tbuckley/cabot-search huggingface dataset:
Interleukin 17 in the tumor microenvironment: A potent target for anticancer immunotherapy?
Authors: Joseph Fabre, Jérôme Giustiniani, Stéphanie Servagi-Vernat, Christian Garbar, Yacine Merrouche, Frank Antonicelli, Armand Bensussan
Journal: Journal of Clinical Oncology (2017)

115 Background: Inflammation has been known to play a critical role in cancer for decades. Tumors build up on the “inflammatory soup” in the surrounding microenvironment to progress, grow, metastasize and evade immune response. Since its discovery in the nineties, interleukin-17 (IL-17A), a proinflammatory cytokine mainly secreted by T helper 17 cells, has been extensively studied in chronic inflammatory diseases like psoriasis or rheumatoid arthritis. In solid malignancies, there is growing evidence that IL-17 enhances cancer cells’ capacity of division, invasion and chemotherapy resistance. Methods: Based on our team's experience and publications, we systematically reviewed the existing literature about the role of IL-17 in cancers, in aim to discuss if developing IL-17 pathway-targeting strategies could be effective. Results: Data from several preclinical studies indicated tumor-promoting effects of IL-17 on diverse cancer models, cellular or murine. In clinical studies, detection of high levels of IL-17 in patients’ blood or tumors was correlated to bad prognosis. Concordantly, we reported recently in triple negative breast cancer cell lines that IL-17A and IL-17E promoted resistance to Docetaxel and failed to induce apoptosis as previously observed for IL-17E by other authors. Interestingly, we also revealed that both cytokines induced the generation of tumorigenic low molecular weight forms of cyclin E (LMW-E), which high levels correlated strongly with a poor survival in breast cancer patients. Lastly, we reported a crosstalk between IL-17E and epidermal growth factor signaling, which confers in vitro resistance to EGFR-targeted therapies. In opposition, a few studies observed that IL-17 inhibited tumor grafts development and metastasis in rodent possibly through the expression of other proinflammatory mediators such as IL-1β, TNFα, IL-6 or GM-CSF and the recruitment of neutrophils to the tumor site. Conclusions: Most of the literature supports a critical role of IL-17 in cancer promotion and development. These results encourage us to present the IL-17 family members and their receptors as potent targets for anticancer biotherapy.
ENGAGE: Evaluation of a streamlined oncologist-led <i>BRCA</i> mutation (<i>BRCA</i>m) testing and counselling model for patients with ovarian cancer.
Authors: Nicoletta Colombo, Giovanni Scambia, Eva Chalas, Gloria S. Huang, Sandro Pignata, James Fiorica, Linda Van Le, Sharad A. Ghamande, Santiago Gonzalez Santiago, Isabel Bover, Begoña Graña Suárez, Andrew Emmons Green, Philippe Huot-Marchand, Yann Bourhis, Sudeep Karve, Christopher Blakeley
Journal: Journal of Clinical Oncology (2017)

5559 Background: Short BRCAm testing turnaround times (TAT) are crucial to making timely treatment decisions for patients (pts) with ovarian cancer. ENGAGE (NCT02406235; D0816R00006) evaluated a streamlined, oncologist-led germline BRCAm testing model, piloted by the Institute of Cancer Research and the Royal Marsden Hospital, London, UK. Results presented are from the final analysis (data cut-off: 30 Sep 2016). Methods: This prospective, observational study enrolled pts with ovarian cancer across sites in the US (n = 11), Italy (n = 8) and Spain (n = 7). Oncologists and nurses at participating sites were trained on genetic counselling techniques relating to BRCAm testing. Primary endpoints were BRCAm testing TAT (time from initial counselling to the provision of test results or post- BRCAm test counselling [whichever occurred latest]); pts’ satisfaction with the oncogenetic testing model, evaluated using pre- and post- BRCAm testing surveys; and clinicians’ opinion on the value of this new testing pathway, evaluated using a post- BRCAm testing survey. Results: For the 700 evaluable pts enrolled (US = 317; EU = 383), pre- BRCAm testing counselling was carried out by either an oncologist (40.7%) or clinical staff (nurse or research coordinator; 59.3%) in the US, and only by oncologists in the EU. The median overall TAT was 9.1 weeks (all pts), with 12.0 weeks in Spain, 20.4 weeks in Italy (17.4 weeks EU median) and 4.1 weeks in the US. The differences were mainly due to the time from BRCAm testing to obtaining the test results. Satisfaction with the overall counselling was high amongst pts, with a mean dimension score rating of 3.8/4 (where 4.0 = highest satisfaction). 93.6% of pts were happy to have received genetic testing as part of an existing oncologist appointment, and more than 80% of oncologists were satisfied with the screening process, agreeing that it was an efficient use of their time. Conclusions: The ENGAGE study results show that a streamlined oncologist-led BRCAm testing model can offer reduced TAT and high levels of satisfaction amongst pts and clinicians. The success of this model is enhanced by access to a BRCAm testing facility, from which results can be obtained quickly. Clinical trial information: NCT02406235; D0816R00006.
