tbuckley/cabot-search huggingface dataset:
ALK alteration association with prognosis in metastatic colorectal cancer: A single institution retrospective cohort study.
Authors: Anup Kasi, Anusha Chidharla, Sarah Schmitt, Ziyan Y. Pessetto, Nikhil Gupta, Ravi Kumar Paluri, Anwaar Mohammed Saeed, Andrew K. Godwin
Journal: Journal of Clinical Oncology (2018)

676 Background: The Anaplastic Lymphoma Kinas (ALK) gene is altered in various malignancies which can be targeted with several inhibitors. However, the incidence of mutations in ALK are not well defined in colorectal cancers (CRC). We aim to study the prevalence of ALK mutations in metastatic CRC (mCRC) patients and correlate with clinical outcomes. Methods: We retrospectively evaluated 54 mCRC patients treated with chemotherapy at Kansas University Cancer Center between June 2010 and September 2017 who underwent our inhouse targeted 17 gene next-generation sequencing test using an illumina MiSeq technology. The panel included AKT1, ALK, BRAF, EGFR, FLT3, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, and TP53 genes. We compared baseline characteristics, tumor location (left vs right) and clinical outcomes between patients with ALK mutations versus ALK wild type. Results: We retrospectively evaluated 54 mCRC patients treated with chemotherapy at Kansas University Cancer Center between June 2010 and September 2017 who underwent our inhouse targeted 17 gene next-generation sequencing test using an illumina MiSeq technology. We compared baseline characteristics, tumor location (left vs right) and clinical outcomes between patients with ALK mutations versus ALK wild type. Results: We found 10 pts (18.5%) with ALK mutations and compared with 44 patients that were ALK wild type. Demographic and baseline characteristics (ALK mutation/wild type) were as follows: Median age 61 vs 61 years, Gender (male): 80% vs 50%, Left sided tumor 70% vs 60%. Of 41 evaluable patients (ALK mutation vs wild type), Objective response rate (stable + partial response) was 50% vs 91% [p = 0.03], 6-month PFS 33% vs 77%, Median PFS 12 months vs 17.7 months [p = 0.2], Median OS was 14.5 months vs not reached [HR 28.98, p = 0.025]. Conclusions: Patients harboring ALK mutations had a statistically significant poorer objective response rate and OS compared to ALK wild type patients. Findings of our study highlight the importance of assessing ALK gene alteration as a prognostic biomarker for mCRC. Therefore ALK mutation appears to be poor prognostic factor and needs to be validated in larger cohorts.
Clinical benefit and toxicity of nivolumab plus ipilimumab in patients with advanced melanoma previously treated with checkpoint blockade inhibitors.
Authors: Claire Frances Friedman, Jedd D. Wolchok, Michael Andrew Postow, Alexander Noor Shoushtari, Margaret K. Callahan, Parisa Momtaz, Paul B. Chapman
Journal: Journal of Clinical Oncology (2017)

100 Background: The combination of nivolumab and ipilimumab (nivo+ipi) prolongs progression-free survival in treatment-naïve patients (pts) with advanced melanoma. However, the efficacy and tolerability of nivo+ipi in pts previously treated with checkpoint blockade inhibitors (CPI) are unknown. Methods: 19 pts previously treated with CPI (ipi or anti-PD-1 as single agents) were treated with nivo+ipi at MSKCC. Ipi (3mg/kg) and nivo (1mg/kg) were administered q3 weeks for 4 doses with the option to continue anti-PD1 maintenance. Pts were followed for time to treatment failure (TTF), defined as the time from the date of first nivo+ipi infusion to the date of one of the following: clinical progression, new locally-directed treatment (ie surgery or radiotherapy), new systemic treatment other than anti-PD-1 monotherapy, or death. Results: 15 pts (79%) had stage M1c disease and 12 (63%) had a cutaneous primary. Pts had received a median of 2 prior systemic treatments (range 1-7). 10 pts (53%) had received prior ipi and 17 pts (89%) had received prior anti-PD-1 treatment; 8 pts (42%) had received both. The median time between anti-PD-1 monotherapy and nivo+ipi was 51 days (range 20-385). Pts received a median of 3 doses of combination therapy; 9 of 19 pts (47%) received all 4 doses. With a median follow-up time of 210 days, 8 pts (42.1%) remained on combination immune therapy, 9 pts (47%) switched systemic treatments or had a local procedure and 6 pts (31.6%) died. Median time on immunotherapy for those still alive and without treatment failure was 105 days (range 26-343). The median TTF was 78 days (range 42-220). The most common systemic treatment after nivo+ipi failure was BRAF-targeted therapy (5/9 or 56.3%). The median number of immune related adverse events (irAEs) was 1 (range 0-3). Rash (26%), Hepatitis (16%) and Colitis (16%) were the most common irAEs. Conclusions: With a short median follow-up, administration of nivo+ipi in CPI-experienced patients with advanced melanoma was associated with a short TTF. 58% of patients died or had treatment failure within the follow-up period. More research is needed to guide the utilization of combination immunotherapy in this setting.
Programmed cell death ligand 1(PD-L1), Programmed death 1+(PD-1) lymphocytes and Tumor infiltrating lymphocytes (TILs): are they playing a role in predicting response to anti-PD-1 therapies?
Authors: Chiara Bennati, Giulia Leonardi, Angelo Sidoni, Alessio Gili, Biagio Ricciuti, Vincenzo Minotti, Rita Chiari, Giulio Metro, Vienna Ludovini, Daniela Colabrese, Roberta Matocci, Lucio Crino
Journal: Journal of Clinical Oncology (2016)

