tbuckley/cabot-search huggingface dataset:
Detection of rare somatic mutational profiles in metastatic colorectal cancer (mCRC) during routine <i>RAS</i> sequencing using next generation sequencing (NGS).
Authors: Jean-Louis Merlin, Marie Husson, Marie Rouyer, Agnès Leroux, Alexandre Harle
Journal: Journal of Clinical Oncology (2015)

11055 Background: In most patients with mCRC who are being considered for anti-EGFR antibody therapy, RAS mutation testing i.e. KRAS and NRAS exon 2, 3 and 4, is routinely assessed using PCR-based assays only detecting major hotspot mutations of exon (ex) 2 (codon 12 and 13), 3 (codon 59 and 61) and 4 (codon 117 and 146). We performed deep sequencing of the entire exons using NGS as an alternative to detect additional rare mutations profiles with significant frequency of mutated allele (FMA). Methods: 188 formalin-fixed paraffin-embedded tumor samples from primary or metastatic lesions of patients (M/F sex ratio 1.27, mean age 69 years, range 32-90) with mCRC (150 colon, 38 rectum) were analyzed. DNA was extracted from macrodissected slides (mean tumor cell content 43.3%, range 5-80). Results: RAS mutation testing was routinely assessed using NGS in 177 mCRC samples. NGS could not be performed in 11 cases (6.2%) due to the insufficient quantity or quality of DNA. NGS sensitivity was 1% at X1000 depth. RAS mutations were found in 103 samples (62%) and relatively distributed as 69.9% KRAS ex2, 3.9% KRAS ex3, 14.6% KRAS ex4, 4.8% NRAS ex2, 1.0% NRAS ex3, 1.0% NRAS ex4 and 4.8% multiple mutations. Uncommon mutational profiles were detected in 10 cases (9.7%): 2 KRAS ex2 c.37G > T p.G13C single mutation with FMA > 30%, 5 silent mutations (4 with FMA > 25%), alone (n = 2) or combined with other rare mutations (n = 3) with lower but significant FMA ( > 1%), and 6 multiple mutation profiles among which 2 double hotspot mutation (KRAS ex2 c.34G > A p.G12S and NRAS ex3 c.181C > A p.Q61K, KRAS ex2 c.34G > A p.G12S and NRAS ex2 c.38G > T p.G13V), 1 secondary rare mutation associated with a KRAS ex2 c.35G > A p.G12D hotspot mutation, and 3 multiple mutations only with rare but potentially deleterious mutations located around the loops responsible for nucleotide (GTP) binding. In only 1 case, the FMA of the secondary mutations was < 1%. As a whole, 7 cases (6.8%) had RAS mutations out of hotspots. Conclusions: NGS proved accurate, sensitive and suitable for routine RAS genotyping in mCRC. It can detect uncommon RAS mutation profiles with significant FMA that can potentially impair the patient response to anti-EGFR antibody.
Effect of Age on Efficacy and Safety Outcomes in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Receiving Lenalidomide and Low-Dose Dexamethasone (Rd): The First Trial
Authors: Cyrille Hulin, Thierry Facon, Chaim Shustik, Andrew Belch, Maria Teresa Petrucci, Ulrich Dührsen, Jin Lu, Kevin Song, Philippe Rodon, Brigitte Pegourie, Laurent Garderet, Hannah Hunter, Isabelle Azais, Richard Eek, Margaret Macro, Shaker Dakhil, Vanessa Houck, Guang Chen, Annette Ervin-Haynes, Fritz Offner
Journal: Blood (2014)
Prognostic score in high-grade gastrointestinal neuroendocrine tumours (GI-NETs).
Authors: Angela Lamarca, Jorge Barriuso, Mairead Geraldine McNamara, Richard Hubner, Juan W. Valle
Journal: Journal of Clinical Oncology (2015)