143PD Competing central nervous system or systemic progression analysis for patients with EGFR mutation-positive NSCLC receiving afatinib in LUX-Lung 3, 6, and 7
Authors: J.C-H. Yang, Y-L. Wu, V. Hirsh, K. O'Byrne, N. Yamamoto, S. Popat, A. Tamiya, A. Märten, M. Schuler
Journal: Journal of Thoracic Oncology (2018)
122P Pathological response rates after induction radio-chemotherapy in stage III NSCLC
Authors: F. Casas, D. Sanchez, D. Martínez, M. Boada, N. Vilariño, R. Martin, P. Paredes, I. Volmer, K.S. Cortés, M. Parera
Journal: Journal of Thoracic Oncology (2018)
A radiosensitivity gene signature and PD-L1 status to predict clinical outcome of patients with invasive breast carcinoma in the cancer genome atlas (TCGA) dataset.
Authors: In Ah Kim, Bum Sup Jang
Journal: Journal of Clinical Oncology (2017)

54 Background: A radiosensitivity gene signature that included 31 genes was identified using microarray data from NCI-60 cancer cells; however, this has not been validated in independent datasets for breast cancer patients. We investigated the link between the radiosensitivity gene signature and programmed cell death ligand 1 (PD-L1) status and clinical outcome to identify a group of patients that would possibly receive clinical benefit of radiotherapy (RT) combined with anti-PD1/PD-L1 therapy. Methods: We validated the identified gene signature related to radiosensitivity and analyzed the PD-L1 status of invasive breast cancer in The Cancer Genome Atlas (TCGA) dataset using bioinformatic tools. To validate the gene signature, 1,065 patients (or samples) were selected and divided into two clusters using a consensus clustering algorithm based on their radiosensitive (RS) or radioresistant (RR) designation according to their prognosis. Patients were also stratified as PD-L1-high or PD-L1-low based on the median value of CD274 mRNA expression level as surrogates of PD-L1. The relationship between the RS/RR groups and PD-L1 status was also assessed. The prognostic value was evaluated by Kaplan-Meier analysis and Cox proportional hazard models. Results: Patents assigned to the RS group had better 5-year recurrence-free survival (RFS) rate than patients in the RR group by univariate analysis (89% vs. 75%, p = 0.017) only when treated with RT. The RS group was independently associated with the PD-L1-high group, and CD274 mRNA expression was significantly higher in the RS group (p&lt;0.001) than the RR group. In the PD-L1-high group, the RS group had better 5-year RFS rate compared to the RR group (89% vs. 72%, p = 0.015), and this difference was also significant by Cox-hazard proportional analysis. Conclusions: The radiosensitivity gene signature and PD-L1 status were important factors for prediction of the clinical outcome of RT in patients with invasive breast cancer and may be used for selecting patients who will benefit from RT combined with anti-PD1/PDL1 therapy.
