tbuckley/cabot-search huggingface dataset:
Current and Emerging Therapies in Metastatic Pancreatic Cancer
Authors: Gulam Abbas Manji, Kenneth P. Olive, Yvonne M. Saenger, Paul Oberstein
Journal: Clinical Cancer Research (2017)

Abstract Targeted therapies and immunotherapy have changed the face of multiple solid malignancies, including metastatic melanoma and lung cancer, but no such therapies exist for pancreatic ductal adenocarcinoma (PDAC) despite the knowledge of key mutations and an increasing understanding of the tumor microenvironment. Until now, most clinical studies have not been biomarker driven in this highly immunosuppressive and heterogeneous cancer. Ongoing basic and translational studies are better classifying the disease in hopes of identifying critical pathways that distinguish the unique PDAC subtypes, which will lead to personalized therapies. In this review, we discuss the current treatment options for metastatic pancreatic cancer and highlight current ongoing clinical trials, which aim to target the stroma and the immune microenvironment either alone or in combination with standard chemotherapy. Identifying biomarkers and key resistance pathways and targeting these pathways in a personalized manner in combination with chemotherapy are likely to yield a more immediate and durable clinical benefit. Clin Cancer Res; 23(7); 1670–8. ©2017 AACR. See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”
miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression
Authors: Geula Hanin, Nadav Yayon, Yonat Tzur, Rotem Haviv, Estelle R Bennett, Shiran Udi, Yoganathan R Krishnamoorthy, Eleni Kotsiliti, Rivka Zangen, Ben Efron, Joseph Tam, Orit Pappo, Eyal Shteyer, Eli Pikarsky, Mathias Heikenwalder, David S Greenberg, Hermona Soreq
Journal: Gut (2017)

Objective Both non-alcoholic fatty liver disease (NAFLD) and the multitarget complexity of microRNA (miR) suppression have recently raised much interest, but the in vivo impact and context-dependence of hepatic miR-target interactions are incompletely understood. Assessing the relative in vivo contributions of specific targets to miR-mediated phenotypes is pivotal for investigating metabolic processes. Design We quantified fatty liver parameters and the levels of miR-132 and its targets in novel transgenic mice overexpressing miR-132, in liver tissues from patients with NAFLD, and in diverse mouse models of hepatic steatosis. We tested the causal nature of miR-132 excess in these phenotypes by injecting diet-induced obese mice with antisense oligonucleotide suppressors of miR-132 or its target genes, and measured changes in metabolic parameters and transcripts. Results Transgenic mice overexpressing miR-132 showed a severe fatty liver phenotype and increased body weight, serum low-density lipoprotein/very low-density lipoprotein (LDL/VLDL) and liver triglycerides, accompanied by decreases in validated miR-132 targets and increases in lipogenesis and lipid accumulation-related transcripts . Likewise, liver samples from both patients with NAFLD and mouse models of hepatic steatosis or non-alcoholic steatohepatitis (NASH) displayed dramatic increases in miR-132 and varying decreases in miR-132 targets compared with controls. Furthermore, injecting diet-induced obese mice with anti-miR-132 oligonucleotides, but not suppressing its individual targets, reversed the hepatic miR-132 excess and hyperlipidemic phenotype. Conclusions Our findings identify miR-132 as a key regulator of hepatic lipid homeostasis, functioning in a context-dependent fashion via suppression of multiple targets and with cumulative synergistic effects. This indicates reduction of miR-132 levels as a possible treatment of hepatic steatosis.
Disease complexity and economic burden on patients with colon cancer in the SEER-Medicare population.
Authors: Maria Alma Rodriguez, Lee Cheng, Alma Yvette DeJesus, Hui Zhao, Sharon Hermes Giordano
Journal: Journal of Clinical Oncology (2017)

