tbuckley/cabot-search huggingface dataset:
Cetuximab combined with infusional 5-fluorouracil/folinic acid (5-FU/FA) and oxaliplatin in metastatic colorectal cancer (mCRC): A pooled analysis of COIN and OPUS study data.
Authors: Julien Taïeb, Tim Maughan, Carsten Bokemeyer, Eric Van Cutsem, Thomas Brodowicz, Gunnar Folprecht, Regina Esser, Michael Schlichting, Josep Tabernero
Journal: Journal of Clinical Oncology (2012)

3574 Background: Infusional 5-FU/FA + oxaliplatin is a widely used schedule in the first-line treatment of mCRC. In the randomized phase II OPUS study, the addition of cetuximab to one such regimen (FOLFOX4) significantly improved response and progression-free survival (PFS) in patients (pts) with KRAS wild-type (wt) mCRC. However, in the randomized phase III COIN study, a benefit for the addition of cetuximab to first-line fluoropyrimidine (administered as either infusional 5-FU or capecitabine) + oxaliplatin was not confirmed in pts with KRAS wt tumors. Methods: A pooled study-based analysis of treatment outcome in pts with KRAS wt tumors from the OPUS study and COIN subgroup who received infusional 5-FU/FA + oxaliplatin (as the OxMdG regimen) was carried out using a random effects model. Outcome in the pooled analysis was considered in the context of other randomized studies investigating first-line chemotherapy regimens +/- cetuximab in pts with mCRC. Results: The pooled KRAS wt population included 179 pts from the OPUS study and 244 from the OxMdG subgroup of the COIN study. A benefit for the addition of cetuximab to infusional 5-FU/FA was suggested for response (odds ratio 1.87, 95% CI 1.07–3.28) and PFS (hazard ratio, HR 0.69, 95% CI 0.52–0.92) but overall survival (OS) did not show a statistically significant improvement (HR 0.90, 95% CI 0.73–1.11). These response and PFS data are similar to those of the KRAS wt population of the CRYSTAL study investigating infusional 5-FU/FA and irinotecan +/- cetuximab (response: odds ratio 2.07, 95% CI 1.52–2.83; PFS: HR 0.70, 95% CI 0.56–0.87) whereas the improvement in OS was statistically significant in that study (HR 0.80, 95% CI 0.67–0.95). Similar efficacy of FOLFOX + cetuximab and FOLFIRI + cetuximab in the first-line treatment of mCRC was also suggested by data from the randomized phase II CORE 1.2.001 and CELIM studies. Overall, the safety profile of infusional 5-FU/FA and oxaliplatin + cetuximab was found to be acceptable and manageable. Conclusions: The pooled analysis supports the use of cetuximab combined with infusional 5-FU/FA and oxaliplatin in the first-line treatment of KRAS wt mCRC.
Improving Outcomes From Transcatheter Aortic Valve Implantation
Authors: Steven R. Messé, Michael J. Mack
Journal: JAMA (2016)

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
High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease
Authors: Ditte L. Hedegaard, Damien C. Tully, Ian A. Rowe, Gary M. Reynolds, David J. Bean, Ke Hu, Christopher Davis, Annika Wilhelm, Colin B. Ogilvie, Karen A. Power, Alexander W. Tarr, Deirdre Kelly, Todd M. Allen, Peter Balfe, Jane A. McKeating
Journal: Journal of Hepatology (2016)

