tbuckley/cabot-search huggingface dataset:
The positive effects of habit reversal treatment of scratching in children with atopic dermatitis: a randomized controlled study
Authors: P. Norén, L. Hagströmer, M. Alimohammadi, L. Melin
Journal: British Journal of Dermatology (2017)

Scratching and itch are common clinical signs of atopic dermatitis (AD). Studies of adult patients have shown that a decrease in scratching behaviour results in regression of inflammation and improved healing of the skin.To investigate whether a modified habit reversal (HR) treatment protocol could be used for the treatment of scratching in children to improve skin status.The study is a single-blind, randomized controlled trial of 39 patients who started with registration a week before randomization into one of two groups (intervention or control). The participants in the intervention group received a habit-breaking therapy of their scratching behaviour (i.e. HR) in addition to a potent steroid (mometasone furoate), whereas the patients in the control group received the steroid alone. The patients were assessed by an independent dermatologist after the first week of registration (baseline assessment) and then after 3 and 8 weeks of treatment. The primary efficacy variable was a change in objective Scoring Atopic Dermatitis (SCORAD).At the end of the 3-week treatment period, the change in mean objective SCORAD was significantly (P = 0·027) higher in the intervention group (-31·9 ± 9·5) than in the control group (-23·8 ± 10·1). After the 8-week follow-up, the change in mean objective SCORAD was significantly (P = 0·0038) higher in the intervention group (-31·7 ± 10·4) than in the control group (-19·7 ± 9·4).The treatment of scratching with the HR method in combination with a potent steroid was found to improve skin status significantly after 3 and 11 weeks.
NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL
Authors: C Prieto, B López-Millán, H Roca-Ho, R W Stam, D Romero-Moya, F J Rodríguez-Baena, A Sanjuan-Pla, V Ayllón, M Ramírez, M Bardini, P De Lorenzo, M G Valsecchi, M Stanulla, M Iglesias, P Ballerini, Á M Carcaboso, J Mora, F Locatelli, A Bertaina, L Padilla, Juan Carlos Rodríguez-Manzaneque, C Bueno, P Menéndez
Journal: Leukemia (2017)

Abstract Mixed-lineage leukemia (MLL)-rearranged (MLLr) infant B-cell acute lymphoblastic leukemia (iMLLr-B-ALL) has a dismal prognosis and is associated with a pro-B/mixed phenotype, therapy refractoriness and frequent central nervous system (CNS) disease/relapse. Neuron-glial antigen 2 (NG2) is specifically expressed in MLLr leukemias and is used in leukemia immunophenotyping because of its predictive value for MLLr acute leukemias. NG2 is involved in melanoma metastasis and brain development; however, its role in MLL-mediated leukemogenesis remains elusive. Here we evaluated whether NG2 distinguishes leukemia-initiating/propagating cells (L-ICs) and/or CNS-infiltrating cells (CNS-ICs) in iMLLr-B-ALL. Clinical data from the Interfant cohort of iMLLr-B-ALL demonstrated that high NG2 expression associates with lower event-free survival, higher number of circulating blasts and more frequent CNS disease/relapse. Serial xenotransplantation of primary MLL-AF4 + leukemias indicated that NG2 is a malleable marker that does not enrich for L-IC or CNS-IC in iMLLr-B-All. However, NG2 expression was highly upregulated in blasts infiltrating extramedullar hematopoietic sites and CNS, and specific blockage of NG2 resulted in almost complete loss of engraftment. Indeed, gene expression profiling of primary blasts and primografts revealed a migratory signature of NG2 + blasts. This study provides new insights on the biology of NG2 in iMLLr-B-ALL and suggests NG2 as a potential therapeutic target to reduce the risk of CNS disease/relapse and to provide safer CNS-directed therapies for iMLLr-B-ALL.
Economic burden of relapsed/refractory chronic lymphocytic leukemia.
Authors: Annie Guerin, Saurabh Ray, Geneviève Gauthier, Ling-I Hsu, Maryia Zhdanava, Julie Héroux, Eric Qiong Wu
Journal: Journal of Clinical Oncology (2015)