e20652 Background: Correlation between PDL-1and treatment with a PD-1 inhibitor in Non-Small-Cell-Lung-Cancer (NSCLC) is still not unraveled. This retrospective study explores the relationship between PD-L1 by tumor cells , PD-1 on lymphocytes and TILs, in their role to predict response to Nivolumab in advanced NSCLC. Methods: 45 Pre-treated NSCLCs were evaluated for response to Nivolumab. A subset of samples from patients (pts) with an high tumor shrinkage, was further analyzed for PD-L1/PD-1 expression by immunoistochemistry (IHC), and for TILs density. We used rabbit monoclonal antibodies anti PD-L1 [clone E1L3N] for tumor cell expression (0-3, negative-intense) and mouse monoclonal antibody anti PD-1 [clone EH33] for TILs. TIL density scored as follows: 1+, < 25% of tumor with lymphocytic infiltrate; 2+, 25-50%; 3+, > 50%. Results: 45 pts were enrolled, mostly smokers, adenocarcinomas (69%), EGFR+ (16%), K-RAS+ (41%). Partial response was achieved in 24%, stable disease 31%, while progressive disease (PD) 44%; median progression free survival (PFS) and overall survival (OS) were 2.86 and 86.7 months (mo), respectively, 1 and 2-y OS 91% and 68%. According to hystology (adeno vs squamous) ORR (objective response rate), PFS, OS were: 16%, 2.79 mo, 86 mo, vs 43%, 3.16 mo, NR, respectively; of note, all EGFR+ had PD as a best response. Severe drug-related adverse events occurred in 28%, without discontinuation. So far, PD-L1, PD-1, TIL expression are available for 5/11 pts with OR (3 squamous; 2 K-RAS+ adenocarcinomas). Higher intensity for PD-L1 expression (IHC 2) was observed in 3 heavy smokers. All samples showed focal intensity of TIL (1+), and no PD-1+ were detected. Conclusions: Nivolumab confirms activity in NSCLC, with an impressive response in squamous and accettable safety profile. Although in a small group analysis, response rates are enhanced in PD-L1+, while TILs presence, as well as TIL PD1 expression, do not correlate with response; interactions among alternative factors (i.e smoking habit, K-RAS+) may have more powerful association with outcome. Updated clinical activity and biomarker analysis will be presented.
Severe peritonitis after successful endoscopic ultrasound-guided gallbladder drainage for acute gangrenous cholecystitis
Authors: Toji Murabayashi, Yoshihide Kanno, Kei Ito, Shinsuke Koshita, Takahisa Ogawa, Masaya Oikawa, Yutaka Noda
Journal: Endoscopy (2018)

Corrected by: Correction: Severe peritonitis after successful endoscopic ultrasound-guided gallbladder drainage for acute gangrenous cholecystitisEndoscopy 2018; 50(06): C8-C8DOI: 10.1055/a-0666-6316
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study
Authors: Carla M. Canuso, Jaskaran B. Singh, Maggie Fedgchin, Larry Alphs, Rosanne Lane, Pilar Lim, Christine Pinter, David Hough, Gerard Sanacora, Husseini Manji, Wayne C. Drevets
Journal: American Journal of Psychiatry (2018)

