tbuckley/cabot-search huggingface dataset:
Reoperation and Medicare Expenditures After Laparoscopic Gastric Band Surgery
Authors: Andrew M. Ibrahim, Jyothi R. Thumma, Justin B. Dimick
Journal: JAMA Surgery (2017)

Following the US Food and Drug Administration approval for laparoscopic gastric band surgery in 2001, as many as 96 000 devices have been placed annually. The reported rates of reoperation range from 4% to 60% in short-term studies; however, to our knowledge, few long-term population-level data on outcomes or expenditures are known.To describe the rate of device-related reoperations occurring after laparoscopic gastric band surgery as well as the associated payments in a longitudinal national cohort.This retrospective review of 25 042 Medicare beneficiaries who underwent gastric band placement between 2006 and 2013 identifies gastric band-related reoperations, including device removal, device replacement, or revision to a different bariatric procedure (eg, a gastric bypass or sleeve gastrectomy). The rates of reoperation were risk adjusted using a multivariable logistic regression model that included patient age, sex, race/ethnicity, Elixhauser comorbidities, and the year that the operation was performed.Rate of device-related reoperation nationally and across individual hospital referral regions. Thirty-day total episode Medicare payments to hospitals for the index operation and any subsequent reoperations.Of the 25 042 patients who underwent gastric band placement, 20 687 (82.61%) were white, 18 143 (72.45%) were women, and the mean age was 57.56 years. Patients (mean age, 57.5; 76.2% women) requiring reoperation had lower rates of hypertension (64.9% vs 73.4%; P < .001) and diabetes (40.4% vs 44.6%; P < .001) and were more likely to have their index operation at a for-profit hospital (34.6% vs 22.0%; P < .001). With an average of 4.5-year follow-up, 4636 patients (18.5%) underwent 17 539 reoperations (an average of 3.8 procedures/patient). Hospital referral regions demonstrated a 2.9-fold variation in risk- and reliability-adjusted rates of reoperation (lower quartile average, 13.3%; upper quartile average, 39.1%). During the study period, Medicare paid $470 million for laparoscopic gastric band associated procedures, of which $224 million (47.6%) of the payments were for reoperations. From 2006 to 2013, the proportion of payments from Medicare for reoperations increased from 16.4% to 77.3% of their annual spending on the gastric band device.Among Medicare beneficiaries undergoing gastric band surgery, device-related reoperation was common, costly, and varied widely across hospital referral regions. These findings suggest that payers should reconsider their coverage of the gastric band device.
Tumor-Associated Macrophages Promote Malignant Progression of Breast Phyllodes Tumors by Inducing Myofibroblast Differentiation
Authors: Yan Nie, Jianing Chen, Di Huang, Yandan Yao, Jiewen Chen, Lin Ding, Jiayi Zeng, Shicheng Su, Xue Chao, Fengxi Su, Herui Yao, Hai Hu, Erwei Song
Journal: Cancer Research (2017)

Abstract Myofibroblast differentiation plays an important role in the malignant progression of phyllodes tumor, a fast-growing neoplasm derived from periductal stromal cells of the breast. Macrophages are frequently found in close proximity with myofibroblasts, but it is uncertain whether they are involved in the myofibroblast differentiation during phyllodes tumor progression. Here we show that increased density of tumor-associated macrophage (TAM) correlates with malignant progression of phyllodes tumor. We found that TAMs stimulated myofibroblast differentiation and promoted the proliferation and invasion of phyllodes tumor cells. Furthermore, we found that levels of the chemokine CCL18 in TAM was an independent prognostic factor of phyllodes tumor. Mechanistic investigations showed that CCL18 promoted expression of α-smooth muscle actin, a hallmark of myofibroblast, along with the proliferation and invasion of phyllodes tumor cells, and that CCL18-driven myofibroblast differentiation was mediated by an NF-κB/miR-21/PTEN/AKT signaling axis. In murine xenograft models of human phyllodes tumor, CCL18 accelerated tumor growth, induced myofibroblast differentiation, and promoted metastasis. Taken together, our findings indicated that TAM drives myofibroblast differentiation and malignant progression of phyllodes tumor through a CCL18-driven signaling cascade amenable to antibody disruption. Cancer Res; 77(13); 3605–18. ©2017 AACR.
Water Concentration Analysis of the Surgical Margin—Letter
Authors: C. Murali Krishna, Aditi Sahu
Journal: Cancer Research (2017)

