tbuckley/cabot-search huggingface dataset:
Precision medicine for gallbladder cancer using somatic copy number amplifications (SCNA) and DNA repair pathway gene alterations.
Authors: Milind M. Javle, Daniel Catenacci, Apurva Jain, Lauren Young, Kai Wang, Jon Chung, Aram F. Hezel, Alexa Betzig Schrock, Lipika Goyal, Laurie M. Gay, Daniel H. Ahn, Robin Kate Kelley, Shridar Ganesan, Phil Stephens, Vincent A. Miller, Siraj Mahamed Ali, Tanios S. Bekaii-Saab, Rachna T. Shroff, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2017)

4076 Background: Gallbladder carcinoma (GBC) is commonly diagnosed at an advanced, unresectable disease stage and has a poor prognosis. Comprehensive genomic profiling (CGP) has a developing role in guiding systemic, precision anti-cancer therapy. Methods: We performed hybrid capture-based CGP on FFPE samples for 491 consecutive advanced GBCs. Mean coverage depth was &gt;550X for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer. All 4 classes of genomic alterations (GA) were detected. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA. Results: Median age was 64 (range 25-88) and 69% (337/491) of patients were female. 96% (470), 2.9% (14), and 1.4% (7) of GBC patients had the diagnosis of adenocarcinoma, adenosquamous, or carcinoma not specified (NOS), respectively. Commonly altered genes were TP53 (62%), CDNK2A (31%), ARID1A (18%), and SMAD4 (15%), and most of the genetic aberrations (GA) were short variants. Potentially targetable SCNAs (including ERBB genes, MET, FGFRs, and the CCND1-FGF3/4/19 11q13 amplicon) were identified in 21% of cases (Table). Oncogenic BRAF, ALK, or FGFR2/3 rearrangements were found in 7 cases (1.4%). Moreover, 7.8% of cases had BRCA2 or ATM GA, and 0.8% had INI1loss suggesting benefit from PARP or EZH2 inhibitors, respectively. TMB was low; the 25th, 50th, and 75th percentiles were 2.5, 3.8 and 6.3 mutations/Mb, respectively. Less than 1% of cases had microsatellite instability. Radiological response to TKIs and immunotherapy was noted. Conclusions: In addition to the significant opportunity for anti-HER targeted therapies, other subsets of GBC cases harbored kinase GA (particularly SCNA), the 11q13 amplicon, or BRCA2/ ATM/ INI1mutations that are linked to therapeutic benefit. How the frequency of both driver SCNA and DNA repair alterations in GBC can be linked with inflammation awaits additional investigation. [Table: see text]
Appropriateness of Antiepileptic Drug Level Monitoring
Authors: Romolo M. Dorizzi
Journal: JAMA (1996)

<h3>To the Editor.</h3> —Although the article by Dr Schoenenberger and colleagues<sup>1</sup>discusses the frequent inappropriateness of antiepileptic drug level monitoring, we suggest that habit and routine, more than diagnostic reasoning, often drive the physician's test requests of therapeutic drug monitoring. The fee-for-service policy of the National Health System in Italy greatly encourages drug monitoring for drugs such as quinidine for which the value of monitoring has not been established.<sup>2,3</sup>Since the dosage of quinidine commonly used in Italy is low (400 to 600 mg per day), an eerie situation developed in all the clinical laboratories in which therepeutic monitoring of quinidine is carried out: its concentration rarely reaches the therapeutic interval (ie, 6 to 15 μmol/L [2 to 5 μg/mL]).<sup>3</sup> To measure this phenomenon, we collected the results of all quinidine assays obtained for inpatients and outpatients during different spans of time since 1990 in four hospital
Severe hidradenitis suppurativa responding to treatment with secukinumab: a case report
Authors: L. Thorlacius, P. Theut Riis, G.B.E. Jemec
Journal: British Journal of Dermatology (2017)