4089 Background: Outcomes of patients with high-grade GI-NETs are poor; prognostic markers for risk-stratification are needed. Methods: Consecutive patients, diagnosed with high-grade GI-NETs between 1997-2014, were included. Prognostic factors were identified by the Log-rank test, Cox regression and logistic regression and ROC curve comparisons performed for prediction accuracy. Internal validation of the score by Bootstrap-corrected Harrell Concordance Index (C-index) and Resampling Model Calibration were performed. Results: One-hundred and nine patients were eligible for analysis. Median follow-up time was 9.7 months (1.3-102.9). Median age: 67.7 years (16.3-84.1); 62% male, 84% metastatic; 19% foregut, 5% midgut, 19% pancreas, 28% hindgut and 29% unknown primary. Median ki67: 70% (20-100); ECOG PS 0: 26%, 1: 52%; 70% received chemotherapy. Baseline median alkaline phosphatase (ALK) and LDH were 109 IU/l (45-2035) and 70 IU/l (258-11069), respectively. The maximum model included stage, PS, LDH, Na, ALK, ki67, number of metastatic sites, presence of liver and presence of lung metastases. The score, selected by the lowest Akaike Index Criterion, included liver metastases, PS, ki67, LDH and ALK with 0-6 points assigned to each, resulting in 4 risk groups (A-D) with predicted risk of death, detailed in Table. There was no difference in the survival prediction accuracy between the maximum model and the score. On multivariable analysis, the score was prognostic for overall survival (HR 1.95, 95%CI 1.55-2.47; p < 0.001) and had good discrimination (C-index, 0.76) and calibration (mean error, 0.021; percentile 90, 0.037). Conclusions: This simple score identified high-grade GI-NET patients with meaningful differences in survival and may inform clinical decision-making and trial design. Prognostic group (points) Risk of death at 3 months (%) Risk of death at 6 months (%) Risk of death at 9 months (%) Risk of death at 12 months (%) Risk of death at 18 months (%) Risk of death at 24 months (%) A (0-1) 0.9 10.1 20.3 32.1 58 71.9 B (2) 4.2 26.01 43.6 57.3 79.7 88.2 C (3) 16.4 52.4 70.3 79.3 91.8 95.6 D (4-6) 46.9 77.5 87.8 91.6 96.9 98.5
Randomized Phase III Study Comparing Gefitinib (G) with Erlotinib (E) in Patients (Pts) with Previously Treated Advanced Lung Adenocarcinoma (La): Wjog 5108L
Authors: A. Nishiyama, N. Katakami, S. Morita, T. Seto, Y. Iwamoto, T. Hirashima, H. Kaneda, T. Kawaguchi, H. Matsuoka, S. Yokota, T. Nishimura, M. Okada, M. Fujita, K. Shibata, Y. Urata, N. Yamamoto, K. Nakagawa, Y. Nakanishi
Journal: Annals of Oncology (2014)
B7–1 Blockade Does Not Improve Post–Transplant Nephrotic Syndrome Caused by Recurrent FSGS
Authors: Marianne Delville, Emilie Baye, Antoine Durrbach, Vincent Audard, Tomek Kofman, Laura Braun, Jérôme Olagne, Clément Nguyen, Georges Deschênes, Bruno Moulin, Michel Delahousse, Gwenaëlle Kesler-Roussey, Séverine Beaudreuil, Frank Martinez, Marion Rabant, Philippe Grimbert, Morgan Gallazzini, Fabiola Terzi, Christophe Legendre, Guillaume Canaud
Journal: Journal of the American Society of Nephrology (2015)

FSGS is a common glomerular disorder that has a high propensity for recurrence after kidney transplant. The pathophysiology of FSGS is unknown, but podocytes seem to be the target of one or several circulating factors that lead to cytoskeleton reorganization and proteinuria. Research on podocytes has identified B7–1 as an important factor in podocyte biology and a new therapeutic target in renal disease. Indeed, in four patients with recurrent FSGS after transplant, treatment with the B7–1 blocker abatacept was associated with proteinuria remission. Here, we prospectively treated nine patients with recurrent FSGS after transplant using either abatacept or belatacept, a B7–1 blocker with higher affinity, and did not induce proteinuria remission. Furthermore, we did not detect B7–1 expression by immunofluorescence in podocytes of biopsy specimens from these or other kidney grafts or podocytes of native kidney biopsy specimens. In conclusion, B7–1 blockade did not induce FSGS remission after transplant in our study.
Genetic Epidemiology of Breast Cancer and Associated Cancers in High-Risk Families. I. Segregation Analysis&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: R C Go, M C King, J Bailey-Wilson, R C Elston, H T Lynch
Journal: JNCI Journal of the National Cancer Institute (1983)