Raman spectroscopy is being pursued as a potential tool in the management of oral cancers that are major cancers and are plagued by very poor survival rates. In the October issue of Cancer Research, Barroso and colleagues demonstrated the utility of high-wave number region (water band) in surgical demarcation (1), an important aspect of oral cancer management. Our in vivo clinical trials, which were carried out in the fingerprint region, demonstrated efficacy of this method in delineating precancers, cancers, and cancer field effects in oral cancers (2–4). As is well known, high-wave number region is free from fiber Raman and offers several advantages, such as further miniaturization of clinical Raman instrumentation for in vivo applications' point of view. Hence, we evaluated fingerprint vis-a-vis high-wave number Raman in buccal and tongue cancers. Raman spectra were recorded from buccal (n = 40) and tongue cancer (n = 40) subjects in 500 to 3500 cm−1 from tumor and contralateral regions. Preprocessed spectra in 1200 to 1800 cm−1 and 2700 to 3500 cm−1 regions were subjected to average spectral comparisons and analyzed by principal component–based linear discriminant analysis. Spectral acquisition, preprocessing, and analysis protocols are described in detail elsewhere (2–4). Results suggest fingerprint region gave better classification for buccal, tongue, and pooled (buccal + tongue) conditions (Fig. 1), which is in contrast to the findings by Barroso and colleagues. This could be due to the instrumentation employed. Our study was carried out using fiber optic Raman with a probing area of 200 μm and 1 mm depth. Some influence of differences in subject population and etiologic factors cannot be ruled out. Tobacco chewing is the major cause of oral cancers among Indians.Our concern is misclassifications between contralaterals and tumor, which are indicative of similarities in biochemical compositions. As contralaterals are from clinically normal appearing areas, no definitive diagnostics could be carried out and was accounted for by the heterogeneity present within tumors, that is, normal islands in tumors. But often, head and neck cancers are known to arise from a preexisting field of genetically altered cells. Field cancerization, which can affect the entire oral cavity and also ascribes to the incidence of recurrences/second primaries despite curative treatment, is a plausible cause of poor survival rates. Our experimental carcinogenesis studies indicated misclassification between control and treated conditions and subsequently corroborated as dysplastic/squamous cell carcinoma (5). Hence, future Raman studies should investigate these advanced cancer fields, in addition to surgical boundaries, as there are no early detection methods of recurrence/secondary primaries, as recurrence/secondary primaries are of serious concern in oral cancer management.See the Response, p. 3123No potential conflicts of interest were disclosed.
Phase I study of oral rigosertib in patients with advanced solid tumors.
Authors: Daniel W. Bowles, Jennifer Robinson Diamond, Elaine Tat Lam, Wells A. Messersmith, Colin D. Weekes, Stephen Leong, Lia Gore, Christopher Hanyoung Lieu, Elizabeth Freas, Chen Ren, Francois Wilhelm, S. Gail Eckhardt, Antonio Jimeno
Journal: Journal of Clinical Oncology (2012)

3017 Background: Rigosertib (ON 01910.Na) is a new multi-targeted inhibitor of several kinases, including polo-like kinase 1 and PI-3 kinase, and is in advanced trials for myelodysplastic syndrome and pancreatic cancer as an IV agent. An oral formulation with good oral bioavailability has entered phase 1 in patients (pts) with advanced solid tumors to determine the dose limiting toxicities (DLT), recommended phase II dose, pharmacokinetic (PK) profiles, and to document any antitumor activity of this compound. Methods: Pts with histologically confirmed solid tumors refractory to standard therapy were given escalating doses of rigosertib (70, 140, 280, 560, 700 mg) twice daily continuously. Doses were escalated until intolerable grade 2 or grade 3/4 toxicities, at which point the previous dose level was expanded to define the MTD. All pts were assessed for safety, PK, PD and response. Urinary PK assessments were also performed at the MTD. Results: 25 pts (median age= 59; median ECOG PS= 1) received a median of 6 weeks of therapy at 5 dose levels: (70 mg n=3; 140 mg n=2 ; 280 mg n=3; 560 mg n=10; 700 mg n=7). The DLT was dysuria at 700 mg and led to expansion at 560 mg bid. There were no DLTs in the expansion cohort. Grade 2/3 toxicities related to rigosertib included dysuria (5/1), cystitis (4/0), urinary frequency (3/0), hematuria (2/1), abdominal pain (2/0), pelvic pain (1/1), nausea (1/0), distention/bloating (1/0) and hyponatremia (0/1). Improvements in dysuria were seen with oral hydration and sodium bicarbonate. A confirmed PR occurred in 1 pt (HN squamous cell ca, 42+ weeks), and SD was observed in 2 pts with ovarian cancer (56 weeks, 28 weeks), and 1 pt each with pancreatic neuroendocrine (40 weeks), carcinoid (32 weeks), nasopharyngeal (24 weeks) and renal cell (32+ weeks) tumors. Preliminary PK data reveal plasma rigosertib levels above the predicted pharmacodynamically active levels. Conclusions: The MTD of oral rigosertib administered twice daily continuously is 560mg. Dysuria is the dose limiting and most common toxicity and can be managed with oral hydration and sodium bicarbonate. Antitumor activity has been observed. Final safety and efficacy results, plasma and urinary PK relationships, and mutational analyses from archival tissue will be presented.
ACTH Stimulation Tests and Plasma Dehydroepiandrosterone Sulfate Levels in Women with Hirsutism
Authors: Selma F. Siegel, David N. Finegold, Roberto Lanes, Peter A. Lee
Journal: New England Journal of Medicine (1990)