The high replication and mutation rate of hepatitis C virus (HCV) results in a heterogeneous population of viral sequences in vivo. HCV replicates in the liver and infected hepatocytes occur as foci surrounded by uninfected cells that may promote compartmentalization of viral variants. Given recent reports showing interferon stimulated gene (ISG) expression in chronic hepatitis C, we hypothesized that local interferon responses may limit HCV replication and evolution.To investigate the spatial influence of liver architecture on viral replication we measured HCV RNA and ISG mRNA from each of the 8 Couinaud segments of the liver from 21 patients undergoing liver transplant.HCV RNA and ISG mRNA levels were comparable across all sites from an individual liver but showed up to 500-fold difference between patients. Importantly, there was no association between ISG and HCV RNA expression across all sites in the liver or plasma. Deep sequencing of HCV RNA isolated from the 8 hepatic sites from two subjects showed a similar distribution of viral quasispecies across the liver and uniform sequence diversity. Single genome amplification of HCV E1E2-envelope clones from 6 selected patients at 2 hepatic sites supported these data and showed no evidence for HCV compartmentalization.We found no differences between the hepatic and plasma viral quasispecies in all patients sampled. We conclude that in end-stage liver disease HCV RNA levels and the genetic pool of HCV envelope sequences are indistinguishable between distant sites in the liver and plasma, arguing against viral compartmentalization.HCV is an RNA virus that exists as a quasispecies of closely related genomes that are under continuous selection by host innate and adaptive immune responses and antiviral drug therapy. The primary site of HCV replication is the liver and yet our understanding of the spatial distribution of viral variants within the liver is limited. High resolution sequencing of HCV and monitoring of innate immune responses at multiple sites across the liver identified a uniform pattern of diversity and argues against viral compartmentalization.
Lives in the Balance: Why Do We Hold onto Potentially Harmful, Disease–Causing Mutations?
Authors: Joseph Caspermeyer
Journal: Molecular Biology and Evolution (2016)

Deleterious mutations are expected to evolve under negative selection and are usually purged from the population.However, deleterious alleles segregate in the human population and some disease-associated variants are maintained at considerable frequencies.Here, we test the hypothesis that balancing selection may counteract purifying selection in neighboring regions and thus maintain deleterious variants at higher frequency than expected from their detrimental fitness effect.We first show in realistic simulations that balancing selection reduces the density of polymorphic sites surrounding a locus under balancing selection, but at the same time markedly increases the population frequency of the remaining variants, including even substantially deleterious alleles.To test the predictions of our simulations empirically, we then use whole-exome sequencing data from 6,500 human individuals and focus on the most established example for balancing selection in the human genome, the major histocompatibility complex (MHC).Our analysis shows an elevated frequency of putatively deleterious coding variants in nonhuman leukocyte antigen (non-HLA) genes localized in the MHC region.The mean frequency of these variants declined with physical distance from the classical HLA genes, indicating dependency on genetic linkage.These results reveal an indirect cost of the genetic diversity maintained by balancing selection, which has hitherto been perceived as mostly advantageous, and have implications both for the evolution of recombination and also for the epidemiology of various MHC-associated diseases.
Recommendation for axillary lymph node dissection in women with early breast cancer and sentinel node metastasis: A systematic review and meta-analysis of randomized controlled trials using the GRADE system
Authors: Tsai-Wei Huang, Ken N. Kuo, Kee-Hsin Chen, Chiehfeng Chen, Wen-Hsuan Hou, Wei-Hwa Lee, Tsu-Yi Chao, Jo-Ting Tsai, Chih-Ming Su, Ming-Te Huang, Ka-Wai Tam
Journal: International Journal of Surgery (2016)
Life History of the Oldest Lentivirus: Characterization of ELVgv Integrations in the Dermopteran Genome
Authors: Tomáš Hron, Helena Farkašová, Abinash Padhi, Jan Pačes, Daniel Elleder
Journal: Molecular Biology and Evolution (2016)

