flow cytometry. Patients treated with VEGFi had significantly increased levels of plasma ECMP. Endothelial cells exposed to post-VEGFi treatment ECMPs induced an increase in pre-pro-ET-1 mRNA expression, corroborating the increase in endothelin-1 (ET-1) production in HAEC stimulated with vatalanib (VEGFi). Post-VEGFi treatment MPs increased generation of reactive oxygen species in HAEC, effects attenuated by ETA (BQ123) and ETB (BQ788) receptor blockers. VEGFi post-treatment MPs also increased phosphorylation of the inhibitory site of endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO), and increased ONOO− levels in HAEC, responses inhibited by ETB receptor blockade. Additionally, gene expression of proinflammatory mediators was increased in HAEC exposed to post-treatment MPs, effects inhibited by BQ123 and BQ788. Our findings define novel molecular mechanism involving interplay between microparticles, the ET-1 system and endothelial cell pro-inflammatory and redox signalling, which may be important in cardiovascular toxicity and hypertension associated with VEGFi anti-cancer treatment. New and noteworthy: our novel data identify MPs as biomarkers of VEGFi-induced endothelial injury and important mediators of ET-1-sensitive redox-regulated pro-inflammatory signalling in effector endothelial cells, processes that may contribute to cardiovascular toxicity in VEGFi-treated cancer patients.
Late Morbidity and Mortality Among Medulloblastoma Survivors Diagnosed Across Three Decades: A Report From the Childhood Cancer Survivor Study
Authors: Ralph Salloum, Yan Chen, Yutaka Yasui, Roger Packer, Wendy Leisenring, Elizabeth Wells, Allison King, Rebecca Howell, Todd M. Gibson, Kevin R. Krull, Leslie L. Robison, Kevin C. Oeffinger, Maryam Fouladi, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2019)

Treatment of medulloblastoma has evolved from surgery and radiotherapy to contemporary multimodal regimens. However, the impact on long-term health outcomes remains unknown.Cumulative incidence of late mortality (5 or more years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of medulloblastoma diagnosed between 1970 and 1999. Outcomes were evaluated by treatment exposure, including historical therapy (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), high risk (CSI ≥ 30 Gy + chemotherapy), standard risk (CSI < 30 Gy + chemotherapy), and by treatment decade (1970s, 1980s, 1990s). Rate ratios (RRs) and 95% CIs estimated long-term outcomes using multivariable piecewise exponential models.Among 1,311 eligible survivors (median age, 29 years [range, 6 to 60 years]; median time from diagnosis, 21 years [range, 5 to 44 years]), the 15-year cumulative incidence rate of all-cause late mortality was 23.2% (diagnosed 1970s) versus 12.8% (1990s; P = .002), with a recurrence-related mortality rate of 17.7% versus 9.6% ( P = .008). Lower late mortality rates as a result of other health-related causes were not observed. Among 997 survivors who completed a baseline survey, the 15-year cumulative incidence of SNs was higher among survivors with multimodal therapy (standard risk, 9.5%; historical, 2.8%; P = .03). Survivors treated in the 1990s had a higher cumulative incidence of severe, disabling, life-threatening, and fatal chronic health conditions (56.5% in 1990s v 39.9% in 1970s; P < .001) and were more likely to develop multiple conditions (RR, 2.89; 95% CI, 1.31 to 6.38). However, survivors of standard-risk therapy were less likely to use special education services than high-risk therapy survivors (RR, 0.84; 95% CI, 0.75 to 0.93).Historical changes in medulloblastoma therapy that improved 5-year survival have increased the risk for SNs and debilitating health conditions for survivors yet reduced the need for special education services.