tbuckley/cabot-search huggingface dataset:
4-1BB Agonist Focuses CD8+ Tumor-Infiltrating T-Cell Growth into a Distinct Repertoire Capable of Tumor Recognition in Pancreatic Cancer
Authors: Donastas Sakellariou-Thompson, Marie-Andrée Forget, Caitlin Creasy, Vincent Bernard, Li Zhao, Young Uk Kim, Mark W. Hurd, Naohiro Uraoka, Edwin Roger Parra, Ya'an Kang, Christopher A. Bristow, Jaime Rodriguez-Canales, Jason B. Fleming, Gauri Varadhachary, Milind Javle, Michael J. Overman, Hector A. Alvarez, Timothy P. Heffernan, Jianhua Zhang, Patrick Hwu, Anirban Maitra, Cara Haymaker, Chantale Bernatchez
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Survival for pancreatic ductal adenocarcinoma (PDAC) patients is extremely poor and improved therapies are urgently needed. Tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) has shown great promise in other tumor types, such as metastatic melanoma where overall response rates of 50% have been seen. Given this success and the evidence showing that T-cell presence positively correlates with overall survival in PDAC, we sought to enrich for CD8+ TILs capable of autologous tumor recognition. In addition, we explored the phenotype and T-cell receptor repertoire of the CD8+ TILs in the tumor microenvironment. Experimental Design: We used an agonistic 4-1BB mAb during the initial tumor fragment culture to provide 4-1BB costimulation and assessed changes in TIL growth, phenotype, repertoire, and antitumor function. Results: Increased CD8+ TIL growth from PDAC tumors was achieved with the aid of an agonistic 4-1BB mAb. Expanded TILs were characterized by an activated but not terminally differentiated phenotype. Moreover, 4-1BB stimulation expanded a more clonal and distinct CD8+ TIL repertoire than IL2 alone. TILs from both culture conditions displayed MHC class I-restricted recognition of autologous tumor targets. Conclusions: Costimulation with an anti-4-1BB mAb increases the feasibility of TIL therapy by producing greater numbers of these tumor-reactive T cells. These results suggest that TIL ACT for PDAC is a potential treatment avenue worth further investigation for a patient population in dire need of improved therapy. Clin Cancer Res; 23(23); 7263–75. ©2017 AACR.
PTU-084 Abdominal obesity and insulin resistance are significant risk factors for liver fibrosis in a cohort of patients with severe psoriasis; results from a prospective, observational cohort study
Authors: C Maybury
Journal: Gut (2017)

Introduction  Psoriasis is a common, chronic inflammatory skin disease. People with psoriasis are at risk of developing liver fibrosis due to increased rates of NAFLD, alcohol use and methotrexate exposure. It is unclear which patients should be screened for fibrosis and the best method of screening. The aims of this single centre, prospective cohort study were to (1) identify the proportion of patients with steatosis and fibrosis,(2) Identify important prognostic factors for fibrosis,(3) Evaluate non-invasive tests for fibrosis.  Method  Participants completed a questionnaire, psoriasis severity score, anthropometric indices and fasting blood draw for lipids, HOMA-IR,liver function tests and a panel of non-invasive markers: P3NP, FIB-4, ELF (Enhanced Liver Fibrosis) and Fibrotest. Steatosis was assessed by ultrasound. Diagnosis of fibrosis was made by liver stiffness measurement (LSM) in kilopascals (kPa) using transient elastography (TE). Those with LSM >7 kPa were referred to hepatology +/- liver biopsy. Diagnostic accuracy of bloods and clinical measures were compared to TE and biopsy.  Results  400 adults were recruited 2012–2015. Means (S.D) of enrolment parameters were: age (years): 49.5±13, 27% female, body mass index: 29.2±7, waist (cm): 102%±16. 48% had steatosis, 20% liver fibrosis (LSM ≥7 kPa); 14% had advanced fibrosis (LSM ≥8.7 kPa).  Prognostic factors significantly associated with fibrosis on univariate analysis included age, BMI, waist, metabolic syndrome, steatosis and HOMA-IR (all p≤0.01). Sex, methotrexate duration, psoriasis duration and alcohol were not significantly associated. Multivariate analysis identified waist measurement, HOMA-IR and AST as the best performing joint model of fibrosis (R 2 =0.379), determined by stepwise variable selection.  47 participants had a liver biopsy. 39 biopsies were available for blinded grading according to NASH-CRN. Transient elastography was the best performing non-invasive test using biopsy as a reference standard (AUC 0.81 for advanced fibrosis).  Using elastography as the reference standard, for both fibrosis and advanced fibrosis HOMA-IR and waist measurements provided the strongest predictive measures with all AUCs>0.78. For fibrosis ELF was the best performing blood test: AUC 0.75 (CI: 0.679–0.828). For advanced fibrosis AST was the best performing blood test: AUC 0.75 (CI: 0.677–0.824).  Conclusion  A significant proportion of our cohort has steatosis and fibrosis. Metabolic parameters were the most important prognostic factors emphasising the risk conferred by abdominal obesity. Waist measurement, an easy test to perform, was superior to non-invasive bloods as a marker of fibrosis and advanced fibrosis. Future work will focus on the development of an algorithm to screen patients with severe psoriasis for fibrosis.  Disclosure of Interest  None Declared
Effect of adenoviral p53 (Ad-p53) tumor suppressor immune gene therapy on checkpoint inhibitor resistance and abscopal therapeutic efficacy.
Authors: Robert E. Sobol, Sunil Chada, Dora Bocangel Wiederhold, Chae-Ok Yun, Hyomin Ahn, Eonju Oh, Ravi Murthy, Vivek Subbiah, Kerstin B. Menander
Journal: Journal of Clinical Oncology (2017)

