tbuckley/cabot-search huggingface dataset:
Maintenance low-dose chemotherapy in patients with high-risk (HR) rhabdomyosarcoma (RMS): A report from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).
Authors: Gianni Bisogno, Gian Luca De Salvo, Christophe Bergeron, Meriel Jenney, Johannes H.M. Merks, Veronique Minard-Colin, Daniel Orbach, Heidi Glosli, Julia Chisholm, Michela Casanova, Soledad Gallego Melcon, Andrea Ferrari
Journal: Journal of Clinical Oncology (2018)

LBA2 Background: Most patients with localized RMS achieve complete remission during standard (std) treatment but approximately 20-30% of them relapse and chance of salvage is poor. We tested whether adding maintenance metronomic chemotherapy after std chemotherapy would improve survival for patients with non metastatic RMS defined as HR according to EpSSG stratification. Methods: Patients (pts) age &gt;6 months &lt;21 years, with N0 alveolar (A)RMS or incompletely resected (Group II or III) embryonal (E)RMS arising in an unfavorable primary site and/or N1 in complete remission after std treatment including 9 cycles of ifosfamide, vincristine and actinomycin D +/- doxorubicin, surgery and/or radiotherapy were eligible for randomization to stop treatment (Std-arm) or receive maintenance chemotherapy (M-arm) with 6 28-day cycles of iv vinorelbine 25 mg/m 2 on day 1,8,15 of each cycle and continuous daily oral cyclophosphamide 25 mg/m 2 . The study was initially designed with 80% power (5% 2-sided alpha level) to detect an increase in 3 yr Event Free Survival (EFS) from 55% to 67%, a Hazard Ratio of 0.67, but was successively amended to allow a detection of a relative reduction in the relapse rate of 50% in the M-arm, with 80% power, testing at the 5% significance level (2-sided). Results: 670 pts were entered between 4/2006-12/2016, with 371 confirmed eligible and 186 assigned to the std-arm and 185 to M-arm. Clinical features were well balanced in the two arms and included ERMS 67%, ARMS 33%, age 10+ years 21%; IRS Group III 86%; N1 16%. Most common primary tumor sites were parameningeal (32%) and “other” sites (23%). With median follow up of 5 years in surviving pts, 3 yr EFS and overall survival (OS) in M-arm vs Std-arm were respectively: EFS 78.4% (95% IC -71.5-83.8) vs 72.3% (95% IC -65.0-78.3) (p 0.061) and OS 87.3% (95% IC 81.2-91.6) vs 77.4 (95% IC 70.1-83.1) (p = 0.011). Toxicity in the M-arm was manageable: grade 3/4 febrile neutropenia in 25% of pts, grade 4 neurotoxicity in 1.1%. Conclusions: The addition of maintenance after std treatment significantly improves OS in HR RMS patients and support its inclusion in future EpSSG trials. Clinical trial information: 2005-000217-35.
Expansion of T follicular helper-T helper 1 like cells through epigenetic regulation by signal transducer and activator of transcription factors
Authors: Xiaoxue Ma, Shingo Nakayamada, Satoshi Kubo, Kei Sakata, Kaoru Yamagata, Yusuke Miyazaki, Maiko Yoshikawa, Yukihiro Kitanaga, Mingzeng Zhang, Yoshiya Tanaka
Journal: Annals of the Rheumatic Diseases (2018)