Association of Survival With Adherence to the American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors After Colon Cancer Diagnosis
Authors: Erin L. Van Blarigan, Charles S. Fuchs, Donna Niedzwiecki, Sui Zhang, Leonard B. Saltz, Robert J. Mayer, Rex B. Mowat, Renaud Whittom, Alexander Hantel, Al Benson, Daniel Atienza, Michael Messino, Hedy Kindler, Alan Venook, Shuji Ogino, Edward L. Giovannucci, Kimmie Ng, Jeffrey A. Meyerhardt
Journal: JAMA Oncology (2018)

<h3>Importance</h3> The American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors (ACS guidelines) include maintaining (1) a healthy body weight; (2) physical activity; and (3) a diet that includes vegetables, fruits, and whole grains. It is not known whether patients with colon cancer who follow these guidelines have improved survival. <h3>Objective</h3> To examine whether a lifestyle consistent with the ACS guidelines is associated with improved survival rates after colon cancer. <h3>Design, Setting, and Participants</h3> This prospective cohort study included 992 patients with stage III colon cancer who were enrolled in the CALGB 89803 randomized adjuvant chemotherapy trial from 1999 through 2001. Data for the present study were analyzed between November 2016 and December 2017. <h3>Exposures</h3> We assigned an ACS guidelines score for each included patient based on body mass index; physical activity; and intake of vegetables, fruits, whole grains, and red/processed meats (score range, 0-6, with higher score indicating healthier behaviors). Secondarily, we examined a score that also included alcohol intake in addition to the other factors (range, 0-8). Lifestyle was assessed during and 6 months after chemotherapy. <h3>Main Outcomes and Measures</h3> Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free, recurrence-free, and overall survival. <h3>Results</h3> Of the 992 patients enrolled in the study, 430 (43%) were women, and the mean (SD) age was 59.6 (11.2) years (range, 21-85 years). Over a 7-year median follow-up, we observed 335 recurrences and 299 deaths (43 deaths without recurrence). Compared with patients with a 0 to 1 ACS guidelines score (n = 262; 26%), patients with a 5 to 6 score (n = 91; 9%) had a 42% lower risk of death during the study period (HR, 0.58; 95% CI, 0.34-0.99;<i>P</i> = .01 for trend) and improved disease-free survival (HR, 0.69; 95% CI, 0.45-1.06;<i>P</i> = .03 for trend). When alcohol consumption was included in the score, the adjusted HRs comparing patients with scores of 6 to 8 (n = 162; 16%) vs those with scores of 0 to 2 (187; 91%) were 0.49 for overall survival (95% CI, 0.32-0.76;<i>P</i> = .002 for trend), 0.58 for disease-free survival (95% CI, 0.40, 0.84;<i>P</i> = .01 for trend), and 0.64 for recurrence-free survival (95% CI, 0.44-0.94;<i>P</i> = .05 for trend). <h3>Conclusions and Relevance</h3> Having a healthy body weight, being physically active, and eating a diet rich in vegetables, fruits, and whole grains after diagnosis of stage III colon cancer was associated with a longer survival. <h3>Trial Registration</h3> clinicaltrials.gov Identifier: NCT00003835
The enigma of rotator cuff tears and the case for uncertainty
Authors: Chris Littlewood, Amar Rangan, David John Beard, Julia Wade, Tina Cookson, Nadine E Foster
Journal: British Journal of Sports Medicine (2018)

Diaryliodonium salts are useful arylating reagents that have been exploited widely.In this Communication, we demonstrate that heating diphenyliodonium triflate in the solvent DMSO leads to an unexpected arylation reaction.It is postulated that arylation of DMSO at oxygen, followed by a thia-Sommelet-Hauser rearrangement, leads to the formation of 2-thiomethylphenols.More substituted diaryliodonium salts and cyclic diaryliodonium salts are shown to be more stable and less likely to react with DMSO.In conclusion, when using iodonium salts dissolved in DMSO, beware of side-reactions.