e14610 Background: Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, most cancer patients do not respond or become resistant to this form of immune therapy. Methods: We evaluated the ability of Ad-p53 to reverse immune checkpoint inhibitor resistance and induce abscopal effects in the immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before initiating Ad-p53 intra-tumoral therapy. Results: Anti-PD-1 had minimal therapeutic efficacy compared to control treatment. A statistical analysis of variance (ANOVA) comparison of tumor volumes revealed that the combined effect of Ad-p53 and anti-PD-1 treatment was synergistic and superior to either therapy alone (p = 0.0001). Surprisingly, there was a statistically significant abscopal effect with decreased growth of contralateral tumors not injected with Ad -p53. The Ad- p53 alone (p = 0.046) and Ad- p53 + anti-PD-1 (p = 0.0243) treatment groups both demonstrated a statistically significant decreased abscopal tumor growth compared to treatment with anti-PD-1 alone. Combined Ad- p53 and anti-PD-1 therapy demonstrated a statistically significant increase in survival compared to Ad- p53 therapy alone (p = 0.0167) and anti-PD-1 therapy alone (p &lt; 0.001) by the log rank test. We have initiated a Phase 1 clinical trial of Ad-p53 intra-hepatic arterial therapy in combination with capecitabine for patients with solid tumor liver metastases. In the first cohort of patients at a dose of 2 x 10 12 viral particles, treatment has been well tolerated with transient fever, chills and rigors. In one patient, decreased SUV uptake on PET scans of distant lymph node metastases suggested possible abscopal effects. Conclusions: These results suggest that Ad-p53 tumor suppressor immune gene therapy may reverse immune checkpoint inhibitor resistance and induce abscopal effects supporting the planned clinical evaluation of combined Ad-p53 and anti-PD-1 therapy in patients resistant to immune checkpoint inhibitor therapy. Clinical trial information: NCT02842125.
Evaluating the Neolithic Expansion at Both Shores of the Mediterranean Sea
Authors: João Pimenta, Alexandra M Lopes, David Comas, António Amorim, Miguel Arenas
Journal: Molecular Biology and Evolution (2017)

