tbuckley/cabot-search huggingface dataset:
Randomized phase III study of observation versus adjuvant capecitabine and oxaliplatin in curatively resected small bowel adenocarcinoma: A Japan Clinical Oncology Group study (JCOG1502C).
Authors: Yoshitaka Honma, Makoto Ueno, Yukihide Kanemitsu, Shinichi Ohkawa, Hideaki Kitahara, Junki Mizusawa, Hiroshi Katayama, Kenichi Nakamura, Junji Furuse, Yasuhiro Shimada
Journal: Journal of Clinical Oncology (2018)

TPS539 Background: Small bowel adenocarcinoma (SBA) is extremely rare tumor. Surgery is broadly applied as a standard treatment for localized SBA. However, the patients with localized SBA have poor prognosis even after curative resection (5-year survival: 40-65%), and most of them experience relapse. To prevent relapse, postoperative therapies are considered as most promising. However, there is no prospective study of postoperative therapies for curatively resected SBA patients and which regimens improve prognoses is unknown. For metastatic SBA, fluoropyrimidine and oxaliplatin is now regarded as global standard chemotherapy. Therefore, Japan Clinical Oncology Group (JCOG) planned a multicenter randomized phase III trial to confirm the superiority of postoperative capecitabine and oxaliplatin (CAPOX) to observation for curatively resected SBA under the Advanced Medical Care System of the Ministry of Health, Labour and Welfare, Japan. This study is a counterpart trial of BALLAD trial conducted in International Rare Cancer Initiative (IRCI) (clinical trials gov; NCT02502370), and the integrated analysis of BALLAD trial and JCOG1502C is planned. Methods: Eligibility criteria include histologically proven adenocarcinoma located in the duodenum (except Ampulla of Vater) / jejunum / ileum, curatively resected with regional lymph nodes dissection, pathological stage I (T1b-2N0M0) / stage II / stage III. Eligible patients are randomized into observation arm or CAPOX arm. CAPOX (130 mg/m 2 of oxaliplatin on day 1, and 1000 mg/m 2 of capecitabine twice a day for 14 days) is repeated every 3 weeks for 6 months (total 8 courses). The primary endpoint is RFS. The 3-year RFS of observation arm is assumed to be 70% and expected a 10% increase in CAPOX arm. The sample size was calculated as 150 (75 per arm) with a one-sided alpha level of 10%, a statistical power of 70%, an accrual period of 6.5 years. This study has been registered in the UMIN Clinical Trials Registry (UMIN000027280). This trial was activated in 9 May 2017, and no patients was enrolled as of Sep 2017. We will increase the number of participating sites up to 20 throughout Japan. Clinical trial information: UMIN000027280.
Early colorectal cancer detection on routine CT to improve patient's 5-year survival.
Authors: Ricky Rodriguez, Bryce Daniel Perkins, Peter Yong Soo Park, Phillip Koo, Madappa N. Kundranda, John Chang
Journal: Journal of Clinical Oncology (2018)

593 Background: Prognosis of colorectal cancer (CRC) is greatly influenced by stage at diagnosis. Early colorectal cancer can be subtle on CT scans showing only mild wall thickening, small polyps, or subtle lymph nodes. Identifying these lesions on CT performed for nonspecific symptoms can help identify interval CRC and improve patient outcome. The purpose of the present study is to classify missed CRC on abdominal CT by their imaging features and whether early identification can downstage CRC patients. Methods: A retrospective analysis was conducted of patients (pts) diagnosed with CRC. Data collection included age, gender, ECOG, KRAS mutation status, overall survival (OS). CT obtained prior to and at diagnosis were evaluated. Images were reviewed for multiple CT features including appearance of mass, mesenteric infiltration, abnormal draining lymph nodes, contrast enhancement relative to adjacent mucosa, and intralesional calcifications. Staging was evaluated using available CT scan and based on the TNM staging system for CRC. Results: The 41 pts with 51 prediagnostic CTs from 1/1/2012 - 12/31/2015 had mean age of 68 years (range:44-90 ) Mean ECOG status for the population was 1.46. 41% of the prediagnostic CTs had missed findings. 52 and 43 % of the missed findings were in the rectosigmoid and ascending colon respectively. Of the 15 missed masses, 9 appeared as asymmetric wall thickening, 3 as concentric wall thickening, and 3 as polyps. Of the 14 missed lymph node groups, 2 were excluded due to stability or nonrelated condition. The remaining lymph nodes were found in the associated draining station and averaged 3±1.2 mm in size. On average, the stage at prediagnostic CT was 3A and the diagnostic CT was 3C (p = 0.0015). Average time lapse between prediagnostic and diagnostic CT was 21 months (3-64 months). Conclusions: High percentage of CRC findings are missed on abdominal CT due to their subtle feature, with most misses in the rectosigmoid and ascending colon. A dedicated search can improve detection by specifically looking for polyps, wall thickening, and small lymph nodes in the draining station. Early detection of CRC can improve survival by lowering the stage from 3C to 3A, thus providing 36% improvement in 5-year survival.
Human cancer growth in the nude mice model is associated with impaired metabolism of the methionine cycle
Authors: Farida Al-Awadi, Meng Yang, Yuying Tan, Qinghong Han, Shukuan Li, Robert Hoffman
Journal: Cancer Research (2008)