Genetic and environmental hypotheses that might explain the patterns of occurrence of breast cancer and associated cancers in 18 large families at high risk of the disease were tested with the use of segregation analysis. For 16 pedigrees, results were consistent with the hypothesis that breast cancer has a genetic etiology. In 2 other families, breast cancer appeared more likely to have an environmental origin. Breast cancer susceptibility is best explained by hypotheses that postulate autosomal dominant susceptibility alleles in 10 families with primarily premenopausal breast cancer and ovarian cancer, in 4 families with primarily postmenopausal breast cancer, and in 2 families with breast cancer, brain tumor, sarcoma, leukemia, and adrenocortical carcinoma in children and young adults. In an accompanying paper, genetic susceptibility in the first 2 groups of families is further explored with the use of linkage analysis.
Should Transcatheter Aortic Valve Replacement Be Performed in Nonagenarians?
Authors: Mani Arsalan, Molly Szerlip, Sreekanth Vemulapalli, Elizabeth M. Holper, Suzanne V. Arnold, Zhuokai Li, Michael J. DiMaio, John S. Rumsfeld, David L. Brown, Michael J. Mack
Journal: Journal of the American College of Cardiology (2016)
Postoperative chemoradiation for resected gastric cancer—The tolerability of the Macdonald regimen in the routine clinical practice setting in Israel
Authors: Y. Kundel, E. Idelevich, O. Purim, S. Kovel, R. M. Pfeffer, R. Catane, N. Karminsky, S. M. Stemmer, E. Fenig, A. Sulkes, B. Brenner
Journal: Journal of Clinical Oncology (2006)

14077 Background: Postoperative chemoradiation as per the Intergroup 116 trial (“the MacDonald regimen”) is considered standard for completely resected high risk gastric cancer. However, concerns remain with regards to the toxicity of this regimen. To evaluate the safety and tolerability of this regimen in a routine clinical practice setting, we analyzed retrospective date of several Oncology Institutes in Israel. As we did not expect a different toxic profile in patients (pts) with positive margins (R1 resection), these were studied together with pts that underwent complete resection (R0). Methods: Treatment was administered according to the original Macdonald report. Overall and disease free survival rates were calculated using the Kaplan-Meier method. Results: Between 6/2000 and 9/2005 100 pts who had R0 (81%) or R1 (19%) resection of locally advanced gastric adenocarcinoma received post-operative chemoradiation; 62% were male and the median age was 64 years (range, 25–78); 77% had T≥3 tumors and 85% had N+ disease; 91% of the pts completed radiotherapy and 62% completed the entire chemoradiation plan. Reason for discontinuation was toxicity in all cases; 48% of the pts had grade ≥ 3 toxicity (30% grade 3 and 23% grade 4), 32% were hospitalized at least once for supportive care .Three patients (3%) died of toxicity: grade 4 diarrhea (1), neutropenic sepsis (1), and neutropenic sepsis complicated by small bowel gangrene (1).The most common hematological toxicity was neutropenia, which was grade ≥3 in 30% of the pts and was complicated by infection in 17%. The most common non-hematological toxicities were nausea, diarrhea and fatigue. With a median follow-up of 24 months (range, 3–64 months), 68% of the R0 patients remain alive and 64% are free of disease. Median disease free survival is 54 months and median overall survival has not been reached. Conclusions: In our experience, postoperative chemoradiation as per Intergroup 116 seems to be highly toxic, with a mortality rate higher than reported in that trial. Preliminary efficacy data seems comparable to the original report. No significant financial relationships to disclose.
Rechallenge with Bevacizumab (Bev) in Patients (P) with Glioblastoma (Gbm) and Previous Objective Response to Bev
Authors: A. Indacochea, A. Estival, S. Ahlal, O. Etxaniz, M.D.L.L. Gil, L. Vila, J.L. Cuadra Urtega, C. Carrato, C. Balana
Journal: Annals of Oncology (2014)
Ageing lungs and very elderly COPD: anytime and anywhere
Authors: Joan B. Soriano, Samy Suissa
Journal: European Respiratory Journal (2016)

