tbuckley/cabot-search huggingface dataset:
Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma
Authors: Sandra P. D'Angelo, Luca Melchiori, Melinda S. Merchant, Donna Bernstein, John Glod, Rosandra Kaplan, Stephan Grupp, William D. Tap, Karen Chagin, Gwendolyn K. Binder, Samik Basu, Daniel E. Lowther, Ruoxi Wang, Natalie Bath, Alex Tipping, Gareth Betts, Indu Ramachandran, Jean-Marc Navenot, Hua Zhang, Daniel K. Wells, Erin Van Winkle, Gabor Kari, Trupti Trivedi, Tom Holdich, Lini Pandite, Rafael Amado, Crystal L. Mackall
Journal: Cancer Discovery (2018)

We evaluated the safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1c259T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects.Significance: Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8+ NY-ESO-1c259T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov; 8(8); 944-57. ©2018 AACR.See related commentary by Keung and Tawbi, p. 914This article is highlighted in the In This Issue feature, p. 899.
Non-superiority of lumen-apposing metal stents over plastic stents for drainage of walled-off necrosis in a randomised trial
Authors: Ji Young Bang, Udayakumar Navaneethan, Muhammad K Hasan, Bryce Sutton, Robert Hawes, Shyam Varadarajulu
Journal: Gut (2018)

Objective Although lumen-apposing metal stents (LAMS) are increasingly used for drainage of walled-off necrosis (WON), their advantage over plastic stents is unclear. We compared efficacy of LAMS and plastic stents for WON drainage. Design Patients with WON were randomised to endoscopic ultrasound-guided drainage using LAMS or plastic stents. Primary outcome was comparing total number of procedures to achieve treatment success defined as symptom relief in conjunction with WON resolution on CT at 6 months. Secondary outcomes were treatment success, procedure duration, clinical/stent-related adverse events, readmissions, length of hospital stay (LOS) and costs. Results 60 patients underwent LAMS (n=31) or plastic stent (n=29) placement. There was no significant difference in total number of procedures performed (median 2 (range 2–7) LAMS vs 3 (range 2–7) plastic, p=0.192), treatment success, clinical adverse events, readmissions, LOS and overall treatment costs between cohorts. Although procedure duration was shorter (15 vs 40 min, p&lt;0.001), stent-related adverse events (32.3% vs 6.9%, p=0.01) and procedure costs (US$12 155 vs US$6609, p&lt;0.001) were higher with LAMS. Significant stent-related adverse events were observed ≥3 weeks postintervention in LAMS cohort. Interim audit resulted in protocol amendment where CT scan was obtained at 3 weeks postintervention followed by LAMS removal if WON had resolved. After protocol amendment, there was no significant difference in adverse events between cohorts. Conclusion Except for procedure duration, there was no significant difference in treatment outcomes between LAMS and plastic stents. To minimise adverse events with LAMS, patients should undergo follow-up imaging and stent removal at 3 weeks if WON has resolved. Trial registration number NCT02685865 .
PTH-068 Endoscopic closure of anterior resection anastomotic dehiscence using padlock clips
Authors: Javed Iqbal, Aleena Tariq, Sudeep Tanwar
Journal: Endoscopy (2018)

<h3>Introduction</h3> Anastomotic leakage is one of the serious complications after anterior resection. The risk of colonic anastomotic leak after anterior resection has been reported to be as high as 23% in some published series. Herein, we present a case of successful endoscopic closure of anastomotic dehiscence using Padlock clipping system, which was used alongside the drainage of pelvic collection. <h3>Method</h3> 43 days after developing anastomotic dehiscence post anterior resection, endoscopic Padlock clips were used to successfully close a 2 cm full thickness defect. <h3>Results</h3> 73 years old male patient underwent laparoscopic anterior resection operation for moderately differentiated recto-sigmoid adenocarcinoma. He developed colonic anastomosis dehiscence on day 5 post-operatively. Emergency laparotomy was performed where drains were inserted with ileostomy formation while through-the-scope endoscopic clips deployed intraoperatively by the surgical team, were unable to successfully close the anastomotic defect. Patient was given parenteral nutrition post-procedure. Two weeks later, faeculent fluid was noted in one of the drains, which suggested on-going leak. Repeat scan showed persistent extra-luminal leakage of the contrast with collection. A flexible sigmoidoscopy was performed which identified a large 2 cm anastomotic site defect. This was then closed by the deployment of three Padlock clips along with three through-the-scope Resolution clips. <h3>Conclusion</h3> Traditionally, surgical 'divert and drain' technique has been the mainstay of treatment for anastomotic leakage. Whereas endoscopic clips have been used successfully for the closure of anastomotic leaks, this case highlights that the Padlock system can be used successfully to close a chronic full thickness defect.
Abstract 13566: Right Ventricular Myocardial Deformation: Differences Between Corrected Tetralogy of Fallot and Atrial Septal Defects
Authors: Myrthe E Menting, Annemien E van den Bosch, Jackie S McGhie, Judith A Cuypers, Maarten Witsenburg, Bas M van Dalen, Marcel L Geleijnse, Jolien W Roos-Hesselink
Journal: Circulation (2013)

