tbuckley/cabot-search huggingface dataset:
Treatment efficacy and survival analysis of extremely elderly (80 years of age or older) patients with metastatic colorectal cancer: Single institute retrospective study
Authors: Y. Liang, C. Wei, J. Tsai, Y. Jeng, K. Chen, A. Cheng, K. Yeh
Journal: Annals of Oncology (2018)

Introduction: With improvement of public health and general medicine, the proportion of elderly cancer patients in daily practice keeps growing. Indeed, the evidence of systemic targeted therapy and chemotherapy to extremely elderly (80 years of age or older) patients remain limited. Methods: This was a single institute, retrospective study. Extremely elderly patients (80 years of age or older) with diagnosis of metastatic colorectal cancer at National Taiwan University Hospital, Hsinchu branch between July 1st, 2014 and June 30th, 2016 were enrolled. Patients received less than 2 cycles of systemic treatment were excluded. The last follow-up date was at August 31st, 2017 Results: In total 19 patients enrolled, sixteen (84.2%) patients were men. Median age was 82.0 years-old (range: 80.1-88.0). Eleven (57.9%) patients had initial diagnosis of metastatic disease. Only four (21.1%) patients had right-sided colon cancer. Seven (46.2%) patients had wile type RAS tumors and all are wild type BRAF tumors. Eight (42.1%) patients had liver-confined metastatic disease and only two (10.5%) patients had peritoneal metastases. Thirteen (68.4%) patients received chemotherapy doublet as first line treatment. Eleven (57.9%) patients received first line chemotherapy in combination with targeted therapy, which mainly comprised by bevacizumab (eight patients). The median progression-free survival (PFS) of first line therapy was 8.2 months (95% confidence interval [CI]: 5.8-10.6 months). Fourteen (73.7%) patients received second line systemic therapy. The median overall survival (OS) was 22.5 months (95% CI: 15.9-29.2 months). In Univariate and multivariate Cox proportional hazards analysis revealed no any independent prognostic factor for longer PFS or OS. Conclusion: Extremely elderly patients with metastatic colorectal cancer who had fair performance status to receive systemic therapy have comparable survival under regular medical care.
How HIPAA Harms Care, and How to Stop It
Authors: Donald M. Berwick, Martha E. Gaines
Journal: JAMA (2018)

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Abstract 14421: Chronic CaMKII Inhibition Induces Diastolic Dysfunction
Authors: Yibing Nong, Jun Cheng, Hyun Joung Lim, Arnaud Guilbert, Sisi Chen, Yanggan Wang
Journal: Circulation (2011)

Background: Recent studies point to CaMKII as a novel therapeutic target in structural heart diseases. However, the role of CaMKII in maintaining normal diastolic function is under investigated. Ob...
EPEN-20. IDENTIFICATION AND INVESTIGATION OF A NOVEL EPIGENETIC MODULATOR IN POSTERIOR FOSSA EPENDYMOMA, SIRT2
Authors: Davis Witt, Andrea Griesinger, Jessica Hansen, Sujatha Venkataraman, Ilango Balakrishnan, Angela Pierce, Irina Alimova, Andrew Donson, Vladimir Amani, Rajeev Vibhakar, Nicholas Foreman
Journal: Neuro-Oncology (2018)

Ependymoma (EPN) is the third most common pediatric central nervous system tumor, associated with poor survival and long-term morbidity. Posterior fossa Group A EPN (PFA) tumors are chemotherapy insensitive and often fatally recur. There is a critical need for new treatments and an untested avenue is targeting of epigenetic modifiers. Our lab has previously shown that the epigenetic suppression of a protein, LDOC1, in PFA drives the NF-kB pathway and constitutive secretion of IL-6. We believe that by targeting specific epigenetic modifiers we can reverse LDOC1 silencing and disrupt this oncogenic pathway in EPN PFA. Using two EPN PFA cell lines, we performed shRNA epigenetic screen identifying key epigenetic regulators including NAD-dependent deacetylase sirtuin 2 (SIRT2). SIRT2 actively inhibits transcription and may silence key tumor suppressing genes. Next, using an epigenetic drug screen we showed that SIRT2 inhibitor AGK2 (2-cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide) reduced proliferation in cell lines. Inhibition of SIRT2 by AGK2 recovered LDOC1 and down regulated many NF-kB genes. In addition, treatment of an EPN PFA organotype culture with AGK2 re-established LDOC1 and down-regulated IL-6 gene expression. We are now targeting SIRT2 in-vivo in murine sub-cutaneous flank and orthotopic intracranial models of EPN using the compound thiomyristoyl lysine (TM), a SIRT2 inhibitor that is available for in-vivo treatments. These studies suggest that targeting epigenetic modifiers, like SIRT2, can be used as a therapy to target EPN PFA.
CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: Data from a randomized phase III trial (AURA3).
Authors: Tony Mok, Myung-Ju Ahn, Ji-Youn Han, Jin Hyoung Kang, Nobuyuki Katakami, HyeRyun Kim, Rachel Hodge, Dana C. Ghiorghiu, Mireille Cantarini, Yi-Long Wu, Vassiliki Papadimitrakopoulou, Marina C Garassino
Journal: Journal of Clinical Oncology (2017)