30 Background: The relatively high cost of cancer care is receiving national attention. Treating cancer includes not only managing this illness, but also the complications and exacerbation of the patients’ underlying comorbid conditions. The purpose of this study was to analyze how the charges for colon cancer care are affected by the complexity of the patients’ underlying health problems. Methods: We searched the Surveillance, Epidemiology, and End Results-Medicare database to identify patients diagnosed with colon cancer from 2009 through 2011. The estimated charges of the patients’ Medicare claims were stratified by survival time, disease stage, patient age, and comorbidity number. We defined patients’ 12 months of care as the 1 month immediately preceding cancer diagnosis plus the 11 months immediately following diagnosis. Results: We identified 10,822 patients newly diagnosed with colon cancer during the study period. Of those patients, one quarter died within 11 months after diagnosis. Treatment for early-stage cancer was significantly less expensive than treatment for advanced disease. For patients with early-stage disease, the charges for surgery, chemotherapy, and/or radiation therapy constituted a smaller contribution to the overall care charges. For patients with advanced-stage disease, the substantially higher overall care charges were largely due to charges for chemotherapy and/or biotherapy. Among patients with the same disease stage at diagnosis (except for patients stage IV disease), those with a survival time of less than 12 months incurred higher charges than those with a survival time of 12 months or more did. Regardless of disease stage, survival time, or age, patients with one and two or more comorbid conditions incurred statistically significant higher charges (7.0% and 29.7%, respectively) than those with no comorbid conditions. Conclusions: These findings demonstrate the important contribution of disease complexity among patients with cancer to the analysis of resource utilization. Using overall cancer care cost or reimbursement models that do not incorporate disease complexity may negatively affect hospitals that care for a high proportion of patients with complex conditions.
Differences in Treatment Effect Size Between Overall Survival and Progression-Free Survival in Immunotherapy Trials: A Meta-Epidemiologic Study of Trials With Results Posted at ClinicalTrials.gov
Authors: Aidan Tan, Raphael Porcher, Perrine Crequit, Philippe Ravaud, Agnes Dechartres
Journal: Journal of Clinical Oncology (2017)

Purpose We aimed to compare treatment effect sizes between overall survival (OS) and progression-free survival (PFS) in trials of US Food and Drug Administration–approved oncology immunotherapy drugs with results posted at ClinicalTrials.gov . Methods We searched ClinicalTrials.gov for phase II to IV cancer trials of Food and Drug Administration–approved immunotherapy drugs and selected those reporting results for both OS and PFS. For each trial, we extracted the hazard ratios (HRs) with 95% CIs for both outcomes and evaluated the differences by a ratio of HRs (rHRs): the HR for PFS to that for OS. We performed a random effects meta-analysis across trials to obtain a summary rHR. We also evaluated surrogacy of PFS for OS by the coefficient of determination and the surrogacy threshold effect, the minimal value of HR for PFS to predict a non-null effect on OS. Results We identified 51 trials assessing 14 drugs across 15 conditions. Treatment effect sizes were 17% greater, on average, with PFS than with OS (rHR, 0.83; 95% CI, 0.79 to 0.88; I 2 = 34.4%; P = .01; τ 2 = 0.0129). Nearly one half of the trials (n = 23, 45%) showed statistically significant benefits for PFS but not for OS. Differences were great for trials of obinutuzumab (rHR, 0.21; 95% CI, 0.08 to 0.54), bevacizumab (rHR, 0.75; 95% CI, 0.67 to 0.84), and rituximab (rHR, 0.79; 95% CI, 0.64 to 0.98). The coefficient of determination was 38% and the surrogacy threshold effect was 0.50. Conclusion Treatment effect sizes in trials of immunotherapy drugs were greater for PFS than for OS, with important differences for some drugs, which is consistent with surrogacy metrics. Caution must be taken when interpreting PFS in the absence of OS data.
Hepatitis C virus genotype and clinical outcome of compensated cirrhosis type C
Authors: G. Fattovich, M.L. Ribero, M. Pantalena, G. Diodati, P. Almasio, F. Nevens, F. Tremolada, F. Degos, G.R. Jhinkoe Rai, A. Solinas, D. Mura, A. Tocco, G. Realdi, R. Corrocher, S.W. Schalm, A. Tagger
Journal: Hepatology (1998)
Annals Story Slam - When You Know What Is Right, There Is No Decision: The Case of a Surgeon Needing Help at Another Hospital
Authors: John M. Porter
Journal: Annals of Internal Medicine (2017)

