tbuckley/cabot-search huggingface dataset:
Randomized, Double-Blind, Placebo-Controlled Trial of Asenapine Maintenance Therapy in Adults With an Acute Manic or Mixed Episode Associated With Bipolar I Disorder
Authors: Armin Szegedi, Suresh Durgam, Mary Mackle, Sung Yun Yu, Xiao Wu, Maju Mathews, Ronald P. Landbloom
Journal: American Journal of Psychiatry (2017)

The authors determined the efficacy and safety of asenapine in preventing recurrence of any mood episode in adults with bipolar I disorder.Adults with an acute manic or mixed episode per DSM-IV-TR criteria were enrolled in this randomized, placebo-controlled trial consisting of an initial 12- to 16-week open-label period and a 26-week double-blind randomized withdrawal period. The target asenapine dosage was 10 mg b.i.d. in the open-label period but could be titrated down to 5 mg b.i.d. After completing the open-label period, subjects meeting stabilization/stable-responder criteria were randomized to asenapine or placebo treatment in the double-blind period. The primary efficacy endpoint was time to recurrence of any mood event during the double-blind period. Kaplan-Meier estimation was performed, and 95% confidence intervals were determined. Safety was assessed throughout.A total of 549 subjects entered the open-label period, of whom 253 enrolled in the double-blind randomized withdrawal period (127 in the placebo group; 126 in the asenapine group). Time to recurrence of any mood episode was statistically significantly longer for asenapine- than placebo-treated subjects. In post hoc analyses, significant differences in favor of asenapine over placebo were seen in time to recurrence of manic and depressive episodes. The most common treatment-emergent adverse events were somnolence (10.0%), akathisia (7.7%), and sedation (7.7%) in the open-label period and mania (11.9% of the placebo group compared with 4.0% of the asenapine group) and bipolar I disorder (6.3% compared with 1.6%) in the double-blind period.Long-term treatment with asenapine was more effective than placebo in preventing recurrence of mood events in adults with bipolar I disorder and was generally well-tolerated.
Commensal Propionibacterium strain UF1 mitigates intestinal inflammation via Th17 cell regulation
Authors: Natacha Colliou, Yong Ge, Bikash Sahay, Minghao Gong, Mojgan Zadeh, Jennifer L. Owen, Josef Neu, William G. Farmerie, Francis Alonzo, Ken Liu, Dean P. Jones, Shuzhao Li, Mansour Mohamadzadeh
Journal: Journal of Clinical Investigation (2017)

Consumption of human breast milk (HBM) attenuates the incidence of necrotizing enterocolitis (NEC), which remains a leading and intractable cause of mortality in preterm infants. Here, we report that this diminution correlates with alterations in the gut microbiota, particularly enrichment of Propionibacterium species. Transfaunation of microbiota from HBM-fed preterm infants or a newly identified and cultured Propionibacterium strain, P. UF1, to germfree mice conferred protection against pathogen infection and correlated with profound increases in intestinal Th17 cells. The induction of Th17 cells was dependent on bacterial dihydrolipoamide acetyltransferase (DlaT), a major protein expressed on the P. UF1 surface layer (S-layer). Binding of P. UF1 to its cognate receptor, SIGNR1, on dendritic cells resulted in the regulation of intestinal phagocytes. Importantly, transfer of P. UF1 profoundly mitigated induced NEC-like injury in neonatal mice. Together, these results mechanistically elucidate the protective effects of HBM and P. UF1-induced immunoregulation, which safeguard against proinflammatory diseases, including NEC.
Next generation sequencing of cell free circulating tumor DNA in blood samples of recurrent and metastatic head and neck cancer patients.
Authors: Ashleigh Porter, Gregory A. Daniels, Sandip Pravin Patel, Assuntina Gesualda Sacco, Kimberly Banks, Ezra E.W. Cohen
Journal: Journal of Clinical Oncology (2017)

