tbuckley/cabot-search huggingface dataset:
Analysis of totally implantable venous access port systems (TIVAPS) related adverse events (AEs) in metastatic colorectal cancer (mCRC) patients treated with and without bevacizumab.
Authors: Takahiro Tsushima, Keita Mori, Kentaro Yamazaki, Tomomi Hikosaka, Taro Funakoshi, Hiroyuki Tabuse, Satoshi Hamauchi, Akiko Todaka, Tomoya Yokota, Nozomu Machida, Akira Fukutomi, Yusuke Onozawa, Narikazu Boku, Hirofumi Yasui
Journal: Journal of Clinical Oncology (2013)

e14623 Background: TIVAPS are widely used for cancer chemotherapy. Bevacizumab, a key drug for mCRC, associates with AEs such as thromboembolism, bleeding, and impaired wound healing. Bevacizumab may complicit in increasing incidence of TIVAPS related AEs. To assess the incidence of TIVAPS related AEs in mCRC patients who received chemotherapy with and without bevacizumab. Methods: We retrospectively reviewed the medical records of consecutive patients whose TIVAPS were placed at our institution between Apr. 2004 and Apr. 2009. Major selection criteria were histologically proven colorectal adenocarcinoma, metastatic disease, and receiving chemotherapy after TIVAPS placement. We assessed the incidence of AEs occurred from the first administration of chemotherapy via TIVAPS to TIVAPS removal, death, or the last follow-up. We compared the incidence of TIVAPS related AEs in the cases bevacizumab was administered (group A) with that in the cases without bevacizumab administration (group B). Results: TIVAPS was placed 549 times for 505 patients, and 544 TIVAPS placements for 501 patients were analyzed. Bevacizumb was administered in 174 patients (32%), and median duration of bevacizumab therapy was 9.2 months. Characteristics of the cases in the group A and B were: male (60% and 59%); primary site colon (60% and 57%); catheterized in left subclavian vein (85% and 81%); history of prior chemotherapy (53% and 60%); median time from TIVAPS placement to administration of chemotherapy (1 day and 1 day). Incidence of common AEs in the group A and B were: infection (7.5% and 6.8%); venous thromboembolism (3.4% and 1.4%); TIVAPS occlusion (2.3% and 1.9%); delay of wound healing (1.1% and 0.5%); hematoma (0.6% vs 0%). Median time to AE in the group A and B was 21 months and 9 months. There was no significant difference in the incidence of TIVAPS related AEs between group A and B. During median observation period of 40.5 months, no arterial thrombotic event or AE resulted in death occurred. Conclusions: Addition of bevacizumab did not increase TIVAPS related AEs during chemotherapy for mCRC.
Neoadjuvant versus concurrent chemotherapy in the management of carcinoma nasopharynx
Authors: R. Sharma, D. Kumar, S. Kaur, P. Kalsotra, A. Gupta
Journal: Journal of Clinical Oncology (2009)

e17053 Background: Chemotherapy is added to radiotherapy in the treatment of nasopharyngeal carcinoma with advanced locoregional disease to enhance therapeutic gain. Thirty percent patients with locally advanced nasopharyngeal carcinoma (LA-NPC) still die of distant metastases despite concurrent chemoradiation being the standard of care. In this retrospective study we performed the pooled analysis of these patients to assess the impact of neoadjuvant chemotherapy versus the concurrent chemoradiation approach. Methods: Between January 2000 and December 2007, 45 patients of stage IIB- IVB nasopharyngeal were treated with 3 cycles of induction chemotherapy with cisplatin and 5FU (n = 23) followed by conventional radical radiotherapy, or concurrent chemoradiation with weekly cisplatin (n = 22). Results: Total numbers of patients eligible for analyses were 45. Median age of the patients was 52 years (range 19–76 years). Median follow up was 17 months (range 6–60 months). At the time of last follow up, 13 patients (out of 23, i.e. 56.53%) were alive and disease free in the neoadjuvant group and 13 patients (out of 22, i.e. 59.1%) were alive and disease free in the concurrent chemoradiation group. The 2-year failure free survival in the concurrent chemoradiation arm was 63% versus 35% in the neoadjuvant arm (p = 0.197). Survival analyses adjusted for the gender male revealed 2-year failure free survival as 81% in the concurrent chemoradiation versus 44% in the neoadjuvant chemotherapy group among male patients (p = 0.0143). On multivariate analysis age and stage were the two significant predictive factors for failure free survival. Conclusions: The neoadjuvant chemotherapy seems to be at least as effective as concurrent chemoradiation in this small cohort of patients. No significant financial relationships to disclose.
Ticagrelor to Reduce Myocardial Injury in Patients With High-Risk Coronary Artery Plaque
Authors: Alastair J. Moss, Marc R. Dweck, Mhairi K. Doris, Jack P.M. Andrews, Rong Bing, Rachael O. Forsythe, Timothy R. Cartlidge, Tania A. Pawade, Marwa Daghem, Jennifer B. Raftis, Michelle C. Williams, Edwin J.R. van Beek, Laura Forsyth, Steff C. Lewis, Robert J. Lee, Anoop S.V. Shah, Nicholas L. Mills, David E. Newby, Philip D. Adamson
Journal: JACC. Cardiovascular imaging (2019)