e18065 Background: Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia where most patients (pts) experience a relapse or become refractory after the first-line treatment. The objective of this study is to assess the incremental economic burden imposed by relapsed/refractory (R/R) CLL on the healthcare system. Methods: CLL pts with an indicator of R/R disease were selected from the Truven MarketScan database ( > 25 million commercially insured lives annually; 2000-2013) based on diagnoses and treatment patterns. Pts were required to be ≥ 18 years in age, continuously enrolled in their health plan for ≥ 6 months prior to and ≥ 1 month after the first indicator of R/R CLL. The index date was defined as the date occurring 30 days prior to the first indicator of R/R CLL. The incremental economic burden of R/R CLL was estimated by comparing the healthcare resource utilization (HRU) and costs of pts between the pre- R/R period (up to 12 months before the index date) and post-R/R period (up to 12 months after the index date). HRU and costs were estimated per-pt-per-month (PPPM) and compared between the pre- and post-R/R periods using generalized linear models and Wilcoxon signed-rank tests, respectively. Results: 5,066 R/R CLL pts were identified; median age of 68 years, 60.3% male, 58.3% with Medicare Supplement Plan coverage. Median time from first observed CLL diagnosis to R/R CLL was 18 months. During the post R/R period, pts had significantly higher HRU: 58% more inpatient (IP) admissions, 77% more IP days, 39% more emergency room visits, and 42% more outpatient (OP) visits compared to the pre-R/R period (all p< .001). Overall, during the post- R/R period, the mean total healthcare costs PPPM almost doubled ($7,303 vs. $3,851) compared to the pre-R/R period, mainly driven by higher OP ($4,983 vs. $2,476) and IP costs ($1,635 vs. $857) (all p< .001). The mean total healthcare costs increased significantly to $14,920 PPPM during the first month following the indicator of R/R CLL, remained above $7,000 PPPM for the next 3 months, and ranged between $4,231 and $5,992 PPPM over the subsequent months of the post-R/R period. Conclusions: The economic burden of CLL increases substantially when pts become relapsed or refractory to CLL.
Abstract 16306: Left Atrial and Ventricular Strain Can Predict Development of New Arrhythmias in Patients With Non-Obstructive Hypertrophic Cardiomyopathy
Authors: Sharma Kattel, Ryoko Ichikawa, Tomoko S Kato, Takatoshi Kasai, Hiroyuki Diada
Journal: Circulation (2016)

Background:  Patients with hypertrophic cardiomyopathy (HCM) frequently develop cardiac arrhythmia that can lead to heart failure and sudden cardiac death. Therefore, the identification of patients at high risk for cardiac arrhythmia while they are still in sinus rhythm can be of great clinical value. We hypothesized that strain analysis of left ventricle (LV) and atrium (LA) would predict new-onset arrhythmia in patients with HCM.   Methods:  We reviewed echocardiograms of 60 patients with non-obstructive HCM who were in sinus rhythm at the time of initial diagnosis. Conventional and 2D speckle echo parameters including strain and strain rates of LA and LV were analyzed, and compared between those who developed and did not develop cardiac arrhythmia during the observation period.   Results:  During 5.8±1.3 years of follow-up, 16 patients (27%) developed cardiac arrhythmia including atrial fibrillation and ventricular arrhythmia requiring ICD. The mean values of LV strain, LV strain rate and LA peak strain were lower (-10.0±1.0 vs.-12.5±0.6%, p=0.041; -0.64±0.16 vs. -0.80±0.24sec -1 , p=0.018; 19.3±5.2 vs. 26.1±6.3%, p=0.0002, respectively), LA volume (LAV) was larger (77.3±23.1 vs. 56.7±17.1mL, p=0.0007) and tissue Doppler derived mitral E’ was smaller (4.3±1.2 vs. 5.7±2.0 cm/s, p=0.0081) in patients who developed arrhythmia. Multivariate logistic analysis revealed that LV strain (odds ratio [OR] 1.17, 95% CI [confidence interval] 1.01-1.39, p=0.035), LA peak strain (OR 0.81, 95% CI 0.69-0.90, p=0.0001) and LAV (OR 1.06, 95% CI 1.02-1.11, p=0.0007) remained significantly associated with new-onset arrhythmia. HCM patients with LV strain>-13.8%, LA peak strain 89mL had 4.9-fold higher risk of developing cardiac arrhythmia than those without any of these echo-findings (OR 3.2, CI 1.92-9.3, p   Conclusion:  In addition to the conventional echo-derived information of dilated LA, reduced LV strain and LA peak strain can independently predict new-onset arrhythmia in HCM patients who are in sinus rhythm. This can be used for risk stratification of HCM patients for development of arrhythmia, allowing close monitoring and early detection.
Abstract 222: Sigmar1 Mediates Mitochondrial Autophagy and Protects the Heart Against Ischemia/Reperfusion Injury
Authors: Md. Shenuarin Bhuiyan, Shafiul Alam, Jonette M. Green, A. Wayne Orr, Jeanne James, Hanna Osinska, Jason Karch, Jeffery D. Molkentin, Burns C. Blaxall, John N. Lorenz, Junichi Sadoshima, Jeffrey Robbins
Journal: Circulation Research (2016)

