Cognitive functioning in children with self-limited epilepsy with centrotemporal spikes: A systematic review and meta-analysis

Summary

Objective

It is now well appreciated that benign epilepsy with centrotemporal spikes (BECTS, or more recently, ECTS) is associated with a range of cognitive and behavioral disturbances. Despite our improved understanding of cognitive functioning in ECTS, there have been to date no efforts to quantitatively synthesize the available literature within a comprehensive cognitive framework.

Methods

The present systematic review and meta-analysis was conducted according to PRISMA guidelines. Forty-two case–control samples met eligibility criteria comprising a total of 1,237 children with ECTS and 1,137 healthy control children. Univariate, random-effects meta-analyses were conducted on eight cognitive factors in accordance with the Cattell–Horn–Carroll model of intelligence.

Results

Overall, children with ECTS demonstrated significantly lower scores on neuropsychological tests across all cognitive factors compared to healthy controls. Observed effects ranged from 0.42 to 0.81 pooled standard deviation units, with the largest effect for long-term storage and retrieval and the smallest effect for visual processing.

Significance

The results of the present meta-analysis provide the first clear evidence that children with ECTS display a profile of pervasive cognitive difficulties and thus challenge current conceptions of ECTS as a benign disease or of limited specific or localized cognitive effect.

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Serrated Colorectal Neoplasia: From Sideshow to Center Stage

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Childhood body mass index and height in relation to site-specific risks of colorectal cancers in adult life

Abstract

As colorectal cancers have a long latency period, their origins may lie early in life. Therefore childhood body mass index (BMI; kg/m²) and height may be associated with adult colorectal cancer. Using a cohort design, 257,623 children from The Copenhagen School Health Records Register born from 1930 to 1972 with measured heights and weights at ages 7 to 13 years were followed for adult colon and rectal adenocarcinomas by linkage to the Danish Cancer Registry. Hazard ratios (HRs) with 95% confidence intervals (CI) were estimated by Cox proportional hazard regressions. During follow-up, 2676 colon and 1681 rectal adenocarcinomas were diagnosed. No sex differences were observed in the associations between child BMI or height and adult colon or rectal cancers. Childhood BMI and height were positively associated with colon cancer; at age 13 years the HRs were 1.09 (95% CI 1.04–1.14) and 1.14 (95% CI 1.09–1.19) per z-score, respectively. Children who were persistently taller or heavier than average, had increased risk of colon cancer. Similarly, growing taller or gaining more weight than average was positively associated with colon cancer. No associations were observed between BMI or height and rectal cancer. Childhood BMI and height, along with above average change during childhood are significantly and positively associated with adult colon cancers, but not with rectal cancer, suggesting different etiologies.

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INST OX-05-024: first line gemcitabine, oxaliplatin, and erlotinib for primary hepatocellular carcinoma and bile duct cancers: a multicenter Phase II trial

Abstract

Hepatocellular Carcinoma (HCC) incidence is increasing in the USA. Gemcitabine (G) and oxaliplatin (O) are active in HCC and biliary duct cancer (BDC). Erlotinib (E) is an EGFR tyrosine kinase inhibitor (TKI) with known activity against both. We sought to evaluate the efficacy of the combination G+O+E. Patients with either of the two diagnosis were treated in a phase II trial. Simons 2 stage design was used. A disease-control rate (DCR), complete response (CR) + partial response (PR)+ stable disease (SD) at 24 weeks of ≤20% and >40% (P0 and P1 of 0.2 and 0.4, respectively) were set as undesirable (null) and desirable results. 26 HCC and 7 BDC patients were accrued. In HCC, 1 PR, 10 SD, and 9 PDs were seen. DCR in HCC was 42%. Among seven (7) patients with BDC, one patient was not evaluable; one achieved a long lasting PR, and five patients had SD and DCR was 86%. Median overall survival (OS) times and progression-free survivals (PFS) were 196 and 149 days in HCC and 238 days and not reached in BDC. PFS at 26 weeks in HCC was 41% and at 21 weeks in BDC was 60%. Grade 3 toxicities in >5% of patients were fatigue (12.9%), neutropenia (9.6%), thrombocytopenia (9.6%), and diarrhea (6.4%). G+O+E exceeded both preset P0a and P1 of the primary objective with a PFS of 41% at 26 weeks for HCC and preliminary BDC data may warrant further investigations.

This is a phase II trial in the first line setting with gemcitabine, oxaliplatin, and erlotinib for primary hepatocellular carcinoma and bile duct cancer. The trial shows interesting results specially in the bile duct cancer arm and this combination should be tested in a randomized setting in comparison with standard of care.

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Immunological tolerance to LCMV antigens differently affects control of acute and chronic virus infection in mice

Cytotoxic T lymphocytes (CTLs) play a key role in the control of lymphocytic choriomeningitis virus (LCMV) infection. In C57BL/6 mice (H-2^b), the CTL response is mainly directed against epitopes from the LCMV glycoprotein (GP) and the nucleoprotein (NP) which represent the two major viral proteins. The role of GP- versus NP-derived epitopes for viral clearance was examined using transgenic (tg) mice ubiquitously expressing LCMV GP and NP respectively. These mice lack GP- or NP-specific CTLs and show decreased levels of GP- or NP-specific antibodies as a result of tolerance induction. During acute LCMV infection, CTLs specific for GP- and NP-derived epitopes are generated with similar frequencies. Nonetheless, we found that lack of GP- but not of NP-specific CTLs abolished control of acute LCMV infection. In contrast, after high-dose or chronic LCMV infection, virus elimination was delayed to a similar extent in GP- and NP-tg mice. Thus, immunological tolerance to LCMV antigens differently affects virus clearance in acute and chronic infection settings. In addition, our data reveal that immunodominance of H-2^b-restricted LCMV-specific CTL epitopes and their antiviral activity do not strictly correlate.

This article is protected by copyright. All rights reserved

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In Response.

No abstract available

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In Response: Concerns With Rate of Rise of Carbon Dioxide During Apnea With Buccal Oxygenation.

No abstract available

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The Subtleties of Language as a Reason for Failure to Follow Preoperative Fasting Guidelines: The Differences Between Restricting, Allowing, and Encouraging.

No abstract available

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Core Temperature Monitoring in Obstetric Spinal Anesthesia Using an Ingestible Telemetric Sensor.

BACKGROUND: Perioperative hypothermia may affect maternal and neonatal outcomes after obstetric spinal anesthesia. Core temperature is often poorly monitored during spinal anesthesia, due to the lack of an accurate noninvasive core temperature monitor. The aim of this study was to describe core temperature changes and temperature recovery during spinal anesthesia for elective cesarean delivery. We expected that obstetric spinal anesthesia would be associated with a clinically relevant thermoregulatory insult (core temperature decrease >1.0[degrees]C). METHODS: A descriptive study was conducted in 28 women. An ingestible telemetric temperature sensor was used to record core temperature over time (measured every 10 seconds). The primary outcome was the maximum core temperature decrease after spinal anesthetic injection. The secondary outcomes were lowest absolute core temperature, time to lowest temperature, time to recovery of core temperature, hypothermic exposure (degree-hours below 37.0[degrees]C), and the time-weighted hypothermic exposure (median number of degrees below 37.0[degrees]C per hour). Basic descriptive statistics, median spline smooth, and integration of the area below the 37.0[degrees]C line of the temperature-over-time curve were utilized to analyze the data. RESULTS: Intestinal temperature decreased by a mean (standard deviation) of 1.30[degrees]C (0.31); 99% confidence interval (CI), 1.14 to 1.46 after spinal anesthetic injection. The median (interquartile range [IQR]) time to temperature nadir was 0.96 (0.73-1.32) hours (95% CI, 0.88-1.22). Fourteen of the 28 participants experienced intestinal temperatures below 36.0[degrees]C after spinal injection. Temperature was monitored for a minimum of 8 hours after spinal injection. In 8 of 28 participants, intestinal temperature did not recover to baseline during the monitored period. A median (IQR) of 4.59 (3.38-5.92) hours (95% CI, 3.45-5.90) was required for recovery to baseline intestinal temperature in the remaining 20 patients. Participants experienced a median (IQR) of 1.97 (1.00-2.68) degree-hours of hypothermic exposure (95% CI, 1.23-2.45). The median (IQR) number of degrees below 37.0[degrees]C per hour was 0.45 (0.35-0.60) (95% CI, 0.36-0.58). CONCLUSIONS: During cesarean delivery under spinal anesthesia, women experienced a rapid decrease in core temperature. Using an intestinal telemetric sensor, the perioperative thermal insult and recovery were documented with high resolution. Fifty percent of participants in this study became hypothermic. Although the surgical procedure is typically of short duration, women undergoing spinal anesthesia for cesarean delivery experience significant hypothermic exposure and compromised thermoregulation for several hours. (C) 2017 International Anesthesia Research Society

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Respiratory Outcomes in Preterm Infants: From Infancy Through Adulthood.

No abstract available

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Reducing Mortality in Acute Kidney Injury.

No abstract available

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Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score, a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome

To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis.

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Pulmonary Calcification in a Congenital Cytomegalovirus Infection

A 1-day-old, small for gestational age male infant was born at 39 weeks of gestation via normal, spontaneous vaginal delivery with a birth weight of 2044 g. Physical examination revealed microcephaly but no other external malformations. Congenital cytomegalovirus (CMV) infection was diagnosed by a positive urine CMV polymerase chain reaction performed on day 1. Serologic tests for other congenital infections caused by toxoplasma, rubella, and herpes simplex virus were negative. There was no evidence of hearing loss, retinitis, or hepatitis.