The goal of this study was to determine whether ticagrelor reduces high-sensitivity troponin I concentrations in patients with established coronary artery disease and high-risk coronary plaque. High-risk coronary atherosclerotic plaque is associated with higher plasma troponin concentrations suggesting ongoing myocardial injury that may be a target for dual antiplatelet therapy. In a randomized, double-blind, placebo-controlled trial, patients with multivessel coronary artery disease underwent coronary 18F-fluoride positron emission tomography/coronary computed tomography scanning and measurement of high-sensitivity cardiac troponin I. Patients were randomized (1:1) to receive ticagrelor 90 mg twice daily or matched placebo. The primary endpoint was troponin I concentration at 30 days in patients with increased coronary 18F-fluoride uptake. In total, 202 patients were randomized to treatment, and 191 met the pre-specified criteria for inclusion in the primary analysis. In patients with increased coronary 18F-fluoride uptake (120 of 191), there was no evidence that ticagrelor had an effect on plasma troponin concentrations at 30 days (ratio of geometric means for ticagrelor vs. placebo: 1.11; 95% confidence interval: 0.90 to 1.36; p = 0.32). Over 1 year, ticagrelor had no effect on troponin concentrations in patients with increased coronary 18F-fluoride uptake (ratio of geometric means: 0.86; 95% confidence interval: 0.63 to 1.17; p = 0.33). Dual antiplatelet therapy with ticagrelor did not reduce plasma troponin concentrations in patients with high-risk coronary plaque, suggesting that subclinical plaque thrombosis does not contribute to ongoing myocardial injury in this setting. (Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND]; NCT02110303)
Disappearance of Icelandic Walruses Coincided with Norse Settlement
Authors: Xénia Keighley, Snæbjörn Pálsson, Bjarni F Einarsson, Aevar Petersen, Meritxell Fernández-Coll, Peter Jordan, Morten Tange Olsen, Hilmar J Malmquist
Journal: Molecular Biology and Evolution (2019)

There is a growing body of evidence demonstrating the impacts of human arrival in new "pristine" environments, including terrestrial habitat alterations and species extinctions. However, the effects of marine resource utilization prior to industrialized whaling, sealing, and fishing have largely remained understudied. The expansion of the Norse across the North Atlantic offers a rare opportunity to study the effects of human arrival and early exploitation of marine resources. Today, there is no local population of walruses on Iceland, however, skeletal remains, place names, and written sources suggest that walruses existed, and were hunted by the Norse during the Settlement and Commonwealth periods (870-1262 AD). This study investigates the timing, geographic distribution, and genetic identity of walruses in Iceland by combining historical information, place names, radiocarbon dating, and genomic analyses. The results support a genetically distinct, local population of walruses that went extinct shortly after Norse settlement. The high value of walrus products such as ivory on international markets likely led to intense hunting pressure, which-potentially exacerbated by a warming climate and volcanism-resulted in the extinction of walrus on Iceland. We show that commercial hunting, economic incentives, and trade networks as early as the Viking Age were of sufficient scale and intensity to result in significant, irreversible ecological impacts on the marine environment. This is to one of the earliest examples of local extinction of a marine species following human arrival, during the very beginning of commercial marine exploitation.
Genetic characteristics of lung metastasis and liver metastasis from left-sided colorectal cancer with microsatellite stability.
Authors: Zhenghang Wang, Xue Zheng, Jian Li, Xicheng Wang, Jing Gao, Zhongwu Li, Jianing Yu, Wanning Yang, Beibei Mao, Henghui Zhang, Lin Shen
Journal: Journal of Clinical Oncology (2019)