An inappropriate immunological response to an unknown antigen has been suggested to play a role in the pathogenesis of hidradenitis suppurativa (HS). Studies have identified elevated levels of several proinflammatory cytokines, including interleukin (IL)‐17A and tumour necrosis factor‐α, nominating these as possible therapeutic targets.1 Secukinumab is an IL‐17A monoclonal antibody, which binds to IL‐17A and inhibits the cytokine interaction with the IL‐17 receptors, inhibiting the inflammatory cascade. Here we report a case of a 47‐year‐old man, with Hurley stage III lesions on the neck, axillae, breasts, genital skin and buttocks, who had experienced only temporary benefit from different medical treatments over several years. After 12 weeks of treatment with secukinumab, the number of lesions reported by the patient within the period of the last 4 weeks was reduced from 23 to seven, his pain visual analogue scale (VAS) score was reduced from 5 to 3 and pain/utility/handicap VAS score was reduced from 7 to 4. These results may be taken to imply that IL‐17 blockade could provide a possible therapeutic approach in the treatment of HS.
Vascular Homocysteine Versus 5-Methyl-Tetrahydrofolate As Regulators of Vascular Redox and Endothelial Function in Human Vessels
Authors: C A Antoniades, C Shirodaria, O Baarholm, P Leeson, T Van-Assche, C Cunnington, D Tousoulis, C Stefanadis, H Refsum, K M Channon
Journal: Journal of the American College of Cardiology (2008)
Single Centre Experience in Treating Newly Diagnosed t(4;14) Multiple Myeloma with and without Planned Front-Line Autologous Stem Cell Transplant
Authors: Henry Siu Him Chan, Madeline Phillips, Sophia Farooki, Giovanni Piza Rodriguez, Esther Masih-Khan, Christine Chen, Vishal Kukreti, Anca Prica, Rodger Tiedemann, Suzanne Trudel, Donna Reece
Journal: Blood (2016)
A Phase II Basket Study of the Oral TRK Inhibitor LOXO-101 in Adult Subjects with NTRK Fusion-Positive Tumors.
Authors: Alexander E. Drilon, David S. Hong, Scott Cruickshank, Maegan Deegan, Nora Ku, David Michael Hyman
Journal: Journal of Clinical Oncology (2016)

TPS2599 Background: The TRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively) and their neurotrophin ligands regulate growth, differentiation and survival of neurons. Fusion of the kinase domain of the NTRK genes with various partners are oncogenic, and have been identified across many common tumor types, but generally at a frequency of < 5%. In rare tumor types, such as mammary analogue secrectory carcinoma (MASC) and secretory breast carcinoma, NTRK fusion genes have been identified in greater than 75% of cases. LOXO-101 is a potent, oral, ATP-competitive pan-TRK inhibitor with IC50 values in the low nanomolar range for inhibition of TRK family members in binding and cellular assays, with > 1000x selectivity over other kinases. LOXO-101 is the only selective pan-TRK inhibitor in clinical development and has demonstrated tumor inhibition in preclinical models and meaningful responses in an adult phase 1 trial. Methods: The phase II study of LOXO-101 (NCT02576431) is an open-label, multi-center trial for adult patients with advanced solid tumors and primary CNS malignancies harboring NTRK fusions. Patients ≥ 18 years old with NTRK1, 2, or 3 fusion-positive cancers who have progressed following standard therapy are eligible and assigned to one of 8 cohorts in a basket trial design. Eight anatomically defined subgroups have been prespecified for patients with: non-small cell lung, thyroid, sarcoma, colorectal, salivary and biliary cancers, CNS malignancies, and all others. Patients are required to have RECIST or RANO measurable disease for eligibility for cohorts 1-7. Patients without measurable disease may enroll in the “all other anatomic sites” cohort, number 8. Patients will undergo radiographic evaluation for their disease at regular intervals. LOXO-101 is administered orally BID in capsule form at 100mg for continuous 28-day cycles. Archival tissue and fresh tissue are required for post hoc central review of NTRK fusion status as well as the characterization of other molecular pathologic features. Clinical trial information: NCT02576431.
Enhanced ETS-like Gene (ELK)-1 Expression Is a Predictor of Inferior Survival in Multiple Myeloma
Authors: Muhamed Baljevic, Baladandayuthapani Veerabhadran, Lin Heather, Leung Cheuk, Zhong Liye, Davis Richard, Wang Huihan, Mmrf Compass Network, Orlowski Robert
Journal: Blood (2016)
Information needs among prostate cancer patients: A comparison of information needs and information given.
Authors: Graham Thomas Watson, Liping Du, Ivy A. Ahmed, John Clayton Allen, Alicia Katherine Morgans
Journal: Journal of Clinical Oncology (2016)