Rationale: Sigma 1 receptor (Sigmar1) is a highly expressed mitochondrion-associated ER membrane resident protein in different cell lines. We recently reported that Sigmar1 is highly expressed in cardiomyocytes but it’s molecular functions and role in the stress response still remains unknown. Objective: We investigated the functional role of Sigmar1 in mediating mitochondrial autophagy, mitochondrial fission and effects on stress resistance in the heart. Methods and Results: Subcellular fractionation and biochemical experiments confirmed Sigmar1 expression in the mitochondria, where it resides as an integral mitochondrial outer membrane protein. Sigmar1 overexpression induced mitochondrial fission, increased autophagosome formation and autophagic flux in cardiomyocytes. Similarly, cardiac specific Sigmar1 transgenic (Tg) mice showed increased levels of mitochondrial fission and mitochondrial autophagy without adverse effects. Conversely, Sigmar1 knockdown induced both mitochondrial elongation and accumulation of damaged mitochondria, whereas autophagosome formation and autophagic flux were reduced at baseline and in response to glucose deprivation in cardiomyocytes. Parallel studies using Sigmar1 knockout mice showed increased accumulation of abnormal mitochondria and significantly altered cardiac contractility. To define the functional significance of Sigmar1 in the cardiac stress response, we subjected the mice to ischemia/reperfusion (I/R) injury. Sigmar1 Tg mouse showed reduced infarct size, protected from I/R-injury induced adverse cardiac remodeling, and improved cardiac function associated with enhanced mitochondrial autophagy even 12 weeks after reperfusion injury. In contrary, knockdown of Sigmar1 evoked mitochondrial dysfunction, accumulation of abnormal mitochondria, enhanced adverse cardiac remodeling, aggravated cardiac dysfunction and increased susceptibility to I/R-injury. Conclusions: Our findings suggested that Sigmar1 is an integral mitochondrial outer membrane protein dispensable for constitutive mitochondrial quality control in normal hearts. Sigmar1 regulates mitochondrial autophagy to protect the heart against I/R injury-induced cardiac remodeling and dysfunction.
Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: A 20 year‐community study
Authors: Alina M. Allen, Terry M. Therneau, Joseph J. Larson, Alexandra Coward, Virend K. Somers, Patrick S. Kamath
Journal: Hepatology (2017)

Recent population-based data on nonalcoholic fatty liver disease (NAFLD) epidemiology in general, and incidence in particular, are lacking. We examined trends in NAFLD incidence in a U.S. community and the impact of NAFLD on incident metabolic comorbidities (MCs), cardiovascular (CV) events, and mortality. A community cohort of all adults diagnosed with NAFLD in Olmsted County, Minnesota, between 1997 and 2014 was constructed using the Rochester Epidemiology Project database. The yearly incidence rate were calculated. The impact of NAFLD on incident MCs, CV events, and mortality was studied using a multistate model, with a 4:1 age- and sex-matched general population as a reference. We identified 3,869 NAFLD subjects (median age, 53; 52% women) and 15,209 controls; median follow-up was 7 (1-20) years. NAFLD incidence increased 5-fold, from 62 to 329 in 100,000 person-years. The increase was highest (7-fold) in young adults, aged 18-39 years. The 10-year mortality was higher in NAFLD subjects (10.2%) than controls (7.6%; P < 0.0001). NAFLD was an independent risk factor for incident MCs and death. Mortality risk decreased as the number of incident MCs increased: relative risk (RR) = 2.16 (95% confidence [CI], 1.41-3.31), 1.99 (95% CI, 1.48-2.66), 1.75 (95% CI, 1.42-2.14), and 1.08 (95% CI, 0.89-1.30) when 0, 1, 2, or 3 MCs were present, respectively. The NAFLD impact on CV events was significant only in subjects without MCs (RR = 1.96; 95% CI = 1.35-2.86). NAFLD reduced life expectancy by 4 years, with more time spent in high metabolic burden.Incidence of NAFLD diagnosis in the community has increased 5-fold, particularly in young adults. NAFLD is a consequence, but also a precursor of MC. Incident MC attenuates the impact of NAFLD on death and annuls its impact on CV disease. (Hepatology 2018;67:1726-1736).
A phase 1 study to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and antitumor activity of MEDI9447 alone and in combination with durvalumab (MEDI4736) in patients with advanced solid tumors.
Authors: Johanna C. Bendell, Vijay Reddy, Fatemeh Tavakkoli, Ching Ching Leow, Xia Li, Rakesh Kumar, John H. Strickler
Journal: Journal of Clinical Oncology (2016)