T follicular helper (Tfh) cells are critical in the development and progression of systemic lupus erythematosus (SLE). To assess the characteristics and mechanisms of differentiation of Tfh cells, we investigated the phenotype of T helper cells in patients with SLE and underlying epigenetic modifications by cytokine-induced signal transducer and activators of transcription (STAT) family factors.Peripheral blood mononuclear cells from patients and healthy donors were analysed by flow cytometry. CD4+ T cells were isolated and cultured under various stimulations. Expression of characteristic markers and phosphorylation of STATs were analysed by flow cytometry and quantitative PCR. Histone modifications were analysed by chromatin immunoprecipitation (ChIP)-PCR.Differentiation of CD4+CXCR5+CXCR3+Bcl-6+T-bet+IL-21+IFN-γ+Tfh-Th1-like cells was induced by interleukin (IL)-12-induced activation of STAT1 and STAT4 simultaneously. The loci of Bcl-6 and T-bet at STAT binding sites were marked by bivalent histone modifications. After IL-12 stimulation, both STAT1 and STAT4 directly bound on BCL6 and TBX21 gene loci accompanied by suppression of repressive histone mark trimethylated histone 3 lysine 27. Levels of serum IL-12 and interferon (IFN)-γ, expression of IL-12 receptors and proportion of CXCR5+CXCR3+ activated Tfh-Th1-like cells were increased in patients with SLE. Furthermore, the level of pSTAT1, pSTAT4 and T-bet were higher in activated Tfh-Th1-like cells than non-Tfh-Th1 cells.Our findings suggest that IL-12-mediated co-activation of STAT1 and STAT4 alters histone modification, resulting in differentiation of Tfh-Th1-like cells that are characteristically expanded in patients with SLE. This could be one of the underlying mechanisms responsible for expansion of Tfh-Th1-like cells and potentially helpful towards development of cell-specific treatment for SLE.
What are the drivers of healthcare cost among patients with metastatic breast cancer (mBC)? Total cost of care analysis to inform value-based reimbursement.
Authors: Chakkarin Burudpakdee, Arpamas Seetasith, Carolina M. Reyes, Sarika Ogale, Julie Munakata, Laura Kay Chu
Journal: Journal of Clinical Oncology (2018)

1092 Background: Given the move toward value-based payment in oncology, total cost of care data are needed to evaluate value. The objective of this study was to quantify cost of care and identify key drivers of healthcare cost in patients (pts) with mBC. Methods: Adults with systemic treatment for mBC from 1/1/2014 – 12/1/2016 were identified from IQVIA’s claims database. Pts were indexed on the first mBC treatment, had ≥2 diagnoses for both breast and metastatic cancer, ≥12 months of continuous medical and drug coverage before and ≥30 days after index. Healthcare resource use and costs were measured during follow up, standardized as per patient per month (PPPM), and compared between overall and high cost (defined as top 10%) pts. Results: 7,032 pts with mBC were included; mean (±SD) age was 55.5 ± 9.6; mean follow up was 14.0 ± 9.1 months. Total cost of care is shown in Table 1. The mean total PPPM cost of high cost pts (n = 703) was 3.7-fold higher than that of the overall population. The largest difference in cost between overall and high cost pts was for outpatient drugs ($7,348 PPPM); 76% was related to breast cancer medications. Other cost drivers in high cost pts included hospitalization ($6,152 PPPM higher), radiology procedures ($2,238 PPPM higher), and pharmacy services ($1,755 PPPM higher). The proportion of total costs due to outpatient surgery, office visits, lab services, and ED visits was lower in high cost pts compared to the overall population (10.5% vs. 7.1%). Conclusions: Our findings suggest that medications, hospitalizations, and radiology services are the main drivers of high costs in mBC pts. Further research is needed to identify if there are services and costs that are unintended and avoidable. Findings from this study can help inform evidence-based decisions when developing alternative payment models for cancer care. Total cost of care. Mean cost PPPM All (N = 7,032) High cost (N = 703) Total $7,828 $28,776 Pharmacy $1,341 $3,096 Medical $6,487 $25,680 Inpatient $1,337 $7,489 Outpatient $5,150 $18,191 Drug $2,189 $9,538 Radiology $1,133 $3,371 Other outpatient service $1,001 $3252 Surgery $320 $742 Office visit $269 $564 Laboratory $183 $544 ED visit $55 $180
King’s Fund warns that access must not trump other essential attributes of general practice
Authors: Jennifer Richardson
Journal: BMJ (2018)

GPs, service commissioners, and policymakers should be wary of focusing on increasing access to general practice, such as through online consultations, at the expense of its other essential attributes, the King’s Fund has warned.

The healthcare think tank highlighted different ways of organising general practice, using examples from around the world, to offer inspiration to primary care in England in a report published on 7 June.1

The report urged GPs to develop new models of care—and commissioners and policymakers to provide support, including funding, for GPs to do so.