Web Exclusives4 April 2017Annals Story Slam - When You Know What Is Right, There Is No Decision: The Case of a Surgeon Needing Help at Another HospitalFREEJohn M. Porter, MDJohn M. Porter, MDFrom Cooper University Hospital, Camden, New Jersey.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W17-0039 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - When You Know What Is Right, There Is No Decision "When You Know What Is Right, There Is No Decision: The Case of a Surgeon Needing Help at Another Hospital," by Dr. John M. Porter (Duration 6:04)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From Cooper University Hospital, Camden, New Jersey.Current Author Address: John M. Porter, MD, Cooper University Hospital; e-mail, [email protected]edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 4 April 2017Volume 166, Issue 7Page: SS1KeywordsSurgeons ePublished: 4 April 2017 Issue Published: 4 April 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.Loading ...
Clinical predictors of 5-year survival in patients with EGFR-mutant metastatic NSCLC treated with EGFR-TKIs.
Authors: Jessica Jiyeong Lin, Stephanie Cardarella, Christine A. Lydon, Suzanne Eleanor Dahlberg, David Michael Jackman, Pasi A. Janne, Bruce E. Johnson
Journal: Journal of Clinical Oncology (2015)

8071 Background: Activating mutations of the epidermal growth factor receptor (EGFR) were discovered over 10 years ago. EGFR mutations predict increased response rates and progression-free survival (PFS) when treated with EGFR tyrosine kinase inhibitors (TKIs) compared to combination chemotherapy in advanced NSCLC. However, long-term outcomes including 5-year survival among patients (pts) with EGFR-mutant metastatic NSCLC treated with EGFR-TKIs remain heterogeneous. Herein, we define clinical factors associated with prolonged overall survival (OS) in this cohort. Methods: A retrospective analysis was performed of pts with metastatic NSCLC harboring a sensitizing EGFR mutation and treated with EGFR-TKIs at Dana-Farber Cancer Institute between Jan 1, 2002 and Sept 31, 2009. Pts alive at time of analysis must have had at least a 5-year survival. OS was compared based on clinical features using log-rank test. Cox’s proportional hazards models were used to estimate hazard ratios. Results: Among 134 pts, median PFS and OS were 13.1 mos (95% CI, 10.8-14.6) and 30.9 mos (95% CI, 28.2-35.7), respectively. 19 pts (14.2%) were long-term survivors (OS ≥ 5 years), of whom 10 remained alive at the time of analysis with median follow-up of 89.8 mos (range, 60.1-91.6). Multivariate analysis adjusted for factors significant at the 0.10 level in univariate models revealed that sensitizing EGFR mutations in exons other than exon 19 (n = 55) (HR 1.53; 95% CI, 1.05-2.23; p = 0.03), extrathoracic mets (n = 77) (HR 1.58; 95% CI, 1.04-2.43; p = 0.03) or brain mets (n = 29) (HR 2.17; 95% CI, 1.34-3.51, p = 0.002) at the time of diagnosis, and current smoking status (n = 5) (HR 4.31; 95% CI, 1.64-11.32; p = 0.003) were independent predictors of shorter OS. Age, gender, disease stage at diagnosis, liver or adrenal mets at diagnosis, specific TKI (erlotinib vs gefitinib), or line of TKI treatment did not correlate with OS. Conclusions: Our data estimate 5-year OS among EGFR-mutant metastatic NSCLC pts treated with EGFR-TKIs at 14%--vs less than 5% in historic results for an unselected population with distant-stage NSCLC. Planned studies will elucidate the genetic alterations that may co-occur with EGFR mutations and influence treatment outcomes.
Good News for Screening for Adult Attention-Deficit/Hyperactivity Disorder
Authors: Philip Shaw, Kwangmi Ahn, Judith L. Rapoport
Journal: JAMA Psychiatry (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
A multicenter international phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H.
Authors: Keith Christopher Bible, Vera J. Suman, Julian R. Molina, Robert C. Smallridge, William James Maples, Michael E. Menefee, Joseph Rubin, Nina J. Karlin, Kostandinos Sideras, John C. Morris, Bryan McIver, Ian D. Hay, Vahab Fatourechi, Jill K. Burton, Anne M. Traynor, Patrick J. Flynn, Boon C. Goh, Crescent R Isham, Pamela Jo Harris, Charles Erlichman
Journal: Journal of Clinical Oncology (2014)