e18009 Background: Evidence suggests that improved patient-provider communication is associated with better health outcomes. Information needs among men with prostate cancer and their caregivers at the time of diagnosis are incompletely described. We assessed the information needs of prostate cancer patients and caregivers and compared these to provider reports of the information delivered at the time of diagnosis. Methods: We used data from an online survey of information needs performed in 2015 by prostate cancer non-profit ZERO – The End of Prostate Cancer to evaluate prostate cancer patients, caregivers and providers. We performed descriptive statistics for each information need and compared the difference between the groups using a Chi-Squared test. Results: In total, 145 patients, 59 caregivers, and 39 providers completed the survey. The three most commonly reported information needs of patients and caregivers were general disease information (71.1%), treatment options (75.0%), and side effects of treatment (78.4%). There were significant differences between patient/caregiver needs and provider reports of information delivered in emotional support (39% vs 18%, p = 0.02), connecting with others (34% vs 13%, p = 0.01), life after treatment (59% vs 18%, p < 0.001), diet and exercise (45% vs 18%, p = 0.003), and caregiver resources (40% vs 10%, p = 0.007). Conclusions: Discordance between information needs reported by patients/caregivers and provider reports of information delivered suggests that unmet needs exist in supporting patients/caregivers at the time of prostate cancer diagnosis. Investigating methods to provide appropriate information in these domains may lead to improved patient/caregiver satisfaction and health outcomes.
FoxM1c counteracts oxidative stress-induced senescence in mouse embryonic fibroblasts by up-regulation of Bmi-1 expression
Authors: Li Kai Man Samuel, Leung Wai Ying, Smith David, Cheung M.S Alice, Lam W.F Eric, Dimri P. Goberdhan, Yao Kwok Ming
Journal: Clinical Cancer Research (2007)

B1  The Forkhead box transcription factor FoxM1 is expressed in proliferating cells. Depletion of FoxM1 in mice and various mouse and human cell lines led to cell cycle defects and chromosomal instability. Mouse embryonic fibroblasts derived from knockout mice displayed premature senescence but the underlying cause remained unclear. To investigate the regulatory role of FoxM1 in stress-induced premature senescence, we established NIH3T3 lines with doxycycline-inducible over-expression of FoxM1c. Treatment of these lines with sub-lethal doses (20 µM and 100 µM) of H2O2 induced senescence with β-galactosidase expression and elevated levels of p53 and p21. Interestingly, induction of FoxM1c expression dramatically suppressed senescence and expression of p53 and p21. Consistent with a down-regulation of the p19Arf-p53 pathway, p19Arf levels decreased while expression of the Polycomb group protein Bmi-1 was induced. Bmi-1 as a downstream target of FoxM1c was supported by the dose-dependent induction of Bmi-1 by FoxM1c which occurred at both the protein and RNA levels. Knockdown of FoxM1 expression by RNA interference decreased Bmi-1 expression and both FoxM1c and Bmi-1 reached maximal levels in cells at G2/M phase. Using Bmi-1 promoter-reporters with wildtype and mutated c-Myc sites and shRNAs targeting against c-Myc, we further demonstrated that FoxM1 activated Bmi-1 expression via c-Myc which was recently reported to be a FoxM1 target gene. Our results revealed a functional link between FoxM1c, c-Myc and Bmi-1 which are major regulators of tumorigenesis and have important implication in the regulation of cell proliferation and senescence.
Sub-100 nm, long tumor retention SN-38-loaded photonic micelles for tri-modal cancer therapy
Authors: Xixiao Yang, Xiangdong Xue, Yan Luo, Tzu-yin Lin, Hongyong Zhang, Diana Lac, Kai Xiao, Yixuan He, Bei Jia, Kit S. Lam, Yuanpei Li
Journal: Journal of Controlled Release (2017)
Immunoglobulin should be given if steroid dosage was &gt;/=0.15 mg/kg/day in preceding three months
Authors: I. Burnett
Journal: BMJ (1995)