e17516 Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is an increasingly prevalent disease but effective targeted therapy is lacking. The use of next generation sequencing (NGS) in the identification of novel targets has been suggested as a way to potentially expand therapeutic options and thereby improve outcomes. Methods: Data was collected on patients with recurrent and metastatic (R/M) head and neck cancers who underwent molecular profiling of blood samples utilizing Guardant360, a 70-gene circulating tumor DNA (ctDNA) NGS platform. CtDNA sequencing data was compared to tumor NGS data, when available. Best response to therapy was assessed using RECIST measures. Results: 60 HNSCC patients were evaluated from February 2015 to June 2016. The most common tumor type and histology was oropharyngeal squamous cell carcinoma (n = 21), which was commonly human papillomavirus (HPV) positive (n = 15). Other cancer types included salivary gland and thyroid cancers. The most common mutations identified by ctDNA analysis were TP53 (98%), PIK3CA (43%), NOTCH1 (38%), and ARID1A (36%). These findings were consistent with results from tumor sequencing data (n = 29) where TP53 (48%) and PIK3CA(24%) were also reported with the highest frequency. Importantly, 73% (n = 22) of patients had alterations identified in ctDNA that were not present in tumor specimens. Actionable mutations were identified in 66% of HNSCC and in 50% salivary gland cancer patients. Of patients with actionable mutations, 10% (n = 6) received matched targeted therapy (MTT): 3 (50%) had stable disease (SD), 1 had progressive disease (PD), and 2 were not evaluated. Of those who did not receive targeted therapy (n = 23), 1 (4.3%) patient had a complete response treated with immunotherapy, 11 (47%) had SD, and 11 (47%) had PD. Conclusions: Analysis of ctDNA may play a role in management decisions in R/M HNSCC. The majority of patients had unique mutations identified on ctDNA. The utility of ctDNA NGS and its role in patient management should be explored in future studies.
Biologic Testing of Carcinogens. II. Pulmonary-Tumor-Induction Technique
Authors: Howard B. Andervont, Michael B. Shimkin
Journal: JNCI Journal of the National Cancer Institute (1940)

Biologic Testing of Carcinogens. II. Pulmonary-Tumor-Induction Technique Get access Howard B. Andervont, Howard B. Andervont senior biologist 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 Michael B. Shimkin Michael B. Shimkin 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 JNCI: Journal of the National Cancer Institute, Volume 1, Issue 2, October 1940, Pages 225–239, https://doi.org/10.1093/jnci/1.2.225 Published: 01 October 1940
MYC Inhibition Depletes Cancer Stem-like Cells in Triple-Negative Breast Cancer
Authors: Aimin Yang, Shenghui Qin, Bradley A. Schulte, Stephen P. Ethier, Kenneth D. Tew, Gavin Y. Wang
Journal: Cancer Research (2017)

There is mounting evidence that cancer stem-like cells (CSC) are selectively enriched in residual tumors after anticancer therapies, which may account for tumor recurrence and metastasis by regenerating new tumors. Thus, there is a critical need to develop new therapeutic agents that can effectively eliminate drug-resistant CSCs and improve the efficacy of cancer therapy. Here, we report that Triptolide (C1572), a small-molecule natural product, selectively depletes CSCs in a dose-dependent fashion in human triple-negative breast cancer (TNBC) cell lines. Nanomolar concentrations of C1572 markedly reduced c-MYC (MYC) protein levels via a proteasome-dependent mechanism. Silencing MYC expression phenocopied the CSC depletion effects of C1572 and induced senescence in TNBC cells. Limited dilution assays revealed that ex vivo treatment of TNBC cells with C1572 reduced CSC levels by 28-fold. In mouse xenograft models of human TNBC, administration of C1572 suppressed tumor growth and depleted CSCs in a manner correlated with diminished MYC expression in residual tumor tissues. Together, these new findings provide a preclinical proof of concept defining C1572 as a promising therapeutic agent to eradicate CSCs for drug-resistant TNBC treatment. Cancer Res; 77(23); 6641-50. ©2017 AACR.
Doctors can withdraw artificial feeding without court approval in some cases, judge rules
Authors: Clare Dyer
Journal: BMJ (2017)

Cases in which doctors and the family of a patient in a permanent vegetative or minimally conscious state agree that artificial feeding should be withdrawn need no longer go to court, a High Court judge has declared in a landmark ruling.1

Mr Justice Peter Jackson ruled that a decision to withdraw clinically assisted nutrition and hydration in such cases, taken in accordance with professional guidance, will be lawful and that doctors who withdraw the treatment without going to court will be protected under the provisions of the Mental Capacity Act.