Hirsutism in women is a clinical manifestation of excessive production of androgens. The source of the excess androgen may be either the ovaries or the adrenal glands, and distinguishing between these sources may be difficult.
An imprinted non-coding genomic cluster at 14q32 defines clinically relevant molecular subtypes in osteosarcoma across multiple independent datasets
Authors: Katherine E. Hill, Andrew D. Kelly, Marieke L. Kuijjer, William Barry, Ahmed Rattani, Cassandra C. Garbutt, Haydn Kissick, Katherine Janeway, Antonio Perez-Atayde, Jeffrey Goldsmith, Mark C. Gebhardt, Mohamed S. Arredouani, Greg Cote, Francis Hornicek, Edwin Choy, Zhenfeng Duan, John Quackenbush, Benjamin Haibe-Kains, Dimitrios Spentzos
Journal: Journal of Hematology & Oncology (2017)

A microRNA (miRNA) collection on the imprinted 14q32 MEG3 region has been associated with outcome in osteosarcoma. We assessed the clinical utility of this miRNA set and their association with methylation status.We integrated coding and non-coding RNA data from three independent annotated clinical osteosarcoma cohorts (n = 65, n = 27, and n = 25) and miRNA and methylation data from one in vitro (19 cell lines) and one clinical (NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) osteosarcoma dataset, n = 80) dataset. We used time-dependent receiver operating characteristic (tdROC) analysis to evaluate the clinical value of candidate miRNA profiles and machine learning approaches to compare the coding and non-coding transcriptional programs of high- and low-risk osteosarcoma tumors and high- versus low-aggressiveness cell lines. In the cell line and TARGET datasets, we also studied the methylation patterns of the MEG3 imprinting control region on 14q32 and their association with miRNA expression and tumor aggressiveness.In the tdROC analysis, miRNA sets on 14q32 showed strong discriminatory power for recurrence and survival in the three clinical datasets. High- or low-risk tumor classification was robust to using different microRNA sets or classification methods. Machine learning approaches showed that genome-wide miRNA profiles and miRNA regulatory networks were quite different between the two outcome groups and mRNA profiles categorized the samples in a manner concordant with the miRNAs, suggesting potential molecular subtypes. Further, miRNA expression patterns were reproducible in comparing high-aggressiveness versus low-aggressiveness cell lines. Methylation patterns in the MEG3 differentially methylated region (DMR) also distinguished high-aggressiveness from low-aggressiveness cell lines and were associated with expression of several 14q32 miRNAs in both the cell lines and the large TARGET clinical dataset. Within the limits of available CpG array coverage, we observed a potential methylation-sensitive regulation of the non-coding RNA cluster by CTCF, a known enhancer-blocking factor.Loss of imprinting/methylation changes in the 14q32 non-coding region defines reproducible previously unrecognized osteosarcoma subtypes with distinct transcriptional programs and biologic and clinical behavior. Future studies will define the precise relationship between 14q32 imprinting, non-coding RNA expression, genomic enhancer binding, and tumor aggressiveness, with possible therapeutic implications for both early- and advanced-stage patients.
CaMKII Autophosphorylation Is Necessary for Optimal Integration of Ca 2+ Signals during LTP Induction, but Not Maintenance
Authors: Jui-Yun Chang, Paula Parra-Bueno, Tal Laviv, Erzsebet M. Szatmari, Seok-Jin R. Lee, Ryohei Yasuda
Journal: Neuron (2017)
Abstract P075: Neuronal Nitric Oxide Synthase Contributes to the Beneficial Cardiac Effects of Exercise
Authors: Steve R Roof, Joseph Ostler, Muthu Periasamy, Mark T Ziolo
Journal: Circulation Research (2011)