9005 Background: CNS metastases (mets) are common in pts with advanced NSCLC. Preclinical studies have shown CNS penetration of osimertinib, and clinical data from a pooled analysis of 2 Phase II trials (AURA extension: NCT01802632, AURA2: NCT02094261) showed activity in the CNS. We report the first evidence of osimertinib efficacy in CNS mets from a randomized Phase III study (AURA3; NCT02151981) in pts with T790M-positive advanced NSCLC who have progressed on or after prior EGFR-TKI therapy. Methods: Pts were randomized 2:1 to osimertinib 80 mg once daily or platinum-based doublet chemotherapy every 3 wks for up to 6 cycles; maintenance pemetrexed was allowed. Pts with stable, asymptomatic CNS mets were eligible for enrolment. A prespecified subgroup analysis was conducted in pts with CNS mets present on baseline brain scan, as assessed by blinded independent central neuroradiology review (BICR), to define CNS objective response rate (ORR), duration of response (DoR) and progression-free survival (PFS) by RECIST v1.1. The CNS full analysis set (cFAS) included pts with ≥1 measurable and/or non-measurable CNS mets present on baseline brain scan by BICR; the CNS evaluable for response set (cEFR) included only pts with ≥1 measurable CNS mets. Results: As of 15 April 2016, 116/419 (28%) pts were included in the cFAS. In the cEFR (n = 46), CNS ORR was 70% (21/30; 95% CI 51, 85) with osimertinib and 31% (5/16; 95% CI 11, 59) with chemotherapy (OR, 5.13; 95% CI 1.44, 20.64; p = 0.015). In the cFAS, CNS ORR was 40% (30/75; 95% CI 29, 52) with osimertinib and 17% (7/41; 95% CI 7, 32) with chemotherapy (OR, 3.24; 95% CI 1.33, 8.81; p = 0.014). In the cEFR and cFAS, median CNS DoR was 8.9 months (m) (95% CI 4.3, NC and 4.3, NC) for osimertinib and 5.7 m (95% CI NC, NC and 4.4, 5.7; respectively) for chemotherapy. Median CNS PFS in the cFAS was significantly longer with osimertinib than with chemotherapy (11.7 vs 5.6 m; HR 0.32; 95% CI 0.15, 0.69; p = 0.004). Conclusions: Consistent with the overall response to osimertinib reported in pts with T790M-positive advanced NSCLC, osimertinib was superior to chemotherapy in the treatment of pts with CNS mets; CNS response rate was higher, responses were more durable and CNS PFS was longer. Clinical trial information: NCT02151981.
Abstract 20750: A Next-Generation Integrated Genetic-Epigenetic Algorithm to Predict Coronary Heart Disease
Authors: Meeshanthini V Dogan, Isabella Grumbach, Jacob Michaelson, Robert Philibert
Journal: Circulation (2017)

Coronary heart disease (CHD) is responsible for over 300,000 deaths annually in the United States. An improved method for detecting CHD could have a substantial clinical impact given that sudden ca...
Non-alcoholic fatty liver disease: features of metabolic changes at different stages of the disease
Authors: Yu.M. Stepanov, N.V. Nedzvetskaya, V.B. Yagmur, I.A. Klenina
Journal: GASTROENTEROLOGY (2018)