The ruling came in the case of a woman with Huntington’s disease, who was dependent on clinically assisted nutrition and hydration since 2003. Neither the …
A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis
Authors: Alma-Martina Cepika, Romain Banchereau, Elodie Segura, Marina Ohouo, Brandi Cantarel, Kristina Goller, Victoria Cantrell, Emily Ruchaud, Elizabeth Gatewood, Phuong Nguyen, Jinghua Gu, Esperanza Anguiano, Sandra Zurawski, Jeanine M. Baisch, Marilynn Punaro, Nicole Baldwin, Gerlinde Obermoser, Karolina Palucka, Jacques Banchereau, Sebastian Amigorena, Virginia Pascual
Journal: The Journal of Experimental Medicine (2017)

The etiology of sporadic human chronic inflammatory diseases remains mostly unknown. To fill this gap, we developed a strategy that simultaneously integrates blood leukocyte responses to innate stimuli at the transcriptional, cellular, and secreted protein levels. When applied to systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory disease of unknown etiology, this approach identified gene sets associated with specific cytokine environments and activated leukocyte subsets. During disease remission and off treatment, sJIA patients displayed dysregulated responses to TLR4, TLR8, and TLR7 stimulation. Isolated sJIA monocytes underexpressed the IL-1 inhibitor aryl hydrocarbon receptor (AHR) at baseline and accumulated higher levels of intracellular IL-1β after stimulation. Supporting the demonstration that AHR down-regulation skews monocytes toward macrophage differentiation, sJIA monocytes differentiated in vitro toward macrophages, away from the dendritic cell phenotype. This might contribute to the increased incidence of macrophage activation syndrome in these patients. Integrated analysis of high-dimensional data can thus unravel immune alterations predisposing to complex inflammatory diseases.
Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial
Authors: Merel J l’Ami, Charlotte LM Krieckaert, Michael T Nurmohamed, Ronald F van Vollenhoven, Theo Rispens, Maarten Boers, Gerrit Jan Wolbink
Journal: Annals of the Rheumatic Diseases (2017)

Objective High adalimumab serum concentrations do not result in better response in patients with rheumatoid arthritis (RA), suggesting overexposure. We investigated whether patients with adalimumab concentrations &gt;8 µg/mL can prolong their dosing interval by 50% without a clinically relevant change in disease activity. Methods Consecutive patients with RA, treated with adalimumab 40 mg every other week for at least 28 weeks, were approached for this randomised, open-label, non-inferiority trial. Patients with adalimumab trough concentrations &gt;8 µg/mL were randomly (1:1) assigned to dose-interval prolongation of once every 3 weeks or continuation of every other week. Primary outcome was the change in disease activity score of 28 joints (ΔDAS28-ESR) after 28 weeks, with a non-inferiority margin of 0.6 points. Results In total, 147 patients were screened. Fifty-five patients had concentrations &gt;8 µg/mL and were randomised. Mean ΔDAS28 after 28 weeks was –0.14±SD 0.61 in the prolongation group and 0.30±0.52 in the continuation group. Mean difference was significantly in favour of the prolongation group: 0.44 (95% CI 0.12 to 0.76, p=0.01). Conclusions Adalimumab-treated patients with RA with trough concentrations &gt;8 µg/mL can prolong their standard dosing interval to once every 3 weeks without loss of disease control. Trial registration number NTR3509; Results.
<i>Aspergillus</i> Galactomannan for Diagnosing Invasive Aspergillosis
Authors: Marisa H. Miceli, Carol A. Kauffman
Journal: JAMA (2017)

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Early PET/CT scan compared with RECIST to predict long-term outcome of patients with liver metastases from colorectal cancer treated with preoperative chemotherapy plus bevacizumab.
Authors: Maria Carmela Piccirillo, Secondo Lastoria, Guglielmo Nasti, Corradina Caraco, Luigi Aloj, Cecilia Arrichiello, Alessandro Ottaiano, Francesco Izzo, Elisabetta De Lutio, Vittorio Albino, Carmen Romano, Raffaele Palaia, Gennaro Daniele, Massimo Di Maio, Pasqualina Giordano, Simona Signoriello, Paolo Delrio, Rosario Vincenz Iaffaioli, Giovanni Romano, Francesco Perrone
Journal: Journal of Clinical Oncology (2013)