During the Neolithic, human populations underwent cultural and technological developments that led to an agricultural revolution. Although the population genetics and evolution of European Neolithic populations have been extensively studied, little is known regarding the Neolithic expansion in North Africa with respect to Europe. One could expect that the different environmental and geological conditions at both shores of the Mediterranean Sea could have led to contrasting expansions. In order to test this hypothesis, we compared the Neolithic expansion in Europe and North Africa accounting for possible migration between them through the Strait of Gibraltar. We analyzed the entire X chromosome of 580 individuals from 20 populations spatially distributed along the North of Africa and Europe. Next, we applied approximate Bayesian computation based on extensive spatially explicit computer simulations to select among alternative scenarios of migration through the Strait of Gibraltar and to estimate population genetics parameters in both expansions. Our results suggest that, despite being more technologically advanced, Neolithic populations did not expand faster than Paleolithic populations, which could be interpreted as a consequence of a more sedentary lifestyle. We detected reciprocal Neolithic migration between the Iberian Peninsula and North Africa through the Strait of Gibraltar. Counterintuitively, we found that the studied Neolithic expansions presented similar levels of carrying capacity and migration, and occurred at comparable speeds, suggesting a similar demic process of substitution of hunter-gatherer populations. Altogether, the Neolithic expansion through both Mediterranean shores was not so different, perhaps because these populations shared similar technical abilities and lifestyle patterns.
Impact of MET inhibitors on survival among patients (pts) with <i>MET</i> exon 14 mutant (<i>MET</i>del14) non-small cell lung cancer (NSCLC).
Authors: Mark M. Awad, Giulia Costanza Leonardi, Sasha Kravets, Suzanne Eleanor Dahlberg, Alexander E. Drilon, Sinead Noonan, D. Ross Camidge, Sai-Hong Ignatius Ou, Daniel Botelho Costa, Shirish M. Gadgeel, Conor Ernst Steuer, Patrick M. Forde, Viola Weijia Zhu, Yoko Korenaga Fukuda, Jeffrey W. Clark, Pasi A. Janne, Tony Mok, Lynette M. Sholl, Rebecca Suk Heist
Journal: Journal of Clinical Oncology (2017)

8511 Background: Dramatic responses to MET inhibitors have been reported in patients with NSCLC harboring activating mutations that cause MET exon 14 ( METdel14) skipping. We conducted a multicenter retrospective analysis of pts with METdel14 NSCLC to determine if treatment with MET inhibitors impacts survival. Methods: We collected clinicopathologic data on pts with METdel14 NSCLC. Event-time distributions were estimated using Kaplan-Meier and compared with the log-rank test. Multivariable Cox models were fitted to estimate hazard ratios. Results: Of the 148 pts with METdel14 mutant NSCLC, the median age was 72 (range 43-88); 57% were women, and 41% were never smokers. The most common histologies were adenocarcinoma (77%) and pulmonary sarcomatoid carcinoma (14%). Overlap with oncogenic driver mutations in other genes was rare. At the time of diagnosis, 70% of pts had stage I-III disease, and 30% had stage IV disease. Of the 34 pts with metastastic disease who never received a MET inhibitor, the median overall survival (mOS) was 8.1 months. In this cohort, cancers that also had concurrent MET amplification had a trend toward worse survival compared to cancers without MET amplification (5.2 months vs 10.5 months, P = 0.06). Of the 27 pts with metastatic disease who received at least one MET inhibitor (including crizotinib, glesatinib, capmatinib, and ABBV-399), the mOS was 24.6 months. A model adjusting for receipt of a MET inhibitor as first- or second-line therapy as a time-dependent covariate demonstrated that treatment with a MET inhibitor was associated with a significant prolongation in survival (HR 0.11, 95% CI 0.01-0.92, P = 0.04). Among 22 patients treated with crizotinib, the median progression-free survival (PFS) was 7.36 months. Conclusions: Forpts with METdel14 NSCLC, treatment with a MET inhibitor is associated with an improvement in overall survival. The prognosis of pts who never received treatment with a MET inhibitor appears to be poor, particularly among METdel14 cancers with concurrent MET amplification.
Real-world treatment patterns of adult multiple myeloma patients treated with carfilzomib in the US community oncology setting.
Authors: Sumeet Panjabi, Rohan Medhekar, Kathleen Aguilar, Thomas Wilson, E. Susan Amirian, Khalid Mezzi, Robert M. Rifkin
Journal: Journal of Clinical Oncology (2017)