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High Flow Nasal Cannula Flow Rates: New Data Worth the Weight

Oxygen delivery via a high flow nasal cannula (HFNC) system has become increasingly common for children with acute viral bronchiolitis.1 HFNC is now used in pediatric intensive care units throughout the world,2-4 and its use has been expanded to the pediatric emergency department5 and, under selected conditions, the general pediatric inpatient unit.6 Nevertheless, questions remain about this respiratory support modality. Does this level of support influence clinical outcomes compared with standard nasal cannula oxygen4 or noninvasive positive pressure ventilation?2 Are there patient-level factors that can predict the response to HFNC therapy? In what locations and under which circumstances can HFNC support be provided safely? What is the predominant mechanism by which it supports breathing?

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Physical Therapy for Fecal Incontinence in Children with Pelvic Floor Dyssynergia

To determine the efficacy of physical therapy (PT) for fecal incontinence in children with pelvic floor dyssynergia (PFD).

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Palliative external beam radiotherapy for the treatment of tumor bleeding in inoperable advanced gastric cancer

Abstract

Background

To assess the outcomes and prognostic factors associated with palliative external beam radiotherapy (EBRT), administered to patients with advanced gastric cancer.

Methods

Forty-two patients with bleeding gastric tumors that received EBRT for palliation were analyzed. The response to EBRT was assessed by the palliation of tumor bleeding. Patients were classified as either responders, or non-responders to EBRT. The prognostic utility of clinical and dosimetric variables was examined in a multivariate logistic regression model. The optimal dose cutoff to classify the two groups was determined with receiver operating characteristic analysis.

Results

The palliation of gastric tumor bleeding after EBRT was achieved in 29 patients (69.0%). The time to resolve tumor bleeding ranged from 1 to 84 days (median, 15 days). The median duration of palliation was 14.9 weeks. The median EBRT dose was 40 Gy in responders vs. 21 Gy in non-responders, with the difference being significant (p < 0.001). The biologically effective dose (using α/β = 10, BED₁₀) for responders was significantly higher than the BED₁₀ for non-responders (median 48 Gy vs. 26.4 Gy, p < 0.001), and the optimal cut off value to separate the two groups was 36 Gy (p < 0.001). The absence of distant metastasis and the use of concurrent chemotherapy generally showed a better EBRT response (p = 0.079 and p = 0.079, respectively). In the multivariate analysis, BED₁₀ ≥ 36 Gy was the most significant factor associated with EBRT response (p = 0.001). Overall survival (OS) and re-bleeding-free survival was median 12.6 weeks and 14.9 weeks. The responders to EBRT showed superior OS (16.6 vs. 5.1 months, p < 0.001). Neither acute nor chronic toxicities of grade 3 or higher were observed.

Conclusions

EBRT is an effective method for treating tumor bleeding in advanced gastric cancer, and does not induce severe toxicity.

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Technique of Laparoscopic Hysterectomy and Pelvic Lymphadenectomy for Endometrial Cancer

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Breast Cancer Immunotherapy: Facts and Hopes

Immunotherapy is revolutionizing the management of multiple solid tumors, and early data have revealed the clinical activity of PD-1/PD-L1 antagonists in small numbers of metastatic breast cancer patients. Clinical activity appears more likely if the tumor is triple negative, PD-L1+, and/or harbors higher levels of TILs. Responses to atezolizumab and pembrolizumab appear to be durable in metastatic triple negative breast cancer (TNBC), suggesting these agents may transform the lives of responding patients. Current clinical efforts are focused on developing immunotherapy combinations that convert non-responders to responders, deepen those responses that do occur, and surmount acquired resistance to immunotherapy. Identifying biomarkers that can predict the potential for response to single agent immunotherapy, identify the best immunotherapy combinations for a particular patient, and guide salvage immunotherapy in patients with progressive disease are high priorities for clinical development. Smart clinical trials testing rational immunotherapy combinations that include robust biomarker evaluations will accelerate clinical progress, moving us closer to effective immunotherapy for almost all breast cancer patients.

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Loss of MutL Disrupts Chk2-dependent Cell Cycle Control Through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer [Research Articles]

Significant endocrine therapy-resistant tumor proliferation is present in ≥20% of estrogen receptor positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates Chk2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit AI-resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of breast cancer patients who exhibit marked resistance to the current standard of care.

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Inducible activation of MyD88 and CD40 in CAR T-cells results in controllable and potent antitumor activity in preclinical solid tumor models [Research Articles]

Adoptive immunotherapy with T-cells expressing chimeric antigen receptors (CARs) has had limited success for solid tumors in early phase clinical studies. We reasoned that introducing into CAR T-cells an inducible co-stimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)-binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T-cells expressing HER2-CAR and a MyD88/CD40-based iCO molecule (HER2.iCO T-cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2.iCO T-cells without CID and T-cells expressing HER2-CAR.CD28. HER2.iCO T-cells with CID also significantly improved survival in vivo in two xenograft models. Repeat injections of CID were able to further increase the antitumor activity of HER2.iCO T-cells in vivo. Thus, expressing MyD88/CD40-based iCO molecules in CAR T-cells has the potential to improve the efficacy of CAR T-cell therapy approaches for solid tumors.

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In the Next Issue

No abstract available

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Quantifying the Effects of Prior Acetyl-Salicylic Acid on Sepsis-Related Deaths: An Individual Patient Data Meta-Analysis Using Propensity Matching.

Objective: The primary objective was to conduct a meta-analysis on published observational cohort data describing the association between acetyl-salicylic acid (aspirin) use prior to the onset of sepsis and mortality in hospitalized patients. Study Selection: Studies that reported mortality in patients on aspirin with sepsis with a comparison group of patients with sepsis not on prior aspirin therapy were included. Data Sources: Fifteen studies described hospital-based cohorts (n = 17,065), whereas one was a large insurance-based database (n = 683,421). Individual-level patient data were incorporated from all selected studies. Data Extraction: Propensity analyses with 1:1 propensity score matching at the study level were performed, using the most consistently available covariates judged to be associated with aspirin. Meta-analyses were performed to estimate the pooled average treatment effect of aspirin on sepsis-related mortality. Data Synthesis: Use of aspirin was associated with a 7% (95% CI, 2-12%; p = 0.005) reduction in the risk of death as shown by meta-analysis with considerable statistical heterogeneity (I2 = 61.6%). Conclusions: These results are consistent with effects ranging from a 2% to 12% reduction in mortality risk in patients taking aspirin prior to sepsis onset. This association anticipates results of definitive studies of the use of low-dose aspirin as a strategy for reduction of deaths in patients with sepsis. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Effects of acclimation to seawater salinity on some blood parameters in wild Caspian brown trout, Salmo trutta caspius

Abstract

In the present study, some hematological indices were assayed after salinity challenge in smolts obtained from wild populations of Caspian brown trout. The experiment was designed into three treatments and one control group containing 90 fish per treatment. In experimental treatment, fish were exposed to salinity challenge (12 mg/l salinity) for 48 h. Fish of control group were not challenged and held in freshwater with 0.37 g/l salinity. After salinity challenge in seawater, the higher values of plasma cortisol and glucose were found in fish acclimated to seawater compared to control group (P < 0.05). No significant differences were found between control group and fish before salinity challenge in terms of plasma glucose and cortisol levels (P > 0.05). Plasma potassium and sodium concentrations were statistically similar between experimental groups and control group (P > 0.05). Also, plasma protein levels were lower in fish exposed to salinity challenge compared to control (P < 0.05). The values of red blood cells (RBC), white blood cells (WBC), and hemoglobin (Hb) increased significantly after salinity challenge (P < 0.05). In addition, there were no significant differences between control group and fish before salinity challenge in terms of plasma RBC, WBC, and Hb (P > 0.05). In conclusion, the results of the present study confirm the ability of the Caspian brown trout smolts in controlling osmoregulation by alternation of some hematological parameters.

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Anticancer drugs and the regulation of Hedgehog genes GLI1 and PTCH1, a comparative study in nonmelanoma skin cancer cell lines.

Nonmelanoma skin cancer is the most common cancer in humans, comprising mainly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC proliferation is highly dependent on the Hedgehog signaling pathway. We aimed to investigate a panel of anticancer drugs with known activity against skin cancer for their therapeutic potential in localized, enhanced topical treatment of SCC and BCC. Cytotoxicity profiles for vismodegib, 5-fluorouracil (5-FU), methotrexate (MTX), cisplatin, bleomycin, and vorinostat were established in terms of half maximal inhibitory concentration values in a panel of immortalized keratinocytes (HaCaT), BCC (UWBCC1 and BCC77015), and SCC (A431 and SCC25) cell lines. The impact of treatment on the regulation of Hedgehog pathway target genes (GLI1 and PTCH1), measured by real-time PCR, was compared between UWBCC1 and HaCaT. Varying cell line sensitivity profiles to the examined anticancer drugs were observed. Generally, 24-h drug exposure was sufficient to reduce cell viability. We found that 5-FU, MTX, and cisplatin significantly downregulated the expression of two genes controlled by the Hedgehog pathway (

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The Fifth Vital Sign: Postoperative Pain Predicts 30-day Readmissions and Subsequent Emergency Department Visits

Objective: We hypothesized that inpatient postoperative pain trajectories are associated with 30-day inpatient readmission and emergency department (ED) visits. Background: Surgical readmissions have few known modifiable predictors. Pain experienced by patients may reflect surgical complications and/or inadequate or difficult symptom management. Methods: National Veterans Affairs Surgical Quality Improvement data on inpatient general, vascular, and orthopedic surgery from 2008 to 2014 were merged with laboratory, vital sign, health care utilization, and postoperative complications data. Six distinct postoperative inpatient patient-reported pain trajectories were identified: (1) persistently low, (2) mild, (3) moderate or (4) high trajectories, and (5) mild-to-low or (6) moderate-to-low trajectories based on postoperative pain scores. Regression models estimated the association between pain trajectories and postdischarge utilization while controlling for important patient and clinical variables. Results: Our sample included 211,231 surgeries—45.4% orthopedics, 37.0% general, and 17.6% vascular. Overall, the 30-day unplanned readmission rate was 10.8%, and 30-day ED utilization rate was 14.2%. Patients in the high pain trajectories had the highest rates of postdischarge readmissions and ED visits (14.4% and 16.3%, respectively, P

