tbuckley/cabot-search huggingface dataset:
Effect of <i>DPYD </i>gene polymorphisms on pharmacokinetics of capecitabine in Chinese cancer patients.
Authors: Ying Luo, Xiujuan Qu, Yibo Fan, Ce Li, Yunpeng Liu
Journal: Journal of Clinical Oncology (2015)

e13561 Background: Capecitabine (Xeloda, Roche) is an oral prodrug of 5-Fluorouracil (5-FU) that is widely used in the treatment for patients with cancers of the gastrointestinal tract, breast, head and neck. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of fluoropyrimidines. It has been shown that DPD deficiency prolonged the half-life of 5-FU, and genetic polymorphisms in DPYD were responsible for DPD deficiency. In Asian populations, several genetic variations, including DPYD*5 and DPYD*9A, were frequently observed, but their predictive values for toxicity of fluoropyrimidines remain uncertain. Furthermore, rare report is done about the relationships between DPYD polymorphisms and pharmacokinetics (PK) of capecitabine. Therefore, we analyzed the relationship between PK of capecitabine and some common DPYD gene polymorphisms. Methods: Forty Chinese cancer patients with various solid tumors from a bioequivalence study were included in the present analysis. All the patients were given a single dose of 2000mg capecitabine. Pharmacokinetic analysis was done using LC-MS/MS. DPYD gene polymorphisms were analyzed by sequencing. Statistic analysis was done by independent-sample t test. Results: Of these 40 patients, four DPYD polymorphisms were tested. The results showed that the frequencies of variant genotype of 85T > C (DPYD*9A), 1627A > G (DPYD*5), 1905+1G > A (DPYD*2A) and 2846A > T were 25%, 32.5%, 0% and 0%, respectively. The mean AUC from 0 to 8 h (AUC0-8 ) of 5-Fu in the 40 patients was 297.73±76.33 ng·h/mL,the AUC from 0 to infinity (AUC0-∞) was 300.75±78.54 ng·h/mL. Compared to patients with wildtype genotype, the AUC0–8 and AUC0–∞ of 5-Fu in patients with DPYD*5 variant increased by 20.8% and 22.2%, respectively(P = 0.022 and P = 0.017). Although no statistical significance was found, there was a trend towards lower AUC of 5-FU in patients with DPYD*9A variant. Our results also showed there were no significant differences in the AUC0–8 and AUC0–∞ of capecitabine and its upstream metabolites between the different DPYD genotypes. Conclusions: DPYD*5 polymorphism might be contributed to severe toxicity of capecitabine through decreasing the clearance of capecitabine.
Mutational Landscape of Chronic Lymphocytic Leukemia Using Next Generation Sequencing Technologies in the Real World Clinical Setting
Authors: Jose D Sandoval-Sus, Facundo E. Stingo, Todd C. Knepper, Lisa Nodzon, Eric Padron, Mohamed A Kharfan-Dabaja, Julio C. Chavez, Javier Pinilla-Ibarz
Journal: Blood (2016)
Clinical predictors of response for coBRIM: A phase III study of cobimetinib (C) in combination with vemurafenib (V) in advanced BRAF-mutated melanoma (MM).
Authors: James M. G. Larkin, Grant A. McArthur, Antoni Ribas, Paolo Antonio Ascierto, Jorge D Gallo, Isabelle Anne Rooney, Ilsung Chang, Brigitte Dréno
Journal: Journal of Clinical Oncology (2016)