2739   The methionine cycle and its metabolites homocysteine and cysteine serve several important functions in cellular metabolism. Abnormalities in metabolism of the cycle are associated with different diseases such as cardiovascular, diabetes mellitus, liver diseases and cancer. We evaluated plasma levels of methionine, homocysteine and cysteine in immunocompromised NCR nude mice implanted with various human cancer cell lines (MDA-MB 435-GFP breast, PC3-GFP prostate, HT29-GFP colon, BX-PC3-RFP pancreas) with tumor growth for a prolonged period. Normal controls were included. Nude mice were injected s.c. in the right flank with 1 × 10 6  green fluorescent protein (GFP) or red fluorescent protein (RFP)-expressing tumor cells. Periodically, the tumor-bearing mice were examined by whole body fluorescence imaging. The experiment was terminated after 5 months from the day of implant and plasma was used to measure methionine by HPLC; cysteine (Clinical Chemistry  48 , 1560-1564, 2002), and homocysteine (Clinical Chemistry  46 , 1686-1688, 2000) by two recombinant enzyme assays. We  observed that the concentrations of cysteine and homocysteine in plasma decreased significantly as a result of growth of three tumor types implanted in the nude mice, breast, prostate and the pancreas. The cysteine concentrations (µmol/L) were 153.5±35.27, 68.8±0.57, 82.5±17.48 with p-values of 0.031, 0.002 and 0.0001, respectively, as compared to normal control nude mice (235±14.21). Similarly, there was a decrease in the plasma levels of homocystiene with the concentration (µmol/L) of 4.45±0.15, 2.2±0.14, 2.33±0.05 with p-values of 0.041, 0.004, and 0.004, respectively, in comparison with the normal control value 7.53±0.62. Data for the effect of growth of the colon tumors were non-significant for both cysteine and homocysteine. In case of methionine (µM/L), the decrease was significant only for pancreas tumors 27.3±1.71 (p= 0.028) as compared to the normal concentration (39.20±1.91) and was non-significant for other tumor types. We expect that the significant reduction in the plasma levels of cysteine and homocystiene as a result of the growth of human breast, prostate and pancreas tumors, and the reduced plasma methionine levels as a result of the growth in the pancreas tumors, may be useful for developing blood tests for these tumor types.
Association of Hypertensive Disorders of Pregnancy With Risk of Neurodevelopmental Disorders in Offspring
Authors: Gillian M. Maher, Gerard W. O’Keeffe, Patricia M. Kearney, Louise C. Kenny, Timothy G. Dinan, Molly Mattsson, Ali S. Khashan
Journal: JAMA Psychiatry (2018)