Endogenous retroviruses are genomic elements formed by germline infiltration by originally exogenous viruses. These molecular fossils provide valuable information about the evolution of the retroviral family. Lentiviruses are an extensively studied genus of retroviruses infecting a broad range of mammals. Despite a wealth of information on their modern evolution, little is known about their origins. This is partially due to the scarcity of their endogenous forms. Recently, an endogenous lentivirus, ELVgv, was discovered in the genome of the Malayan colugo (order Dermoptera). This represents the oldest lentiviral evidence available and promises to lead to further insights into the history of this genus. In this study, we analyzed ELVgv integrations at several genomic locations in four distinct colugo specimens covering all the extant dermopteran species. We confirmed ELVgv integrations in all the specimens examined, which implies that the virus originated before the dermopteran diversification. Using a locus-specific dermopteran substitution rate, we estimated that the proviral integrations occurred 21-40 Ma. Using phylogenetic analysis, we estimated that ELVgv invaded an ancestor of today's Dermoptera in an even more distant past. We also provide evidence of selective pressure on the TRIM5 antiviral restriction factor, something usually taken as indirect evidence of past retroviral infections. Interestingly, we show that TRIM5 was under strong positive selection pressure only in the common dermopteran ancestor, where the ELVgv endogenization occurred. Further experiments are required to determine whether ELVgv participated in the TRIM5 selection.
The potential danger of empiric antimicrobial therapy for nosocomial SBP
Authors: Alastair O'Brien, Louise China, Vanya Gant
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We feel that Piano et al.'s suggestion in their study of empiric treatment of nosocomial spontaneous bacterial peritonitis (SBP) that these antibiotics of last resort should become standard in areas with high multidrug‐resistant bacteria is potentially dangerous.1 We agree that nosocomial SBP represents a worryingly evidence‐free zone with few prospective studies and opinion‐based guidelines, in turn making this study capable of considerable impact for policy.2 One size definitely does not fit all, but we would go further to state that the challenge of antimicrobial resistance requires a more thoughtful approach, rather than automatic deployment of broad‐spectrum antibiotics.3 Italy has high cephalosporin and carbapenem resistance rates, with some organisms exceeding 50% resistance, and fluoroquinolone‐based antibiotic prophylaxis may drive this.4 Therefore, it would be both incorrect and irresponsible to advocate such a combination in countries with lower resistance. The Piano et al. study relies on surrogate markers of infection and resolution with no difference in survival. Although a polymorphonuclear cell (PMNC) count >250/mm3 demonstrated 100% sensitivity and 89% specificity in culture‐positive SBP, bacteria were isolated in 51.6% of patients, which is consistent with previous reports.3 This percentage was greater in the ceftazidime group (62.5% vs. 40%). Patients with positive cultures have significantly worse outcomes, and this confounder was not considered. Patients with a PMNC count >250/mm3 will be treated with antibiotics in many countries regardless of culture results; consequently, half of these patients may be treated unnecessarily. Greater attempts should be made to understand the characteristics of patients with negative ascitic culture and elevated PMNCs. In particular, can antibiotics be stopped? The key finding of Piano et al.'s study is that the efficacy of first‐line treatment independently predicted survival; it therefore follows that we must focus on delivering the correct antibiotics to the correct patients. We believe that adoption of their recommendations for empiric antibiotics will lead to further antibiotic pressure, both in terms of spectrum and treatment duration. Neither is necessary; many patients may not need antibiotics in the first place, and rapid de‐escalation flowing from antibiotic sensitivity data should be the rule. There is no choice; to continue to deploy increasingly precious antibiotics without thought for alternative strategies will fail, and patients will die for lack of effective therapy. The value of Piano et al.'s paper therefore lies in its potential to stimulate multicenter studies and strategies to improve antibiotic use before they are lost altogether.
P0887 : C-edge co-infected: phase 3 study of grazoprevir/elbasvir in patients with HCV/HIV
Authors: J.K. Rockstroh, M. Nelson, C. Katlama, J. Lalezari, J. Mallolas, M. Bloch, G. Matthews, M. Saag, P. Zamor, C. Orkin, J. Gress, S. Klopfer, H. Platt, M. Robertson, M. Sulkowski
Journal: Journal of Hepatology (2015)
Oral Contraceptives and Thromboembolic Disease
Authors: Richard Doll
Journal: JAMA (1972)

<h3>To the Editor.—</h3> The recent article by Drill<sup>1</sup>covers much the same ground as an earlier paper by Drill and Calhoun,<sup>2</sup>and to avoid reiteration we refer the reader to our comments on that earlier paper.<sup>3</sup>One or two observations on the more recent article might, however, help the reader to judge its scientific value. In Table 3, Drill summarizes the findings in a number of large-scale clinical trials of oral contraceptives in which 63 cases of thromboembolism were recorded. According to Drill, 151 cases of thromboembolism would have been expected in these trials if the women taking part had experienced the "normal incidence" of the disease. Drill states that this difference is not statistically significant. This is clearly untrue. In fact, such a difference would occur by chance less than once in 1,000 times. In the study carried out by Inman and Vessey,<sup>4</sup>26 deaths
Intense 99mTc-MDP and 18F-NaF Activity in Long-standing Subcutaneous Implants
Authors: Li Chen, Yue Chen, Zhanwen Huang, Liang Cai, He Huang
Journal: Clinical Nuclear Medicine (2016)