9528 Background: The coBRIM study showed significant improvement in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) in patients (pts) with BRAFV600 mutation–positive mm treated with V+C, compared with V alone. Herein we report an exploratory analysis of baseline characteristics (BLCs) that may help predict complete response (CR) and the impact of CR and dose modification (DM) on OS and PFS. Methods: Study methods were previously described (Larkin J et al. N Engl J Med 2014;371:1867-1876.). Kaplan-Meier curves for OS and PFS by tumor response (RECIST v1.1) were performed. Tumor responses were tabulated by BLC. Results: A total of 247 pts were randomly assigned to receive C+V and 248 pts to receive P+V. PFS and OS favored the C+V arm, with hazard ratio (HR) of 0.58 (P< 0.0001) and 0.70 (P= 0.005), respectively. ORR (data cutoff Jan 16, 2015) was 70% (16% CR) in the C+V arm vs 50% (10% CR) in the P+V arm. Pts treated with C+V generally have a higher ORR and CR across BLCs than pts on P+V (Table). Pts with normal and high LDH levels treated with C+V had higher CR rates than those treated with P+V. Median PFS for pts on C+V who attained CR was 19.8 mo and for pts with partial response (PR) (70%) was 13.3 mo. In contrast, pts on C+V who had either stable disease (SD) or progressive disease (PD) (30%) as best response achieved median PFS of 3.9 mo and 1.9 mo, respectively. Similar trends were observed for OS. DM (dose reduction or temporary interruption of 1 or both drugs) did not seem to affect efficacy outcomes. Pts in the C+V arm with DM of both drugs achieved median PFS comparable with the median PFS of pts without DM. Conclusions: C+V resulted in high ORR and CR rates. In the C+V arm, high response rates were apparent across the assessed BLCs, but higher rates of CR are achieved in pts with certain BLCs. Better response (PR, CR) was associated with improved PFS and OS in the C+V arm. DM of 1 or both drugs did not seem to affect efficacy of the combination. Clinical trial information: NCT01689519.BLC P+V C+V CR, % PR, % CR, % PR, % Age < 65 11 43 13 61 Age ≥65 11 33 28 43 Sex F 13 42 23 58 Sex M 9 39 13 56 Stg IIIC-M1b 22 45 26 50 Stg M1c 4 38 11 61 ECOG PS 0 15 39 18 57 ECOG PS 1 3 44 14 55 LDH normal 16 48 23 56 LDH high 4 32 9 57 V600E 11 43 14 58 V600K 7 34 23 55
Abstract 16247: Personalized MRI-Based Modeling Predicts Ventricular Tachycardia Vulnerability in Patients Receiving Primary Prevention ICDs
Authors: Ravi Ranjan, Elyar Ghafoori, Joshua Blauer, Deng Dongdong, Hermenegild Arevalo, Adityo Prakosa, Fred Han, Scott Wall, Roger Freedman, Tom Mcgarry, Rob McLeod, Natalia Trayanova
Journal: Circulation (2016)

Introduction: Patients with ischemic cardiomyopathy and low ejection fraction (<35%) are at risk of sudden cardiac death (SCD) from ventricular tachycardia (VT). Under current guidelines, such pati...
Longitudinal Cell-Free DNA Analysis in Patients with Small Cell Lung Cancer Reveals Dynamic Insights into Treatment Efficacy and Disease Relapse
Authors: Karinna Almodovar, Wade T. Iams, Catherine B. Meador, Zhiguo Zhao, Sally York, Leora Horn, Yingjun Yan, Jennifer Hernandez, Heidi Chen, Yu Shyr, Lee P. Lim, Christopher K. Raymond, Christine M. Lovly
Journal: Journal of Thoracic Oncology (2017)
Real world experience of palbociclib in hormone receptor-positive metastatic breast cancer.
Authors: Faizan Malik, Naveed Ali, Syed Imran Mustafa Jafri, Mark L. Sundermeyer, Michael Jeffrey Seidman, Christian Joseph Fidler
Journal: Journal of Clinical Oncology (2017)

e18094 Background: Palbociclib has been approved as a first line therapy in hormone-receptor positive (HR+) and HER-2 negative metastatic breast cancer(MBC) manifesting significant improvement in progression free survival (PFS). We studied this drug in a community setting. The endpoints were estimated PFS, objective response, toxicities and patient outcomes. Methods: This was a single-center, retrospective study of HR+MBC patients receiving palbociclib after its FDA approval. 22 patients were selected Results: A total of 22 patients were included (Male = 2, Female = 20). Median age was 60-years (range, 49-84). About 90% patients had received at least one previous therapy and the median number was 1.5. 13% patients were on fulvestrant, 86% on letrozole and 4.5% on exemestane. About 64% of patients had ECOG status of ≥ 1. Median duration of palbociclib treatment was 5-months, therefore, an estimated PFS at 18-months was 50%. 4.5% patients attained complete response. 22% patients achieved partial response, 22% had stable disease and 50% patients demonstrated disease progression. 72% patients had neutropenia, of which 45% were grade ≥ 3. Thrombocytopenia and anemia were common (63% and 58%, respectively) but grade ≥ 3 thrombocytopenia or anemia was not observed. 50% patients required dose reductions and 18% required drug cessation owing to side effects. Conclusions: PFS was much lower as compared to actual trials in our real-world experience. Despite, several interesting observations were good objective response rates in males and HER-2+ patients underscoring its potential clinical efficacy in these subsets. Furthermore, apart from myelosuppressive side effects, pneumonitis was observed in one patient necessitating vigilance in clinical practice
The antibody–drug conjugate target landscape across a broad range of tumour types
Authors: K.L. Moek, D.J.A. de Groot, E.G.E. de Vries, R.S.N. Fehrmann
Journal: Annals of Oncology (2017)