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Intraoperative Molecular Imaging Combined With Positron Emission Tomography Improves Surgical Management of Peripheral Malignant Pulmonary Nodules

Objective: To determine if intraoperative molecular imaging (IMI) can improve detection of malignant pulmonary nodules. Background: 18-Fluorodeoxyglucose positron emission tomography (PET) is commonly utilized in preoperative assessment of patients with solid malignancies; however, false negatives and false positives remain major limitations. Using patients with pulmonary nodules as a study model, we hypothesized that IMI with a folate receptor targeted near-infrared contrast agent (OTL38) can improve malignant pulmonary nodule identification when combined with PET. Methods: Fifty patients with pulmonary nodules with imaging features suspicious for malignancy underwent preoperative PET. Patients then received OTL38 before pulmonary resection. During resection, IMI was utilized to evaluate known pulmonary nodules and identify synchronous lesions. Tumor size, PET standardized uptake value, and IMI tumor-to-background ratios were compared for known and synchronous nodules via paired and unpaired t tests, when appropriate. Test characteristics of PET and IMI with OTL38 were compared. Results: IMI identified 56 of 59 (94.9%) malignant pulmonary nodules identified by preoperative imaging. IMI located an additional 9 malignant lesions not identified preoperatively. Nodules only detected by IMI were smaller than nodules detected preoperatively (0.5 vs 2.4 cm; P 0.05). Additionally, utilization of IMI clinically upstaged 6 (12%) subjects and improved management of 15 (30%) subjects. Conclusions: These data suggest that combining IMI with PET may provide superior oncologic outcomes for patients with resectable lung cancer.

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Surgical Mentorship: A Great Tradition, But Can We Do Better for the Next Generation?

No abstract available

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A Prospective Randomized Multicenter Trial of Distal Pancreatectomy With and Without Routine Intraperitoneal Drainage

Objective: The objective of this study was to test the hypothesis that distal pancreatectomy (DP) without intraperitoneal drainage does not affect the frequency of grade 2 or higher grade complications. Background: The use of routine intraperitoneal drains during DP is controversial. Prior to this study, no prospective trial focusing on DP without intraperitoneal drainage has been reported. Methods: Patients undergoing DP for all causes at 14 high-volume pancreas centers were preoperatively randomized to placement of a drain or no drain. Complications and their severity were tracked for 60 days and mortality for 90 days. The study was powered to detect a 15% positive or negative difference in the rate of grade 2 or higher grade complications. All data were collected prospectively and source documents were reviewed at the coordinating center to confirm completeness and accuracy. Results: A total of 344 patients underwent DP with (N = 174) and without (N = 170) the use of intraperitoneal drainage. There were no differences between cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, or operative technique. There was no difference in the rate of grade 2 or higher grade complications (44% vs. 42%, P = 0.80). There was no difference in clinically relevant postoperative pancreatic fistula (18% vs 12%, P = 0.11) or mortality (0% vs 1%, P = 0.24). DP without routine intraperitoneal drainage was associated with a higher incidence of intra-abdominal fluid collection (9% vs 22%, P = 0.0004). There was no difference in the frequency of postoperative imaging, percutaneous drain placement, reoperation, readmission, or quality of life scores. Conclusions: This prospective randomized multicenter trial provides evidence that clinical outcomes are comparable in DP with or without intraperitoneal drainage.

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Should Patients With Cystic Lesions of the Pancreas Undergo Long-term Radiographic Surveillance?: Results of 3024 Patients Evaluated at a Single Institution

Objective: In 2015, the American Gastroenterological Association recommended the discontinuation of radiographic surveillance after 5 years for patients with stable pancreatic cysts. The current study evaluated the yield of continued surveillance of pancreatic cysts up to and after 5 years of follow up. Methods: A prospectively maintained registry of patients evaluated for pancreatic cysts was queried (1995–2016). Patients who initially underwent radiographic surveillance were divided into those with 5 mm increase in diameter), cross-over to resection, and development of carcinoma were performed. Results: A total of 3024 patients were identified, with 2472 (82%) undergoing initial surveillance. The ≥5 year group (n = 596) experienced a greater frequency of cyst growth (44% vs. 20%; P

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Firearm Deaths in America: Can We Learn From 462,000 Lives Lost?

Objective: We sought to determine whether state firearm legislation correlated with firearm-related fatality rates (FFR) during a 15-year period. Background: The politicized and controversial topic of firearm legislation has been grossly understudied when the relative impact of American firearm violence is considered. Scientific evidence regarding gun legislation effectiveness remains scant. Methods: Demographic and intent data (1999–2013) were collected from the Centers for Disease Control and Prevention's Web-Based Injury Statistics Query and Reporting System database and compared by state firearm legislation rankings with respect to FFR. State scorecards were obtained from firearm-restrictive (Brady Campaign/Law Center against Gun Violence [BC/LC]) and less-restrictive (National Rifle Association) groups. FFR were compared between restrictive and least-restrictive states during 3 periods (1999–2003, 2004–2008, 2009–2013). Results: During 1999 to 2013, 462,043 Americans were killed by firearms. Overall FFR did not change during the 3 periods (10.89 ± 3.99/100,000; 10.71 ± 3.93/100,000; 11.14 ± 3.91/100,000; P = 0.87). Within each period, least-restrictive states had greater unintentional, pediatric, and adult suicide, White and overall FFR than restrictive states (all P

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Results of the First Prospective Multi-institutional Treatment Study in Children With Bilateral Wilms Tumor (AREN0534): A Report From the Children's Oncology Group

Objective: The Children's Oncology Group study AREN0534 aimed to improve event-free survival (EFS) and overall survival (OS) while preserving renal tissue by intensifying preoperative chemotherapy, completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response. Background: No prospective therapeutic clinic trials in children with bilateral Wilms tumors (BWT) exist. Historical outcomes for this group were poor and often involved prolonged chemotherapy; on NWTS-5, 4-year EFS for all children with BWT was 56%. Methods: Patients were enrolled and imaging studies were centrally reviewed to assess for bilateral renal lesions. They were treated with 3-drug induction chemotherapy (vincristine, dactinomycin, and doxorubicin) for 6 or 12 weeks based on radiographic response followed by surgery and further chemotherapy determined by histology. Radiation therapy was provided for postchemotherapy stage III and IV disease. Results: One hundred eighty-nine of 208 patients were evaluable. Four-year EFS and OS were 82.1% (95% CI: 73.5%–90.8%) and 94.9% (95% CI: 90.1%–99.7%. Twenty-three patients relapsed and 7 had disease progression. After induction chemotherapy 163 of 189 (84.0%) underwent definitive surgical treatment in at least 1 kidney by 12 weeks and 39% retained parts of both kidneys. Surgical approaches included: unilateral total nephrectomy with contralateral partial nephrectomy (48%), bilateral partial nephrectomy (35%), unilateral total nephrectomy (10.5%), unilateral partial nephrectomy (4%), and bilateral total nephrectomies (2.5%). Conclusion: This treatment approach including standardized 3-drug preoperative chemotherapy, surgical resection within 12 weeks of diagnosis and response and histology-based postoperative therapy improved EFS and OS and preservation of renal parenchyma compared with historical outcomes for children with BWT.

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Expanding the Margins: High Volume Utilization of Marginal Liver Grafts Among >2000 Liver Transplants at a Single Institution

Objective: Marginal livers (ML) have been used to expand the donor pool. National utilization of MLs is variable, and in some centers, they are never used. We examined the outcomes of MLs in the largest single center series of MLs used to date and compared outcomes to standard (SL) and living donor (LD) livers. Methods: Analysis of a prospectively maintained database of all liver transplants performed at our institution from 1998 to 2016. ML grafts were defined as livers from donors >70, livers discarded regionally and shared nationally, livers with cold ischemic time >12 hours, livers from hepatitis C virus positive donors, livers from donation after cardiac death donors, livers with >30% steatosis, and livers split between 2 recipients. Results: A total of 2050 liver transplant recipients were studied, of these 960 (46.8%) received ML grafts. ML recipients were more likely to have lower MELDs and have hepatocellular carcinoma. Most MLs used were from organs turned down regionally and shared nationally (69%) or donors >70 (22%). Survival of patients receiving MLs did not significantly differ from patients receiving SL grafts (P = 0.08). ML and SL recipients had worse survival than LDs (P

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Trending Fibrinolytic Dysregulation: Fibrinolysis Shutdown in the Days After Injury Is Associated With Poor Outcome in Severely Injured Children