<h3>Importance</h3> Although research suggests an association between hypertensive disorders of pregnancy (HDP) and autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and other neurodevelopmental disorders in offspring, consensus is lacking. Given the increasing prevalence of hypertension in pregnancy, it is important to examine the association of HDP with neurodevelopmental outcome. <h3>Objective</h3> To synthesize the published literature on the association between HDP and risk of neurodevelopmental disorders in offspring in a systematic review and meta-analysis. <h3>Data Sources</h3> On the basis of a preprepared protocol, a systematic search of PubMed, CINAHL, Embase, PsycINFO, and Web of Science was performed from inception through June 7, 2017, supplemented by hand searching of reference lists. <h3>Study Selection</h3> Two investigators independently reviewed titles, abstracts, and full-text articles. English-language cohort and case-control studies were included in which HDP and neurodevelopmental disorders were reported. <h3>Data Extraction and Synthesis</h3> Data extraction and quality appraisal were performed independently by 2 reviewers. Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed throughout. <h3>Main Outcomes and Measures</h3> Random-effects meta-analyses of estimated pooled odds ratios (ORs) for HDP and ASD and for HDP and ADHD. Stand-alone estimates were reported for all other neurodevelopmental disorders. <h3>Results</h3> Of 1166 studies identified, 61 unique articles met inclusion criteria. Twenty studies reported estimates for ASD. Eleven of these (including 777 518 participants) reported adjusted estimates, with a pooled adjusted OR of 1.35 (95% CI, 1.11-1.64). Ten studies reported estimates for ADHD. Six of these (including 1 395 605 participants) reported adjusted estimates, with a pooled adjusted OR of 1.29 (95% CI, 1.22-1.36). Subgroup analyses according to type of exposure (ie, preeclampsia or other HDP) showed no statistically significant differences for ASD or ADHD. Thirty-one studies met inclusion criteria for all other neurodevelopmental disorders. Individual estimates reported for these were largely inconsistent, with few patterns of association observed. <h3>Conclusions and Relevance</h3> Exposure to HDP may be associated with an increase in the risk of ASD and ADHD. These findings highlight the need for greater pediatric surveillance of infants exposed to HDP to allow early intervention that may improve neurodevelopmental outcome.
Mobile and pervasive computing technologies and the future of Alzheimer’s clinical trials
Authors: P. Murali Doraiswamy, Vaibhav A. Narayan, Husseini K. Manji
Journal: npj Digital Medicine (2018)

The rapid growth of mobile phones, automated speech recognizing personal assistants, and internet access among the elderly provides new opportunities for incorporating such technologies into clinical research and personalized medical care. Alzheimer's disease is a good test case given the need for early detection, the high rate of clinical trial failures, the need to more efficiently recruit patients for trials, and the need for sensitive and ecologically valid trial outcomes.
Future cost-effectiveness and equity of the NHS Health Check cardiovascular disease prevention programme: Microsimulation modelling using data from Liverpool, UK
Authors: Chris Kypridemos, Brendan Collins, Philip McHale, Helen Bromley, Paula Parvulescu, Simon Capewell, Martin O’Flaherty
Journal: PLoS Medicine (2018)

Background Aiming to contribute to prevention of cardiovascular disease (CVD), the National Health Service (NHS) Health Check programme has been implemented across England since 2009. The programme involves cardiovascular risk stratification—at 5-year intervals—of all adults between the ages of 40 and 74 years, excluding any with preexisting vascular conditions (including CVD, diabetes mellitus, and hypertension, among others), and offers treatment to those at high risk. However, the cost-effectiveness and equity of population CVD screening is contested. This study aimed to determine whether the NHS Health Check programme is cost-effective and equitable in a city with high levels of deprivation and CVD. Methods and findings IMPACTNCD is a dynamic stochastic microsimulation policy model, calibrated to Liverpool demographics, risk factor exposure, and CVD epidemiology. Using local and national data, as well as drawing on health and social care disease costs and health-state utilities, we modelled 5 scenarios from 2017 to 2040: Scenario (A): continuing current implementation of NHS Health Check; Scenario (B): implementation 'targeted' toward areas in the most deprived quintile with increased coverage and uptake; Scenario (C): 'optimal' implementation assuming optimal coverage, uptake, treatment, and lifestyle change; Scenario (D): scenario A combined with structural population-wide interventions targeting unhealthy diet and smoking; Scenario (E): scenario B combined with the structural interventions as above. We compared all scenarios with a counterfactual of no-NHS Health Check. Compared with no-NHS Health Check, the model estimated cumulative incremental cost-effectiveness ratio (ICER) (discounted £/quality-adjusted life year [QALY]) to be 11,000 (95% uncertainty interval [UI] −270,000 to 320,000) for scenario A, 1,500 (−91,000 to 100,000) for scenario B, −2,400 (−6,500 to 5,700) for scenario C, −5,100 (−7,400 to −3,200) for scenario D, and −5,000 (−7,400 to −3,100) for scenario E. Overall, scenario A is unlikely to become cost-effective or equitable, and scenario B is likely to become cost-effective by 2040 and equitable by 2039. Scenario C is likely to become cost-effective by 2030 and cost-saving by 2040. Scenarios D and E are likely to be cost-saving by 2021 and 2023, respectively, and equitable by 2025. The main limitation of the analysis is that we explicitly modelled CVD and diabetes mellitus only. Conclusions According to our analysis of the situation in Liverpool, current NHS Health Check implementation appears neither equitable nor cost-effective. Optimal implementation is likely to be cost-saving but not equitable, while targeted implementation is likely to be both. Adding structural policies targeting cardiovascular risk factors could substantially improve equity and generate cost savings.
Magnetic Resonance Imaging–Based Prostate Cancer Screening
Authors: Timothy J. Wilt, Philipp Dahm
Journal: JAMA Network Open (2018)