Introduction:  Due to different underlying mechanisms, patients with tetralogy of Fallot (ToF) and atrial septal defect (ASD) have right ventricular (RV) volume overload.   Objectives:  Using speckle-tracking echocardiography, we evaluated regional RV deformation in patients with corrected ToF and those with corrected ASD, and compared both groups with healthy controls.   Methods:  Echocardiograms including the standard apical views, were acquired in adult patients with corrected ToF or ASD, and in healthy controls. With speckle-tracking echocardiography, we analyzed longitudinal strain and the strain rate of the RV lateral wall, left ventricular (LV) septum, and LV lateral wall.   Results:  We included 166 subjects: 60 with ToF (62% male, age 34.4±8.0 years, age at correction 3.8±3.0 years); 53 with ASD (40% male, age 43.0±5.0 years, age at correction 7.7±3.8 years); and 53 healthy controls (49% male, age 29.7±6.8 years). RV global longitudinal strain of the lateral wall was significantly lower in ToF patients than ASD patients (p=0.02). In both patient groups, RV strain was significantly lower than in controls (p   Conclusion:  RV longitudinal strain is significantly reduced in corrected ASD patients and even more reduced in ToF patients, particularly in the apical segment. This suggests that apical function is affected most in RV overloaded ventricles.
Comparison of tissue genotyping (TG) vs circulating tumor DNA (ctDNA) for selection of matched therapy and impact on clinical outcomes among patients with metastatic breast cancer (MBC).
Authors: Neelima Vidula, Dejan Juric, Andrzej Niemierko, Laura Spring, Beverly Moy, Giuliana Malvarosa, Megan Yuen, Karleen R. Habin, Jennifer Adrienne Shin, Jeffrey M. Peppercorn, Steven J. Isakoff, Leif W. Ellisen, A. John Iafrate, Aditya Bardia
Journal: Journal of Clinical Oncology (2018)

1020 Background: Oncogenic mutations are attractive targets for targeted therapies, but the clinical impact is unclear. We evaluated the impact of TG or ctDNA on the selection of matched therapy and clinical outcomes in MBC patients. Methods: MBC patients with TG (Next Generation Sequencing/NGS, institutional platform) or ctDNA (NGS, Guardant360) at Massachusetts General Hospital between 1/2016-12/2017 were identified. A review of records to identify tumor subtype, demographics, treatment, outcomes, and TG or ctDNA results was performed. Associations between genomic results and the selection of matched therapy targeted to an actionable mutation, progression free survival, and overall survival (OS) were determined. Results: Among 252 patients with ctDNA testing, 232 (92%) had detectable mutations. Of those 232 cases, 196 (84%) had actionable mutations and 86 patients with actionable mutations received matched therapy with agents including CDK 4/6, mTOR, PI3K, AKT, PARP, androgen receptor, and FGFR inhibitors, SERDs, HER2 directed therapy, and DNA damaging chemotherapy. Among 118 patients with TG, 90 (76%) had detectable mutations. Of those 90 cases, 59 (66%) were actionable and 13 patients with actionable mutations received matched therapy with agents including mTOR, PI3K, or AKT inhibitors, or SERDs. There were significantly more actionable mutations detectable by ctDNA vs TG (84.5% vs 65.6%, p < 0.0005) and a significantly higher proportion of patients with ctDNA vs TG received matched therapy (46.7% vs 27.7%, p = 0.018). On multivariate Cox regression analysis adjusted for tumor subtype in ctDNA patients, OS was significantly better for patients with matched therapy vs those with unmatched therapy (HR 0.45, 95% CI 0.25-0.80, p = 0.007). Additional survival analyses will be presented at the meeting. Conclusions: ctDNA testing resulted in higher detection and greater application of matched therapy as compared with TG. Patients who had matched therapy based on ctDNA results had better OS compared to those with unmatched therapy post-ctDNA testing. These novel findings require confirmation in additional studies.
ENCORE 601: A phase II study of entinostat (ENT) in combination with pembrolizumab (PEMBRO) in patients with melanoma.
Authors: Melissa Lynne Johnson, Rene Gonzalez, Mateusz Opyrchal, Dmitry Gabrilovich, Peter Ordentlich, Susan Brouwer, Serap Sankoh, Emmett V. Schmidt, Michael L. Meyers, Sanjiv S. Agarwala
Journal: Journal of Clinical Oncology (2017)