e19513 Background: The purpose of this retrospective cohort study was to describe the treatment regimens received by adult multiple myeloma (MM) patients who were exposed to carfilzomib (K) in the US Oncology Network (USON). Methods: Eligible patients received K-based regimens for MM at least once between 11/01/2013 and 02/29/2016, were ≥18 years old, were not in a clinical trial, and had at least 2 visits at a USON clinic. Data on systemic therapies, lines of therapy (LOT), clinic visits and treatment administration dates were abstracted from the electronic health records (EHR). Treatment sequencing logic was used to identify progression by LOT. Sequencing rules were based on regimens, duration, and administration dates. Treatment regimens utilized at any time during the study period were analyzed by LOT. Results: 718 MM patients received a K-containing regimen at least once over the course of treatment. The frequency distribution of regimens for K-exposed patients by LOT (2 to 5) are provided (see Table). Among these patients, K-based regimens comprised 66.6% of LOT2 regimens, 55.3% of LOT3 regimens, and 45.9% of regimens used beyond LOT3. K+ lenalidomide + dex (KRd) was the most common K-containing regimen used in LOT2 (24.7%). K-triplets containing an immunomodulatory agent were most frequent in LOT 2 and K-doublets (Kd) were most frequent in LOT 3. Conclusions: In our study, K-based regimens were used across LOTs 2 to 5 with highest frequency observed in LOT2. K-triplets with immunomodulatory drugs were more common in earlier LOTs. [Table: see text]
Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial
Authors: Michel Bazinet, Victor Pântea, Valentin Cebotarescu, Lilia Cojuhari, Pavlina Jimbei, Jeffrey Albrecht, Peter Schmid, Frédéric Le Gal, Emmanuel Gordien, Adalbert Krawczyk, Hrvoje Mijočević, Hadi Karimzadeh, Michael Roggendorf, Andrew Vaillant
Journal: The Lancet. Gastroenterology & hepatology (2017)
Training for children with chronic fatigue works better than medical care alone, finds study
Authors: Nigel Hawkes
Journal: BMJ (2017)

A widely publicised technique for treating chronic fatigue syndrome (CFS) in children actually works, to the surprise of the researcher who conducted the first randomised controlled trial of it.

The Lightning Process, developed by osteopath Phil Parker, has made bold claims that it can cure CFS in children. It is not available on the NHS, and costs around £620 (€702; $837) per case treated.

Esther Crawley, professor of child health at the University of Bristol, runs a clinic for children with CFS. She conducted a randomised controlled trial comparing specialised medical care, of the sort her unit already provided, with the same care as well as the Lightning Process.

“I never expected it would work,” she told a briefing at the Science Media Centre in London. But the trial, published in Archives of Disease in Childhood ,1 showed positive results. The …
Clinician-Level Predictors for Ordering Low-Value Imaging
Authors: Arthur S. Hong, Dennis Ross-Degnan, Fang Zhang, J. Frank Wharam
Journal: JAMA Internal Medicine (2017)

Clinicians who order unnecessary radiographic imaging may cause financial harm to patients who have increasing levels of cost sharing. Clinician predictors of low-value imaging are largely unknown.To characterize clinician predictors of low-value imaging for acute uncomplicated back pain and headache, including clinicians who saw both conditions.Multivariate logistic regression modeling of imaging rates after acute uncomplicated back pain and headache visits as indicated by January 2010 to December 2014 commercial insurance claims and demographic data from a large US health insurer. Participants included 100 977 clinicians (primary care physicians, specialist physicians, and chiropractors).Imaging after acute uncomplicated back pain and headache visits was recorded. We identified whether the clinician's prior patient received imaging, whether the clinician was an owner of imaging equipment, and the varying impact by clinician specialty. We then used high rates of low-value back imaging as a predictor for low-value headache imaging.Clinicians conducted 1 007 392 visits for 878 720 adults ages 18 to 64 years with acute uncomplicated back pain; 52 876 primary care physicians conducted visits for 492 805 adults ages 18 to 64 years with acute uncomplicated headache; 34 190 primary care clinicians conducted 405 721 visits for 344 991 adults ages 18 to 64 years with headache and had also conducted at least 4 visits from patients with back pain. If a primary care physician's prior patient received low-value back imaging, the patient had 1.81 higher odds of low-value imaging (95% CI, 1.77-1.85). This practice effect was larger for chiropractors (odds ratio [OR], 2.80; 95% CI, 2.74-2.86) and specialists (OR, 2.98; 95% CI, 2.88-3.07). For headache, a prior low-value head image predicted 2.00 higher odds of a subsequent head imaging order (95% CI, 1.95-2.06). Clinician ownership of imaging equipment was a consistent independent predictor of low-value imaging (OR, 1.65-7.76) across clinician type and imaging scenario. Primary care physicians with the highest rates of low-value back imaging also had 1.53 (95% CI, 1.45-1.61) higher odds of ordering low-value headache imaging.Clinician characteristics such as ordering low-value imaging on a prior patient, high rates of low-value imaging in another clinical scenario, and ownership of imaging equipment are strong predictors of low-value back and headache imaging. Findings should inform policies that target potentially unnecessary and financially burdensome care.
Will Transcatheter Aortic Valve Replacement Echo Surgical Aortic Valve Replacement Durability?
Authors: Stephen H. Little, Michael J. Reardon
Journal: JAMA Cardiology (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 Cardiology 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 Cardiology journal
Most cases of otitis media should not be treated with antibiotics, says NICE
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