Objective: To trend fibrinolysis after injury and determine the influence of traumatic brain injury (TBI) and massive transfusion on fibrinolysis status. Background: Admission fibrinolytic derangement is common in injured children and adults, and is associated with poor outcome. No studies examine fibrinolysis days after injury. Methods: Prospective study of severely injured children at a level 1 pediatric trauma center. Rapid thromboelastography was obtained on admission and daily for up to 7 days. Standard definitions of hyperfibrinolysis (HF; LY30 ≥3), fibrinolysis shutdown (SD; LY30 ≤0.8), and normal (LY30 = 0.9–2.9) were applied. Antifibrinolytic use was documented. Outcomes were death, disability, and thromboembolic complications. Wilcoxon rank-sum and Fisher exact tests were performed. Exploratory subgroups included massively transfused and severe TBI patients. Results: In all, 83 patients were analyzed with median (interquartile ranges) age 8 (4–12) and Injury Severity Score 22 (13–34), 73.5% blunt mechanism, 47% severe TBI, 20.5% massively transfused. Outcomes were 14.5% mortality, 43.7% disability, and 9.8% deep vein thrombosis. Remaining in or trending to SD was associated with death (P = 0.007), disability (P = 0.012), and deep vein thrombosis (P = 0.048). Median LY30 was lower on post-trauma day (PTD)1 to PTD4 in patients with poor compared with good outcome; median LY30 was lower on PTD1 to PTD3 in TBI patients compared with non-TBI patients. HF without associated shutdown was not related to poor outcome, but extreme HF (LY30 >30%, n = 3) was lethal. Also, 50% of massively transfused patients in hemorrhagic shock demonstrated SD physiology on admission. All with HF (fc31.2%) corrected after hemostatic resuscitation without tranexamic acid. Conclusions: Fibrinolysis shutdown is common postinjury and predicts poor outcomes. Severe TBI is associated with sustained shutdown. Empiric antifibrinolytics for children should be questioned; thromboelastography-directed selective use should be considered for documented HF.

http://ift.tt/2utDt6M

Impact of Pretransplant Bridging Locoregional Therapy for Patients With Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation: Analysis of 3601 Patients From the US Multicenter HCC Transplant Consortium

Objective: To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC). Summary Background Data: Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited. Methods: Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002–2013). Results: Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P

http://ift.tt/2uu1sTp

Pharmacological Thromboembolic Prophylaxis in Traumatic Brain Injuries: Low Molecular Weight Heparin Is Superior to Unfractionated Heparin

Objective: We hypothesized that low molecular weight heparin (LMWH) is superior to unfractionated heparin (UH) for venous thromboembolism (VTE) prophylaxis in patients with severe traumatic brain injuries (TBI). Summary Background Data: Pharmacological VTE prophylaxis with LMWH or UH is the current standard of care in TBI. Clinical work suggests that LMWH may be more effective than UH for VTE prophylaxis in trauma patients. Experimental work shows that heparinoids may have neuroprotective properties. Methods: ACS TQIP database study including patients with blunt severe TBI (AIS ≥ 3), those that received LMWH or UH VTE prophylaxis. Patients with severe extracranial injuries (AIS ≥ 3), death within 72 hours, or hospital stay 72 hours). Outcomes included VTE complications, mortality, and unplanned return to the operating room. Multivariate analysis was performed to compare outcomes between patients receiving LMWH and UH. Results: Overall, 20,417 patients met the criteria for inclusion in the study, 10,018 (49.1%) received LMWH and 10,399 (50.9%) UH. Multivariate analysis showed that LMWH was an independent protective factor against mortality and thromboembolic complications, regardless of timing of prophylaxis initiation. The type of prophylaxis had no effect on the need for unplanned return to the operating room. Conclusions: LMWH prophylaxis in severe TBI is associated with better survival and lower thromboembolic complications than UH.

http://ift.tt/2uulTjf

A Randomized Controlled Trial of Postoperative Thoracic Epidural Analgesia Versus Intravenous Patient-controlled Analgesia After Major Hepatopancreatobiliary Surgery

Objectives: The primary objective of this randomized trial was to compare thoracic epidural analgesia (TEA) to intravenous patient-controlled analgesia (IV-PCA) for pain control over the first 48 hours after hepatopancreatobiliary (HPB) surgery. Secondary endpoints were patient-reported outcomes, total narcotic utilization, and complications. Background: Although adequate postoperative pain control is critical to patient and surgeon success, the optimal analgesia regimen in HPB surgery remains controversial. Methods: Using a 2.5:1 randomization strategy, 140 patients were randomized to TEA (N = 106) or intravenous patient-controlled analgesia (N = 34). Patient-reported pain was measured on a Likert scale (0–10) at standard time intervals. Cumulative pain area under the curve was determined using the trapezoidal method. Results: Between the study groups key demographic, comorbidity, clinical, and operative variables were equivalently distributed. The median area under the curve of the postoperative time 0- to 48-hour pain scores was lower in the TEA group (78.6 vs 105.2 pain-hours, P = 0.032) with a 35% reduction in patients experiencing ≥7/10 pain (43% vs 62%, P = 0.07). Patient-reported outcomes and total opiate use further supported the benefit of TEA on patient experience. Anesthesia-related events requiring change in analgesic therapy were comparable (12.2% vs 2.9%, respectively, P = 0.187). Grade 3 or higher surgical complications (6.6% vs 9.4%), median length of stay (6 days vs 6 days), readmission (1.9% vs 3.1%), and return to the operating room (0.9% vs 3.1%) were similar (all P > 0.05). There were no mortalities in either group. Conclusions: In major HPB surgery, TEA provides a superior patient experience through improved pain control and less narcotic use, without increased length of stay or complications.

http://ift.tt/2uu6bEz

Focal Increased Tc-99m MDP Uptake in the Nutrient Foramen of the Femoral Diaphysis on Bone SPECT/CT

Abstract

We present images of an 83-year-old female with a history of osteoporosis and bilateral total knee replacement arthroplasty, referred for bone scintigraphy and single-photon emission computed tomography (SPECT)/computed tomography (CT), owing to left knee pain. No trauma to, or intense exercise of, the knee was reported. The bone scan and SPECT/CT revealed a focally increased Tc-99m methylene diphosphonate (MDP) uptake in the medial cortex of the left femoral diaphysis with matched linear radiolucency on CT images. This was misinterpreted as atypical femoral stress fracture; however, focal stress reaction injury to the nutrient foramen was confirmed on contrast-enhanced magnetic resonance imaging.

http://ift.tt/2uwHbN8

Editorial introductions

No abstract available

http://ift.tt/2uOLsXn

The genetics of Hodgkin lymphoma: an overview and clinical implications

Purpose of review: The goal of this review is to give an overview of the genetics of classical Hodgkin lymphoma. Copy number changes, somatic mutations, genome-wide association studies, changes in gene expression, familial classical Hodgkin lymphoma and epigenetic changes will be reviewed. In doing so, special focus is placed on the way recent discoveries have influenced clinical research, diagnostics, treatment and remission monitoring. Furthermore, emphasis is put on how these advances can help to advance the treatment of elderly patients who have a markedly worse prognosis than younger patients. Recent findings: Frequent amplifications of the 9p24.1 locus in classical Hodgkin lymphoma could be the basis for the success of immune checkpoint inhibitors targeting PD-1 or PD-L1 in this disease. The same amplification also affects the JAK/STAT pathway, which has also been targeted in recent clinical trials. Hodgkin lymphoma-specific copy number alterations and mutations have recently been found to be detectable in cell-free DNA. This could provide the basis for advances in the detection of residual disease during treatment and while monitoring patients in remission. Summary: The advent of new technologies such as massive parallel sequencing has improved our understanding of the genetics of classical Hodgkin lymphoma. Some of these discoveries are now being translated into clinical research in the form of new diagnostics and treatments.

http://ift.tt/2uOLr5L

Targeting EZH2 in cancer therapy

Purpose of review: The present review introduces recent outstanding progress pertaining to Enhancer of zeste homolog 2 (EZH2), especially regarding its mode of action as a master regulator of chromatin, and provides molecular-based evidence for targeting EZH2 in cancer therapy. We discuss the active development of small molecules targeting the enzymatic activity of EZH2/polycomb repressive complex 2 (PRC2). Recent findings: Genetic, transcriptional, and posttranscriptional dysregulation of EZH2 is frequently observed in many cancer types. EZH2 promotes tumorigenesis by altering the expression of numerous tumor suppressor genes. Furthermore, the executive molecular processes initiated by EZH2, such as NF-κB activation, microRNA silencing, tumor immune evasion, and noncanonical transcription regulation, appear to be the fundamental characteristics of each cancer. Systematic investigations have suggested coordinated regulation of the cancer epigenome wherein antagonistic complexes of both polycomb and SWI/SNF are involved. Frequent loss-of-function mutations in epigenetic factors, such as ARID1A, SMARCA4, SMARCB1, BAP1, and KDM6A, are likely to elicit the EZH2/PRC2-addicted situation. Our comprehensive understanding encourages the development of advanced strategies for the appropriate manipulation of the cancer epigenome. Moreover, a couple of small molecules that can effectively inhibit the enzymatic activity of EZH2/PRC2 have been translated into early-phase clinical trials. Summary: The EZH2-mediated epigenome and subsequent transcriptome define cellular identity. Effective and specific strategies for the manipulation of EZH2/PRC2 may lead to the development of more precise cancer medicines.

http://ift.tt/2uOCw4t

Therapeutic oncolytic viruses: clinical advances and future directions

Purpose of review: The present review will highlight recent advances in the clinical application of oncolytic viral therapy. Recent findings: Until recently, oncolytic viral researchers saw the immune system as an enemy that would clear the virus from the bloodstream. However, researchers now understand that sustained responses are seen in those patients with more robust antitumor immune responses. Much of the current focus in oncolytic viral research is trained on manipulation of the immune system to affect cancer cell killing in the tumor microenvironment and to facilitate durable systemic antitumor immunity. Many investigators have demonstrated synergistic effects of checkpoint inhibition and other immune therapies with viral administration. At the same time, insertion of various markers enables noninvasive deep tissue imaging. Finally, following regulatory approval in the United States and Europe, unbridled clinical use of T-VEC for patients with metastatic melanoma is also generating large volumes of patient data that will help elucidate strengths and weaknesses of oncolytic viral therapy. Perhaps the most telling sign of the field's future is a seismic shift in clinical trials with more investigators combining virus and immunotherapies. Summary: This article reviews the current state of therapeutic oncolytic viruses in clinical use, and explores future directions of the field.

http://ift.tt/2uOKtqc

Rational therapeutic choice for older patients with lymphoma

Purpose of review: The choice for an optimal treatment in older lymphoma patients is a real challenge for hemato-oncologists. They have to treat a potentially curative lymphoma, and concomitantly protect their patients from unacceptable toxicities. Some recommendations are provided for the major subtypes of lymphomas including the antitumoral treatment and primarily the optimal supportive care. Recent findings: All the recent literature data converge to say that the approach of an older patient with a malignant hemopathy is a multistep procedure. This process comprises the appraisal of life expectancy of the patient with or without the disease, the prognostic factors of the tumor, the functional, physiological and cognitive functions evaluation, the socio-economical environment and the patient's expectancy in terms of quality of life. Major progresses have been achieved in the management of diffuse large B cell lymphoma and mantle cell lymphoma in patients up to 80 and above 80 years old. Summary: With all these information in hands, the hematologist will decide if the treatment's objective is the standard treatment with optimal supportive care (fit patients), tailor-made adapted chemotherapy (unfit patients) or preservation of quality of life (frail patients).

http://ift.tt/2uOgpv1

Surgery for patients with newly diagnosed advanced ovarian cancer: which patient, when and extent?