The recent European Respiratory Society/American Thoracic Society Task Force for COPD Research statement [1] requested new studies that "…evaluate the impact of age on the importance of identifying an airflow limitation ( i.e. is it more important to identify asymptomatic airflow limitation in a 30-year-old than an 80-year-old?)", as well as those studies that compare outcomes among individuals diagnosed with chronic obstructive pulmonary disease (COPD) on the basis of the fixed ratio versus lower limit of normal (LLN) thresholds. In this issue of the European Respiratory Journal ( ERJ ), Luoto et al . [2] report the results of a study that fulfils both goals. Within the current epidemiological transition, expect and find incident COPD cases anytime, anywhere <http://ow.ly/UOccW>
The continuing uncertainty about cancer risk in inflammatory bowel disease
Authors: Hans-Olov Adami, Michael Bretthauer, Louise Emilsson, Miguel A Hernán, Mette Kalager, Jonas F Ludvigsson, Anders Ekbom
Journal: Gut (2016)

An increased risk of colorectal cancer (CRC) among individuals with IBD was suggested in the 1920s and later supported by epidemiologic studies.1 The association between IBD and CRC is not thought to arise from shared risk factors,2 but rather from a causal effect of IBD on CRC through chronic inflammation and other mechanisms that promote malignant transformation of the colonic mucosa.3 As a result, patients with IBD are considered at high risk of CRC and therefore receive anti-inflammatory treatment, colonoscopic surveillance with biopsies and prophylactic colectomy.

Multiple reviews and meta-analyses have tried to estimate CRC risk in patients with IBD (see table 1 for a summary from six such analyses4–9) and several additional studies were published during the last year.10–13 Few of these studies are large, prospective, population-based studies, which reflect the substantial methodological challenges. Here, we first outline the criteria for valid studies on IBD and cancer and then use those criteria to critically review the existing studies.

View this table:

Table 1 
Summary of meta-analyses of the association between IBD, UC and Crohn's disease (CD) and risk of colorectal cancer (CRC)



### Defining disease onset

Failure to accurately ascertain the onset of IBD may bias the effect estimates of IBD on cancer if increasing duration of disease increases the probability of somatic mutations that lead to malignant transformation. However, IBD may only be detected years after onset during colonoscopy screening14 or after early symptoms of CRC. As a result, the relative risk of CRC may be overestimated. Unfortunately, the identification of IBD onset in existing population-based registers is challenging. Its replacement by first hospitalisation due to IBD may misclassify disease onset because outpatient management may suffice until exacerbations, surgical treatment or complications require inpatient care.

A better choice for an operational definition of disease onset would be the date of first …
A Population-Based Case-Control Study of Renal Cell Carcinoma
Authors: J K McLaughlin, J S Mandel, W J Blot, L M Schuman, E S Mehl, J F Fraumeni
Journal: JNCI Journal of the National Cancer Institute (1984)

