tbuckley/cabot-search huggingface dataset:
JAMA Surgery 2016 Year in Review
Authors: Melina R. Kibbe
Journal: JAMA Surgery (2017)

has been an exciting year for JAMA Surgery.As Editor in Chief, I would like to convey some of our accomplishments to the readers, authors, and peer reviewers of the journal.First, as evidence of the high-quality publications in JAMA Surgery, the Impact Factor rose significantly from 4.4 to 5.7.This accomplishment reflects the hard work of our authors, the peer reviewers, and the editorial team.The 2015 Impact Factor of 5.7 positions JAMA Surgery as the number 2 ranked general surgery journal, a tremendous accomplishment.Second, an important goal for JAMA Surgery was to reduce the time from acceptance to online publication.We have succeeded with our goal, with the time from acceptance to online publication averaging 2.5 months for 2016 (Table ).We accomplished this goal while preserving our overall acceptance rate, which was 22.7% for 2016.Acceptance rate for Original Investigations was 11.4% and for Research Letters was 27.6%.We are also happy to report that the overall number of submissions has increased by 3.3% from 2015 to 2016, a continuing trend.An initiative that helped us to reduce the time from acceptance to online publication was the adoption of onlineonly articles.In 2016, JAMA Surgery began publishing 2 Original Investigations each month as online only.Another accomplishment we are happy to share is our extended reach through social media.Amalia Cochran, MD, our Web and Social Media Editor, has led the charge to increase our presence on Twitter and Facebook.We currently have 15 600 Twitter followers and 14 793 Facebook likes.JAMA Surgery has 54% (27 articles) of the top 50 articles in Altmetric scores (among the top 4 surgery journals in terms of Impact Factor), including the number 1 article and 5 of the top 10.Combined with the visits to our website, the electronic Table of Contents, and our print distribution, JAMA Surgery reaches more than 50 000 individuals each week.2016 has been the year of consistent implementation of our new article types.Under the leadership of Gerard Doherty, MD, the Review Editor, JAMA Surgery now publishes an evidencebased review on common topics of interest to our readers each month.Under the leadership of Justin Dimick, MD, the Surgical Innovation Editor, the journal publishes 1 Surgical Innovation article each month.Most recently, JAMA Surgery, along with the entire JAMA Network, unveiled a new website.This website has been designed with the reader in mind.Content is displayed in a more user-friendly manner and tailored to the device being used to access the website.Last, I would like to thank the readers, authors, peer reviewers, and editorial board for contributing to the journal.Through your support, we aim to fulfill our mission "to promote the art and science of surgery by publishing relevant peer-reviewed research to assist the surgeon in optimizing patient care" and to "serve as a forum for the discussion of issues pertinent to surgery, such as the education and training of the surgical workforce, quality improvement, and the ethics and economics of health care delivery."
Phase I and pharmacokinetic study of docetaxel (D), irinotecan (I), and celecoxib (C) in patients with advanced non-small cell lung cancer (NSCLC)
Authors: V. Kut, M. Avram, L. Luong, A. Argiris
Journal: Journal of Clinical Oncology (2004)

7312 Background: C is a selective cyclooxygenase-2 inhibitor that has been shown to enhance the activity of chemotherapeutics in preclinical lung cancer models. The combination of D and I is active in NSCLC [ASCO 2001;A1312]. We sought to determine the maximum tolerated doses of the combination of irinotecan (I) and docetaxel (D) with celecoxib (C) and whether the pharmacokinetics (PK) of D and I were affected by C. Methods: D and I were administered intravenously on days 1 and 8, every 21 days. Dose levels: level 1: D 30 mg/m2, I 50 mg/m2; 2: D 30, I 60; 3: D 35, I 60. C, 400mg, was administered orally twice daily starting on day 2 of cycle 1. Concomitant use of non-steroidal anti-inflammatory drugs was not permitted. PK studies were performed on day 1 of cycle 1 (off C) and day 1 of cycle 2 (on C). Results: Sixteen patients (pts) with advanced NSCLC with measurable disease have been enrolled to date (dose level 1: 8 pts; 2: 3, 3: 5) and have collectively received 66 cycles. Ages: 42–79 years (median: 56); 10 males, 6 females; PS 0/1 in 8/8. Dose-limiting toxicities were: myocardial infarction (MI) at dose level 1 and grade 4 neutropenia/grade 5 urosepsis at dose level 3. MI occurred in a pt with history of coronary artery disease, hyperlipidemia and stroke; it is unclear whether the MI was treatment-related. Other significant toxicities were: neutropenia, G3: 2; diarrhea, G2: 1; G3: 3; G4: 1; nausea, G2: 1, G3: 2; vomiting, G2: 1, G3: 1; rash, G2: 1; pneumonitis, G3: 1. Two patients had dose reductions for grade 3 diarrhea. The best responses in 13 evaluable pts (5 pretreated) were: PR (5); stable disease (4); and progressive disease (4). The PKs of D were not affected by the addition of C (N=8, paired t-tests). Conclusions: The addition of C to D and I is generally well tolerated but unpredictable fatal toxicity (urosepsis) occurred in 1 pt. Diarrhea was the most common toxicity. Accrual continues on dose level 3. No significant financial relationships to disclose.
Contribution of platelets to tumor aggressivity.
Authors: Judith Delage, Hong Li, He Lu, Lionel Cazin, Jeannette Soria, Evelyne Dupuy, Ludovic Drouet, Jean-Pierre Vannier, Rémi Varin, Claudine Soria
Journal: Journal of Clinical Oncology (2012)