Актуальность. Неалкогольная жировая болезнь печени (НАЖБП) — хроническое диффузное заболевание печени, которое включает простой стеатоз, неалкогольный стеатогепатит (НАСГ) с возможностью прогрессирования до цирроза или даже гепатоцеллюлярной карциномы. Известно много причин стеатоза печени, однако НАЖБП ассоциируется преимущественно с инсулинорезистентностью и метаболическим синдромом (МС), что дало основание рассматривать НАЖБП как печеночную манифестацию последнего. Печень играет ключевую роль в обмене жирных кислот (ЖК) и триглицеридов, обеспечивая синтез, накопление, секрецию и окисление ЖК. При свойственном МС абдоминальном ожирении отмечается эксцессивный поток ЖК от висцерального жира через портальную вену в печень с развитием стеатоза. Накопление липидов в печени запускает каскад прооксидативных гепатотоксических событий, которые приводят к развитию НАСГ и возможного его прогрессирования. Цель: определение особенностей метаболических изменений на разных этапах развития НАЖБП. Материалы и методы. В исследование вошли пациенты с НАЖБП, которые проходили обследование и лечение в отделении заболеваний печени и поджелудочной железы ГУ «Институт гастроэнтерологии НАМН Украины». Всем больным проводилось ультразвуковое исследование органов брюшной полости, проводились стандартные биохимические исследования и определения в сыворотке крови общего холестерина, b-липопротеидов, триглицеридов, липопротеидов низкой плотности, липопротеидов очень низкой плотности, липопротеидов высокой плотности, глюкозы, инсулина. Результаты. Метаболические изменения в виде инсулинорезистентности и проатерогенных изменений липидограммы, характерные для всех больных с НАЖБП, были более выражены при стеатозе печени. Выводы. Полученные результаты обусловливают необходимость обязательного исследования показателей липидного и углеводного обмена у пациентов со стеатозом печенки для своевременной коррекции нарушений, что уменьшит прогрессирование НАЖБП.
Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption
Authors: Francis W. B. Sanders, Animesh Acharjee, Celia Walker, Luke Marney, Lee D. Roberts, Fumiaki Imamura, Benjamin Jenkins, Jack Case, Sumantra Ray, Samuel Virtue, Antonio Vidal-Puig, Diana Kuh, Rebecca Hardy, Michael Allison, Nita Forouhi, Andrew J. Murray, Nick Wareham, Michele Vacca, Albert Koulman, Julian L. Griffin
Journal: Genome biology (2018)

Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. We conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16–18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis. A subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat.
First-line FOLFOX plus panitumumab followed by 5-FU/LV plus panitumumab or single-agent panitumumab as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC): The VALENTINO study
Authors: F. Pietrantonio, F. Morano, S. Corallo, A. Raimondi, F. Loupakis, C. Cremolini, V. Smiroldo, R. Berenato, A. Sartore Bianchi, M. Tampellini, S. Bustreo, M. Clavarezza, R. Murialdo, A. Zaniboni, G. Tomasello, G. Peverelli, C. Antoniotti, L. Procaccio, S. Cinieri, L. Antonuzzo, M. Di Bartolomeo, F. de Braud
Journal: Annals of Oncology (2018)

Introduction: Since mCRC registration first-line trials scheduled the continuation of doublets plus anti-EGFRs until progressive disease (PD), there is still no evidence if de-escalating treatment intensity after an anti-EGFR-based induction phase might be not inferior in terms of disease control, while reducing toxicity burden and improving quality of life. The MACRO-2 trial suggested that maintenance with cetuximab alone after mFOLFOX + cetuximab achieved a progression-free survival (PFS)% not inferior than mFOLFOX + cetuximab until PD in KRAS exon 2 wild-type patients. Methods: 229 RAS wild-type unresectable mCRC patients were enrolled and received FOLFOX + panitumumab induction (8 cycles) followed, in absence of PD, by 1:1 randomly-assigned maintenance with panitumumab (arm B) or panitumumab + 5-FU/LV (arm A) until PD/unacceptable toxicity/death. The primary endpoint was to demonstrate the non-inferiority of 10-month (10-m) PFS% of arm B vs A. An overall sample size of 224 subjects (112 in the control group and 112 in the study group) achieved 90% power to detect a 50% 10-m PFS in arm A and a maximum 15% difference in arm B, with a significance level of 0.1 and a 15% drop-out rate. Secondary endpoints were safety, PROs, response rate, duration of response, time to treatment failure and overall survival. Results: Will be provided after primary analysis with central RAS and BRAF molecular analyses. Conclusion: NA
GERM-24. PRIMARY CENTRAL NERVOUS SYSTEM GERM CELL TUMORS IN DOWN SYNDROME
Authors: Margaret Lamb, Mohamed AbdelBaki, Joseph Stanek
Journal: Neuro-Oncology (2018)