Most cases of otitis media in children can be managed with paracetamol or ibuprofen rather than antibiotics, new guidance from the National Institute for Health and Care Excellence (NICE) has said.1

The draft guidance says that most children with symptoms are in less pain within 24 hours and that antibiotics do not help.

The evidence shows that antibiotics make little difference to how long symptoms last or the proportion …
Treatment of renal cell carcinoma: Current status and future directions
Authors: Pedro C. Barata, Brian I. Rini
Journal: CA A Cancer Journal for Clinicians (2017)

Abstract Answer questions and earn CME/CNE Over the past 12 years, medical treatment for renal cell carcinoma (RCC) has transitioned from a nonspecific immune approach (in the cytokine era), to targeted therapy against vascular endothelial growth factor (VEGF), and now to novel immunotherapy agents. Multiple agents—including molecules against vascular endothelial growth factor, platelet‐derived growth factor, and related receptors; inhibitors of other targets, such as the mammalian target of rapamycin and the MET and AXL tyrosine‐protein kinase receptors; and an immune‐checkpoint inhibitor—have been approved based on significant activity in patients with advanced RCC. Despite these advances, important questions remain regarding biomarkers of efficacy, patient selection, and the optimal combination and sequencing of agents. The purpose of this review is to summarize present management and future directions in the treatment of metastatic RCC. CA Cancer J Clin 2017;67:507‐524. © 2017 American Cancer Society.
Efficacy and safety of abemaciclib combined with either LY3023414 or pembrolizumab in stage IV NSCLC
Authors: P. Garrido Lopez, J. Goldman, K. Kelly, E.S. Kim, T.J. Beck, M. Alonso Garcia, Z. Yang, K-J. Ingram, L. Amstutz, W.J. John, M. Provencio Pulla
Journal: Annals of Oncology (2017)
Chemical Studies on Human Cancer. I. Cytochrome Oxidase, Cytochrome &lt;italic&gt;C&lt;/italic&gt;, and Copper in Normal and Neoplastic Tissues&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/xref&gt;
Authors: Jesse P. Greenstein, Jacob Werne, Allen B. Eschenbrenner, Florence M. Leuthardt
Journal: JNCI Journal of the National Cancer Institute (1944)

Journal Article Chemical Studies on Human Cancer. I. Cytochrome Oxidase, Cytochrome C, and Copper in Normal and Neoplastic Tissues Get access Jesse P. Greenstein, Jesse P. Greenstein senior biochemist National Cancer Institute, National Institute of Health, United States Public Health ServiceNational Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Jacob Werne, Jacob Werne assistant medical examiner of the City of New York National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Allen B. Eschenbrenner, Allen B. Eschenbrenner passed assistant surgeon National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Florence M. Leuthardt Florence M. Leuthardt laboratory technician National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 5, Issue 1, August 1944, Pages 55–76, https://doi.org/10.1093/jnci/5.1.55 Published: 01 August 1944