Objective: The authors compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk. Method: In a double-blind, multicenter, proof-of-concept study, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment. The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the Montgomery-Åsberg Depression Rating Scale (MADRS). Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary endpoints included these measures at 24 hours and double-blind endpoint at day 25. Results: A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference=−5.3, SE=2.10; effect size=0.61) and at ∼24 hours (least-square mean difference=−7.2, SE=2.85; effect size=0.65), but not at day 25 (least-square mean difference=−4.5, SE=3.14; effect size=0.35). Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67), but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache. Conclusions: These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide.
195TiP A phase 3, randomized, double-blind study of epacadostat plus pembrolizumab vs pembrolizumab as first-line therapy for metastatic non-small cell lung cancer (mNSCLC) expressing high PD-L1 levels (ECHO-305/KEYNOTE-654)
Authors: L. Paz-Ares, S. Rubin, Y. Zhao, L. Xu, A. Samkari, M. Awad
Journal: Journal of Thoracic Oncology (2018)
The outcome of severe varicella pneumonia with respiratory failure admitted to the intensive care unit for mechanical ventilation
Authors: Kiran George John, Thadathilankal-Jess John, Jantjie J. Taljaard, Usha Lalla, Tonya M. Esterhuizen, Elvis M. Irusen, Coenraad F.N. Koegelenberg
Journal: European Respiratory Journal (2018)

<b>Varicella pneumonia still carries a high mortality rate (29.2% in this study). Metabolic acidosis, a higher APACHE II score and the presence of acute renal failure on admission predicted poor outcome.</b>http://ow.ly/CdQM30jAY5q
Plinabulin as a novel small molecule clinical stage immuno-oncology agent for NSCLC.
Authors: Ramon W. Mohanlal, Ken LLoyd, Lan Huang, Lyudmila Bazhenova
Journal: Journal of Clinical Oncology (2017)

139 Background: Plinabulin (Plin) is a small molecule with tumor-inhibiting and immune-enhancing effects. In preclinical studies, Plin induces dendritic cell maturation and related IL-1β, IL-6 and IL-12 release, enhances antigen-specific CD4 T-cell proliferation, reduces regulatory T-cells and M2 macrophages in tumor tissue. Plin had synergistic efficacy with checkpoint inhibitors (PD-1 +/- CTLA-4) in animal models of tumor growth. Plin is targeting critical steps in the immune-cascade, independent from that of PD-1/PD-L1 binding. Methods: In a Phase 2 clinical trial, patients (pts) with and without measurable lung lesion were randomized to docetaxel (D) alone at 75 mg/m 2 or Plin with D (Plin+D), in 30 mg/m 2 or 20 mg/m 2 Plin cohorts, given every 3 weeks (NCT00630110). The primary efficacy endpoint was mOS. Secondary endpoints were safety assessments, DOR, PFS, ORR. PD-L1 tumor status was not characterized. Results: In the 30 mg/m 2 cohort, n=50 patients received 30 mg/m 2 Plin+ D and n=55 patients received D alone; 72% had measurable lung lesion. In pts with a measurable lung tumor, Plin+D (n=38) was numerically more effective vs. D alone (n=38). mOS, PFS and ORR were 11.3 mo, 3.7 mo, and 18% respectively for Plin+ Doc, and 6.7 mo, 2.9 mo, and 10.5% resp for D alone. DOR (a marker of immune effect) with the Plin+D vs. D alone was 12.7 mo vs. 1 mo (p&lt;0.05). Plin+D did not induce immune-related adverse events (IR-AEs), but prevented D- induced neutropenia (p&lt;0.0002), and D-dose-reduction due to toxicity. The 30 mg/m 2 Plin cohort was more effective than the 20 mg/m 2 cohort as an anticancer agent. Conclusions: Plin added to D increases efficacy vs. D alone most likely through an immune-related mechanism independent from PD1/PD-L1 intervention and mitigates the known D-related safety concerns, without increasing IR-AEs. The Plin+D combination might represent an effective and cost-effective alternative to Nivolumab, in particular in PD-L1 negative NSCLC. A global phase 3 trial with Plin+D vs. D alone is underway in pts with at least one measurable NSCLC lesion. Clinical trial information: NCT00630110.
Concordance of tumor and immune cell staining with Ventana SP142, Ventana SP263, Dako 28-8 and Dako 22C3 PD-L1 tests in NSCLC patient samples.
Authors: Marietta Scott, Marianne J Ratcliffe, Alan Sharpe, Craig Barker, Paul Scorer, Marlon Rebelatto, Hytham Al-Masri, Jill Walker
Journal: Journal of Clinical Oncology (2017)