EDITOR,—The report on near fatal chickenpox in a steroid user raises the importance of defining clearly, in mg/kg/day, the dosage of systemic steroid at which the scarce and costly varicella-zoster immunoglobulin should be given to non-immune steroid users in contact with people with chickenpox.1 The authors of the report suggest prophylaxis for users of “supraphysiological” dosages …
Re-Creating Hereditary Persistence of Fetal Hemoglobin (HPFH) to Treat Sickle Cell Disease (SCD) and β-Thalassemia
Authors: Michelle I Lin, Elizabeth J Paik, Bibhu P Mishra, Song Chou, Ying Zhang, Kaleigh Tomkinson, Michael A Pettiglio, Andrew Sanginario, Amanda Woo, Min Jin Lee, Melanie Allen, Thomas J Cradick, Tirtha Chakraborty, Matthew Porteus, Ciaran M Lee, Gang Bao, Annarita Miccio, Annalisa Lattanzi, Fulvio Mavilio, Chad A Cowan, Rodger Novak, Ante S Lundberg
Journal: Blood (2016)
Microscale arrays for the profiling of start and stop signals coordinating human-neutrophil swarming
Authors: Eduardo Reátegui, Fatemeh Jalali, Aimal H. Khankhel, Elisabeth Wong, Hansang Cho, Jarone Lee, Charles N. Serhan, Jesmond Dalli, Hunter Elliott, Daniel Irimia
Journal: Nature Biomedical Engineering (2017)
Analysis of prognostic factors of clinical outcome in children and adolescents enrolled in phase I trials: a multicentre European collaborative study.
Authors: Fernando Carceller Lechon, Francisco Bautista, Irene Jimenez, Raquel Hladun-Alvaro, Cecile Giraud, Luca Bergamaschi, Madhumita Dandapani, Isabelle Aerts, Francois Doz, Didier Frappaz, Michela Casanova, Bruce Morland, Darren R Hargrave, Lynley V Marshall, Gilles Vassal, Andrew DJ Pearson, Birgit Geoerger, Lucas Moreno
Journal: Journal of Clinical Oncology (2015)

10049 Background: Phase I trials play a key role in the evaluation of novel agents for pediatric patients with advanced cancer. One of the major challenges remains the selection of patients who are most likely to benefit from investigational treatments and have a life expectancy ≥ 8-12 weeks. Two clinical scores have been validated in adult oncology to optimise patient selection: the Royal Marsden (RM) score (albumin, lactate dehydrogenase (LDH), number of metastatic sites); and the MD Anderson Cancer Centre (MDACC) score (RM score plus performance status (PS) and gastrointestinal tumor type). These scores have not been validated for children/adolescents enrolled in phase I trials. Methods: Retrospective study of patients aged < 18 years, with solid tumors, enrolled in phase I trials at Innovative Therapies for Children with Cancer (ITCC) centres between 2000-2014. Descriptive and uni/multivariate analyses of overall survival (OS) were carried out. Results: 172 patients were studied; median age 9 years. Tumor types included: primary central nervous system 42%, bone sarcomas 23%, neuroblastoma 10%, others 25%. Best response: complete/partial in 21 patients (12%); stable disease in 42 (24%). Overall, 30 and 90-day mortality on study were, respectively, 8% and 29%. Median OS (months) as per RM score was: 15.2 ± 2.4 for scores 0-1 Vs 5.7 ± 1.7 for scores ≥ 2 (p = 0.015); and, as per MDACC score, 15.9 ± 2.6 for scores 0-1 Vs 7.7 ± 2.3 for scores ≥ 2 (p = 0.022). In univariate analysis, tumor type, PS, school/work attendance at inclusion, use of opioids, creatinine above upper limit of normal ( > ULN), total bilirubin > ULN, LDH > ULN, albumin < 35 g/dl, prior radiotherapy, and prior autologous stem cell rescue (ASCR) significantly correlated with OS. In multivariate analysis, poor PS, LDH > ULN and no prior ASCR correlated with lower OS. Conclusions: The RM and MDACC scores select patients with an inferior OS in pediatric phase I studies, but cannot be deemed fully fit for purpose in children. Clinical characteristics which independently predict impaired survival will identify children who are unlikely to benefit from participation in phase I trials and improve the efficiency of these studies.
Undernutrition and Reduced Muscle Funcion Is Common in Young Patients with Crohns Disease (Cd)
Authors: T Nic Suibhne, CA O'Morain, M O'Sullivan
Journal: Endoscopy (2006)