e21156 Background: The interaction between cancer and coagulation process has been shown since many years. The aim of our study is to understand the mechanisms implicated and to propose new therapeutic approaches. Methods: Two breast cancer cell lines were used: a very aggressive (MDA-MB231) and a much less aggressive (MCF-7). Platelet aggregation tests were done with washed platelets, normal or fibrin removed plasma and cancer cells (20 to 2.10 5 cells/ml). Procoagulant activity of cancer cells was studied. Aspirin, Apyrase (ADPase), a direct thrombin inhibitor (Hirudin), two Xa inhibitors (Fondaparinux, Rivaroxaban) were the inhibitors tested. Interaction between platelets and cancer cells was visualized by confocal microscopy. Angiogenic effect of supernatants from platelets-cancer cells co-incubation was investigated. Results: The data obtained show that a platelet aggregation is induced by cancer cells in the presence of a small amount of plasma. This aggregation depends on both the type and number of cancer cells. Aggressive MDA-MB231 cells have a more potent pro-aggregating activity than MCF-7. This aggregation appears to be due to thrombin generation since it is inhibited by Hirudin. Rivaroxaban, a direct inhibitor of factor Xa, inhibits platelets aggregation but not Fondaparinux, an indirect anti Xa inhibitor which binds to Antithrombin III. Aspirin and Apyrase have no effect. Moreover, the procoagulant activity of cancer cells with plasma is inhibited by Hirudin and Rivaroxaban but not by Fondaparinux. This suggests that the Fondaparinux-Antithrombin III complex cannot access to cell membrane-bound factor Xa. It may be due to its steric hindrance since thromboplastin induced coagulation is inhibited by Rivaroxaban but not by Fondaparinux. The confocal microscopic study shows that platelets protect tumor cells from immune attack via the formation from a protective envelope around cancer cells. Angiogenesis assays show that activation of platelets by cancer cells releases angiogenesis stimulating factors and cytokines. Conclusions: The present work confirms the crucial role of platelets in cancer aggressiveness and reveals that Rivaroxaban or Thrombin inhibitors could be efficient drugs to reduce cancer progression, metastasis and thrombosis.
Combination of 5-Azacytidine and ABT-199 Has a Synergistic Apoptotic Effect in High-Risk MDS/sAML after HMA Failure
Authors: Stefanie Jilg, Johanna Kauschinger, Veronika Reidel, Catharina Müller-Thomas, Richard Hauch, Johannes Schauwecker, Burkhard Schmidt, Ulrike Höckendorf, Christian Peschel, Katharina Götze, Philipp J. Jost
Journal: Blood (2016)
Prospective analysis of predictors of survival in melanoma patients with brain metastases
Authors: J. A. Zakrzewski, L. Geraghty, H. Hamilton, P. Christos, D. Krich, M. Mazumdar, D. Polsky, F. Darvishian, A. Pavlick, I. Osman
Journal: Journal of Clinical Oncology (2009)