6026 Background: Pazopanib is a small molecule inhibitor of kinases principally including vascular endothelial growth factor receptors (VEGFR)-1,-2, and -3, platelet-derived growth factor receptors (PDGFR)-α and –β; and c-Kit. We previously reported a tumor response rate of 49% in patients with advanced differentiated thyroid cancer and 0% in patients with advanced anaplastic thyroid cancer. The present report details results of pazopanib therapy in advanced medullary thyroid cancer (MTC). Methods: Having noted preclinical activity of pazopanib in MTC, patients with advanced MTC who had disease progression within the preceding 6 months were accrued to this multi-institutional international Phase II clinical trial to assess tumor response rate (by RECIST criteria) and safety of pazopanib given orally once daily at 800 mg until disease progression or intolerability. Results: From September 22, 2008 to December 11, 2011, 35 individuals (80% males, median age 60 years) were enrolled. All patients have been followed until treatment discontinuation or for a minimum of 4 cycles. Eight patients (23%) are still on study treatment. The median number of therapy cycles was 8. Five patients attained partial RECIST responses (14.3%; 90% CI: 5.8- 27.7%) with median progression-free survival and overall survival 9.4 and 19.9 months respectively. Side effects included treatment-requiring (new) hypertension (33%), fatigue (14%), diarrhea (9%) and abnormal liver tests (6%); three of 35 patients (8.6%) discontinued therapy due to adverse events. There was one death of a study patient after withdrawal from the trial deemed potentially treatment-related. Conclusions: Pazopanib has promising clinical activity in metastatic MTC with overall manageable toxicities. Supported by NCI CA15083 and CM62205. Clinical trial information: NCT00625846.
Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling
Authors: Wa'el Al Rawashdeh, Simin Zuo, Andrea Melle, Lia Appold, Susanne Koletnik, Yoanna Tsvetkova, Nataliia Beztsinna, Andrij Pich, Twan Lammers, Fabian Kiessling, Felix Gremse
Journal: Theranostics (2017)

Fluorescence-mediated tomography (FMT) is a quantitative three-dimensional imaging technique for preclinical research applications.The combination with micro-computed tomography (µCT) enables improved reconstruction and analysis.The aim of this study is to assess the potential of µCT-FMT and kinetic modeling to determine elimination and retention of typical model drugs and drug delivery systems.We selected four fluorescent probes with different but well-known biodistribution and elimination routes: Indocyanine green (ICG), hydroxyapatite-binding OsteoSense (OS), biodegradable nanogels (NG) and microbubbles (MB).µCT-FMT scans were performed in twenty BALB/c nude mice (5 per group) at 0.25, 2, 4, 8, 24, 48 and 72 h after intravenous injection.Longitudinal organ curves were determined using interactive organ segmentation software and a pharmacokinetic whole-body model was implemented and applied to compute physiological parameters describing elimination and retention.ICG demonstrated high initial hepatic uptake which decreased rapidly while intestinal accumulation appeared for around 8 hours which is in line with the known direct uptake by hepatocytes followed by hepatobiliary elimination.Complete clearance from the body was observed at 48 h.NG showed similar but slower hepatobiliary elimination because these nanoparticles require degradation before elimination can take place.OS was strongly located in the bones in addition to high signal in the bladder at 0.25 h indicating fast renal excretion.MB showed longest retention in liver and spleen and low signal in the kidneys likely caused by renal elimination or retention of fragments.Furthermore, probe retention was found in liver (MB, NG and OS), spleen (MB) and kidneys (MB and NG) at 72 h which was confirmed by ex vivo data.The kinetic model enabled robust extraction of physiological parameters from the organ curves.In summary, µCT-FMT and kinetic modeling enable differentiation of hepatobiliary and renal elimination routes and allow for the noninvasive assessment of retention sites in relevant organs including liver, kidney, bone and spleen.
A novel AHI-1–BCR-ABL–DNM2 complex regulates leukemic properties of primitive CML cells through enhanced cellular endocytosis and ROS-mediated autophagy
Authors: X Liu, K Rothe, R Yen, C Fruhstorfer, T Maetzig, M Chen, D L Forrest, R K Humphries, X Jiang
Journal: Leukemia (2017)