197TiP A phase 1/2 trial of selinexor combined with docetaxel for previously treated, advanced KRAS mutant non-small cell lung cancer
Authors: A. Gupta, H. West, D.R. Camidge, T.E. Stinchcombe, L. Horn, J. Saltarski, J. Bolluyt, M.A. White, D.E. Gerber
Journal: Journal of Thoracic Oncology (2018)
Zinc Inhibits Phosphate-Induced Vascular Calcification through TNFAIP3-Mediated Suppression of NF-κB
Authors: Jakob Voelkl, Rashad Tuffaha, Trang T.D. Luong, Daniel Zickler, Jaber Masyout, Martina Feger, Nicolas Verheyen, Florian Blaschke, Makoto Kuro-o, Andreas Tomaschitz, Stefan Pilz, Andreas Pasch, Kai-Uwe Eckardt, Juergen E. Scherberich, Florian Lang, Burkert Pieske, Ioana Alesutan
Journal: Journal of the American Society of Nephrology (2018)

Background The high cardiovascular morbidity and mortality of patients with CKD may result in large part from medial vascular calcification, a process promoted by hyperphosphatemia and involving osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Reduced serum zinc levels have frequently been observed in patients with CKD, but the functional relevance of this remains unclear. Methods We performed experiments in primary human aortic VSMCs; klotho-hypomorphic ( kl/kl ), subtotal nephrectomy, and cholecalciferol-overload mouse calcification models; and serum samples from patients with CKD. Results In cultured VSMCs, treatment with zinc sulfate (ZnSO 4 ) blunted phosphate-induced calcification, osteo-/chondrogenic signaling, and NF- κ B activation. ZnSO 4 increased the abundance of zinc-finger protein TNF- α –induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF- κ B pathway, by zinc-sensing receptor ZnR/GPR39-dependent upregulation of TNFAIP3 gene expression. Silencing of TNFAIP3 in VSMCs blunted the anticalcific effects of ZnSO 4 under high phosphate conditions. kl/kl mice showed reduced plasma zinc levels, and ZnSO 4 supplementation strongly blunted vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO 4 ameliorated vascular calcification in mice with chronic renal failure and mice with cholecalciferol overload. In patients with CKD, serum zinc concentrations inversely correlated with serum calcification propensity. Finally, ZnSO 4 ameliorated the osteoinductive effects of uremic serum in VSMCs. Conclusions Zinc supplementation ameliorates phosphate-induced osteo-/chondrogenic transdifferentiation of VSMCs and vascular calcification through an active cellular mechanism resulting from GPR39-dependent induction of TNFAIP3 and subsequent suppression of the NF- κ B pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.