TPS3096 Background: The success of immune checkpoint inhibitors in various cancers has triggered the identification of novel approaches to modulate the immune system. CD73, an ectonucleotidase, catalyzes the rate-limiting step for the production of adenosine in the extracellular space. Adenosine may aid tumors in evading immune recognition and destruction. MEDI9447 is a human IgG1λ monoclonal antibody (mAb) that selectively binds to and inhibits the ectonucleotidase activity of CD73. Durvalumab (MEDI4736) is a selective, high-affinity human IgG1 mAb that blocks PD-L1 binding to PD-1 (IC50 0.1 nM) and CD80 (B7.1; IC50 0.04 nM). Preclinical data suggests additive activity of MEDI9447 with checkpoint inhibitor antibodies.1 Methods: This is a first-time-in-human Phase 1, multicenter, open-label, dose-escalation and dose-expansion study (NCT02503774) of MEDI9447 administered as a single agent or in combination with durvalumab. Eligible patients include those with selected advanced solid tumors that have progressed, are refractory to, or are intolerant to standard therapy appropriate for the specific tumor type. The primary objectives are to assess safety and tolerability, describe dose-limiting toxicity (DLT), and determine the maximum tolerated dose. The secondary objectives are to evaluate antitumor efficacy, pharmacokinetics, immunogenicity, and biomarker activity in tumor biopsy specimens. Antitumor activity is assessed using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Subjects in the monotherapy arm will receive one of four dose levels of MEDI9447; subjects in the combination arm will receive one of four dose levels of MEDI9447 and a fixed dose level of durvalumab. Subjects will receive MEDI9447 as monotherapy or in combination with durvalumab for up to 52 weeks. Dose escalation will follow a 3 + 3 design. Recruitment is ongoing. 1. Cancer Res 2015;75(15 Suppl):Abstract nr 285. doi:10.1158/1538-7445.AM2015-285 Clinical trial information: NCT02503774.
Pembrolizumab in patients with recurrent thymic carcinoma: Results of a phase II study.
Authors: Giuseppe Giaccone, Jillian Thompson, Colleen McGuire, Maria Manning, Bhaskar Kallakury, Joeffrey J Chahine, Deepa Suresh Subramaniam, Stephen V. Liu, Geoffrey Thomas Gibney, Chul Kim, Justine N McCutcheon
Journal: Journal of Clinical Oncology (2017)

8573 Background: There are few treatment options for thymic carcinoma after chemotherapy. We completed a single institution phase II study of pembrolizumab (P) in patients with recurrent thymic carcinomas. Methods: Main eligibility criteria included: progression after ≥ 1 chemotherapy line, ECOG PS 0-2, no history of autoimmune disease, and adequate organ function. P was given at 200mg IV every 3 weeks. The primary objective of the study was response rate (RR) by RECIST v1.1 criteria; secondary objectives were PFS and OS, and safety. Results: From 3/2015 to 12/2016 we accrued 41 patients. Of 40 eligible patients, 29 were male, 19 Caucasians, median age was 57 years (range 25-80), 14 had squamous carcinoma histology, and 19 ECOG PS 0. Median number of cycles delivered was 6 (range 1-31). The most common side effects were mild fatigue (10), diarrhea (4) and rhinorrhea (4). Six patients developed multiple grade 3-4 immune-relates AEs (irAEs): myocarditis/myositis (1), myositis/myocarditis/hepatitis/myasthenia gravis (1), myositis/hepatitis (1), bullous pemphigoid (1), hepatitis (1), hepatitis/pancreatitis/diabetes mellitus type 1 (1). There were no treatment related deaths. The 2 patients who developed myocarditis required a pacemaker. Three patients interrupted treatment because of irAEs (all responders) and 3 because of progression around the time of the irAE. irAEs were more frequent in females (4/6; p = .026). Five patients developed hypothyroidism and 1 hyperthyroidism. RR assessed in all 40 eligible patients was 22.5%: 1 complete response, 8 partial responses (plus 1 unconfirmed), 20 stable disease and with 11 progressions. Two partial responses show minimal residual disease with no PET uptake. Two responders have progressed and 5 responses are beyond 12 months duration. Of 29 cases tested for PD-L1 staining (Dako 22C3), high PD-L1 (≥50% tumor cells positive) was seen in 8 (28%); 6/9 responders had high PD-L1 expression. Targeted NGS in 15 cases did not show correlation between mutational burden and response. Conclusions: P has activity in patients with thymic carcinoma. irAEs are more frequent than in other tumors. Further analysis of NGS, Nanostring and PD-L1 expression and updated survival will be presented. Clinical trial information: NCT02364076.
Analysis of Postoperative Recurrence in Stage I–III Midgut Neuroendocrine Tumors
Authors: Mauro Cives, Daniel A Anaya, Heloisa Soares, Domenico Coppola, Jonathan Strosberg
Journal: JNCI Journal of the National Cancer Institute (2017)