Purpose of review: Cytoreduction to no residual disease is the mainstay of primary treatment for advanced epithelial ovarian cancer (AdvEOC). This review addresses recent insights on optimal patient selection, timing, and extent of surgery, intended to optimize cytoreduction in patients with AdvEOC. Recent findings: Clinical guidelines recommend primary cytoreductive surgery (PCS) for AdvEOC patients with a high likelihood of achieving complete cytoreduction with acceptable morbidity. In line with this, preoperative prediction markers such as cancer antigen-125, histologic and genomic factors, innovative imaging modalities, and the performance of a diagnostic laparoscopy have been suggested to improve clinical decision-making with regard to optimal timing of cytoreductive surgery. To determine whether these strategies should be incorporated into clinical practice validation in randomized clinical trials is essential. Summary: The past decade has seen a paradigm shift in the number of AvdEOC patients that are being treated with upfront neoadjuvant chemotherapy instead of PCS. However, although neoadjuvant chemotherapy may reduce morbidity at the time of interval cytoreductive surgery, no favorable impact on survival has been demonstrated and it may induce resistance to chemotherapy. Therefore, optimizing patient selection for PCS is crucial. Furthermore, surgical innovations in patients diagnosed with AvdEOC should focus on improving survival outcomes.

http://ift.tt/2uOzZY5

Cancer in pregnancy: safety and efficacy of systemic therapies

Purpose of review: Cancer in pregnancy has become increasingly frequent. It has become clear that for specific cancers under well defined circumstances, oncological treatment in pregnancy can be well tolerated and feasible for both mother and fetus. Continued critical assessment of the available literature and registration of cancer in pregnancy cases and outcomes for mother and child are necessary to work toward implementing optimal cancer treatment during pregnancy. Recent findings: Physiologic changes in pregnancy may alter distribution and efficacy of systemic therapy. Data on systemic therapy including, chemotherapy, hormonal therapy, and targeted therapy during pregnancy are available but incomplete. Outcomes of fetuses exposed to chemotherapy in utero are generally reassuring, but new targeted therapies are mostly discouraged in pregnancy. Summary: Cancer treatment during pregnancy is possible, depending on type and timing of systemic therapy and treatment modality. Available data are reassuring with a modest increase in complications such as growth restriction and preterm birth. The effect of new targeted therapies is often still unclear and therefore discouraged.

http://ift.tt/2uOCt8H

Immunotherapy-based combinations: current status and perspectives

Purpose of review: Since the approval of ipilimumab, different immune checkpoint inhibitors, vaccines and costimulatory agonists have been developed with success, improving patient's survival in a number of different tumour types. However, immunotherapy results in durable responses but only in a fraction of patients. In order to improve this, combination of different immune agents is currently being attempted in the clinic with the potential of becoming one day the next wave of immune treatments available for our cancer patients. Recent findings: Combinatory regimens may have synergistic effects by acting at different points of the cancer immune cycle, from initiation and propagation of anticancer immunity, to stimulation of neoantigen presentation and priming, promotion of trafficking of immune cells to access the tumour and, finally, cancer-cell recognition and killing. Summary: In this article, the most relevant combination strategies that are currently under research are reviewed, as they are expected to become a new standard of care in the near future.

http://ift.tt/2uwPSqD

Emerging cancer-specific therapeutic aptamers

Purpose of review: We will describe recently discovered smart aptamers with tumor specificity, with an emphasis on targeted delivery of novel therapeutic molecules, cancer-specific biomarkers, and immunotherapy. Recent findings: The development of cancer-specific aptamers has facilitated targeted delivery of potent therapeutic molecules to cancer cells without harming nontumoral cells. This specificity also makes it possible to discover novel cancer biomarkers. Furthermore, alternative immune-checkpoint blockade aptamers have been developed for combinational immunotherapy. Summary: Aptamers selected against cancer cells show cancer specificity, which has great potential for targeting. First, functionalizing targeted aptamers with therapeutic molecule payloads (e.g., small activating RNAs, antimitotic drugs, therapeutic antibodies, and peptides) facilitates successful delivery into cancer cells. This approach greatly improves the therapeutic index by minimizing side-effects in nontumoral cells. Second, cancer-specific proteins have been identified as cancer biomarkers through in-vitro and in-vivo selection, aptamer pull-down assays, and mass spectrometry. These newly discovered biomarkers improve therapeutic intervention and diagnostic specificity. In addition, the development of alternative immune-checkpoint blockade aptamers is suggested for use in combinational immunotherapeutic with current immune blockade regimens, to reduce the resistance and exhaustion of T cells in clinical trials. Video abstract: http://ift.tt/2sLQ5Bq .

http://ift.tt/2uwO2WF

Novel imaging techniques in gynaecological cancer

Purpose of review: To describe the added value of novel functional MRI techniques towards detection, staging, characterization, response monitoring and prognostication in gynaecological cancer. Recent findings: Functional MRI including diffusion-weighted imaging (DWI)-MRI and dynamic contrast-enhanced (DCE)-MRI adds structural, hemodynamic and physiological information to anatomical MRI. In endometrial and cervical cancer, the addition of DWI-MRI and DCE-MRI improves tumour detection as well as staging of uterine and extra-uterine pelvic spread. Quantitative assessment of DWI and DCE-MRI reflecting tissue properties of biological aggressiveness or treatment resistance may enable the prediction of risk of extra-uterine or extra-ovarian disease spread, predict risk of recurrence and assess treatment response. DWI shows high accuracy for detecting peritoneal metastases and allows for comprehensive staging of (recurrent) ovarian cancer following the clinical development of whole body DWI-MRI. Summary: The added value of DWI/DCE-MRI for characterization and staging of gynaecological malignancy is becoming increasingly established and may improve treatment stratification. Ongoing multicentre studies are expected to further consolidate its use in clinical routine. Quantitative evaluation of functional MRI may help in prognostication and risk stratification.

http://ift.tt/2uw4OFE

Re-irradiation of cervical and endometrial cancer

Purpose of review: Re-irradiation historically has been associated with unacceptable toxicity and limited benefit. Recent advances in radiotherapy can change the treatment paradigm to provide new salvage treatments for recurrences of cervical and endometrial cancer. Recent findings: Image-guided brachytherapy is an effective method for salvaging central pelvic recurrence, although it has resulted in 20–25% severe late toxicity. Pelvic sidewall disease is not accessible to brachytherapy, so a combined modality approach with radical surgery and intraoperative radiotherapy is an alternative approach. Stereotactic body radiotherapy (SBRT) now provides the option of radical re-irradiation with local control rates of 50–80% and a low incidence of severe late complications. Summary: Initial outcomes using SBRT and image-guided brachytherapy for re-irradiation of gynaecological cancer are encouraging. There has been good local control and acceptable toxicity. Further, large-scale studies are required to define optimal target doses and OAR limits.

http://ift.tt/2uwBMpm

How to emerge from the conservatism in clinical research methodology?

Purpose of review: Despite recent changes in clinical research methodology, many challenges remain in drug development methodology. Recent findings: Advances in molecular biology and cancer treatments have changed the clinical research landscape. Thus, we moved from empirical clinical oncology to molecular and immunological therapeutic approaches. Along with this move, adapted dose-limiting toxicities definitions, endpoints, and dose escalation methods have been proposed. Moreover, the classical frontier between phase I, phase II, and phase III has become unclear in particular for immunological approaches. So, investigators are facing major challenges in drug development methodology. Summary: We propose to individualize clinical research using innovative approaches to significantly improve patient outcomes and targeting what is considered unmet need. Integrating high level of translational research and performing well designed biomarker studies with great potential for clinical practice are of utmost importance. This could be performed within new models of clinical research networks and by building a strong collaboration between academic, cooperative groups, on-site investigators, and pharma.

http://ift.tt/2uwoUzB

Intricate and Cell-type-specific Populations of Endogenous Circular DNA (eccDNA) in Caenorhabditis elegans and Homo sapiens

Investigations aimed at defining the 3-D configuration of eukaryotic chromosomes have consistently encountered an endogenous population of chromosome-derived circular genomic DNA, referred to as extrachromosomal circular DNA (eccDNA). While the production, distribution, and activities of eccDNAs remain understudied, eccDNA formation from specific regions of the linear genome has profound consequences on the regulatory and coding capabilities for these regions. Here, we define eccDNA distributions in C. elegans and in three human cell types, utilizing a set of DNA-topology dependent approaches for enrichment and characterization. The use of parallel biophysical, enzymatic, and informatic approaches provides a comprehensive profiling of eccDNA robust to isolation and analysis methodology. Results in human and nematode systems provide quantitative analysis of the eccDNA loci at both unique and repetitive regions. Our studies converge on and support a consistent picture in which endogenous genomic DNA circles are present in normal physiological states, and in which the circles come from both coding and noncoding genomic regions. Prominent among the coding regions generating DNA circles are several genes known to produce a diversity of protein isoforms, with mucin proteins and titin as specific examples.