A population-based case-control study of renal cell carcinoma (495 cases and 697 controls) in the Minneapolis-St. Paul seven-county metropolitan area implicated cigarette smoking as a risk factor with an odds ratio (OR) among men of 1.6 (95% confidence intervals: 1.1-2.4) and among women of 1.9 (1.3-3.0). A statistically significant dose response was observed in both sexes for pack-years of cigarette use. On the basis of calculations of attributable risk, it was estimated that 30% of renal cell cancers among men and 24% among women were due to smoking. High relative adult weight as measured by the body mass index (BMI) was found to be a major risk factor among women but not among men, with those in the highest 5% of the BMI having an OR of 5.9 (1.8-20.4) in comparison to the lowest quartile. This association with excess weight was not seen at age 20, but it became more pronounced with increasing age, suggesting that the primary influence of weight gain is during the late stages of renal carcinogenesis. Excess risks were also related to ethnic background (particularly, German), which may account in part for the elevated incidence of renal cancer in the North Central area of the United States. In addition, positive associations were observed for long-term use of phenacetin-containing analgesics, heavy meat consumption, and heavy tea drinking (females only). An occupational clue was provided by an increased risk for exposure to petroleum, tar, and pitch products. Excesses of certain urologic and cardiovascular diseases were also observed among the cases compared to controls.
Long-term outcomes of covered self-expandable metal stents for treating benign biliary strictures
Authors: Jin-Seok Park, Sang Lee, Tae Song, Do Park, Dong-Wan Seo, Sung Lee, Seungbong Han, Myung-Hwan Kim
Journal: Endoscopy (2016)

<b>Background and study aim:</b> Fully covered, self-expandable metal stents (FCSEMSs) are acceptable tools for treating benign biliary stricture (BBS). However, little is known about the long-term outcomes of this technique. The aim of the present study was to evaluate the procedural and long-term outcomes of FCSEMSs for treating BBSs. <b>Patients and methods:</b> A total of 134 consecutive patients (median age 56 years; range 21 – 83) with BBS were retrospectively reviewed. The main outcomes were technical and clinical success, stricture resolution, recurrence, and adverse events. Outcomes were analyzed by reviewing patient medical records. <b>Results:</b> The success rates of FCSEMS placement and removal were 99.3 % and 98.2 %, respectively. Stricture resolution occurred in 103/132 (78.0 %) of the patients (median stent duration, 93 days; range 1 – 489). The associated factors for stricture resolution were longer stent indwelling period (≥ 120 days) and absence of stent migration. Stricture recurrence was seen in 26/103 patients (25.2 %; 95 % confidence interval [CI] 0.17 – 0.34) within a median of 390 days (range 4 – 903 days). Chronic pancreatitis was associated with stricture recurrence (hazard ratio [HR] 2.59, 95 %CI 1.20 – 5.61; <i>P</i> = 0.02). Stent migration occurred in 41/132 patients (31.1 %; 95 %CI 0.23 – 0.39). The FCSEMS with anchoring flaps appeared to protect against stent migration (HR 0.22, 95 %CI 0.08 – 0.63; <i>P</i> < 0.01). <b>Conclusion: </b>FCSEMSs had a high success rate for BBS resolution. Longer indwelling periods and the absence of stent migration might be important factors for stricture resolution.
Haploidentical CD3 TCRαβ and CD19-depleted second stem cell transplant for steroid-resistant acute skin graft versus host disease
Authors: Mary Slatter, Zohreh Nademi, T. Ronan Leahy, Beatriz Morillo-Gutierrez, Janice Dunn, Dawn Barge, Roderick Skinner, Clodagh Ryan, Sophie Hambleton, Mario Abinun, Terence Flood, Andrew Cant, Andrew Gennery
Journal: Journal of Allergy and Clinical Immunology (2016)
Direct peroral pancreatoscopy with a pediatric gastroscope for preoperative evaluation of the pancreatic duct in a patient with pancreatic intraductal papillary mucinous neoplasm
Authors: Petko Karagyozov, Ivan Tishkov, Zhenya Georgieva, Biliana Teneva, Galina Kirova, Kiril Draganov
Journal: Endoscopy (2015)

Intraductal papillary mucinous neoplasms (IPMNs) are one of several types of mucinous tumors of the pancreas. They are uncommon ductal epithelial tumors, comprising approximately 10 % to 15 % of cystic pancreatic neoplasms.
Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins
Authors: Chan Zhou, Samuel R. York, Jennifer Y. Chen, Joshua V. Pondick, Daniel L. Motola, Raymond T. Chung, Alan C. Mullen
Journal: Genome Medicine (2016)