7 Background: PD-1/PD-L1 directed antibodies are emerging as effective therapeutics in multiple oncology settings. Multiple diagnostic PD-L1 tests are being used to understand how PD-L1 expression predicts response to these therapies. It is vital to compare these assays to understand the risk if assays are used interchangeably. Tumor cell (TC) PD-L1 expression by the Ventana SP263 and the Dako 28-8 and 22C3 assays has proven concordant at multiple clinically relevant cut offs.(Ratcliffe et al AACR 2016 [LB-094]); (Ratcliffe et al ESMO 2016 [955PD]). The current study builds on the previous study by inclusion of immune cell (IC) scoring and the Ventana SP142 assay. Methods: 493 tumor biopsy samples from NSCLC patients stained with the Ventana SP263 and Dako 22C3 and 28-8 were scored for IC PD-L1 expression, calculated as % of infiltrating IC expressing PD-L1 at any intensity. A subset of 200 tumor blocks from this cohort were sectioned and stained with SP142 and serial sections restained with SP263 to ensure an appropriate comparison. Concordance between IC and TC between these 2 assays is reported. Results: There was strong agreement in IC scoring with the Ventana SP263 and Dako 22C3 and 28-8 assays. The SP142 assay showed lower concordance for IC and reduced TC PD-L1 staining/concordance vs SP263 (Table). Conclusions: This study shows analytical similarity between the Ventana SP263, Dako 28-8 or 22C3 assays when measuring TC or IC PD-L1 expression, and high concordance between patient classification at matching TC or IC cut offs. This strengthens the evidence that these 3 assays could be used interchangeably. The Ventana SP142 assay shows clear analytical differences for both IC and TC staining, suggesting it is not appropriate to interchange with the other assays. [Table: see text]
The Millennium Villages Project: a retrospective, observational, endline evaluation
Authors: Shira Mitchell, Andrew Gelman, Rebecca Ross, Joyce Chen, Sehrish Bari, Uyen Kim Huynh, Matthew W Harris, Sonia Ehrlich Sachs, Elizabeth A Stuart, Avi Feller, Susanna Makela, Alan M Zaslavsky, Lucy McClellan, Seth Ohemeng-Dapaah, Patricia Namakula, Cheryl A Palm, Jeffrey D Sachs
Journal: The Lancet Global Health (2018)

BackgroundThe Millennium Villages Project (MVP) was a 10 year, multisector, rural development project, initiated in 2005, operating across ten sites in ten sub-Saharan African countries to achieve the Millennium Development Goals (MDGs). In this study, we aimed to estimate the project's impact, target attainment, and on-site spending.MethodsIn this endline evaluation of the MVP, we retrospectively selected comparison villages that best matched the project villages on possible confounding variables. Cross-sectional survey data on 40 outcomes of interest were collected from both the project and the comparison villages in 2015. Using these data, as well as on-site spending data collected during the project, we estimated project impacts as differences in outcomes between the project and comparison villages; target attainment as differences between project outcomes and prespecified targets; and on-site spending as expenditures reported by communities, donors, governments, and the project. Spending data were not collected in the comparison villages.FindingsAveraged across the ten project sites, we found that impact estimates for 30 of 40 outcomes were significant (95% uncertainty intervals [UIs] for these outcomes excluded zero) and favoured the project villages. In particular, substantial effects were seen in agriculture and health, in which some outcomes were roughly one SD better in the project villages than in the comparison villages. The project was estimated to have no significant impact on the consumption-based measures of poverty, but a significant favourable impact on an index of asset ownership. Impacts on nutrition and education outcomes were often inconclusive (95% UIs included zero). Averaging across outcomes within categories, the project had significant favourable impacts on agriculture, nutrition, education, child health, maternal health, HIV and malaria, and water and sanitation. A third of the targets were met in the project sites. Total on-site spending decreased from US$132 per person in the first half of the project (of which $66 was from the MVP) to $109 per person in the second half of the project (of which $25 was from the MVP).InterpretationThe MVP had favourable impacts on outcomes in all MDG areas, consistent with an integrated rural development approach. The greatest effects were in agriculture and health, suggesting support for the project's emphasis on agriculture and health systems strengthening. The project conclusively met one third of its targets.FundingThe Open Society Foundations, the Islamic Development Bank, and the governments of Japan, South Korea, Mali, Senegal, and Uganda.
24P Proviral integration site for Moloney murine leukemia virus-1 (PIM-1) inhibition with AZD1208 to prevent resistance to osimertinib in EGFR mutant NSCLC
Authors: J. Bracht, N. Karachaliou, J. Berenguer, I. Attili, M. Ito, C. Codony-Servat, J. Codony-Servat, M. Filipska, N. Gil, R. Rosell
Journal: Journal of Thoracic Oncology (2018)
Correcting Errors That Modify Descriptive Statistics
Authors: Krisda H. Chaiyachati, David Grande
Journal: JAMA Internal Medicine (2018)