11008 Background: Early changes in tumor metabolism measured with positron-emission-tomography/computerized tomography (PET/CT) could predict the long-term efficacy of treatment better than dimensional RECIST response. Methods: We performed PET/CT before and after 1 cycle of treatment in patients with resectable liver metastases from colorectal cancer, within a phase II trial of preoperative FOLFIRI plus bevacizumab. For each lesion, the maximum SUV (SUVmax) and the total lesion glycolisis (TLG) were determined. For both, based on previous studies, a ≤-50% change from baseline was used as threshold for significant response. Metabolic response was categorized no/yes by using three different methods that enter into the calculation (i) the largest observed value (highest SUVmax/TLG), or (ii) the sum of all the observed values (Total SUVmax/TLG), or (iii) each observed values (SUVmax/TLG-by-lesion). Standard RECIST response was assessed after 3 months of treatment. The association between metabolic and RECIST response was tested with the Mc Nemar’s test and their agreement was expressed as Kappa statistics; the ability to predict progression-free (PFS) and overall (OS) survival was tested with Log-rank test and a multivariable Cox model. Results: 33 patients were analyzed. After treatment, there was a notable decrease of all PET/CT parameters, with a median change of -33.9% for the highest SUVmax, -61.5% for the highest TLG, -34.9% for the total SUVmax, and -65.5% for the total TLG. The association of SUV-based metabolic response (but not the TLG-based) with RECIST was statistically significant. However, the agreement between RECIST and PET/CT responses was consistently small. PFS and OS were significantly longer among PET/CT responding patients, whichever the measure used. On the contrary, no significant outcome difference was evident according to RECIST response. Conclusions: Early PET/CT response was significantly predictive of long-term outcomes during preoperative treatment of patients with liver metastases from colorectal cancer and its predictive ability was higher than that of RECIST response. Clinical trial information: 2006-006572-38.
Effect of inpatient palliative care during hematopoietic stem cell transplantation (HCT) hospitalization on psychological distress at six months post-HCT.
Authors: Areej El-Jawahri, Lara Traeger, Harry VanDusen, Joseph A. Greer, Vicki A. Jackson, William F. Pirl, Jason Telles, Sarah Fishman, Alison Rhodes, Thomas R. Spitzer, Steven L. McAfee, Yi-Bin Albert Chen, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2017)

10005 Background: Patients’ experience during HCT hospitalization leads to significant psychological distress post-HCT. Inpatient palliative care integrated with transplant care improves patient-reported QOL and symptom burden during hospitalization for HCT. We assessed the impact of the inpatient palliative care intervention on patients’ QOL, mood, and post-traumatic stress disorder (PTSD) at 6 months post-HCT. Methods: We randomized 160 patients with hematologic malignancies admitted for autologous or allogeneic HCT to an inpatient palliative care intervention (n=81) integrated with transplant care compared to transplant care alone (n=79). At baseline and 6 months post-HCT, we assessed QOL, mood, and PTSD symptoms using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ-9), and the PTSD checklist, respectively. To assess symptom burden during HCT hospitalization, we used the Edmonton Symptom Assessment Scale. We utilized linear regression models controlling for baseline values to analyze the intervention effects on outcomes at 6 months. We conducted causal mediation analyses to examine whether symptom burden during HCT mediated the effect of the intervention on o utcomes at 6 months. Results: Between 8/14 and 1/16, we enrolled 160/186 (86%) of potentially eligible patients. At 6 months post-HCT, the intervention led to improvements in depression and PTSD symptoms, but not QOL or anxiety [Table]. Improvement in symptom burden during HCT hospitalization partially mediated the effect of the intervention on patient-reported outcomes at six months post-HCT. Conclusions: Inpatient palliative care integrated with transplant care leads to improvements in depression and PTSD symptoms at 6 months post-HCT. Addressing symptom burden during HCT hospitalization partially accounts for the effect of the intervention on these long-term outcomes. Clinical trial information: NCT02207322. [Table: see text]
Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia
Authors: S Fujita, D Honma, N Adachi, K Araki, E Takamatsu, T Katsumoto, K Yamagata, K Akashi, K Aoyama, A Iwama, I Kitabayashi
Journal: Leukemia (2017)
Doxycycline compared with prednisolone therapy for patients with bullous pemphigoid: cost-effectiveness analysis of the BLISTER trial
Authors: J.M. Mason, J.R. Chalmers, T. Godec, A.J. Nunn, G. Kirtschig, F. Wojnarowska, M. Childs, D. Whitham, E. Schmidt, K. Harman, S. Walton, A. Chapman, H.C. Williams
Journal: British Journal of Dermatology (2017)