Hepatic fibrosis is the underlying cause of cirrhosis and liver failure in nearly every form of chronic liver disease, and hepatic stellate cells (HSCs) are the primary cell type responsible for fibrosis. Long noncoding RNAs (lncRNAs) are increasingly recognized as regulators of development and disease; however, little is known about their expression in human HSCs and their function in hepatic fibrosis. We performed RNA sequencing and ab initio assembly of RNA transcripts to define the lncRNAs expressed in human HSC myofibroblasts. We analyzed chromatin immunoprecipitation data and expression data to identify lncRNAs that were regulated by transforming growth factor beta (TGF-β) signaling, associated with super-enhancers and restricted in expression to HSCs compared with 43 human tissues and cell types. Co-expression network analyses were performed to discover functional modules of lncRNAs, and principle component analysis and K-mean clustering were used to compare lncRNA expression in HSCs with other myofibroblast cell types. We identified over 3600 lncRNAs that are expressed in human HSC myofibroblasts. Many are regulated by TGF-β, a major fibrotic signal, and form networks with genes encoding key components of the extracellular matrix (ECM), which is the substrate of the fibrotic scar. The lncRNAs directly regulated by TGF-β signaling are also enriched at super-enhancers. More than 400 of the lncRNAs identified in HSCs are uniquely expressed in HSCs compared with 43 other human tissues and cell types and HSC myofibroblasts demonstrate different patterns of lncRNA expression compared with myofibroblasts originating from other tissues. Co-expression analyses identified a subset of lncRNAs that are tightly linked to collagen genes and numerous proteins that regulate the ECM during formation of the fibrotic scar. Finally, we identified lncRNAs that are induced during progression of human liver disease. lncRNAs are likely key contributors to the formation and progression of fibrosis in human liver disease.
Estradiol blood levels: New biomarker for diagnostics and therapy outcome of testicular mature teratoma: Pilot study.
Authors: M. Gamulin, M. Grgic, M. Coric, M. Cacic, A. Fucic
Journal: Journal of Clinical Oncology (2010)

e15147 Background: Although in some testicular cancer patients the elevated concentrations of the serum estradiol may be detected, the role of steroids in the etiology and progression of testicular germ cell cancers is poorly understood. Sex steroids control cellular phenotypes by binding to receptor proteins that in turn regulate downstream genetic and epigenetic expression. As fetal and neonatal testis is very sensitive to estrogen, we introduced the hypothesis that the blood levels of estradiol may be a target biomarker of tumor progression and regression during the chemotherapy for testicular mature teratoma. Methods: In twenty patients with testicular germ cell tumors (TGCT), (4 seminomas, 5 non-seminomas and 11 mixed-germ cell tumors) during chemotherapy (4xBEP) and twenty referent subjects estradiol, testosterone, LH and FSH levels were measured. Patients and referent subjects were matched by age (the mean value 29 years). Results: Only in two cases of mature teratoma stage IIIC, estradiol levels were significantly higher (950 and 12422 pmol/L) than in other testicular cancer patients and referent subjects. Testosterone levels, LH and FSH were in all within the referent values. After four cycles of treatment by BEP, estrogen levels in mature teratoma patients reached referent values (148 and 115, respectively). After 4 cycles of the BEP chemotherapy in 2 testicular mature teratoma patients, we noticed that the decrease of estradiol correlates with the decrease of bHCG (186 440 to 17 and 612 110 to 29 IU/L) and the decrease of the tumor mass. In patients with higher estradiol significant increase of testosterone was detected (39 pmol/L) after the decrease of estradiol levels. After 4xBEP patients were treated with 2xPEI. After 6 cycles of chemotherapy estradiol levels were within the control range and bHCG was negative in both cases.These preliminary results support the estrogen-dependency of testicular mature teratoma. Conclusions: Estradiol blood levels my be a new biomarker for diagnostics and therapy outcome of metastatic testicular mature teratoma. Immunohistochemical analysis of the steroid receptors and HER/2neu in all 20 patients of testicular cancer tissues is in progress. No significant financial relationships to disclose.