Abstract 14407: Regression of Cardiac AL Amyloid by Cardiovascular Magnetic Resonance
Authors: Ana Martinez-Naharro, Amna Abdel-Gadir, Thomas A Treibel, Giulia Zumbo, Daniel S Knight, Stefania Rosmini, Thirusha Lane, Shameem Mahmood, Sajitha Sachchithanantham, Carol J Whelan, Helen J Lachmann, Ashutosh D Wechalekar, Peter Kellman, Julian D Gillmore, James C Moon, Philip N Hawkins, Marianna Fontana
Journal: Circulation (2016)

Introduction:  Cardiac involvement in immunoglobulin light chain (AL) amyloidosis is the major determinant of survival; Cardiac response to chemotherapy is conventionally assessed by serum brain natriuretic peptide (NT-proBNP) and echocardiography, but neither quantify amyloid burden and the latter seldom suggests improvement.   Hypothesis:  The aim of this study was to evaluate cardiac AL amyloid serially using cardiovascular MR (CMR) including extracellular volume measurement (ECV), which is the site of the amyloid deposits.   Methods:  28 patients with cardiac AL amyloidosis who had chemotherapy were studied serially using ECG, echocardiography,  123 I-labeled serum amyloid P component (SAP) scintigraphy, NT-proBNP measurements and CMR with T1 mapping and ECV measurements.   Results:  Eighteen patients achieved a complete or very good partial haematological response (CR n=10; VGPR n=8). Ten patients attained a partial response (PR) or no response (NR). At follow-up (mean 18±12months), the amyloid burden had decreased substantially among patients attaining a CR or VGPR (ECV 56±11% falling to 43±10%; estimated amyloid burden 91±34ml falling to 72±35ml p=0.03). There was significant reduction in NT-proBNP concentration, LV mass, left atrial area and improvement in diastolic function in patients whose amyloid burden decreased. Regression of cardiac amyloid by CMR correlated with regression of amyloid in other organs measured by SAP scintigraphy. Concordance between regression of cardiac amyloid and reduction in NT-proBNP was 66%.   Conclusions:  In contrast to traditional echocardiography, CMR with T1 mapping and ECV measurements demonstrates that cardiac AL amyloid deposits frequently regress following chemotherapy that substantially suppresses clonal light chain production.
European evidence-based guidelines on pancreatic cystic neoplasms
Journal: Gut (2018)

Evidence-based guidelines on the management of pancreatic cystic neoplasms (PCN) are lacking. This guideline is a joint initiative of the European Study Group on Cystic Tumours of the Pancreas, United European Gastroenterology, European Pancreatic Club, European-African Hepato-Pancreato-Biliary Association, European Digestive Surgery, and the European Society of Gastrointestinal Endoscopy. It replaces the 2013 European consensus statement guidelines on PCN. European and non-European experts performed systematic reviews and used GRADE methodology to answer relevant clinical questions on nine topics (biomarkers, radiology, endoscopy, intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm, rare cysts, (neo)adjuvant treatment, and pathology). Recommendations include conservative management, relative and absolute indications for surgery. A conservative approach is recommended for asymptomatic MCN and IPMN measuring &lt;40 mm without an enhancing nodule. Relative indications for surgery in IPMN include a main pancreatic duct (MPD) diameter between 5 and 9.9 mm or a cyst diameter ≥40 mm. Absolute indications for surgery in IPMN, due to the high-risk of malignant transformation, include jaundice, an enhancing mural nodule &gt;5 mm, and MPD diameter &gt;10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery. The European evidence-based guidelines on PCN aim to improve the diagnosis and management of PCN.
Quantitative immunohistochemistry of ErbB cellular signaling pathways using automated digital microscopy
Authors: Keith A. Gottlieb, Scott Webster, Kenneth D. Bauer
Journal: Cancer Research (2004)