http://ift.tt/2uyO64r

G-Shock highlights watches that stand up to tough jobs this summer

Select models built to withstand the unpredictability of the summer months

http://ift.tt/2fzZOZY

Rattus norvegicus BN/SHR liver and heart left ventricle ribosomal RNA depleted directional RNA sequencing

The spontaneously hypertensive rat strain is a frequently used disease model. In a previous study, we measured translational efficiency from this strain and BN-Lx animals. Here, we describe long RNA sequencing re...

http://ift.tt/2vuK6TK

Bioprospecting saline gradient of a Wildlife Sanctuary for bacterial diversity and antimicrobial activities

Antibiotic-resistant bacteria are becoming a global crisis, causing death of thousands of people and significant economic impact. The discovery of novel antibiotics is crucial to saving lives and reducing heal...

http://ift.tt/2vNH1AM

Maternal sleep and small for gestational age infants in the Japan Environment and Children’s Study: a cohort study

Small for gestational age infants have an increased risk of immediate complications, short-term morbidity and mortality, and long-term neurologic and metabolic disorders in adulthood. Previous research has sho...

http://ift.tt/2vuG8KG

Anaemia in pregnancy and associated factors: a cross sectional study of antenatal attendants at the Sunyani Municipal Hospital, Ghana

Anaemia in pregnancy is an important health issue resulting in high maternal morbidity and mortality. The purpose of the current study was to identify factors associated with anaemia among pregnant women recei...

http://ift.tt/2vNcDGP

Knowledge of pharmacy students about doping, and the need for doping education: a questionnaire survey

Anti-doping activities are carried out on a global scale. Based on these activities, the specialty of "sports pharmacist," which entails a deeper comprehension of doping, use of supplements, and appropriate dr...

http://ift.tt/2vuqteE

Genotypes of hepatitis a virus in Turkey: first report and clinical profile of children infected with sub-genotypes IA and IIIA

Hepatitis A virus (HAV) is a food and water-borne virus causing clinical (mainly hepatitis) and subclinical disease in humans. It is important to characterize circulating strains of HAV in order to prevent HAV...

http://ift.tt/2uwERpu

From the Cellular Standpoint: is DNA Sequence Genetic ‘Information’?

Abstract

Constructivist biosemiotics foundations (CBF) imply the first-person basis of cognition. CBF are developed by the biology of cognition, relational biology, enactive approach, ecology of mind, second order cybernetics, genetic epistemology, gestalt, ecological perception and affordances, and active inference by minimization of free energy. CBF reject the idea of an objective independent reality to be represented (cognitivism) by information processing (computationalism) in order to be the fittest (adaptationism). CBF assumes that perception is the behavioral configuration of an object and objects are tokens for eigen-behaviors. Cognition takes place in the organism-environment structural coupling during the ontogeny and phylogeny of all biological unities including unicellular organisms. Therefore, if exogenous DNA particles (virus or trans-sequence) are just tokens for the cell signalling eigen-behaviors, if there is no 'information' in the DNA sequence, how can we explain that the same virus or trans- sequence is associated with a similar phenotype? We call this 'exogenomic problem'. With this basic example, but sufficiently generic to the whole biological world, we agree respectively with Autopoiesis, (Metabolism, Repair)-system, and Gaia theory: i) 'Information, code and meaning' in the DNA sequence belong to the domain of the observer's description. ii) Genetic 'information' is not a program or algorithmic software in DNA sequence. Rather it is a microphysical observable mode of eigen-behaviors in biological unities. iii) The transfer and acquisition of DNA particles is a biospheric phenomenon that maintains its homeorhesis, symbiotic and biosemiotic entailment. Based on the theoretical and experimental results of these theories, it is concluded that genetic 'information' is not a genomic sequence, nor any kind of information (algorithmic or semantic), but for the cell DNA must embody physical forcing. Genetic characters are the effects and not the cause of phenotype and DNA particles do not 'use or manipulate' cellular metabolism. Rather, any cellular configuration change that occurred before or during DNA perturbation (coincident or not with the observation of certain phenotype) is determined on the basis of the cellular standpoint.

http://ift.tt/2vXUsh0

Physiological artifacts in scalp EEG and ear-EEG

A problem inherent to recording EEG is the interference arising from noise and artifacts. While in a laboratory environment, artifacts and interference can, to a large extent, be avoided or controlled, in real...

http://ift.tt/2uOHM86

Doug Wolfberg chosen as interim chair for inaugural EMS Interstate Compact Commission

MECHANICSBURG, Pa. — Page, Wolfberg & Wirth, the National EMS Industry Law Firm® is proud to announce that founding partner, Douglas Wolfberg, has been selected as the interim chairperson for the Recognition of EMS Personal Licensure CompAct (REPLICA). REPLICA is intended to facilitate the day to day movement of EMS personnel across state boundaries, by allowing EMS offices to afford immediate ...

http://ift.tt/2uxR8WF

Epithelial desquamation observed in a Phase I study of an oral cathepsin C inhibitor (GSK2793660)

Abstract

Aims

Cathepsin C (CTSC) is necessary for the activation of several serine proteases including neutrophil elastase (NE), cathepsin G, and proteinase 3. GSK2793660 is an oral, irreversible inhibitor of CTSC that is hypothesized to provide an alternative route to achieve NE inhibition and was tested in a Phase I study.

Methods

Single escalating oral doses of GSK2793660 0.5 mg to 20 mg or placebo were administered in a randomized crossover design to healthy male subjects; a separate cohort received once daily doses of 12 mg or placebo for 21 days. Data were collected on safety, pharmacokinetics, CTSC enzyme inhibition and blood biomarkers.

Results

Single, oral doses of GSK2793660 were able to dose-dependently inhibit whole blood CTSC activity. Once daily dosing of 12 mg GSK2793660 for 21 days achieved > 90% inhibition (95% CI: 56, 130) of CTSC within 3 hours on day 1. Only modest reductions of whole blood enzyme activity of approximately 20% were observed for NE, cathepsin G, and proteinase 3. Seven of 10 subjects receiving repeat doses of GSK2793660 manifested epidermal desquamation on palmar and plantar surfaces beginning 7–10 days after dosing commencement. There were no other clinically important safety findings.

Conclusions

GSK2793660 inhibited CTSC activity but not the activity of downstream neutrophil serine proteases. The palmar-plantar epidermal desquamation suggests a previously unidentified role for CTSC or one of its target proteins in the maintenance and integrity of the epidermis at these sites, with some similarities to the phenotype of CTSC-deficient humans.

http://ift.tt/2uwe9gt

Suboptimal Cotrimoxazole prophylactic concentrations in HIV-infected children according to the WHO guidelines

Abstract

Aims

A clinical study was conduct in HIV-infected children to evaluate the prophylactic doses of cotrimoxazole (sulfamethoxazole (SMX) and trimethoprim (TMP)) advised by WHO.

Methods

Children received lopinavir-based antiretroviral therapy with cotrimoxazole prophylaxis (200 mg of SMX/ 40 mg of TMP once daily). Nonlinear mixed effects modelling approach was used to analyze plasma concentrations. Factors that could impact the pharmacokinetic profile were investigate. The model was subsequently used to simulate individual exposure and evaluate different administration schemes.

Results

The cohort counted 136 children (average age: 1.9 years (range: [0.7-4]), average weight: 9.5 kg (range: [6-16.3]). A dose per kg was justified by the significant influence of implementing an allometrically scaled body size covariate on SMX and TMP pharmacokinetic. SMX and TPM clearance were estimated at 0.49 L/h/9.5 kg and 3.06 L/h/9.5 kg respectively. The simulated exposures obtained after administration of oral dosing recommended by WHO for children from 10 to 15 kg were significantly lower than in adult for SMX and TMP. This could induce a reduction of effectiveness of cotrimoxazole. Simulations show that regimens of 30 mg/kg of SMX and 6 mg/kg of TMP in the group of 5 to 10 kg and 25 mg/kg of SMX and 5mg/kg of TMP in the group of 10 to 15 are more pertinent doses

Conclusions

In this context of high prevalence of opportunistic infections, a lower exposure to cotrimoxazole in children than adults was noted. To achieve comparable exposure to adult a dosing scheme per kg was proposed.

http://ift.tt/2uNJp63

In vivo and in vitro palatability testing of a new paediatric formulation of valaciclovir

Abstract

Aim

The palatability of a new paediatric formulation of valaciclovir was assessed in children and their parents: non-inferiority of the new paediatric formulation (test formulation) compared to the reference formulation was investigated.

Methods

In vivo palatability testing was performed in a randomized, two-period, multicentre, cross-over study. Children and their parents scored the liking of the new paediatric valaciclovir formulation and the reference formulation on a 100 mm visual analogue scale (VAS). To support formulation development and palatability testing, electronic tongue measurements were applied.

Results

The electronic tongue measurement indicated taste-masking capabilities for three different formulations in the developmental phase. A glycerol-based formulation was further tested and compared to the reference formulation prepared out of crushed and suspended tablets. The mean difference (95%CI) in VAS scores between both formulations, as indicated by the children (n=20), was 2.4 (-8.5, 13) mm, in favour of the new paediatric valaciclovir formulation. The mean (95%CI) difference in VAS scores indicated by the parents (n=20) was -0.9 (-12, 9.8) mm.