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder associated with significant morbidity and mortality. Doxycycline and prednisolone to treat bullous pemphigoid were compared within a randomized controlled trial (RCT).To compare the cost-effectiveness of doxycycline-initiated and prednisolone-initiated treatment for patients with BP.Quality-of-life (EuroQoL-5D-3L) and resource data were collected as part of the BLISTER trial: a multicentre, parallel-group, investigator-blinded RCT. Within-trial analysis was performed using bivariate regression of costs and quality-adjusted life-years (QALYs), with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost-effectiveness from a health service perspective.In the base case, there was no robust difference in costs or QALYs per patient at 1 year comparing doxycycline- with prednisolone-initiated therapy [net cost £959, 95% confidence interval (CI) -£24 to £1941; net QALYs -0·024, 95% CI -0·088 to 0·041]. However, the findings varied by baseline blister severity. For patients with mild or moderate blistering (≤ 30 blisters) net costs and outcomes were similar. For patients with severe blistering (> 30 blisters) net costs were higher (£2558, 95% CI -£82 to £5198) and quality of life poorer (-0·090 QALYs, 95% CI -0·22 to 0·042) for patients starting on doxycycline. The probability that doxycycline would be cost-effective for those with severe pemphigoid was 1·5% at a willingness to pay of £20 000 per QALY.Consistently with the clinical findings of the BLISTER trial, patients with mild or moderate blistering should receive treatment guided by the safety and effectiveness of the drugs and patient preference - neither strategy is clearly a preferred use of National Health Service resources. However, prednisolone-initiated treatment may be more cost-effective for patients with severe blistering.
Reply
Authors: Eric Marietta, Ashutosh Mangalam, Joseph Murray, Veena Taneja
Journal: Arthritis & Rheumatology (2017)

We thank Dr. Giancarlo and Dr. Vincenzo for their comments on our recent publication Marietta et al (1) on the use of gut-derived commensals as a treatment option for autoimmune diseases like rheumatoid arthritis (RA). Dysbiosis in RA patients has been well established (2, 3). We believe that reduced abundance of certain taxa might lead to an expansion of opportunist pathogens or perhaps loss of the homeostatic effects of those microbes.

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Image Gallery: Juvenile cutaneous chronic graft‐versus‐host disease presenting as bullous pemphigoid
Authors: R. Haber, E. Bourrat, A.‐F. Derache, J. Rivet, M. Bagot, J.‐H. Dalle, J.‐D. Bouaziz
Journal: British Journal of Dermatology (2017)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, A 5‐year‐old boy had skin blisters 8·5 months after allogeneic haematopoietic stem cell transplantation (AHSCT, cord blood cells) for a juvenile myelomonocytic chronic leukaemia. Bullous pemphigoid was confirmed using histology and direct immunofluorescence analysis. It healed with systemic and topical steroids. Only a few cases of autoimmune blistering diseases after AHSCT have been reported, and only in adult patients.1 The mechanism may be an allogeneic B‐cell response against the BP180 antigen related to minor human leucocyte antigen mismatch between the donor and the recipient.1,2 Bullous pemphigoid occurring after AHSCT is a chronic graft‐versus‐host manifestation with autoimmune features.
HERDOO2 identified women at low risk for recurrence after 5 to 12 mo of anticoagulation for a first unprovoked VTE
Authors: Paul Kruger, John Eikelboom
Journal: Annals of Internal Medicine (2017)

Source Citation Rodger MA, Le Gal G, Anderson DR, et al; REVERSE II Study Investigators. Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. BMJ. 2017;356:j1065. 28314711