A 64-year-old woman with a newly diagnosed left breast cancer underwent a presurgical Tc-MDP whole-body imaging, which showed 1 intense activity in the midline upper abdomen and another overlapping the upper thoracic spine. An F-NaF PET/CT scan performed a day later also revealed the elevated activity in the same regions. The activity corresponded to calcified subcutaneous implants, which were placed there more than 30 years ago.
Repeated monthly epicutaneous challenges with diphenylcyclopropenone result in a clinically reproducible level of contact allergy in <i>de novo</i> sensitized individuals
Authors: K.F. Mose, F. Andersen, L. Skov, M.A. Røpke, T. Litman, P.S. Friedmann, K.E. Andersen
Journal: British Journal of Dermatology (2016)

Diphenylcyclopropenone (DPCP) has been used as an experimental contact allergen in humans and for topical immunotherapy of patients with alopecia areata. However, the efficacy is mostly based on case series. Randomized controlled clinical trials are lacking1, as is detailed descriptions of how repeated topical exposure to DPCP affect the level of hypersensitivity.

This article is protected by copyright. All rights reserved.
Using mutational load in next generation sequencing (NGS) to identify mismatch repair (MMR) deficiency in colorectal cancer (CRC).
Authors: Francesca Battaglin, Zsofia Kinga Stadler, Andrea Cercek, Rona D. Yaeger, Neil Howard Segal, Anna M. Varghese, Nancy E. Kemeny, Martin R. Weiser, Julio Garcia-Aguilar, Jinru Shia, Michael F. Berger, Jaclyn Frances Hechtman, Maria E. Arcila, David B. Solit, Leonard Saltz
Journal: Journal of Clinical Oncology (2015)

3565 Background: NCCN guidelines recommend screening all CRC patients diagnosed at age ≤ 70 years and those > 70 who meet Bethesda Criteria with either immunohistochemistry (IHC) for MMR protein expression or PCR for microsatellite instability (MSI), and also recommend tumor sequencing for RAS/BRAF mutations in all CRC patients with metastatic disease. MMR status is also needed for management of all stage II colon cancer patients, and BRAF mutational status is useful in work up of MMR-deficient (dMMR) tumors. We hypothesized that the higher mutational burden of dMMR tumors would permit their identification on the basis of the mutation count in an NGS panel, thus allowing a single multi-gene NGS assay to reliably detect not only RAS/RAF mutations but also MMR deficiency. Methods: Under an IRB waiver, an institutional electronic database was queried to identify all CRC analyzed with MSK-IMPACT, our custom 341-gene NGS assay. Tumor mutational load, defined as the raw number of somatic mutations identified, was determined for each case and compared between MMR-proficient and MMR-deficient cases. Results: We identified 149 unique CRC patients tested with MSK-IMPACT. Of these, 93 had MMR status available, including 8 dMMR cases. 83 of 85 (98%) of MMR-proficient cases had 16 or fewer mutations, while two outliers with 158 and 250 mutations each were found to be POLE-mutant. MMR-deficient tumors had a higher mutational load with a significantly higher median number of somatic mutations (49, range 23-67) than MMR-proficient tumors (6, range 0-16), p = 0.0024. Conclusions: This preliminary analysis suggests that using a cut-off for mutational load, such as 20 mutations for MSK-IMPACT, may provide a highly sensitive and specific means of screening for MMR deficiency with the same assay used for tumor genotyping. If validated, the use of a single multi-gene sequencing assay to screen for both dMMR and RAS/BRAF mutations could be cost effective, particularly in metastatic CRC, but also in early stage disease, while providing additional genetic information that may be useful for research purposes. Larger numbers of known dMMR tumors are currently being analyzed with MSK-IMPACT to validate this hypothesis.
68Ga-PSMA PET/CT False-Positive Tracer Uptake in Paget Disease
Authors: Arun Sasikumar, Ajith Joy, Raviteja Nanabala, M.R.A Pillai, Hari T.A
Journal: Clinical Nuclear Medicine (2016)