One case study …
Efficacy and safety of epacadostat plus pembrolizumab treatment of NSCLC: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.
Authors: Tara C. Gangadhar, Bryan J. Schneider, Todd Michael Bauer, Jeffrey S. Wasser, Alexander I. Spira, Sandip P. Patel, Ani Sarkis Balmanoukian, Joshua Bauml, Emmett V. Schmidt, Yufan Zhao, Mark M. Jones, Ahmad A. Tarhini
Journal: Journal of Clinical Oncology (2017)

9014 Background: ECHO-202/KEYNOTE-037 is an open-label, phase 1/2 study of epacadostat (a potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus pembrolizumab (E + P) in patients (pts) with advanced tumors. We report preliminary efficacy and safety outcomes for the phase 1/2 NSCLC cohort. Methods: Adult pts with prior platinum-based therapy (tx) and no prior checkpoint inhibitor tx were eligible. Phase 1 dose-escalation tx was E (25, 50, 100, 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) tx doses were selected for phase 2 cohort expansion. Efficacy was evaluated by tumor proportion score (TPS [% viable tumor cells, PD-L1 staining]: &lt; 50% and ≥50%) and by prior lines of tx in RECIST 1.1 evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: As of 29OCT2016,43 pts (phase 1, n = 12; phase 2, n = 31) were evaluated. Median age was 65 years, 58% of pts were women, 12% were EGFR-positive, and 23% were KRAS-positive. Most pts had a history of smoking (84%), ≤2 prior lines of tx (84%), and no prior TKI tx (93%). For the 40 efficacy-evaluable pts, ORR (CR+PR) and DCR (CR+PR+SD) were 35% (14/40; 14 PR) and 60% (24/40; 10 SD), respectively. PD-L1 TPS test results were available in 28/40 efficacy-evaluable pts. ORR and DCR for pts with TPS ≥50% and ≤2 prior tx were 43% (3/7; all PR) and 57% (4/7; 1 SD), respectively; for pts with TPS &lt; 50% and ≤2 prior tx, ORR and DCR were 35% (6/17; all PR) and 53% (9/17; 3 SD). Among the 40 efficacy-evaluable pts, 12/14 responses were ongoing (range, 1+ to 519 days) at data cutoff. PFS and biomarker analyses are ongoing. Across all 43 pts, most frequent TRAEs were fatigue (19%), arthralgia (9%), and increased AST (9%); 16% of pts had grade ≥3 TRAEs, and increased lipase (asymptomatic) was the only grade ≥3 TRAE that occurred in &gt; 1 pt (n = 2). Two pts discontinued due to TRAEs (grade 3 increased AST, grade 2 increased ALT [n = 1]; grade 2 brain edema [n = 1]). Conclusions: E + P was generally well tolerated and associated with promising responses in pts with NSCLC. A phase 3 NSCLC study is planned. Clinical trial information: NCT02178722.
Inhibition of Tissue Factor Pathway Inhibitor (TFPI) as a Treatment for Haemophilia: Rationale with Focus on Concizumab
Authors: Pratima Chowdary
Journal: Drugs (2018)

Replacement therapy with missing factor (F) VIII or IX in haemophilia patients for bleed management and preventative treatment or prophylaxis is standard of care. Restoration of thrombin generation through novel mechanisms has become the focus of innovation to overcome limitations imposed by protein replacement therapy. Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type serine protease inhibitor that regulates tissue factor (TF)-induced coagulation through a FXa-dependent feedback inhibition of the TF.FVIIa complex in plasma and on endothelial surfaces. Concizumab is a monoclonal, humanised antibody, specific for the second Kunitz domain of TFPI that binds and inhibits FXa, abolishing the inhibitory effect of TFPI. Concizumab restored thrombin generation in FVIII and FIX deficient plasmas and decreased blood loss in a rabbit haemophilia model. Phase 1 single and multiple dose escalation studies in haemophilia patients demonstrated a dose dependent decrease in TFPI levels and a pro-coagulant effect with increasing d-dimers and prothrombin fragment 1 + 2. A dose dependent increase in peak thrombin and endogenous thrombin potential was observed with values in the normal range when plasma TFPI levels were nearly undetectable. A few haemophilia patients in the highest dose cohorts with complete inhibition of plasma TFPI showed a decreased fibrinogen concentration with normal levels of anti-thrombin and platelets and no evidence of thrombosis. Pharmacokinetic parameters were influenced by binding to the target (TFPI), demonstrating target mediated drug disposition. A trend towards decreasing bleeding tendency was observed and this preventative effect is being studied in Phase 2 studies with additional data gathered to improve our understanding of the therapeutic window and potential for thrombosis.
Identification and characterization of HIV-specific resident memory CD8 <sup>+</sup> T cells in human lymphoid tissue
Authors: Marcus Buggert, Son Nguyen, Gonzalo Salgado-Montes de Oca, Bertram Bengsch, Samuel Darko, Amy Ransier, Emily R. Roberts, Daniel del Alcazar, Irene Bukh Brody, Laura A. Vella, Lalit Beura, Sathi Wijeyesinghe, Ramin S. Herati, Perla M. Del Rio Estrada, Yuria Ablanedo-Terrazas, Leticia Kuri-Cervantes, Alberto Sada Japp, Sasikanth Manne, Josephine R. Giles, Shant Vartanian, Austin Huffman, Johan K. Sandberg, Emma Gostick, Gregory Nadolski, Guido Silvestri, David H. Canaday, David A. Price, Constantinos Petrovas, Laura F. Su, Golnaz Vahedi, Yoav Dori, Ian Frank, Maxim G. Itkin, E. John Wherry, Steven G. Deeks, Ali Naji, Gustavo Reyes-Terán, David Masopust, Daniel C. Douek, Michael R. Betts
Journal: Science Immunology (2018)