Exercise results in beneficial adaptations to the heart. These adaptations are observed at the level of the cardiomyocyte as increased Ca2+ cycling through the sarcoplasmic reticulum (SR) and greater fractional shortening. Interestingly, these adaptations are similar to the contractile effects of neuronal nitric oxide synthase (NOS1) signaling. Thus our objective is to determine if the exercise induced adaptations at the level of the cardiomyocyte are NOS1 mediated. After an 8 week high-intensity aerobic interval training program, exercise (Ex) mice had a higher VO2max, greater citrate synthase activity, decreased weight, increased heart-to-body ratio (P&lt;0.05), but similar heart-to-tibia ratio compared to sedentary (Sed) mice. Isolated ventricular myocytes from the Ex mice exhibited larger Ca2+ transient and shortening amplitudes and faster Ca2+ transient decline rates (RT50) compared to Sed myocytes (P&lt;0.05). There was also greater NOS1 expression levels in Ex ventricular myocytes (P&lt;0.05 vs Sed). The greater NOS1 expression was observed functionally in myocyte contraction. That is, acute inhibition of NOS1 by S-methyl-L-thiocitrulline (SMLT) resulted in a greater reduction in Ca2+ transient amplitude, Ca2+ transient RT50, shortening amplitude, SR Ca2+ load, and SR Ca2+ fractional release in Ex versus Sed (P&lt;0.05). Furthermore, acute NOS1 inhibition (SMLT) normalized the Ex induced increase in contraction (Ca2+ transients and shortening) and Ca2+ decline rates to Sed levels. These data demonstrate that the enhanced Ca2+ cycling through the SR observed after a training period is, in part, due to NOS1 signaling. Thus, NOS1 is a major contributor to the increased contractile amplitudes and relaxation observed with exercise. Hence, mimicking the beneficial effects of exercise to the heart may be obtainable by enhancing NOS1 signaling. This pathway may be a novel therapeutic for cardiac patients that are unable/unwilling to exercise.
Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses
Authors: Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Rolando Perez-Lorenzo, Basil Horst, Matei Banu, Kevin A. Roth, Jeffrey N. Bruce, Peter Canoll, Dario C. Altieri, Markus D. Siegelin
Journal: Cancer Research (2017)

Rational therapeutic approaches based on synthetic lethality may improve cancer management. On the basis of a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL, and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and obatoclax) or selective (ABT199, WEHI-539, and A1210477), along with the established mitochondrial matrix chaperone inhibitor gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer, and patient-derived orthotopic xenografts (PDX) of human glioblastoma. We found that combining BH3 mimetics and gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL, or Mcl-1 recapitulated the effects of BH3 mimetics and enhanced the effects of gamitrinib-TPP. Mechanistic investigations revealed that gamitrinib-TPP activated a PERK-dependent integrated stress response, which activated the proapoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments. Cancer Res; 77(13); 3513-26. ©2017 AACR.
Hepatic infiltration by silicone in a patient With ASIA syndrome
Authors: Iván Posso‐Osorio, Tatiana Méndez‐Rayo, Carlos‐Andrés Jimenez, Diana Escobar, Mauricio Sepúlveda, Erika‐Paola Navarro, Gabriel J. Tobón
Journal: Hepatology (2017)

Posso‐Osorio, Iván; Méndez‐Rayo, Tatiana; Jimenez, Carlos‐Andrés; Escobar, Diana; Sepúlveda, Mauricio; Navarro, Erika‐Paola; Tobón, Gabriel J. Author Information
18F-FDG PET/CT of Malignant Angiomyolipoma With Tumor Thrombus
Authors: Andrew Griffin
Journal: Clinical Nuclear Medicine (2017)

Renal angiomyolipomas are the most common renal mesenchymal tumors. While classic angiomyolipomas are benign, there are a number of other subtypes. Epithelioid variants are potentially malignant and may be indistinguishable from renal cell carcinoma on imaging. We present a 52-year-old woman who underwent left nephrectomy for an aggressive-appearing malignant renal epithelioid angiomyolipoma. At 6 months postoperatively, restaging FDG PET/CT demonstrated a hypermetabolic left adrenal mass extending to the left adrenal vein, left renal vein, inferior vena cava, and right atrium (SUVmax = 12). Multiple hypermetabolic pulmonary metastases were also noted.
RNF8 mediates histone H3 ubiquitylation and promotes glycolysis and tumorigenesis
Authors: Yan Xia, Weiwei Yang, Ming Fa, Xinjian Li, Yugang Wang, Yuhui Jiang, Yanhua Zheng, Jong-Ho Lee, Jing Li, Zhimin Lu
Journal: The Journal of Experimental Medicine (2017)