9074 Background: Melanoma patients (pts) with brain metastases (BM) have limited survival, and BM remains an exclusion criterion in most clinical trials. A recent retrospective analysis at Memorial Sloan Kettering Cancer Center (MSKCC) identified 4 clinical variables that were associated with worse post BM survival (Raizer J et al, Neuro Oncol 2008). In this study, we investigated whether primary tumor features could improve the predictability of post BM survival and examined the reproducibility of the variables identified in MSKCC study. Methods: Melanoma pts with BM prospectively enrolled in an interdisciplinary database at NYU Medical Center from 2002 to 2008 were studied. Six primary tumor characteristics, 21 clinical variables, and treatments were examined. Univariate associations were analyzed using Kaplan Meier survival analysis and the independent effect of identified predictors was assessed by multivariate cox proportional hazards regression analysis. Results: Eighty-nine pts (36 F, 53 M, median age 57) were identified. Median post BM survival was 5.75 months. Median follow-up time based on survivors was 4.2 months. Ulceration and mitotic index ≥3/field were univariately associated with worse post BM survival (p=0.004, p=0.009 respectively). Age &gt;65, ≥3 BM lesions, presence of neurological symptoms, and extracranial metastases were also univariately associated with worse post BM survival (the same 4 variables identified in MSKCC retrospective study). An additional 4 clinical parameters were significant by univariate analysis: frontal lobe location (p=0.01), bilateral lesions (p=0.01), ≥2 neurological symptoms (p=0.005), and weakness/fatigue (p&lt;0.0001). After reproducing the significance of the 4 MSKCC variables in a multivariate model, ulceration of the primary tumor was also an independent predictor of post BM survival (hazard ratio [HR] = 2.75; 95% CI = 1.30, 5.83; p=0.008) whereas mitotic index ≥3/field was not (HR=1.24; 95% CI = 0.57, 2.71; p=0.59). Conclusions: Data suggest that ulceration of the primary melanoma might indicate an adverse biologic behavior that impacts post BM survival. Our data also lend independent support for the predictive model of post BM survival. No significant financial relationships to disclose.
Detection of MSC-like cells in soft tissue sarcoma cell lines and primary tumors
Authors: S. Wirths, E. Malenke, T. Wiesner, H. Buehring, J. Hartmann, H. G. Kopp
Journal: Journal of Clinical Oncology (2009)

11000 Background: Soft tissue sarcomas (STS) are a heterogeneous group of mesodermal tumors hypothetically originating from mesenchymal stem cells (MSC). While the expression profile of bone marrow derived MSCs and their in vitro differentiation potential have been examined extensively, knowledge regarding the in vivo counterparts of MSC is still evolving. We hypothesized that MSC-like cells within STS could represent sarcoma initiating cells. Methods: To target rare human cell populations including MSCs, an exclusive antibody panel was developed. The target antigens include platelet-derived growth factor receptor-β (CD140b), HER-2/erbB2 (CD340), TNFRSF16 (CD217), frizzled-4 (CD344), the recently described W8B2 antigen, as well as several surface antigens identified by novel antibodies. To define the expression pattern of MSC-markers in STS, both cell lines and primary tumor samples in suspension and in snap frozen sections were investigated. To reveal functional differences between identified rare tumor populations single cell proliferation kinetics were investigated after FACS-sorting. Results: All cell lines und primary tumor samples revealed expression of selected markers. Antigens identifying subpopulations within all sarcoma samples investigated, were selected for functional studies. These included frizzled-4, TNFRSF16, W5C5 and W8B2. Liposarcoma (SW872), leiomyosarcoma (SK-LMS) and fibrosarcoma (HT1080) cell lines enclosed subpopulations with differential expression of above markers and by FACS based limiting dilution it was demonstrated that only fractions of viable cells contained proliferative capacity. Cells lacking expression of CD271 had lower proliferative capacity compared to mock sorted HT1080 or SK-LMS, while CD271+ SW872 had significantly higher proliferation. The antigen defined by W5C5 identified cells with high proliferative capacity compared to control in SW872 and SK-LMS and its lack in HT1080 identified a subpopulation with largely reduced proliferation. Conclusions: Subpopulations within STS cell lines and primary sarcoma tissue express novel MSC-markers and display increased proliferative capacity, potentially reflecting the existence of sarcoma initiating cells. No significant financial relationships to disclose.
Association of Suicidality and Depression With 5α-Reductase Inhibitors
Authors: Blayne Welk, Eric McArthur, Michael Ordon, Kelly K. Anderson, Jade Hayward, Stephanie Dixon
Journal: JAMA Internal Medicine (2017)