Current paradigms of CD8 + T cell–mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL), and LTs in different species, we show that many LT memory CD8 + T cells bear phenotypic, transcriptional, and epigenetic signatures of resident memory T cells (T RMs ). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8 + T cells in LTs also resemble T RMs . Moreover, high frequencies of HIV-specific CD8 + T RMs with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA sequencing analysis confirmed that HIV-specific T RMs are enriched for effector-related immune genes and signatures compared with HIV-specific non-T RMs in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8 + T cell responses resident within LTs.
Effects of Pentoxifylline on Soluble Klotho Concentrations and Renal Tubular Cell Expression in Diabetic Kidney Disease
Authors: Juan F. Navarro-González, María Dolores Sánchez-Niño, Javier Donate-Correa, Ernesto Martín-Núñez, Carla Ferri, Nayra Pérez-Delgado, José Luis Górriz, Alberto Martínez-Castelao, Alberto Ortiz, Carmen Mora-Fernández
Journal: Diabetes Care (2018)

OBJECTIVE The effect of pentoxifylline on Klotho levels in patients with type 2 diabetes mellitus with chronic kidney disease (CKD) was assessed in a post hoc analysis of the Pentoxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) trial. RESEARCH DESIGN AND METHODS Circulating and urinary tumor necrosis factor-α (TNF-α) and Klotho were measured before and after 1 year of pentoxifylline. The effect on Klotho expression was assessed in cultured renal tubular cells. RESULTS Pentoxifylline administration resulted in decreased serum and urinary TNF-α, whereas serum and urinary Klotho increased significantly. Changes in urinary Klotho, urinary TNF-α, and phosphorus were associated with changes in serum Klotho; changes in estimated glomerular filtration rate, urinary TNF-α, and albuminuria were related to urinary Klotho variation. In renal tubular cells, pentoxifylline prevented the decrease in Klotho expression induced by inflammatory cytokines or albumin. CONCLUSIONS Pentoxifylline increased Klotho levels in patients with diabetes with stage 3–4 CKD and prevented reduced Klotho expression in vitro. This beneficial effect may be related to anti-inflammatory and antialbuminuric activity.
Abstract 057: Estimating the Benefits of the Proposed FDA Sodium Reformulation Policy on Cardiovascular Disease, Disparities and Economic Costs
Authors: Jonathan Pearson-Stuttard, Chris Kypridemos, Brendan Collins, Yue Huang, Piotr Bandosz, Laurie Whitsel, Simon Capewell, Dariush Mozaffarian, Parke Wilde, Martin O'Flaherty, Renata Micha
Journal: Circulation (2018)