e15097 Background: Metastases from colorectal cancer (CRC) are common and develop in 40 to 60% of the patients. The liver and lung are the most frequently metastatic sites. Although lung metastasis (LuM) is characterized with slower growth rate and longer survival duration compared to liver metastasis (LiM). Little is known about the genetic differences between LuM and LiM CRC patients. Methods: The LuM cohort was composed of 18 patients with isolated lung metastasis and LiM cohorts was composed of 18 patients with liver metastasis. All the 36 patients were left-sided CRC and all lesions were microsatellite stability (MSS). The two cohorts were matched case by case according to age, gender, primary location, T stage and N stage. The Control cohort involved 10 patients who had locally advanced tumors, received R0 resection and suffered no relapse in at least five years. Based on a 1408 cancer-related gene panel (covering 967010 bases), the next-generation sequencing (NGS) of primary tumors and metastases was performed on the primary and metastatic lesions of these patients. Results: For primary tumors, results showed that the frequency of BRD4 amplification in the LuM cohort (n = 16 ) was 50%, which was much higher than that in the LiM (n = 16) and Control cohorts (n = 10) ( p &lt; 0.05). U2AF1 amplification in the LuM (30%) was more common than that in LiM (0%) patients ( p= 0.043). For metastatic lesions, amplification of MET and SDHC and Hippo pathway activation were more frequently observed in LuM cohort (n = 15) than that in LiM (n = 18). Median TMB of the primary tumors and metastases in the LuM cohort were 9.518 and 6.022 mutations/Mb, respectively, which were both much higher than that in the LiM and Control cohorts ( p&lt; 0.05). Conclusions: Amplification of BRD4 and U2AF1 was the characteristic feature of primary tumors which metastasized to the lungs, indicating this genetic alteration might be used in identifying patients at risk of developing LuM. MET amplification and Hippo pathway activation were promising therapeutic targets of left-sided CRC-LuM with MSS. Patients with LuM might respond well to immunotherapies due to relatively high level of TMB. Expanded prospective cohorts are warranted to further elucidate these findings.
Vacationing More Often May Reduce Metabolic Syndrome Risk
Authors: Rebecca Voelker
Journal: JAMA (2019)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Re: Giuseppe Simone, Umberto Anceschi, Gabriele Tuderti, et al. Robot-assisted Partial Adrenalectomy for the Treatment of Conn’s Syndrome: Surgical Technique, and Perioperative and Functional Outcomes. Eur Urol 2019;75:811–6
Authors: Franco Gaboardi, Guglielmo Mantica, Nazareno Suardi
Journal: European Urology (2019)
Survival of epidermal keratinocyte on different extracellular matrix components-the involvement of MEK, PI3K/AKTand NFκB pathways.
Authors: Qing Ren, Csaba Kari, Marlene Quadros, Adam Dicker, Ulrich Rodeck
Journal: Cancer Research (2005)

181  Homeostasis in multicellular organisms depends on the efficient disposal of superfluous, dangerous or damaged cells by programmed cell death or apoptosis. Apoptosis thresholds are set by survival signals emanating from attachment to other cells or the extracellular matrix (ECM) or from activation of growth factor/cytokine receptors. It is poorly known how these signals are integrated to steer cell fate decisions. Here we demonstrate that specific matrix components protected human immortalized keratinocytes (HaCaT) against apoptosis induced by blockade of either the epidermal growth factor receptor (EGFR) or MEK or PI3-kinase. In contrast, nuclear factor NFκB activation was indispensable to HaCaT cell survival regardless of matrix availability. Conversely, tumor necrosis factor (TNF)-α supported anchorage-independent survival of HaCaT cells in an NFκB-dependent fashion. These results highlight previously unrecognized patterns of signal integration between survival pathways relevant to wound healing and malignant transformation of the skin. This work is supported by NIH grant (R01 CA106633, R01 CA81001)
The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition
Authors: Kalindi Parmar, Bose S. Kochupurakkal, Jean-Bernard Lazaro, Zhigang C. Wang, Sangeetha Palakurthi, Paul T. Kirschmeier, Chunyu Yang, Larissa A. Sambel, Anniina Färkkilä, Elizaveta Reznichenko, Hunter D. Reavis, Connor E. Dunn, Lee Zou, Khanh T. Do, Panagiotis A. Konstantinopoulos, Ursula A. Matulonis, Joyce F. Liu, Alan D. D'Andrea, Geoffrey I. Shapiro
Journal: Clinical Cancer Research (2019)