There have been concerns raised by patients and regulatory agencies regarding serious psychiatric adverse effects associated with 5α-reductase inhibitors.To determine if there is an increased risk of suicide, self-harm, or depression among older men starting a 5α-reductase inhibitor for prostatic enlargement.A population-based, retrospective, matched cohort study using linked administrative data for 93 197 men ages 66 years or older (median [IQR] age, 75 [70-80] years) in Ontario, Canada, who initiated a new prescription for a 5α-reductase inhibitor during the study period (2003 through 2013). Participants were matched (using a propensity score that included 44 of our 96 covariates that included medical comorbidities, medication usage, and health care system utilization) to an equal number of men not prescribed a 5α-reductase inhibitor.Duration of finasteride or dutasteride usage.Suicide. Secondary outcomes were self-harm and depression.Men who used 5α-reductase inhibitors were not at a significantly increased risk of suicide (HR, 0.88; 95% CI, 0.53-1.45). Risk of self-harm was significantly increased during the initial 18 months after 5α-reductase inhibitor initiation (HR, 1.88; 95% CI, 1.34-2.64), but not thereafter. Incident depression risk was elevated during the initial 18 months after 5α-reductase inhibitor initiation (HR, 1.94; 95% CI, 1.73-2.16), and continued to be elevated, but to a lesser degree, for the remainder of the follow-up period (HR, 1.22; 95% CI, 1.08-1.37). The absolute increases in the event rates for these 2 outcomes were 17 per 100 000 patient-years and 237 per 100 000 patient-years, respectively. The type of 5α-reductase inhibitor (finasteride or dutasteride) did not significantly modify the observed associations with suicide, self-harm, and depression.In a large cohort of men ages 66 years or older, we did not demonstrate an increased risk of suicide associated with 5α-reductase inhibitor use. However, the risk of self-harm and depression were increased compared with unexposed men. This is in keeping with postmarketing experience and patient concerns, and discontinuation of the medication in these circ umstances may be appropriate.
Layered Fibrotic Plaques Are the Predominant Component in Cardiac Allograft Vasculopathy
Authors: Tor Skibsted Clemmensen, Niels Ramsing Holm, Hans Eiskjær, Brian Bridal Løgstrup, Evald Høj Christiansen, Jouke Dijkstra, Trine Ørhøj Barkholt, Christian Juhl Terkelsen, Michael Maeng, Steen Hvitfeldt Poulsen
Journal: JACC. Cardiovascular imaging (2017)
Using next-generation sequencing (NGS) to identify causative mutations in Asian cancer (CA) patients with suspected Lynch syndrome.
Authors: Samuel Guan Wei Ow, Kar Tong Tan, Henry Yang, Hui-Ling Yap, Nur Sabrina Binte Sapari, Richie Chuan Teck Soong, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2014)

1540 Background: Although at least 6 known genes are implicated in the causation of Lynch Syndrome (LS), up to 50% of suspected cases are due to undefined genes. We utilised NGS to characterize the mutation profile of high risk CA patients suspected with LS. Methods: We enrolled 96 Asian CA patients from our CA Genetics Clinic from 2000 to 2012 with family history (FH) suspicious for LS, and obtained germline DNA for targeted sequencing of 94 CA-predisposition genes using TruSight Cancer (Illumina Inc, San Diego, USA) on the MiSeq platform. Polymorphisms at >1% frequency were removed using 1000 Genomes (Asian) and the remaining non-synonymous variants were classified with reference from InSiGHT database. Results: Of the 96 index patients, 81.3% were Chinese, median age at CA diagnosis was 45.5 (range 18-82), 85.4% and 8.3% each had colon CA (CRC) and a LS-like CA. 5/96 patients had FH that fulfilled Amsterdam I/II Criteria (AC), 38 had FH of CRC and at least 1 first degree relative (FDR) with LS-like CA, 28 had CRC with histopathological features suggestive of LS, 30 had young-onset CA <50y (26 CRC, 4 LS-like CA), and 4 had more than 1 primary LS-related CA. 24 cases (not fulfilling AC) have been sequenced to date with a minimum depth of 400X. Among classical LS-related genes, 2/24 patients were found with deleterious mutations in MSH2 (nonsense mutation at 1255C>T; splicing mutation at 942G>A), 2/24 with insertion mutation in MSH6 resulting in frameshift (4065_4066insTTGA) and 1/24 had a possibly deleterious missense mutation in MLH1 (1058C>T). In addition, 18 nonsense mutations were found in the coding regions of AIP, BRIP1, BMPR1A, CEP57, CHRNA3, ERCC2, FANCD2, FANCM, GATA4, GPC3, MLPH, NSD1, PTCH1, TIMM10B and XPC which warrant further investigations. 15 novel variants in the classical LS-related genes were detected (2 MLH1, 6 MSH2, 2 MSH6, 1 PMS1, 1 PMS2, 3 EPCAM) of which EPCAM 344T>A and 515C>A occurred in 21 and 6 index patients respectively. Conclusions: Genetic variants unique to Asian high risk CA patients have been revealed in this study. NGS is a feasible and cost-efficient way to screen for causative mutations in a spectrum of genes in CA patients suspected to have a hereditary predisposition.
Immunological effects as a biomarker of chemotherapy in metastatic colorectal cancer.
Authors: Teruo Sasatomi, Yutaka Ogata, Hideaki Yamana, Yoshito Akagi, Kazuo Shirouzu
Journal: Journal of Clinical Oncology (2012)