Antibody-drug conjugates (ADCs), consisting of an antibody designed against a specific target at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Because ADC tumour cell targets do not have to be drivers of tumour growth, ADCs are potentially relevant for a wide range of tumours currently lacking clear oncogenic drivers. Therefore, we aimed to define the landscape of ADC targets in a broad range of tumours.PubMed and ClinicalTrials.gov were searched for ADCs that are or were evaluated in clinical trials. Gene expression profiles of 18 055 patient-derived tumour samples representing 60 tumour (sub)types and 3520 healthy tissue samples were collected from the public domain. Next, we applied Functional Genomic mRNA-profiling to predict per tumour type the overexpression rate at the protein level of ADC targets with healthy tissue samples as a reference.We identified 87 ADCs directed against 59 unique targets. A predicted overexpression rate of ≥ 10% of samples for multiple ADC targets was observed for high-incidence tumour types like breast cancer (n = 31 with n = 23 in triple negative breast cancer), colorectal cancer (n = 18), lung adenocarcinoma (n = 18), squamous cell lung cancer (n = 16) and prostate cancer (n = 5). In rare tumour types we observed, amongst others, a predicted overexpression rate of 55% of samples for CD22 and 55% for ENPP3 in adrenocortical carcinomas, 81% for CD74 and 81% for FGFR3 in osteosarcomas, and 95% for c-MET in uveal melanomas.This study provides a data-driven prioritization of clinically available ADCs directed against 59 unique targets across 60 tumour (sub)types. This comprehensive ADC target landscape can guide clinicians and drug developers which ADC is of potential interest for further evaluation in which tumour (sub)type.
Abstract 11237: Safety and Efficacy of Radiofrequency versus Second-Generation Cryoballoon Ablation for Treatment of Atrial Fibrillation - A Meta-analysis of Current Evidence
Authors: Bhavi Pandya, Valay Parikh, David Kenigsberg, Padraig Gearoid O’Neill, Charles H Koo, Arash Aryana, Marcin Kowalski
Journal: Circulation (2016)

Background: To compare the strategies of point-by-point radiofrequency ablation (RFA) to second-generation cryoballoon ablation (CBA) in terms of safety and efficacy, we pooled data for systematic review and meta-analyses from all available literature comparing their clinical performance. Methodology: The Cochrane Library, PubMed, Google Scholar and studies presented at various meetings were searched for any published literature comparing safety and efficacy of the CBA with RFA. A total of 7published studies, with 2,969 patients were included in this meta-analysis with 1322 patients in RFA group and 1647 patients in CBA group. Results: The pooled analysis showed non-significant differences in procedure time (SMD=4.04, [CI: -16.16, 24.23], p=0.7, I 2 =97%), fluoroscopic time (SMD=-2.49, [CI: -5.82, 0.84], p=0.14, I 2 =93%) and access site complication (OR=1.44, [CI: 0.82, 2.54], p=0.2, I 2 =0%) between the two techniques of ablation. While RFA was found to have lower odds of phrenic nerve palsy (OR=0.04, [CI: 0.01, 0.15], p&lt;0.00001, I 2 =0%) and higher odds of cardiac tamponade (OR=2.67, [CI: 1.17, 6.08], p=0.02, I 2 =0%) compared to CBA. Comparing efficacy amongst two groups, there was no statistically significant difference in terms of arrhythmia recurrences (OR=1.35, [CI: 0.94, 1.93], p=0.1, I 2 =69%). Conclusion: Point-by-point radiofrequency ablation was found to have less incidences of phrenic nerve palsy and higher incidences of cardiac tamponade compared to second-generation cryoballoon ablation. However efficacy profiles were similar in both groups.
Abstract 14333: Irregular Protrusion and Uncover Stent Struts Correlate With Acute Coronary Syndrome - An OCT Study
Authors: Tomoya Ueda, Akihiko Okamura, Daisuke Kamon, Yu Sugawara, Takuya Isojima, Tsunenari Soeda, Makoto Watanabe, Hiroyuki Kawata, Rika Kawakami, Hiroyuki Okura, Yoshihiko Saito
Journal: Circulation (2016)