5371  Background: The overexpression/aberrant activation of the epidermal growth factor receptor and its downstream signaling pathways are common factors associated with the progression of many human tumors. While western blot (WB), RIA, or ELISA are typically used to evaluate relative levels of expression/activation, immunohistochemistry (IHC) provides the ability to quantify and localize intracellular molecules in individual cells and/or within regions of the malignancy and the use of archival pathological specimens. We have validated an approach of IHC staining combined with automated digital microscopy (ADM) analysis against WB using a series of cell culture model systems. This has provided a system by which routine IHC can be optimized to maintain reproducible, precise, and objective quantification. Methods: PhosphoEGFR (pEGFR) was evaluated in A431 cells following stimulation with EGF. Similarly, phosphoMAPK (pMAPK) and phosphoAkt (pAKT) were assessed in Jurkat cells stimulated with PMA or LY294002, respectively. EGFR and HER2 were evaluated in A431, MDA-231, MDA-175, HeLa-S3, and SKBR-3 cell lines. Cell suspensions were split immediately following treatment for WB analysis and formalin fixation/paraffin embedding and IHC with ADM analysis. Immunoblots were digitally scanned and quantified by image analysis. Further refinement of the IHC staining procedure was performed, included varying antigen retrieval, antibody, and substrate conditions, to develop optimal quantitative conditions. Results: Average measurement of pEGFR, pAkt and pMAPK in cell pellets by ADM revealed 5- to 20-fold changes in signal with varying treatments, correlating well with WB analysis (r = 0.960, p
186P Thyroid toxicity as an immune-related adverse event in patients with non-small cell lung cancer during treatment with immune checkpoint inhibitors
Authors: K. Syrigos, A. Charpidou, A. Asimakopoulou, I. Vathiotis, I. Gkiozos, S. Tsagouli, P. Boura, D. Grapsa, E. Kotteas
Journal: Journal of Thoracic Oncology (2018)
Abstract 13995: Decreased Circulating Omega-6 Fatty Acid Levels Are Associated With Total Mortality in Patients Admitted to Cardiac Intensive Care Unit
Authors: Shohei Ouchi, Tetsuro Miyazaki, Kazunori Shimada, Yurina Sugita, Megumi Shimizu, Azusa Murata, Takao Kato, Tatsuro Aikawa, Shoko Suda, Tomoyuki Shiozawa, Masaru Hiki, Shuuhei Takahashi, Takatoshi Kasai, Katsumi Miyauchi, Hiroyuki Daida
Journal: Circulation (2016)

Introduction: Polyunsaturated fatty acids (PUFAs), especially omega-3 fatty acids, have several important roles in the pathogenesis of cardiovascular diseases. Several studies have reported the anti-inflammatory and anti-atherogenic effects of omega-6 and omega-3 fatty acids. However, the clinical significance of PUFAs metabolism in the acute phase of cardiovascular diseases remains unknown. Therefore, we investigated the association between circulating PUFAs levels and clinical prognosis in patients admitted to the cardiac intensive care unit. Methods: We recruited 414 consecutive patients (acute decompensated heart failure: 36.0%, acute coronary syndrome: 38.4%) admitted to the cardiac intensive care unit in our University Hospital from April 2012 to October 2013. Fasting plasma PUFAs levels, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-gamma-linolenic acid (DGLA), were measured within 24 h after admission. After excluding patients with malignant diseases, end stage kidney disease, and received EPA therapy, 328 patients were followed up until December 2015. Results: During the 2.4 year mean follow-up period, 51 patients died. The levels of DGLA (31.3 ± 12.2 vs. 23.6 ± 11.3 μg/mL, P &lt; 0.01) and AA (171.6 ± 51.9 vs. 147.8 ± 44.2 μg/mL, P &lt; 0.01), but not EPA (53.6 ± 34.8 vs. 47.5 ± 26.4 μg/mL, NS) and DHA (127.2 ± 43.1 vs. 116.7 ± 36.4 μg/mL, NS), were significantly lower in the non-survivor group compared with the survivor group. Kaplan-Meier survival analysis showed that low DGLA, AA levels and DGLA/AA, but not EPA and DHA levels, were associated with all-cause mortality. Furthermore, Kaplan-Meier survival analysis showed that low DGLA, AA levels and DGLA/AA were associated with all-cause mortality in 114 patients with acute decompensated heart failure (ADHF), whereas each PUFAs levels were not significantly associated with all-cause mortality in 137 patients with acute coronary syndrome. Conclusion: Decreased levels of circulating DGLA and AA in patients admitted to the cardiac intensive care unit were significantly associated with total mortality, especially patients with ADHF. The present study showed it is possible DGLA levels predict long-term mortality.
137PD Prognostic factors in oligometastatic non-small-cell lung cancer (OM-NSCLC)
Authors: O. Juan, J.A. Méndez, B. Domingo-Arrué, D. Lorente Estelles, C. Escoín, C. Salvador Coloma, E. Navarro, M. Melian Sosa, N. Mancheño, J. Gomez Codina
Journal: Journal of Thoracic Oncology (2018)