There is a well-known association between central nervous system (CNS) germ cell tumors (GCTs) and Down syndrome (DS). Current standard of care for CNS GCTs includes surgery, chemotherapy and radiation therapy (RT). We describe our institutional experience regarding the management of DS patients with CNS GCT. Additionally, we have performed a comprehensive literature review of CNS GCTs in DS patients. Patient # 1: An infant with posterior fossa immature teratoma is currently without any evidence of disease two years following gross total resection of the tumor without requiring any adjuvant therapy. Patient #2: A 17-year-old female with suprasellar CD30 positive embryonal carcinoma underwent subtotal resection of the tumor. RT was spared by using an induction chemotherapy regimen followed by myeloablative chemotherapy with autologous stem cell support. Moreover, she received six cycles of the anti-CD30 antibody-drug conjugate Brentuximab-vedotin. She is 16 months off therapy with no evidence of disease. Twenty-four cases were reported in the literature; diagnosed at 1 month-35 years of age (median 10 years). Of the 24 cases; 10 were germinoma (42%), 7 yolk sac tumor (29%), 3 immature teratoma (12.5%), 3 mature teratoma (12.5%), 1 embryonal carcinoma (4%). Five-year overall survival for all cases was 53%. Four patients died from infectious complications of chemotherapy while four died from tumor progression. Patients with DS have an increased risk of mortality from cerebrovascular disease following RT. Treatment-related toxicities should be considered while planning the management of GCTs in DS patients.
Identification and Functional Characterization of Long Non-coding RNA<i> MIR22HG</i> as a Tumor Suppressor for Hepatocellular Carcinoma
Authors: Dong-Yan Zhang, Xue-Jing Zou, Chuan-Hui Cao, Ting Zhang, Ling Lei, Xiao-Long Qi, Li Liu, De-Hua Wu
Journal: Theranostics (2018)

Long non-coding RNAs (lncRNAs) have recently been identified as critical regulators in tumor initiation and development.However, the function of lncRNAs in human hepatocellular carcinoma (HCC) remains largely unknown.Our study was designed to explore the biological function and clinical implication of lncRNA MIR22HG in HCC.Methods: We evaluated MIR22HG expression in 52-patient, 145-patient, TCGA, and GSE14520 HCC cohorts.The effects of MIR22HG on HCC were analyzed in terms of proliferation, invasion, and metastasis, both in vitro and in vivo.The mechanism of MIR22HG action was explored through bioinformatics, luciferase reporter, and RNA immunoprecipitation analyses.Results: MIR22HG expression was significantly down-regulated in 4 independent HCC cohorts compared to that in controls.Its low expression was associated with tumor progression and poor prognosis of patients with HCC.Forced expression of MIR22HG in HCC cells significantly suppressed proliferation, invasion, and metastasis in vitro and in vivo.Mechanistically, MIR22HG derived miR-22-3p to target high mobility group box 1 (HMGB1), thereby inactivating HMGB1 downstream pathways.Additionally, MIR22HG directly interacted with HuR and regulated its subcellular localization.MIR22HG competitively bound to human antigen R (HuR), resulting in weakened expression of HuR-stabilized oncogenes, such as β-catenin.Furthermore, miR-22-3p suppression, HuR or HMGB1 overexpression rescued the inhibitory effects caused by MIR22HG overexpression.Conclusion: Our findings revealed that MIR22HG plays a key role in tumor progression by suppressing the proliferation, invasion, and metastasis of tumor cells, suggesting its potential role as a tumor suppressor and prognostic biomarker in HCC.
CanStem303C trial: A Phase 3 Study of napabucasin (NAPA) in combination with 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI) in adult patients (pts) with previously treated metastatic colorectal cancer (mCRC) - Trial in progress
Authors: M. Shah, A. Grothey, N. Tebbutt, R. Xu, T. Yoshino, A. Cervantes, J. Tabernero, J. Taieb, A. Falcone, B. Xu, M. Fontaine, L. Borodyansky, E. Van Cutsem
Journal: Annals of Oncology (2018)