Introduction:  In these drug eluting era, the adverse event after stent implantation still remains clinically important problem. Patients with acute coronary syndrome (ACS) suffered from a higher incidence of adverse event than stable angina pectoris (SAP). Optical coherence tomography (OCT) enable us to detect various OCT findings after stent implantation. Irregular protrusion detected after stent implantation, malapposition for uncovered strut at follow up are one of the cause of adverse event at follow up. Using OCT, we evaluated the difference of OCT findings after stenting and for at follow up according to ACS and for SAP culprit lesions.   Methods:  We examined 118 culprit coronary lesions treated with drug eluting stents which has OCT examination at baseline and 9-month follow up (ACS 26 lesions and SAP 92 lesions). OCT evaluation at baseline includes presence of edge dissection, irregular protrusion and malapposition just after stent implantation. At 9-month follow up, the frequency of uncovered strut was evaluated at every 1 mm interval.   Results:  The incidence of irregular protrusion was significantly higher in ACS culprit lesion than in SAP at baseline (88.5% vs. 55.4%, P=0.002). The incidence of edge dissection and malapposition were similar between the two groups. A total of 29,103 stent struts was analyzed and the percentage of uncovered strut was 8.5% in overall subjects. ACS culprit lesion showed a higher incidence of uncovered strut than SAP (11.3±9.3% vs. 6.9±7.8%, P=0.009). Logistic regression analysis showed that ACS culprit lesion was a predictor of irregular protrusion at baseline (OR: 6.16, 95%CI: 1.97-27.26, P=0.001). Moreover, in liner regression, ACS culprit lesion was associated with the rate of uncover stent struts (P=0.018).   Conclusions:  ACS culprit lesions correlates to presence of irregular protrusion at baseline for uncovered struts at 9-month follow up. These findings may be one of the reasons for a higher incidence of adverse event in ACS.
A Great Gift
Authors: Jerry A. Molitor
Journal: Annals of Internal Medicine (2017)

On Being a Doctor19 September 2017A Great GiftJerry A. Molitor, MD, PhDJerry A. Molitor, MD, PhDFrom University of Minnesota, Minneapolis, Minnesota.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M16-2739 Audio Reading - “A Great Gift” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "A Great Gift," by J.A. Molitor. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail I was halfway through my second year of internal medicine residency. It was winter, and the nights were long and dark. The days somehow felt even longer, darker. Neither was a match for my mood, the darkest of all.I was barely 18 months into my postgraduate training, but I increasingly felt as though nothing I did really mattered. Patients came, left, and returned, often sicker than ever. Medical advances seemed to make very little real difference in the lives of my patients.One of these dark evenings promised early on to be a hard one. These were the early ... Author, Article, and Disclosure InformationAffiliations: From University of Minnesota, Minneapolis, Minnesota.Corresponding Author: Jerry A. Molitor, MD, PhD, University of Minnesota, 420 Delaware Street SE, MMC108, Minneapolis, MN 55455; e-mail, [email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “A Great Gift” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "A Great Gift," by J.A. Molitor. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 19 September 2017Volume 167, Issue 6Page: 444KeywordsAscitesChildrenCirrhosisFeversGratitudeHospitalsMouthResidencySpontaneous bacterial peritonitisVision ePublished: 19 September 2017 Issue Published: 19 September 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Understanding and Communicating Measures of Treatment Effect on Survival: Can We Do Better?
Authors: Everardo D Saad, John R Zalcberg, Julien Péron, Elisabeth Coart, Tomasz Burzykowski, Marc Buyse
Journal: JNCI Journal of the National Cancer Institute (2017)

Time-to-event end points are the most frequent primary end points in phase III oncology trials, both in the adjuvant and advanced settings. The evaluation of these end points is important to inform clinical practice. However, although different measures can be used to describe the effect of treatment on these end points, we believe that any treatment benefit in a given trial is best reported using various absolute and relative measures. Our goal is to help clinicians understand the strengths and limitations of the traditional and novel measures used to denote the effect of treatment in randomized trials. Although none of these measures can reliably predict the outcome of individual patients, some measures could be added to the commonly used hazard ratio to provide a more patient-oriented assessment of treatment benefit. In particular, the difference of mean survival times quantifies the average survival benefit for a patient receiving a new treatment compared with a patient treated with standard of care, whereas the net benefit quantifies the probability of a patient receiving the new treatment to live longer by at least m months (for any number of months m of interest) than a patient receiving the standard treatment. We encourage statisticians and clinical scientists to include various measures of treatment benefit in the reports of phase III trials, acknowledging that different clinical situations may call for different measures of treatment effect. By using the various available measures, we may better inform ourselves and communicate results to our patients.
The global burden of scabies: a cross-sectional analysis from the Global Burden of Disease Study 2015
Authors: Chante Karimkhani, Danny V Colombara, Aaron M Drucker, Scott A Norton, Roderick Hay, Daniel Engelman, Andrew Steer, Margot Whitfeld, Mohsen Naghavi, Robert P Dellavalle
Journal: The Lancet Infectious Diseases (2017)