Conclusion

The palatability of the new paediatric valaciclovir formulation was considered non-inferior to the reference formulation prepared out of crushed tablets. We were able to optimize the study design and number of children to be included in the palatability testing by using electronic tongue measurements.

http://ift.tt/2uwQWuN

Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients – a pilot study

Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to asses...

http://ift.tt/2vqB0ZU

Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome with multiorgan failure

International Journal of Hematologic Oncology, Ahead of Print.


http://ift.tt/2uNDvSr

Anthelminthic properties of Methylene chloride-methanol (1:1) extracts of two Cameroonians medicinal plants on Heligmosomoides bakeri (Nematoda: Heligmosomatidea)

The resistance of some medico-veterinary parasite strains as well as the unavailability and toxicity of synthetic anthelminthics on humans, animals and the impacts of their residues in the environment have pus...

http://ift.tt/2vXwhiK

Failure of Cleaning Verification in Pharmaceutical Industry Due to Uncleanliness of Stainless Steel Surface

The lack of a well-defined procedure that consistently cleaned coupon surfaces was identified as the major contributor to low and variable recoveries in cleaning verification. This manuscript describes the correct protocol of cleaning stainless steel coupons.

http://ift.tt/2wPXMYY

Prognostic Value of Pre- and Post-Treatment FDG PET/CT Parameters in Small Cell Lung Cancer Patients

Abstract

Purpose

To evaluate the prognostic value of PET parameters obtained from pre- and post-treatment FDG PET/CT examinations in patients with SCLC.

Methods

Fifty-nine patients with initially diagnosed SCLC from 2009 to 2014 were included and had chemotherapy and/or concurrent chemoradiotherapy. FDG PET/CT examinations were performed before (PET1) and after (PET2) treatment to evaluate treatment response. A region of interest was placed over the primary lesion and metastatic lymph nodes within the thoracic cavity. PET parameters including change from PET1 to PET2 (Δ in %) were acquired: SUVmax, SUVpeak, MTV2.5, TLG, ΔSUVmax, ΔSUVpeak, ΔMTV and ΔTLG. Patient characteristics including staging, age, sex, LDH and response evaluation by RECIST were surveyed. Statistical analysis was done using Kaplan-Meier method and Cox regression analysis with respect to OS and PFS.

Results

The median follow-up was 9.6 months (2.5–80.5 months). 27 patients were LD and 32 were ED. Forty-six patients (78.0%) had died, and median OS was 8.6 months; 51 patients (86%) showed disease progression, and median PFS was 2.5 months. On univariate analysis, patients with ED, high interval change (ΔSUVmax and ΔSUVpeak) and low PET2 parameters showed longer OS and PFS. Multivariate analyses demonstrated that ΔSUVpeak (HR 2.6, P = 0.002) was an independent prognostic factors for OS, and MTV2.5 of PET2 (HR 2.8, P = 0.001), disease stage (HR 2.7, P = 0.003) and RECIST (HR 2.0, P = 0.023) were independent prognostic factors for PFS.

Conclusions

Metabolic and volumetric PET parameters obtained from pre- and post-treatment FDG PET/CT examinations in patients with SCLC have significant prognostic information.

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Unusual Contralateral Axillary Lymph Node Metastasis in a Second Primary Breast Cancer Detected by FDG PET/CT and Lymphoscintigraphy

Abstract

Contralateral metastatic axillary lymph nodes in a patient with breast cancer is a rare condition. Here, we present a 55-year-old woman with a second primary breast cancer. The patient underwent ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) for staging work-up. Additionally, preoperative lymphoscintigraphy was performed to detect sentinel lymph nodes. FDG PET/CT demonstrated increased FDG uptake in the left nipple and right axillary lymph nodes. Lymphoscintigraphy identified the right axillary lymph nodes which was consistent with the FDG PET/CT findings. This case emphasizes the usefulness of FDG PET/CT and lymphoscintigraphy for identifying unpredictable contralateral axillary lymph node metastasis from a second primary breast cancer.

http://ift.tt/2wPvKNc

Medicare Telehealth Parity Act of 2017 Would Expand Role of Audiology

Much of the focus of the Over-the-Counter (OTC) Hearing Aid Act of 2017 (S.670 and H.R.1652) has been on improving accessibility and affordability to hearing aids by providing a "do it yourself" (DIY) distribution channel for patients who are comfortable with self-assessment and fitting of hearing aids.

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Grading of diffuse astrocytic gliomas: Broders, Kernohan, Zülch, the WHO… and Shakespeare

http://ift.tt/2hRD8F0

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

An in vitro method for establishing dual resistance to an EGFR-TKI and a MET-TKI in cancer cells is described. This method is useful for developing treatments for patients with EGFR-mutations, who exhibit disease progression despite EGFR-TKI treatment with MET-amplification. It can also be modified for inhibitors targeting other molecules.

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Editorial Report

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A New Classification System is Helpful in Diagnosing Intracranial Complications of Acute Mastoiditis in CT

Abstract

Purpose

To assess the usefulness of the new computed tomography (CT) classification criteria proposed by Horowitz et al. and their effect on inter-observer agreement when estimating intracranial complications of acute mastoiditis.

Methods

In this study 53 contrast-enhanced CT scans of patients with acute mastoiditis were each retrospectively reviewed by two radiologists, using two different assessment criteria for intracranial complications. According to the new criteria, intracranial CT findings in the perisinuous area were graded into four classes (I normal, II linear halo, III nodular halo ≤4 mm thick and IV nodular halo >4 mm thick), where classes III and IV indicate a high risk for epidural abscesses. Inter-reader agreement was estimated by weighted kappa analysis for both methods.

Results

With the old method, epidural abscesses were suspected in six and venous sinus thrombosis in five patients. With the new method, high-risk perisinuous lesions (classes III or IV) were detected in 11 patients, and sinus thrombosis outside the perisinuous area in 3 patients. All epidural abscesses were in the perisinuous area. Of the patients four, in whom intracranial pathology was not suspected with the old method, fell into the high-risk group (class III) according to the new method. All class IV lesions were also determined to be pathological with the old method. The inter-observer agreement (weighted kappa) rose from 0.21 (old method) to 0.80 (new method) when assessing epidural abscesses and from 0.44 (old method) to 0.85 (new method) when assessing sinus thrombosis.

Conclusion

The new assessment method raised the inter-observer agreement for detection of intracranial acute mastoiditis complications, namely epidural abscesses and venous sinus thrombosis.

http://ift.tt/2vtNNsF

Microfluidic Bioprinting for Engineering Vascularized Tissues and Organoids

We provide a generalized protocol based on a microfluidic bioprinting strategy for engineering a microfibrous vascular bed, where a secondary cell type could be further seeded into the interstitial space of this microfibrous structure to generate vascularized tissues and organoids.

http://ift.tt/2uNXVKN

Optical Quantification of Intracellular pH in Drosophila melanogaster Malpighian Tubule Epithelia with a Fluorescent Genetically-encoded pH Indicator

Cellular ion transport can often be assessed by monitoring intracellular pH (pHi). Genetically Encoded pH-Indicators (GEpHIs) provide optical quantification of intracellular pH in intact cells. This protocol details the quantification of intracellular pH through cellular ex vivo live-imaging of Malpighian tubules of Drosophila melanogaster with pHerry, a pseudo-ratiometric genetically encoded pH-indicator.

http://ift.tt/2uOkzmw

Combined effect of anti-BAG3 and anti-PD-1 treatment on macrophage infiltrate, CD8+ T cell number and tumour growth in pancreatic cancer

We read with great interest the article by Zhang et al1 showing that CD8⁺ cell infiltration in pancreatic tumours can be enhanced by depletion of myeloid cells (CD11b⁺ macrophages and myeloid-derived suppressor cells) and that the depletion of CD11b⁺ cells resulted in decreased PD-L1 expression on cancer cells thus impairing the triggering of the inhibitory receptor PD-1 on T cells.1 Recruitment and activation of CD8⁺ lymphocytes in tumours are suppressed by mechanisms only partially understood and rescuing CD8⁺ cell infiltrate in tumours is one of the objectives of immunotherapies.1 2 Tumour-associated macrophages (TAMs) play a crucial role in the relation between tumour cells and their environment.3 Here, we confirm the interplay between macrophages and CD8⁺ cells in pancreatic cancer and identify a potential way to exploit this enhancing effect of anti-PD-1 treatment. Indeed, we show that reduction of macrophage infiltrate,...

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EM Nerd-The Case of the Bridge to Nowhere Continues

So often we apply qualitative dichotomies to quantitative differences even when questionable clinical distinction exists. Such is the case with the general interpretation of a recent article published in Resuscitation. Huis in 't Veld et al examined video recordings of real life Emergency Department resuscitations of patients in cardiac arrest (1). Over a one year […]

EMCrit by Rory Spiegel.

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Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials

Abstract

Background

Elucidation of mechanisms regulating bone metastasis has progressed significantly in recent years and this has translated to many new therapeutic options for patients with bone metastatic cancers. However, the rapid rate of progress in both the basic science literature and therapies undergoing clinical trials makes staying abreast with current developments challenging. This review seeks to provide an update on the current state of the science in bone metastasis research and give a snap shot of therapies in clinical trials for bone metastatic cancer.

Main body

Bone metastasis represents a difficult to treat clinical scenario due to pain, increased fracture risk, decreased quality of life and diminished overall survival outcomes. Multiple types of cancer have the specific ability to home to the bone microenvironment and cause metastatic lesions. This osteotropism was first described by Stephen Paget nearly 100 years ago as the 'seed and soil' hypothesis. Once cancer cells arrive at the bone they encounter a variety of cells native to the bone microenvironment which contribute to the establishment of bone metastatic lesions. In the first part of this review, the 'seed and soil' hypothesis is revisited while emphasizing recent developments in understanding the impact of native bone microenvironment cells on the metastatic process. Next, approved therapies for treating bone metastasis at the systemic level as well as those that target the bone microenvironment are discussed and current National Comprehensive Cancer Network (NCCN) guidelines relating to treatment of bone metastases are summarized. Finally, all open interventional clinical trials for therapies relating to treatment of bone metastasis have been complied and categorized.