Lars Boesen, MD, PhD; Nis Nørgaard, MD; Vibeke Løgager, MD; Ingegerd Balslev, MD; Rasmus Bisbjerg, MD; Karen-Cecilie Thestrup, MD; Mads D. Winther; Henrik Jakobsen, MD; Henrik S. Thomsen, DMC
Safety of trifluridine/tipiracil (FTD/TPI) in elderly patients with metastatic colorectal cancer.
Authors: Robert J. Mayer, Howard S. Hochster, Steven J. Cohen, Robert Winkler, Lukas Makris, Axel Grothey
Journal: Journal of Clinical Oncology (2018)

752 Background: Elderly patients (≥65 yrs) with metastatic colorectal cancer (mCRC) are more likely to have comorbid conditions than younger patients ( &lt; 65 yrs), limiting their therapeutic options. As previously reported (Mayer et al. J Clin Oncol 2017;35:abs 3559), FTD/TPI confirmed its clinical profile in mCRC in a real-world setting. Here, we report the safety and tolerability profile of FTD/TPI from the expanded-access program (EAP) in patients aged ≥65 yrs. Methods: Patients (≥18 yrs) with mCRC following ≥2 regimens of anticancer therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled to this open-label EAP. Patients received FTD/TPI 35 mg/m 2 twice daily for 5 days followed by 2 days’ rest for 2 weeks, with a 14-day rest period (28-day treatment cycle). Data were collected for therapy duration, treatment discontinuation, and adverse events (AEs). Results: Of 549 patients, 377 (68.7%) were aged &lt; 65 and 172 (31.3%) were ≥65. The treatment duration of FTD/TPI was similar between &lt; 65 and ≥65 yrs (Table). A lower proportion of those aged ≥65 had fatigue and nausea compared with &lt; 65 (Table). However, the frequency of neutropenia and diarrhea was slightly increased in those ≥65 compared with &lt; 65 (Table). One patient (0.6%) in the ≥65 group developed febrile neutropenia compared with 9 (2.4%) in the &lt; 65 group, with no associated deaths in either group. Conclusions: This analysis from the EAP showed that the safety profile and treatment duration of FTD/TPI in patients aged ≥65 with mCRC were similar to those in patients aged &lt; 65. FTD/TPI is well tolerated and can be considered in patients aged ≥65 with mCRC. Clinical trial information: NCT-02286492. [Table: see text]
Diabetes and Trajectories of Estimated Glomerular Filtration Rate: A Prospective Cohort Analysis of the Atherosclerosis Risk in Communities Study
Authors: Bethany Warren, Casey M. Rebholz, Yingying Sang, Alexandra K. Lee, Josef Coresh, Elizabeth Selvin, Morgan E. Grams
Journal: Diabetes Care (2018)