Introduction: NAPA is an oral investigational agent, which has been hypothesized to inhibit cancer stemness pathways, including STAT3 pathway implicated in cancer stem-cell viability. Preclinical studies suggest that NAPA may sensitize cancer cells to chemotherapeutics, including 5-FU and irinotecan. Encouraging anticancer activity in advanced CRC was observed in a phase 1b/2 study (NCT02024607). In the subset of FOLFIRI-naive patients with an on-study RECIST evaluation, disease control rate (DCR) was 85% (33/39) and objective response rate (ORR) was 21% (8/39).1 On the basis of these data, a phase 3 trial is being conducted in North America, Europe, Australia, and Asia. Methods: This randomized, multicenter, open-label study (NCT02753127) will assess the efficacy of NAPA + FOLFIRI vs FOLFIRI in pts with mCRC (N = 1250). Addition of bevacizumab (bev) to FOLFIRI backbone is permissible per investigator decision. Pts must have failed 1 prior line of therapy with oxaliplatin and a fluoropyrimidine +/- bev for metastatic disease. Pts are randomized 1:1 to receive NAPA 240 mg PO BID plus FOLFIRI bi-weekly (5-FU at 400 mg/m 2 bolus followed by 1200 mg/m 2 continuous infusion, leucovorin 400 mg/m 2, and irinotecan 180 mg/m 2) , or FOLFIRI biweekly. Patients are stratified by geography (North America/Western Europe/Australia vs. Japan/Korea vs. rest of the world), time to progression on 1st-line therapy (<6 months vs. ≥6 months), RAS mutation status (mutant vs. wild type), bev as part of study treatment (yes vs. no), and primary tumor location (left vs. right colon). Treatment will continue until disease progression or another discontinuation criterion. The primary endpoint is overall survival (OS) in the general study population (HR 0.80 for OS improvement from 12.54 to 15.68 months); secondary endpoints include progression free survival (PFS), ORR and DCR, safety and quality of life. Blood and tumor archival tissue will be assessed for PK and biomarker analyses. An interim analysis for non-binding futility set at HR > 1 will be performed on OS at 50% of events (424). Additionally, early efficacy analysis based on OS will be performed at the time of the interim analysis. Should the trial not stop at time of the interim analysis, study will continue to final analysis at 850 events. Study enrollment is ongoing with >50% of planned patients enrolled to date.
TBIO-02. INHIBITION OF mTORC1 THROUGH AMINO ACID TRANSPORTER CD98/LAT1 MAINTAINS THE STEMNESS OF GLIOMA STEM CELL
Authors: Yipeng Han, Atsushi Enomoto, Masahide Takahashi, Jie Ma
Journal: Neuro-Oncology (2018)

Tumor stem cells (CSCs) are considered to be involved in tumor relapse. Mammalian Target of Rapamycin Complex 1 (mTORC1) plays an important role in tumor development and growing. However, the significance of mTORC1 in CSCs remains controversial. This study aims to provide more information for further understanding the mechanisms in down regulating mTORC1 activity in glioma stem cells (GSC). GSC lines BTSC222, BTSC316 and BTSC1228 were used and their differentiated progenies DIFF222, DIFF316 and DIFF1228 were prepared. Expression levels of CD98/LAT1 in BTSCs and DIFFs were compared. Dynamic activation of mTORC1 and re-localization of CD98/LAT1 by stimulation mediums was examined in BTSCs and DIFFs. Further experiments were conducted on Hek293 and Hela cells to study the lysosomal CD98/LAT1 levels. Lower basic levels of mTORC1 in BTSCs than DIFFs were confirmed. Preliminary data revealed identical expression levels of amino acid transporter CD98/LAT1, the upper stream of mTORC1, in BTSCs and DIFFs. Interestingly, amino acid stimulation test showed slower and weaker activation of mTORC1 in BTSCs than DIFFs. And CD98/LAT1 could be localized onto lysosome membrane from cell membrane. The different dynamic activations of mTORC1 in BTSCs and DIFFs were not due to the expression levels of CD98/LAT1, the starter of amino acid upper stream in mTOR pathway. The re-localization of CD98/LAT1 from cell membrane to lysosome membrane after amino acid stimulation may contribute to the different activations in BTSCs and DIFFs. Our findings indicate new explanation and possible new target of the chemo-resistance in glioma stem cells.