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A multicenter randomized phase II study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line therapy for patients with advanced unresectable biliary tract cancer (BilT-01).
Authors: Vaibhav Sahai, Kent A. Griffith, Muhammad Shaalan Beg, Walid Labib Shaib, Devalingam Mahalingam, David Bing Zhen, Dustin A. Deming, Sumi Dey, Mishal Mendiratta-Lala, Mark Zalupski
Journal: Journal of Clinical Oncology (2020)

4582 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis with a median overall survival (OS) less than 12 months (mos). This randomized phase 2, multi-institutional, study was designed to investigate the role of combinational immunotherapy, using nivolumab (nivo) with gemcitabine (gem)/cisplatin (cis), or nivo with ipilimumab (ipi) in pts with untreated advanced BTC. Methods: Key eligibility criteria include histologically confirmed unresectable or metastatic BTC without prior systemic therapy, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease or chronic steroid use. Arm A included gem 1000 mg/m 2 and cis 25 mg/m 2 d1, 8 Q3w + nivo 360 mg d1 Q3w for 6 mos followed by nivo 240 mg Q2w monotherapy for a total duration of 2 yrs; Arm B included nivo 240 mg Q2w and ipi 1 mg/kg Q6w for 2 yrs, in absence of disease progression. Primary endpoint is progression-free survival (PFS) rate at 6 mos with an alternative hypothesis of 80% (null hypothesis of 59%, one-sided alpha 0.05, power 80%) for each non-comparative arm. Secondary endpoints include overall response rate (ORR) per immune related (ir)RECIST, median PFS and OS and safety. Exploratory objectives include biomarker analysis using include sequential whole exome/transcriptome and immune cell subsets in tissue and blood. Results: 71 eligible pts (49% male, 83% Caucasian) with 35 in Arm and 36 in Arm B with a median age of 62 (range 20-80) yrs, and majority with metastatic disease (90%) were enrolled across 6 US sites. PFS rate at 6 mos was 70% in Arm A and 18.6% in Arm B. The median PFS was 8.8 mos (95% CI, 6.1 to 11.3) in Arm A and 4.1 mos (95% CI, 2.4-5.2) in Arm B. Ten patients on Arm A and 2 on Arm B remain on active treatment; additional 7 are in follow-up for OS. ORR, safety data and median OS evaluation are underway and will be presented at the meeting. Exploratory analyses are pending. Conclusions: The observed PFS rates at 6 mos in either arm are insufficient to reject the null hypothesis of 59% PFS at 6 months. While Arm B is inferior, Arm A appears to be as effective as standard of care although OS estimates are pending maturity. Clinical trial information: NCT03101566 .
Abstract 18777: The Low-Density Lipoprotein Cholesterol and Body Mass Index/Type-2 Diabetes Signals in the HMGCR Region Are Not Explained by a Single Variant
Authors: Hilma Holm, Patrick Sulem, Hannes Helgason, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Daniel Gudbjartsson, Kari Stefansson
Journal: Circulation (2016)

Introduction: Statin use has been linked to risk of type-2 diabetes (T2D). Swerdlow et al. explored this relationship in a genetic analysis published in the Lancet, 2014, using two correlated varia...