Methods: Nutritional and clinical assessments were conducted on 181 subjects (101 CD and 80 healthy matched controls). Undernutrition was defined as protein or fat stores under the 15 th centile and functional muscle strength was assessed using grip strength (GS). Serum Tumour Necrosis Factor alpha (TNFa) was measured by ELISA.
Phase II trial of neoadjuvant bevacizumab with modified FOLFOX7 (BEVmFOLFOX) in Patients (pts) with stage II and III rectal adenocarcinoma (RCA)
Authors: Afsaneh Barzi, Dongyun Yang, Ramona Lujan, Dana Agafitei, Anthony El-Khoueiry, Syma Iqbal, Diana Hanna, Adrian Ortega, Andreas Kaiser, Kyle Cologne, Sang Lee, Heinz-Josef Lenz
Journal: Annals of Oncology (2017)
Frailty Index Developed From a Cancer-Specific Geriatric Assessment and the Association With Mortality Among Older Adults With Cancer
Authors: Emily J. Guerard, Allison M. Deal, YunKyung Chang, Grant R. Williams, Kirsten A. Nyrop, Mackenzi Pergolotti, Hyman B. Muss, Hanna K. Sanoff, Jennifer L. Lund
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: An objective measure is needed to identify frail older adults with cancer who are at increased risk for poor health outcomes. The primary objective of this study was to develop a frailty index from a cancer-specific geriatric assessment (GA) and evaluate its ability to predict all-cause mortality among older adults with cancer. Patients and Methods: Using a unique and novel data set that brings together GA data with cancer-specific and long-term mortality data, we developed the Carolina Frailty Index (CFI) from a cancer-specific GA based on the principles of deficit accumulation. CFI scores (range, 0–1) were categorized as robust (0–0.2), pre-frail (0.2–0.35), and frail (>0.35). The primary outcome for evaluating predictive validity was all-cause mortality. The Kaplan-Meier method and log-rank tests were used to compare survival between frailty groups, and Cox proportional hazards regression models were used to evaluate associations. Results: In our sample of 546 older adults with cancer, the median age was 72 years, 72% were women, 85% were white, and 47% had a breast cancer diagnosis. Overall, 58% of patients were robust, 24% were pre-frail, and 18% were frail. The estimated 5-year survival rate was 72% in robust patients, 58% in pre-frail patients, and 34% in frail patients (log-rank test, P<.0001). Frail patients had more than a 2-fold increased risk of all-cause mortality compared with robust patients (adjusted hazard ratio, 2.36; 95% CI, 1.51–3.68). Conclusions: The CFI was predictive of all-cause mortality in older adults with cancer, a finding that was independent of age, sex, cancer type and stage, and number of medical comorbidities. The CFI has the potential to become a tool that oncologists can use to objectively identify frailty in older adults with cancer.
Computerized textural analysis of lung CT to enable quantification of tumor infiltrating lymphocytes in NSCLC.
Authors: Mahdi Orooji, Sagar Rakshit, Niha Beig, Anant Madabhushi, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2016)

11584 Background: Tumor infiltrating lymphocytes (TILs) are a part of the dynamic immune microenvironment. Clinical trials with immune checkpoint inhibitors report significant increase in TILs in responders in follow up tumor biopsies. Monitoring TILs on treatment using radiomic features extracted from routine follow up computed tomographic (CT) images can be a non-invasive surrogate to biopsy to detect early response. We conducted a proof of concept study to find out if radiomic features extracted from CT images can identify patients with high and low TILs in non-small cell lung cancer (NSCLC). Methods: A cohort of 50 consecutive patients who underwent lobectomy for early stage NSCLC were identified and TIL were characterized using routine hematoxylin and eosin (H&Es) slides. TILs were quantified on a previously reported scale of 0 to 3 based on intensity of TIL. Of the 50 cases 17 outliers who had high TILs (3+) or low TILs (0) were identified. The study team was provided with CT images from 4 patients with ‘0’ TILs, 8 tumors with ‘3+’ TILs and 5 tumors were blinded. Corresponding pre-surgical CT scans were annotated on slicer-3D software. A total of 669 radiomic (textural and shape) features of the lung nodule were investigated. These features were evaluated and ranked in their ability to discriminate TIL extent using a linear discriminant classifier, both in terms of univariate and multivariate analysis. Results: Sphericity, a shape based feature was the most discriminating feature. Standard deviation and Laws were ranked as the most promising texture based features. Of the 5 blinded tumors, 4 were classified correctly leaving only one misclassified case. Conclusions: Computerized textural analysis using shape and texture features extracted from the lung nodule on CT images could be used to identify tumors with high TILs. Further validation of these findings in larger independent cohorts is required. These novel imaging based biomarkers could be a useful diagnostic tool for predicting response and monitoring patients on immunotherapy.