9529 Background: Entinostat is an oral, class I selective histone deacetylase inhibitor shown preclinically to enhance immune checkpoint inhibitor activity by regulation of immune suppressor cells in the tumor microenvironment. ENCORE 601 is designed to evaluate safety and efficacy of ENT in combination with PEMBRO. Phase 1b identified ENT 5 mg PO weekly and PEMBRO 200 mg IV every 3 weeks as the recommended Phase 2 dose for further investigation. Methods: Phase 2 of ENCORE 601 employs a Simon 2-stage design to assess activity across 3 cohorts: 1) NSCLC not previously treated with a PD-1/L1 blocking antibody, 2&amp;3) NSCLC &amp; melanoma previously progressing on or after a PD-1/L1 blocking antibody. Patients were enrolled irrespective of PD-L1 expression levels. The primary endpoint is ORR as assessed by irRECIST. Results of the first stage of Cohort 3 are reported. Criteria for advancing to Stage 2 are ≥2 responses out of 13 evaluable patients. Results: Stage 1 enrollment has been completed (n = 13). All patients received a prior PD-1 inhibitor; in addition, 7 patients received prior ipilimumab and 2 patients received a prior BRAF inhibitor. 9 patients are still on treatment; 4 patients have discontinued due to progression. To date, 1 confirmed and 1 unconfirmed objective response have been observed. The confirmed response (PR) was in a patient who was previously treated with ipilimumab/nivolumab for 6 months (best response of SD with subsequent progression on therapy). Treatment-related AEs occurred in 5 patients (most common being nausea and fatigue occurring in 2 patients); one patient experienced Gr3/4 events (fatigue and rash). Blood samples and pre-treatment biopsies were obtained in all patients along with paired post-treatment biopsies in 8 patients. Evaluation of PD-L1 expression, gene expression, myeloid and lymphoid compartments in blood and tumor samples is in progress. Of note, the patient with a confirmed PR converted from a PD-L1 negative, non-inflamed gene signature to PD-L1 positive, inflamed after 2 weeks of treatment. Conclusions: ENT combined with PEMBRO demonstrates acceptable safety and encouraging preliminary activity in melanoma patients refractory to checkpoint inhibitors. Clinical trial information: NCT02437136.
Personalized Dietary Management of Overweight and Obesity Based on Measures of Insulin and Glucose
Authors: Mads F. Hjorth, Yishai Zohar, James O. Hill, Arne Astrup
Journal: Annual Review of Nutrition (2018)

During the past several decades, numerous trials have compared various diets for the management of overweight and obesity, assuming that a single dietary strategy would be appropriate for all individuals. These studies have failed to provide strong evidence for the efficacy of any particular diet, and it is likely that different people will have different levels of success on different diets. We identified studies investigating pretreatment glycemia or insulinemia status, or both, of the individual as prognostic markers of weight loss during periods in which the composition of a participant's diet was known. Overall, research suggests that providing specific diets for weight management based on pretreatment glycemia and insulinemia statuses holds great promise for advancing personalized nutrition.
Docetaxel-carboplatin-bevacizumab (TCV): A novel combination that promises a high activity in triple-negative breast cancer: A pilot study.
Authors: Jose Ignacio Chacon, Ana Rosa Rubio Salvador(2), Nazaret Cordero Franco(1), Begona Martinez Carrasco (1), Sonia Alonso Soler(1), Laura Diaz Paniagua(1), Lourdes Fernandez Franco(1), Alberto San Juan del Moral(1), Carmen Esteban Esteban(1), Paloma Moya Gomez(2), Miguel Angel Cruz Mora(1)
Journal: Journal of Clinical Oncology (2012)