Surgery represents the only curative treatment for stage I-III midgut neuroendocrine tumors (NETs). At present, there are very limited data on the risk of postoperative recurrence. The optimal modality, duration and frequency of surveillance have not been well established. In this work, we investigated the long-term risk of recurrence, peak timing of recurrence, and potential predictors of relapse in patients with stage I-III midgut NETs.We retrospectively evaluated 129 patients with stage I-III midgut NETs who were seen at the Moffitt Cancer Center between 2000 and 2010 following an R0/R1 resection. Disease-free survival (DFS) was estimated using the Kaplan-Meier method. Demographic, clinical, and pathological features were assessed as potential predictors of recurrence. All statistical tests were two-sided.After a median postoperative follow-up of 81 months (range = 1-295 months), recurrence was diagnosed in 40 out of 129 patients (31.0%, 95% confidence interval [CI] = 23.0% to 39.0%). Liver, mesentery, and pelvic lymph nodes were the main sites of relapse. The median DFS was 138 months (95% CI = 117 to 223 months). Resection of 17 or fewer lymph nodes predicted relapse (P = .01) and shorter DFS (P = .04). Among patients who relapsed, the cumulative risks of recurrence at one, five, and 10 years were 15.0% (95% CI = 3.9% to 26.1%), 50.0% (95% CI = 34.5% to 65.5%), and 85.0% (95% CI = 73.9% to 96.0%). No recurrence was observed among patients (n = 6) with stage I tumors, whereas similar rates of relapse were noted in patients with stage II or III NETs (n = 118).An annual surveillance interval may allow early detection of recurrence. Given the apparent decline in recurrence after eight years from surgery, a decade-long duration of active surveillance may be proposed.
Consider Quality of Life to Improve Quality of Cancer Guidelines
Authors: Giuseppe Schepisi, Giuseppe Luigi Banna, Ugo De Giorgi
Journal: JAMA Internal Medicine (2017)

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Use of quantitative RT-PCR assay to predict metastases size of sentinel node from breast cancer patients
Authors: V. Durbecq, S. Majjaj, J. Nogaret, N. Sirtaine, J. Schobbens, D. Noterman, D. Hertens, V. Filipov, D. Larsimont, I. Veys
Journal: Journal of Clinical Oncology (2009)

621 Background: A RT-PCR Assay (GeneSearch, Veridex, LLC), FDA approved and CE marked to detect metastases &gt; 0.2 mm in sentinel lymph nodes (SLNs) of breast cancer patients, has been in clinical use in our institute for 25 months. The assay gives qualitative (negative/positive) results by applying cutoff values to cycle times (Cts) of mammaglobin (MG) and cytokeratin 19 (CK19) (cutoff values = 30 / 31 Cts). This study evaluates if quantitative Ct values can be used to estimate the probable size of nodal metastases. Methods: To date 384 patients have been clinically tested with the BLN Assay at Institut Jules Bordet. An additional 74 patients were tested in a pilot study. Both sets had SLNs of breast cancer patients divided in ∼2 mm pieces. Alternating pieces were homogenized and intra-operatively processed by the assay. The remaining pieces were used for histological analysis (positive when &gt; 0.2 mm). During clinical use, same-surgery complete axillary dissection was performed when the assay was positive (n=59). Results: Performance of the assay's qualitative results against permanent section H&amp;E was similar for both groups (total N = 458), for a total sensitivity 89% (68/76), specificity 95% (364/382) and overall agreement 94%. The marker Ct values are correlated with metastases size as determined by H&amp;E on adjacent node pieces (r = -0.74 for MG and -0.77 for CK19, p &lt; 0.001). Lower Ct values indicate increased likelihood of macrometastases reported by H&amp;E, as described in the table. Additionally, Assay Ct values in the SLN were predictive of metastases in non-SLN nodes. For example when CK19 and MG &lt; 24 Cts, the non-SLN positivity rate jumps from 29% to 58%. Conclusions: The BLN Assay's high intra- operative qualitative performance minimizes the need for second surgeries for complete axillary dissections. Results from this investigational study examining the marker Ct values suggest that the assay may provide valuable individual tumor volume data intra- operatively or post-operatively. [Table: see text] [Table: see text]