Disassembly of nucleosomes in which genomic DNA is packaged with histone regulates gene expression. However, the mechanisms underlying nucleosome disassembly for gene expression remain elusive. We show here that epidermal growth factor receptor activation results in the binding of the RNF8 forkhead-associated domain to pyruvate kinase M2-phosphorylated histone H3-T11, leading to K48-linked polyubiquitylation of histone H3 at K4 and subsequent proteasome-dependent protein degradation. In addition, H3 polyubiquitylation induces histone dissociation from chromatin, nucleosome disassembly, and binding of RNA polymerase II to MYC and CCND1 promoter regions for transcription. RNF8-mediated histone H3 polyubiquitylation promotes tumor cell glycolysis and proliferation and brain tumorigenesis. Our findings uncover the role of RNF8-mediated histone H3 polyubiquitylation in the regulation of histone H3 stability and chromatin modification, paving the way to gene expression regulation and tumorigenesis.
Factors influencing telomere length in BRCA-mutation carriers.
Authors: Emer M. Guinan, Sarah A. McGarrigle, Michael John Kennedy, Juliette M. Hussey, David James Gallagher, Terence Boyle, Dhafir Alazawi, E. M. Connolly
Journal: Journal of Clinical Oncology (2015)

e12584 Background: Lifestyle mediators of sporadic breast cancer (BC) risk include physical inactivity, obesity and dysmetabolism. Little is known about the influence of these factors on genetically mediated BC risk. Increasingly, telomere length is being investigated as a biomarker of accumulated cellular damage that may be influenced by lifestyle behaviors. We report results from an ongoing prospective investigation of factors influencing breast cancer risk in BRCA1/2-mutation carriers unaffected by BC examining the association between telomere length and lifestyle factors. Methods: Female BRCA1/2-mutation carriers unaffected by BC were recruited from St James’s Hospital Dublin Ireland. Fasting blood samples were drawn to measure metabolic profile (insulin, glucose glycosylated haemoglobin A1c (HBA1C) and lipid profile) and peripheral blood mononuclear cells (PBMCs). Telomere length was measured from DNA isolated from PBMCs. Body composition was assessed by body mass index and waist circumference and physical activity was assessed objectively by accelerometry and subjectively by the Minnesota Leisure Time Physical Activity Questionnaire. Associations were examined by correlation analysis. Results: To date, data has been analyzed from 73 participants (mean age 42.8 (9.3) years). Over two-thirds of participants were either overweight (37%) or obese (34%) and 72% were centrally obese (waist circumference > 80cm). Metabolic syndrome was diagnosed in 24% of participants and 93% were physically inactive. An association was observed between age-adjusted relative telomere length and measures of dysmetabolism including prevalence of metabolic syndrome features (r = 0.43, p = 0.01) and HBA1c (r = 0.4, p = 0.03). No association was observed between telomere length and either body composition or physical activity. Conclusions: Unhealthy lifestyle patterns (physical inactivity, overweight, obesity and metabolic syndrome) are evident in this Irish cohort of BRCA-mutation carriers. An association between dysmetabolism and shorter telomere length was observed in this population. This may indicate a mechanism through which the consequences of an unhealthy lifestyle influence BC risk and warrants prospective investigation.
Oil-Based or Water-Based Contrast for Hysterosalpingography in Infertile Women
Authors: Kim Dreyer, Joukje van Rijswijk, Velja Mijatovic, Mariëtte Goddijn, Harold R. Verhoeve, Ilse A.J. van Rooij, Annemieke Hoek, Petra Bourdrez, Annemiek W. Nap, Henrike G.M. Rijnsaardt-Lukassen, Catharina C.M. Timmerman, Mesrure Kaplan, Angelo B. Hooker, Anna P. Gijsen, Ron van Golde, Cathelijne F. van Heteren, Alexander V. Sluijmer, Jan-Peter de Bruin, Jesper M.J. Smeenk, Jacoba A.M. de Boer, Eduard Scheenjes, Annette E.J. Duijn, Alexander Mozes, Marie J. Pelinck, Maaike A.F. Traas, Machiel H.A. van Hooff, Gijsbertus A. van Unnik, Cornelia H. de Koning, Nan van Geloven, Jos W.R. Twisk, Peter G.A. Hompes, Ben W.J. Mol
Journal: New England Journal of Medicine (2017)

Pregnancy rates among infertile women have been reported to increase after hysterosalpingography, but it is unclear whether the type of contrast medium used (oil-based or water-soluble contrast) influences this potential therapeutic effect.