Abstract Purpose: PARP inhibitors are approved for the treatment of high-grade serous ovarian cancers (HGSOC). Therapeutic resistance, resulting from restoration of homologous recombination (HR) repair or replication fork stabilization, is a pressing clinical problem. We assessed the activity of prexasertib, a checkpoint kinase 1 (CHK1) inhibitor known to cause replication catastrophe, as monotherapy and in combination with the PARP inhibitor olaparib in preclinical models of HGSOC, including those with acquired PARP inhibitor resistance. Experimental Design: Prexasertib was tested as a single agent or in combination with olaparib in 14 clinically annotated and molecularly characterized luciferized HGSOC patient-derived xenograft (PDX) models and in a panel of ovarian cancer cell lines. The ability of prexasertib to impair HR repair and replication fork stability was also assessed. Results: Prexasertib monotherapy demonstrated antitumor activity across the 14 PDX models. Thirteen models were resistant to olaparib monotherapy, including 4 carrying BRCA1 mutation. The combination of olaparib with prexasertib was synergistic and produced significant tumor growth inhibition in an olaparib-resistant model and further augmented the degree and durability of response in the olaparib-sensitive model. HGSOC cell lines, including those with acquired PARP inhibitor resistance, were also sensitive to prexasertib, associated with induction of DNA damage and replication stress. Prexasertib also sensitized these cell lines to PARP inhibition and compromised both HR repair and replication fork stability. Conclusions: Prexasertib exhibits monotherapy activity in PARP inhibitor–resistant HGSOC PDX and cell line models, reverses restored HR and replication fork stability, and synergizes with PARP inhibition.
Preclinical toxicology studies with Y15, a novel focal adhesion kinase (FAK) inhibitor.
Authors: William G. Cance, Leslie Curtin, Sandra Buitrago, Vita Golubovskaya
Journal: Journal of Clinical Oncology (2013)

e13561 Background: Focal Adhesion Kinase (FAK) is overexpressed in many types of tumors and plays a major role in survival signaling. Recently, we developed a FAK scaffolding inhibitor, Y15 that targeted the main FAK autophosphorylation site (Y397) and had high efficacy in blocking tumor growth in many xenograft mice models. We performed a small animal toxicology study of Y15 and detected the maximal tolerated dose of this drug in mice. Methods: The toxicology study was performed in CD-1 albino [Hsd:ICR(CD-1)] mice with Y15 inhibitor delivered either by intraperitoneal injection (IP) or by oral delivery. Clinical chemistry data were collected by Hemagen Analyst II automatic Chemistry analyzer. In addition, hematology, body weight, mortality, and histopathology on different organs were analyzed in all mice. Results: We delivered Y15 by IP injection at 15 (low), 30 (medium) and 45 mg/kg (high) doses daily for 5 days/week during a 28 day study, or orally by gavage at 100 and 200 mg/kg daily during a 7 day study. The maximal tolerated dose by IP during 28 day study was 30 mg/kg. The maximal tolerated dose during single oral dose administration was 200 mg/kg and 100 mg/kg during 7 day study. Y15 did not cause any mortality or statistically significant differences in the body weight at 30mg/kg IP delivery during a 28-day study and at 100 mg/kg by oral delivery during a 7 day study. There were no significant clinical chemistry changes in alkaline phosphatase, gamma glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, amylase, blood urea nitrogen, glucose, phosphorus, calcium, albumin, cholesterol, creatine kinase, total bilirubin, total protein and globulin. Finally, no significant histopathological changes were observed by necropsy in different organs at 30 mg/kg by IP and at 100 mg/kg dose by oral delivery. Conclusions: The Y15 FAK autophosphorylation inhibitor is well tolerated in mice and caused no significant toxicity by IP and oral delivery, suggesting it is a promising candidate for further large animal toxicology study prior to human trials.
Inclusion of key populations in clinical trials of new antituberculosis treatments: Current barriers and recommendations for pregnant and lactating women, children, and HIV-infected persons
Authors: Amita Gupta, Michael D. Hughes, Anthony J. Garcia-Prats, Katherine McIntire, Anneke C. Hesseling
Journal: PLoS Medicine (2019)