e11543 Background: Triple negative breast cancer (TNBC) is an anthracycline resistant subtype, for which there is no standard chemotherapy. Taxanes, platinum-derived drugs and bevacizumab all seem to be active drugs in this setting, but definitive data are still lacking. Our purpose is to report our experience with the combination Docetaxel-Carboplatin-Bevacizumab (TCV) in TNBC. Methods: We retrospectively analysed our database using medical claims for patients diagnosed with TNBC and treated with TCV in neoadjuvant (NAJ) or metastasic( MD), between July 1, 2009, and December 31, 2011. Informed consent was obtained from all patients. Results: 13 pts have received 86 TCV cycles, 8 in NAJ and 5 for MD. NAJ: Median age: 48(28-60) y. T3-T4 tumors: 62,5% . N+: 62.5%. All pts received 6 TCV cycles, except 1 pt, still on therapy. 5 (62.5%) pts received quadrantectomy, 2(25%) mastectomy as surgical treatment after TCV. One pt has not received surgery yet. Sentinel lymph node biopsy was done in 5/8 (62.5%) pts, the other 3 received axillary dissection for clinically N+ metastasis. After surgery, pathologic complete response (pCR) in breast in 6/7 pts (85.7%); in axillary nodes, pCR in 5/7 pts (71,4%). One has not been surgically evaluated yet. Median follow-up: 10 months (2-18). Only one pt has relapsed with cerebral metastasis. MD: Median age: 54.4 (40-71) y. 4 pts received TCV as first line, one as third line therapy. 3 pts obtained complete response, 2 partial responses, but both progressed in three months. Median follow-up: 14.4 months. Only one of these pts has died. Toxicity: Was mild, without any grade 3 or 4 toxic effect. Only one pt showed grade 2 hypertension after bevacizumab infusion. Neutropenia was not evaluable for use of G-CSF per protocol. Conclusions: Although this is a short series, it suggests that TCV may be a highly active combination in TNBC with a good tolerability profile. These data warrant continuing testing of this combination in TNBC.
A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts
Authors: Ingrid Pabinger, Nick van Es, Georg Heinze, Florian Posch, Julia Riedl, Eva-Maria Reitter, Marcello Di Nisio, Gabriela Cesarman-Maus, Noémie Kraaijpoel, Christoph Carl Zielinski, Harry Roger Büller, Cihan Ay
Journal: The Lancet Haematology (2018)

Venous thromboembolism is a common complication of cancer, but the risk of developing venous thromboembolism varies greatly among individuals and depends on numerous factors, including type of cancer. We aimed to develop and externally validate a clinical prediction model for cancer-associated venous thromboembolism.We used data from the prospective Vienna Cancer and Thrombosis Study (CATS) cohort (n=1423) to select prognostic variables for inclusion in the model. We then validated the model in the prospective Multinational Cohort Study to Identify Cancer Patients at High Risk of Venous Thromboembolism (MICA) cohort (n=832). We calculated c-indices to show how the predicted incidence of objectively confirmed venous thromboembolism at 6 months compared with the cumulative 6-month incidences observed in both cohorts.Two variables were selected for inclusion in the final clinical prediction model: tumour-site risk category (low or intermediate vs high vs very high) and continuous D-dimer concentrations. The multivariable subdistribution hazard ratios were 1·96 (95% CI 1·41-2·72; p=0·0001) for high or very high versus low or intermediate and 1·32 (95% CI 1·12-1·56; p=0·001) per doubling of D-dimer concentration. The cross-validated c-indices of the final model were 0·66 (95% CI 0·63-0·67) in CATS and 0·68 (0·62-0·74) in MICA. The clinical prediction model was adequately calibrated in both cohorts.An externally validated clinical prediction model incorporating only one clinical factor (tumour-site category) and one biomarker (D-dimer) predicted the risk of venous thromboembolism in ambulatory patients with solid cancers. This simple model is a considerable improvement on previous models for predicting cancer-associated venous thromboembolism, and could aid physicians in selection of patients who will likely benefit from thromboprophylaxis.Austrian Science Fund, Austrian National Bank Memorial Fund, and participating hospitals.
A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis
Authors: Christophe Corpechot, Olivier Chazouillères, Alexandra Rousseau, Antonia Le Gruyer, François Habersetzer, Philippe Mathurin, Odile Goria, Pascal Potier, Anne Minello, Christine Silvain, Armand Abergel, Maryline Debette-Gratien, Dominique Larrey, Olivier Roux, Jean-Pierre Bronowicki, Jérôme Boursier, Victor de Ledinghen, Alexandra Heurgue-Berlot, Eric Nguyen-Khac, Fabien Zoulim, Isabelle Ollivier-Hourmand, Jean-Pierre Zarski, Gisèle Nkontchou, Sara Lemoinne, Lydie Humbert, Dominique Rainteau, Guillaume Lefèvre, Luc de Chaisemartin, Sylvie Chollet-Martin, Farid Gaouar, Farid-Hakeem Admane, Tabassome Simon, Raoul Poupon
Journal: New England Journal of Medicine (2018)

Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition.In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months.The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group.Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).