Background: Sodium consumption is a leading modifiable risk factor for CVD mortality and morbidity in the US. In 2016, the US Food and Drug Administration (FDA), following recent effective examples in several other countries, proposed voluntary sodium targets for industry to reduce sodium in processed foods. Aim: We aimed to estimate the potential CVD, equity and economic impacts of implementing this policy. Methods: We used the validated US IMPACT Food Policy microsimulation model to estimate the CVD cases averted, quality-adjusted life-years (QALYs) gained and cost-effectiveness from 2017-2036 of the FDA sodium reformulation policy in US adults (30+ years). Model inputs included national demographics and sodium intakes from NHANES, FDA short- and long-term sodium reformulation targets, sodium effects on blood pressure and of blood pressure on CVD from meta-analyses, government costs to administer and monitor the policy and industry reformulation costs, and validated healthcare and productivity costs. We modelled 3 scenarios: a) Optimal, 100% compliance of 10-year reformulation targets b) Modest, 50% compliance of 10-year reformulation targets c) Pessimistic, 100% compliance of 2-year reformulation targets with no further progress Costs were inflated to 2017 US dollars and outputs were discounted annually by 3%. We took a societal perspective for this analysis. Rigorous probabilistic sensitivity analyses were conducted. Results: The optimal scenario achieving the 10-year sodium reduction targets could prevent ~ 450,000 CVD cases (95% Uncertainty Interval: 240,000-740,000), gain 2.1 million QALYs (1.7m-2.4m), and produce $41billion ($14bn-$81bn) cost-savings from 2017-2036. The modest and pessimistic scenarios were also cost-saving, with both health gains and savings about one half and one quarter, respectively, of the optimal scenario. Relative disparities between non-Hispanic white and non-Hispanic black populations would be reduced in all scenarios. The pessimistic scenario yielded the largest reduction in absolute disparities (70,000 CVD cases (33,000-120,000) prevented in non-Hispanic blacks vs. 13,000 (0-54,000) in non-Hispanic whites). The optimal scenario would prevent approximately 4.6% (130,000 cases (65,0000-220,000)) of all CVD cases in non-Hispanic blacks compared to 1.5% (220,000 cases (120,000-360,000)) in non-Hispanic whites. Despite a smaller population, total net savings would be over 50% larger in non-Hispanic blacks than non-Hispanic whites ($19bn vs $12bn) in the optimal scenario. Conclusions: Implementing and even partly achieving the FDA sodium reduction targets could generate substantial health gains and net cost savings. Crucially, this policy could also reduce CVD disparities between non-Hispanic black and non-Hispanic white populations.
Toward a Neuroscience of Long-term Recovery From Addiction
Authors: Keith Humphreys, Warren K. Bickel
Journal: JAMA Psychiatry (2018)

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
Patterns of Immediate-Release and Extended-Release Opioid Analgesic Use in the Management of Chronic Pain, 2003-2014
Authors: Catherine S. Hwang, Elizabeth M. Kang, Yulan Ding, Josephine Ocran-Appiah, Jana K. McAninch, Judy A. Staffa, Cynthia J. Kornegay, Tamra E. Meyer
Journal: JAMA Network Open (2018)

Many stakeholders are working to improve the safe use of immediate-release (IR) and extended-release/long-acting (ER/LA) opioid analgesics. However, little information exists regarding the relative use of these 2 formulations in chronic pain management.To describe the distribution of IR and ER/LA opioid analgesic therapy duration and examine adding and switching patterns among patients receiving long-term IR opioid analgesic therapy, defined as at least 90 consecutive days of IR formulation use.A retrospective cohort study of 169 million individuals receiving opioid analgesics from across 90% of outpatient retail pharmacies in the United States from January 1, 2003, to December 31, 2014, using the IQVIA Health Vector One: Data Extract Tool. Analyses were conducted from March 2015 to June 2017.Receipt of dispensed IR or ER/LA opioid analgesic prescription.Distribution of therapy frequency and duration of IR and ER/LA opioid analgesic use, and annual proportions of patients receiving long-term IR opioid analgesic therapy who added an ER/LA formulation while continuing to use an IR formulation, switched to an ER/LA formulation, or continued receiving IR opioid analgesic therapy only.Among the 169 280 456 patients included in this analysis, 168 315 458 patients filled IR formulations and 10 216 570 patients filled ER/LA formulations. A similar percentage of women received ER/LA (55%) and IR (56%) formulations, although those receiving ER/LA formulations (72%) were more likely to be aged 45 years or older compared with those receiving IR formulations (46%). The longest opioid analgesic episode duration was 90 days or longer for 11 563 089 patients (7%) filling IR formulations and 3 103 777 patients (30%) filling ER/LA formulations. The median episode duration was 5 days (interquartile range, 3-10 days) for patients using IR formulations and 30 days (interquartile range, 21-74 days) for patients using ER/LA formulations. From January 1, 2003, to December 31, 2014, a small and decreasing proportion of patients with long-term IR opioid analgesic therapy added (3.8% in 2003 to 1.8% in 2014) or switched to (1.0% in 2003 to 0.5% in 2014) an ER/LA formulation.Most patients receiving opioid analgesics, whether for short or extended periods, use IR formulations. Once receiving long-term IR opioid analgesic therapy, patients are unlikely to add or switch to an ER/LA formulation.