BackgroundNumerous population-based studies have documented high prevalence of scabies in overcrowded settings, particularly among children and in tropical regions. We provide an estimate of the global burden of scabies using data from the Global Burden of Disease (GBD) Study 2015.MethodsWe identified scabies epidemiological data sources from an extensive literature search and hospital insurance data and analysed data sources with a Bayesian meta-regression modelling tool, DisMod-MR 2·1, to yield prevalence estimates. We combined prevalence estimates with a disability weight, measuring disfigurement, itch, and pain caused by scabies, to produce years lived with disability (YLDs). With an assumed zero mortality from scabies, YLDs were equivalent to disability-adjusted life-years (DALYs). We estimated DALYs for 195 countries divided into 21 world regions, in both sexes and 20 age groups, between 1990 and 2015.FindingsScabies was responsible for 0·21% of DALYs from all conditions studied by GBD 2015 worldwide. The world regions of east Asia (age-standardised DALYs 136·32), southeast Asia (134·57), Oceania (120·34), tropical Latin America (99·94), and south Asia (69·41) had the greatest burden of DALYs from scabies. Mean percent change of DALY rate from 1990 to 2015 was less than 8% in all world regions, except North America, which had a 23·9% increase. The five individual countries with greatest scabies burden were Indonesia (age-standardised DALYs 153·86), China (138·25), Timor-Leste (136·67), Vanuatu (131·59), and Fiji (130·91). The largest standard deviations of age-standardised DALYs between the 20 age groups were observed in southeast Asia (60·1), Oceania (58·3), and east Asia (56·5), with the greatest DALY burdens in children, adolescents, and the elderly.InterpretationThe burden of scabies is greater in tropical regions, especially in children, adolescents, and elderly people. As a worldwide epidemiological assessment, GBD 2015 provides broad and frequently updated measures of scabies burden in terms of skin effects. These global data might help guide research protocols and prioritisation efforts and focus scabies treatment and control measures.FundingBill & Melinda Gates Foundation.
A new class of compound for pancreatic carcinoma targeting the tyrosine kinase receptor (TKR) ROR1.
Authors: Hakan Mellstedt, Amir Hossein Daneshmanesh, Ali Moshfegh, Mohammad Hojat Farsangi, Salam Khan, Eva Mikaelsson, Jan Vagberg, Styrbjorn Bystrom, Johan Schultz, Thomas Olin, Anders Österborg
Journal: Journal of Clinical Oncology (2014)

e13561 Background: There is a medical need to develop novel compounds for treatment of pancreatic carcinoma. Members of the TKR families are attractive therapeutic candidates. One of the families is ROR receptors. ROR1 is of importance during embryogenesis but down-regulated in most adult human tissues. ROR1 has been shown to be overexpressed in hematological malignancies and solid tumors as pancreatic carcinoma. ROR1 siRNA transfection of CLL cells and pancreatic carcinoma cells induced apoptosis. Antibodies against the CRD region of ROR1 evoked specific apoptosis of CLL cells and dephosphorylation of ROR1 (PLOS One 8(10) e78339, 2013). In the present report we have explored the activity of a new class of compound, ROR1 tyrosine kinase inhibitors (ROR1-TKI), inhibiting phosphorylation of the TK domain of ROR1. Methods: ROR1 kinase inhibitorswere derived from a high-through-put screening (HTS) using HTRF assay based on recombinant intracellular kinase domain of ROR1. One chemical lead series was optimized for activity on target, physico-chemical properties and in vitro ADME properties as hERG and CYP inhibition, bioavailability and metabolic stability in plasma and hepatocytes. In the present study IN0439365 was used. Results: PaCa2 and PANC1 pancreatic carcinoma cells expressed ROR1 as determined by flow-cytometry and Western blot (WB). In both cell lines ROR1 was constitutively phosphorylated (pROR1 antibody) (WB). After 72 h of incubation with 2-3 µM IN0439365, 70% of PaCa2 cells were dead and 40% of PANC1. ROR1 TKI induced a strong dephosphorylation of ROR1 (<2h) as well as of src, PI3K, AKT, mTOR and of CREB. (As a control gemcitabine induced cell death but not dephosphorylation of ROR1.) Conclusions: The TKR ROR1 is overexpressed in pancreatic carcinoma and of importance for survival. Targeting ROR1 by a TKI induced a strong killing of the tumor cells. The drug dephosphorylated ROR1 as well as PI3K/AKT/mTOR. This pathway might be a survival signal in pancreatic cancer cells associated with an aberrant expression of ROR1. This is a first report of a novel class of drugs targeting ROR1 (ROR1-TKI). The drug candidates will be further evaluated in preclinical in vivo models before proceeding to clinical evaluation.