Tyrosine kinase inhibitor (TKI) therapies induce clinical remission with remarkable effects on chronic myeloid leukemia (CML). However, very few TKIs completely eradicate the leukemic clone and persistence of leukemic stem cells (LSCs) remains challenging, warranting new, distinct targets for improved treatments. We demonstrated that the scaffold protein AHI-1 is highly deregulated in LSCs and interacts with multiple proteins, including Dynamin-2 (DNM2), to mediate TKI-resistance of LSCs. We have now demonstrated that the SH3 domain of AHI-1 and the proline rich domain of DNM2 are mainly responsible for this interaction. DNM2 expression was significantly increased in CML stem/progenitor cells; knockdown of DNM2 greatly impaired their survival and sensitized them to TKI treatments. Importantly, a new AHI-1–BCR-ABL–DNM2 protein complex was uncovered, which regulates leukemic properties of these cells through a unique mechanism of cellular endocytosis and ROS-mediated autophagy. Thus, targeting this complex may facilitate eradication of LSCs for curative therapies.
Intraperitoneal immunotherapy of peritoneal carcinomatosis from solid tumors by trifunctional antibodies
Authors: M. Stroehlein, M. Jaeger, H. Lindhofer, C. Peschel, K. W. Jauch, M. M. Heiss
Journal: Journal of Clinical Oncology (2004)

2532 Background: Peritoneal carcinomatosis from solid tumors is a fatal diagnosis without standard treatment procedures, as concepts like peritonectomy and i.v./i.p. chemotherapy showed disappointing results. In this pilot study, we describe a new immunotherapeutic concept using trifunctional antibodies (trAb), which are able to redirect CTL to tumor cells and to induce active tumor immunity by activating Fcγ receptor type I and III positive accessory cells by their intact Fc region. Methods: In 9 patients with peritoneal carcinomatosis due to gastric cancer (6), ovarian cancer (2) and CUP (1) i.p. application of trAb was performed after surgery and/or ineffective chemotherapy. According to the antigen expression of autologous tumor cells, 2–5 doses of the trAb EpCAM x CD3 (5–80μg) or HER2/neu x CD3 (10–100 μg) were applicated by intraperitoneal infusion. After 4 weeks, patients received i.d./s.c. trAb + PBMC + irradiated tumor cells for restimulation. Immunological reactivity was tested by analyzing PBMC (1 week after boost) for specific tumor reactive CD4+/CD8+ T lymphocytes after restimulation with autologous tumor cells with the Miltenyi IFN Secretion Assay. Results: Antibody application was well tolerated without severe side effects. In 5/9 patients, tumor reactive CD4+/CD8+ T lymphocytes increased significantly indicating specific anti tumor immunity. Follow-up showed a mean survival of 11.8 months (median 8.0 months) after trAb therapy. 5/9 patients had a clinical response (stable disease, partial regression) with a mean time to progression of 4.6 months. Conclusions: In conclusion, immunotherapy using trAb may provide a new option for active treatment of peritoneal carcinomatosis, which is now evaluated in ongoing clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration TRION Pharma TRION Pharma TRION Pharma