OBJECTIVE To characterize long-term kidney disease trajectories in persons with and without diabetes in a general population. RESEARCH DESIGN AND METHODS We classified 15,517 participants in the community-based Atherosclerosis Risk in Communities (ARIC) study by diabetes status at baseline (1987–1989; no diabetes, undiagnosed diabetes, and diagnosed diabetes). We used linear mixed models with random intercepts and slopes to quantify estimated glomerular filtration rate (eGFR) trajectories at four visits over 26 years. RESULTS Adjusted mean eGFR decline over the full study period among participants without diabetes was −1.4 mL/min/1.73 m2/year (95% CI −1.5 to −1.4), with undiagnosed diabetes was −1.8 mL/min/1.73 m2/year (95% CI −2.0 to −1.7) (difference vs. no diabetes, P &amp;lt; 0.001), and with diagnosed diabetes was −2.5 mL/min/1.73 m2/year (95% CI −2.6 to −2.4) (difference vs. no diabetes, P &amp;lt; 0.001). Among participants with diagnosed diabetes, risk factors for steeper eGFR decline included African American race, APOL1 high-risk genotype, systolic blood pressure ≥140 mmHg, insulin use, and higher HbA1c. CONCLUSIONS Diabetes is an important risk factor for kidney function decline. Those with diagnosed diabetes declined almost twice as rapidly as those without diabetes. Among people with diagnosed diabetes, steeper declines were seen in those with modifiable risk factors, including hypertension and glycemic control, suggesting areas for continued targeting in kidney disease prevention.
Role of circulating miRNAs in detecting metastasis and having prognostic significance in metastatic breast cancer.
Authors: Sofia Agelaki, Chara Papadaki, Ioannis Stoupis, Lefteris Tsalikis, Maria A. Papadaki, Alexia Monastirioti, Georgios Markakis, Dimitrios Mavroudis
Journal: Journal of Clinical Oncology (2018)

1086 Background: Metastasis is the leading cause of breast cancer associated death. In the current study we evaluated the expression of (a) micro-RNA (miR)-23b and miR-190 which are involved in tumor dormancy (b) miR-21 which is involved in metastasis and (c) miR-200b and miR-200c which are involved in EMT and metastasis, in the plasma of patients with early and metastatic breast cancer (BC) in order to investigate whether they could distinguish the two disease states. Furthermore the prognostic significance of the above miRNAs was investigated in patients with metastatic disease. Methods: Plasma samples were obtained from patients with early (n = 84) or metastatic (n = 57) BC before adjuvant or 1st-line treatment, respectively. Plasma miR-21, miR-23b, miR-190, miR-200b and miR-200c expression levels were assessed by RT-qPCR and expression was classified as high or low according to the median values. Results: miR-21 (p < 0.001), mir-23b (p = 0.012), miR-200b (p < 0.001) and miR-200c (p = 0.001) were higher and miR-190 (p = 0.013) was lower in metastatic compared to early BC patients. ROC analysis showed that miR-21 (AUC = 0.772; p < 0.001), miR-23b (AUC = 0.625; p = 0.012), miR-190 (AUC = 0.629; p = 0.013), miR-200b (AUC = 0.744; p < 0.001) and miR-200c (AUC = 0.668; p = 0.001) could distinguish between patients with metastatic and early BC. However, logistic regression and combined ROC analysis revealed that a panel of four miRs (miR-21, miR-190, miR-200b and miR-200c) discriminated with higher accuracy (AUC = 0.857; p < 0.001) between the two disease states. In patients with metastatic disease, miR-21 high was correlated with premenopausal (p = 0.013) and HER2 status (p = 0.017). The combined expression of miR-23b high and miR-190 high was correlated with progressive disease at the end of treatment (p = 0.034). Patients with miR-23b high had shorter PFS and OS (p = 0.024 and p = 0.031, respectively). Conclusions: Circulating micro-RNAs discriminate between patients with metastatic and early breast cancer. In addition, their expression holds predictive information in patients undergoing first-line chemotherapy.
Enough Power to Build a Strong Case for Clinical Pharmacy Services?—Reply
Authors: Jesper Hallas, Lene Vestergaard Ravn-Nielsen, Anton Pottegård
Journal: JAMA Internal Medicine (2018)

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