65-year-old man with left-sided pelvic pain on evaluation was found to have features suggestive of either Paget disease or prostatic bone metastasis of the left hemipelvis based on Tc-MDP bone scan and MRI. Ga-PSMA PET/CT to assess the possibility of primary prostate cancer and if present to stage it helped to rule out prostate cancer because of absence of focal abnormal increased tracer uptake in the prostate gland. However, false-positive tracer uptake was noted in the left hemipelvis, which was subject to biopsy and histopathologically proven to be Paget disease involvement.
Ewing sarcoma of the head and neck.
Authors: H. Juergens, K. Grevener, U. Dirksen, A. Ranft
Journal: Journal of Clinical Oncology (2010)

e20516 Background: Ewing Sarcoma rarely occurs in the head and neck region, representing less than 5% of all Ewing sarcoma cases. Consequently, data of the clinical background and outcome are quite limited. Methods: We analyzed event-free- survival (EFS) und overall-survival (OS) of 52 patients with Ewing sarcoma of the head and neck region diagnosed from 1999 to 2008. All patients were treated according to the EURO-E.W.I.N.G.99 protocol of the German Society of Pediatric Oncology and Hematology (GPOH). 44 patients (85%) had local disease, 8 patients (15%) presented with metastases. Primary sites were: skull (46%), mandible (12%), maxilla (13%), scalp (4%), neck (10%), face (2%) and other (13%). 11% of the patients had a tumor volume <200ml. Local therapy of the primary tumor consisted of surgery in 35%, surgery and radiotherapy in 42%, and radiotherapy alone in 17% of the cases. Three patients (6%) received no local therapy, in two for progression during initial chemotherapy. Results: 3y-EFS for patients with local disease was 0.74 (SE = 0.07), and 0.25 (SE = 0.15) for patients with primary metastases. Corresponding 3y-OS rates were 0.87 (SE = 0.06) and 0.38 (SE = 0.17). Localized patients with surgery had a 3y-EFS of 0.81 (SE = 0.13), with combined local therapy of 0.72 (SE = 0.10), and 0.80 (SE = 0.18) with radiotherapy alone. Multivariate analysis identified metastatic disease (Risk Ratio: 6.05; 95%CI 1.93-18.93; p = .002) and tumor volume (Risk Ratio: 5.27; 95%CI 1.45-19.23; p = .012) as major risk factors. Conclusions: The outcome of Ewing sarcoma of the head and neck appears to be in the upper range of Ewing sarcoma subgroup analyses. This may be influenced by a relatively small proportion of large primary tumors in the head and neck subgroup. No significant financial relationships to disclose.
Metabolic Tumor Volume and Total Lesion Glycolysis in PET/CT Correlate With the Pathological Findings of Colorectal Cancer and Allow Its Accurate Staging
Authors: Yoshiyuki Suzuki, Koji Okabayashi, Hirotoshi Hasegawa, Masashi Tsuruta, Kohei Shigeta, Koji Murakami, Yuko Kitagawa
Journal: Clinical Nuclear Medicine (2016)

Introduction PET/CT plays an important role in cancer diagnosis. Recently, novel metabolic parameters in PET/CT such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have been reported to be diagnostic and prognostic biomarkers of various cancers. We evaluated the diagnostic value of these metabolic parameters in colorectal cancer (CRC). Methods The study included 138 patients who underwent surgical resection of CRCs between August 2012 and March 2014. The MTVs and TLGs of tumors were measured using various SUV thresholds. The diagnostic abilities of the metabolic parameters were analyzed using ROC curves and classification and regression trees. Results The AUCs of the MTVs and TLGs for predicting T stage (0.881–0.892) were significantly higher than the AUC of the SUVmax (0.824). In the M stage, the AUCs of MTVs and TLGs (0.688–0.723) were significantly higher than that of the SUVmax (0.606). Recursive partitioning applying classification and regression trees demonstrated that the optimal cutoff values of the most important variables for discriminating T, N, and M stages are MTV2.5 = 9.35 and 63.33 mL, TLG50% = 328.1, and TLG50% = 94.81, respectively. Conclusion Metabolic tumor volumes and TLGs in PET/CT are reliable diagnostic biomarkers. Using these parameters, more accurate preoperative diagnoses for CRC can be made.