e14077 Background: Many multiple anti cancer drugs regimens have been established for metastatic colorectal cancer recently. We investigated cellular immunoreaction of these patients to their cancer. Methods: 26 metastatic colorectal cancer patients have been started chemotherapies. Their PBMC were harvested and investigated their character by Fac scan with fluorescent labeled antibodies (CD3, CD8, CD4, CD25, Foxp3) at before and after chemotherapy. Results: After chemotherapy, both CTLs (CD3, CD8 positive) and regulatory T cells (CD4, CD25, Foxp3 positive) were decreased in number among all patients. On the other hand, CTL/T reg ratio were significantly increased among tumor marker decreased patients and significantly decreased among tumor marker increased or stable patients. CEA levels among 85.7% of increased CTL/T reg ratio patients became to decrease less than half. CEA levels among 66.7% of decreased CTL/T reg ratio patients became to increase or to be stable, if their regimens have not been changed. The Reactive Rate of chemotherapy of CTL/T reg ratio increased patients was significantly higher than that of ratio decreased patients. (p=0.021) The Disease Control Rate of chemotherapy of CTL/T reg ratio increased patients was higher than that of ratio decreased patients. Conclusions: We found that the CTL/T reg ratio of PBMC in metastatic colorectal cancer patients were useful for prediction of the effect of chemotherapy.
Exploratory biomarker analyses from ECOG 4508: Three-arm randomized phase II study of carboplatin (C) and paclitaxel (P) in combination with cetuximab (CET), IMC-A12, or both for advanced non-small cell lung cancer (NSCLC) patients (pts).
Authors: Charu Aggarwal, Suzanne Eleanor Dahlberg, Nasser Hanna, Jill Kolesar, Fred R. Hirsch, Suresh S. Ramalingam, Joan H. Schiller
Journal: Journal of Clinical Oncology (2013)

8106 Background: ECOG 4508 was a phase II study that randomized advanced NSCLC pts that were not candidates for bevacizumab to receive: C + P iv on day 1 every 3 wks with either CET iv weekly (arm A, n=39), IMC-A12 iv every 2 wks (arm B, n=42), or both (arm C, n=48). The study was closed prematurely due to safety concerns after 129 eligible pts were treated. The study failed to meet its primary objective (Hanna et al ASCO 2012). Methods: Tumor samples were analyzed by immunohistochemistry (IHC; EGFR, IGF-1R and IGF-2R expression), fluorescent in-situ hybridization (FISH; EGFR gene copy number) and DNA sequencing (EGFR, KRAS gene mutations). Time-to-event distributions were estimated using the Kaplan-Meier method, and differences were tested using the logrank test. Cox proportional hazards models were fitted to estimate hazard ratios. Results: Histology: 38% squamous cell, 39% adenocarcinoma, 2% BAC, 5% NOS and 6% other. OS was similar in EGFR FISH+ (Colorado classification system, n=30/70, 43%) vs EGFR FISH- pts (57%), (9.5 mos vs 8.6 mos, HR=0.62, p=0.08). For EGFR FISH+ pts, there was no difference in outcomes with CET (n=19, OS=9.7 mos, PFS=4.1 mos) vs no CET (n=11, OS=9.5 mos, PFS=5.5 mos). EGFR and KRAS mutations were detected in 6% (5/80) and 22% (6/27) of the pts respectively, but sample sizes were not large enough for robust testing. EGFR and IGFR IHC hybrid (H) scores were assessed on 98/102 available samples (Arm A=29, Arm B=34, Arm C=35). Median H scores (and range): IGF-1R: 190 (30-390), IGF-2R: 145 (20-350), EGFR membrane and cytoplasm: 190 (0-380) and EGFR membrane only: 160 (0-390). With IGF-1R and IGF-2R H score &gt; 200, there was no association with OS (HR 1.3, p=0.26; HR 1.4, p=0.28) or PFS (HR=1.1, p=0.67; HR=1.2, p=0.56), adjusted for whether or not IMCA12 was received. Similarly, no associations with OS or PFS were seen with EGFR membrane H score &gt; 200, adjusted for CET administration (OS HR=0.89, p=0.64; PFS HR 1.1, p=0.62). Conclusions: There was no correlation between EGFR FISH or H score and outcomes with CET. IGF-1R and IGF-2R expression was not predictive of favorable outcome with IMC-A12. Clinical trial information: NCI-2011-01976.