points• Pregnant women, children < 15 years old and, HIV-infected persons contribute approximately 20% of the global tuberculosis (TB) burden, with an estimated 216,000, 1,000,000, and 1,040,000 cases each year, respectively, yet these populations are currently largely excluded from TB clinical trials, leading to suboptimal treatment and poor access to new therapeutics.• Special considerations in these populations include specific TB disease spectrum and severity, lower sensitivity of commonly used TB diagnostic tests, potential differential drug dosing and treatment responses, drug-drug interactions, and challenges in acquiring high-quality data through clinical trials.• To counter the automatic exclusion of pregnant and lactating women that currently pervades the TB trial landscape, early discussions among trialists, pharmaceutical companies, maternal-child clinical experts, ethicists, and regulatory bodies are needed to address risks, benefits, and compelling rationale for inclusion.Reconsenting women when pregnancy occurs on a trial to allow continuation of study drug by informed choice is a practical and valuable approach to expand the currently limited evidence base.• Children tend to have less severe, often paucibacillary TB disease and may respond better to treatment than adults.Consequently, trials of shorter, less intense TB treatment regimens in children are needed; pharmacokinetic and safety studies should be initiated earlier and involve age groups in parallel rather than in an age-de-escalation approach.More rapid development of child-friendly drug formulations is needed.• All HIV-infected populations, including those with advanced disease, who are likely to be the intended population of the TB therapy, should be involved in Phase IIb and/or
The complex relationship between body mass index and response to immune checkpoint inhibition in metastatic melanoma patients
Authors: Douglas Donnelly, Shirin Bajaj, Jaehong Yu, Miles Hsu, Arjun Balar, Anna Pavlick, Jeffrey Weber, Iman Osman, Judy Zhong
Journal: Journal for ImmunoTherapy of Cancer (2019)

Despite major improvements in combatting metastatic melanoma since the advent of immunotherapy, the overall survival for patients with advanced disease remains low. Recently, there is a growing number of reports supporting an "obesity paradox," in which patients who are overweight or mildly obese may exhibit a survival benefit in patients who received immune checkpoint inhibitors. We studied the relationship between body mass index and progression-free survival and overall survival in a cohort of 423 metastatic melanoma patients receiving immunotherapy, enrolled and prospectively followed up in the NYU Interdisciplinary Melanoma Cooperative Group database. We analyzed this association stratified by first vs. second or greater-line of treatment and treatment type adjusting for age, gender, stage, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, number of metastatic sites, and body mass index classification changes. In our cohort, the patients who were overweight or obese did not have different progression-free survival than patients with normal body mass index. Stratifying this cohort by first vs. non-first line immunotherapy revealed a moderate but insignificant association between being overweight or obese and better progression-free survival in patients who received first line. Conversely, an association with worse progression-free survival was observed in patients who received non-first line immune checkpoint inhibitors. Specifically, overweight and obese patients receiving combination immunotherapy had a statistically significant survival benefit, whereas patients receiving the other treatment types showed heterogeneous trends. We caution the scientific community to consider several important points prior to drawing conclusions that could potentially influence patient care, including preclinical data associating obesity with aggressive tumor biology, the lack of congruence amongst several investigations, and the limited reproduced comprehensiveness of these studies.
High Risk of Infections in Chronic Lymphocytic Leukemia Patients Treated with B-Cell Receptor Inhibitors
Authors: Annalynn M Williams, Andrea M Baran, Philip J Meacham, Megan Herr, Hugo E. Valencia, Catherine Newsom, Nealansh Gupta, Michelle Janelsins, Paul M. Barr, Clive S Zent
Journal: Blood (2016)