Conclusion

Understanding the recent advancements in bone metastasis research is important for continued development of novel bone targeted therapies. The plethora of ongoing clinical trials will hopefully translate into improved treatments options for patients suffering from bone metastatic cancers.

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How to rehab firefighters in extreme heat, cold

Rehab is difficult and doubly so when the temperatures soar or plunge; here's a look at how to handle those challenging days

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Novel concepts of antiangiogenic therapies in metastatic renal cell cancer

Summary

The era of antiangiogenic drugs targeting the vascular endothelial growth factor (VEGF) signaling pathway has become a mainstay in the treatment of metastatic renal cell carcinoma (mRCC), showing primary responses in 65–70% of patients. Nevertheless, most of those patients progress to angiogenesis inhibitors over time due to different modes of resistance (adaptive and intrinsic). Both in vitro and in vivo analyses provided evidence that PD-L1 upregulation in hypoxia conditions is dependent on hypoxia-inducible factor (HIF)-2alpha and is associated with an overexpression of VEGF. Thus, additional blockade of PD-L1 along with inhibition of angiogenesis pathways seems to represent a novel and innovative treatment concept in mRCC. In this short review, we provide an overview on ongoing phase III trials combining antiangiogenic therapies with checkpoint inhibitors in the first-line setting. Moreover, we critically analyze the impact of recently approved therapeutic antiangiogenic agents and checkpoint inhibitors after progression to first-generation tyrosine kinase inhibitors and their mode of action. In addition, response and resistance hypotheses and biomarkers to antiangiogenic therapy in clinical practice are critically discussed.

http://ift.tt/2hRd0Kv

Unresectable squamous cell carcinoma of upper trachea with long-term survival after concurrent chemoradiotherapy

Upper tracheal malignancies are rare, and long-term survival is even rarer, especially among the unresectable malignancies. A 66-year-old chronic smoker was diagnosed as a locally advanced, non-metastatic squamous cell carcinoma of the upper trachea. Being unresectable, he was treated with six cycles of concurrent weekly cisplatin and three-dimensional conformal radiotherapy to a dose of 60 Gy in 30 fractions over 6 weeks. Follow-up imaging at 6 and 12 months revealed no disease. Our patient is presently 36 months post-treatment and is disease free without tracheal necrosis, fistula or radiation pneumonitis but developed hypothyroidism and is presently euthyroid. Concurrent chemoradiotherapy appears safe up to 3 years at least without any necrosis and is effective in controlling local disease. Meticulous planning obviates the need for higher technology like motion management techniques or intensity-modulated radiotherapy.

http://ift.tt/2vpm9P8

Paraneoplastic mucous membrane pemphigoid with ocular and laryngeal involvement

A 73-year-old woman was treated 8 years previously for synchronous breast and uterine neoplasms. She presented with a severe sore throat, odynophagia, dysphonia, dyspnoea, ocular irritation and weight loss over the last 3 months. Physical examination revealed ulcerations in the oral cavity, posterior pharyngeal wall and supraglottic larynx, nasal crusting, bilateral conjunctivitis and three cutaneous blisters. A diagnosis of anti-laminin 5 mucous membrane pemphigoid was retained, based on skin biopsy, direct immunofluorescence and immunoprecipitation. A positron emission tomography (PET)-CT detected multiple adenopathies. Cytology revealed adenocarcinoma with an immunocytology compatible with a breast origin and this was considered as a late metastatic recurrence of her previous breast cancer. A treatment of prednisone, dapsone and hormonotherapy was introduced, but intravenous immunoglobulin and rituximab were added due to new mucosal lesions. Despite treatment, a posterior laryngeal scar and bilateral symblepharon were developed. After 3 years, the patient is still alive and reports a satisfactory quality of life.

http://ift.tt/2wBeX0P

Isolated intraductal variant of hepatocellular carcinoma

Description

A 70-year-old male teetotaller, with a history of chronic obstructive lung disease and hypertension, presented to the emergency department with a 2-day history of right upper quadrant pain and melaena. Investigations revealed total bilirubin 6.8 mg/dL, aspartate and alanine transaminases 88 and 122 IU/L, respectively, alkaline phosphatase 338 IU/L and gamma-glutamyl transpeptidase 223 IU/L. Tests for chronic hepatitis B, hepatitis C and HIV were negative. Serum alpha-fetoprotein was 22.8 ng/mL, whereas carcino-embryonic antigen (CEA), CA 19–9, prostate specific antigen and chromogranin levels were normal. Contrast CT of the abdomen revealed fatty liver with moderate dilation of bilateral intrahepatic biliary radicles (figure 1A) and dilated common bile duct (CBD) with hyperdense contents, without identifiable mass lesions in the liver or biliary tree. Upper gastrointestinal endoscopy revealed haemobilia, and cholangiogram showed normal calibre CBD with filling defects. Endoscopic intraductal ultrasound revealed focal thickening of segment three hepatic duct, and Spyglass cholangioscopy confirmed a...

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Bilateral painful tic convulsif

'Painful tic convulsif' (PTC) describes the coexistence of hemifacial spasm and trigeminal neuralgia. In this report, we describe a unique presentation of bilateral PTC in a man with bilateral hemifacial spasm and trigeminal neuralgia secondary to neurovascular conflict of all four cranial nerves. Following failed medical and radiofrequency therapy, microvascular decompression of three of the four involved nerves was performed, where the offending vessels were mobilised and Teflon used to prevent conflict recurrence. He continues to respond to Botox for right hemifacial spasm. Since surgery, he remains pain free bilaterally and spasm free on the left.

http://ift.tt/2wAWS39

Lenalidomide-associated arterial thrombosis in a patient with JAK2 positive atypical myeloproliferative neoplasm

Description

A 71-year-old woman, with a recent diagnosis of JAK2 positive atypical myeloproliferative neoplasm, presented to the emergency room (ER) for bilateral foot pain and purplish discolouration of her toes (figure 1). She started her first cancer treatment 3 weeks ago using lenalidomide with prednisone 20 mg daily. Venous thromboprophylaxis was not prescribed then due to anaemia and history of intracranial haemorrhage. ER work up included simple X-rays of her feet that were normal. Lower extremity ultrasound did not show any deep vein thrombosis, so she was discharged home. The patient did not have atrial fibrillation or hyperviscosity. No history of arterial thrombosis or smoking. Two weeks later, she was re-evaluated by her haematologist, and a hospital admission was arranged given worsening symptoms. Her physical exam now showed the purplish discolouration has progressed over both feet, associated with some toes turning black (figure 2). She had strong lower extremity...

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Right hepatic artery 'caterpillar hump and dual cystic arteries: relevance of critical view of safety in a 'straightforward cholecystectomy

Description

A 60-year-old woman with unremarkable medical history, underwent elective laparoscopic cholecystectomy for symptomatic cholelithiasis. A four-port technique was performed. Initial exploration of Calot's triangle was carried out by upward traction of the fundus and lateral retraction of the Hartmann's pouch; after dissection of the peritoneum medially at the level of the infundibulum, two tubular structures entering the gallbladder were visible, as usually expected. However, to obtain a 'critical view of safety',1 dissection was continued by opening up the lateral aspect of the peritoneum; hepatobiliary triangle was dissected free of areolar tissue and the bottom of the gallbladder was dissected off the lower part of the liver bed. At this stage, an anatomical variation became evident (figure 1): the right hepatic artery made a 'caterpillar-like' loop inside Calot's triangle and two short cystic arteries reached the gallbladder. According to a recent review, among clinically...

http://ift.tt/2wAV0Y6

Therapeutic options for bleeding oesophageal varices: cyanoacrylate and balloon-occluded retrograde obliteration (BRTO)

A 56-year-old male with cirrhosis presented with acute bleeding from cardiofundal gastroesophageal varices (GOV) and was treated with endoscopic cyanoacrylate glue. Glue therapy achieved stabilisation of the patient in the emergent setting. Three months later, the patient suffered rebleeding. At that time, he underwent retreatment with balloon-occluded retrograde obliteration (BRTO), with no recurrence at a follow-up of 14 months.

Available treatments for bleeding GOV include methods to (a) directly obstruct the varices (endoscopic variceal ligation , sclerotherapy and cyanoacrylate glue, BRTO) or to (b) decrease portal pressure (surgical portacaval shunts; transportal intrahepatic portosystemic shunt). No precise guidelines are available regarding when to use which modality, and few centres have experience with all of them. This case report illustrates a setting in which both options of cyanoacrylate glue therapy and BRTO were used for acute gastric variceal bleeding.

http://ift.tt/2vqpP3q

Ibrutinib Becomes First FDA-Approved Drug for Chronic Graft-Versus-Host Disease

A drug used to treat several blood cancers, ibrutinib, has been approved by FDA to treat chronic graft-versus-host disease, making it the first approved therapy for this potentially fatal side effect of cancer-related stem cell transplants.

http://ift.tt/2wAZLkk

A cost-effectiveness comparison of the NICE 2015 and WHO 2013 diagnostic criteria for women with gestational diabetes with and without risk factors

Objectives

To compare the cost-effectiveness (CE) of the National Institute for Health and Care Excellence (NICE) 2015 and the WHO 2013 diagnostic thresholds for gestational diabetes mellitus (GDM).

Setting

The analysis was from the perspective of the National Health Service in England and Wales.

Participants

6221 patients from four of the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study centres (two UK, two Australian), 6308 patients from the Atlantic Diabetes in Pregnancy study and 12 755 patients from UK clinical practice.

Primary and secondary outcome measures planned

The incremental cost per quality-adjusted life year (QALY), net monetary benefit (NMB) and the probability of being cost-effective at CE thresholds of £20 000 and £30 000 per QALY.

Results

In a population of pregnant women from the four HAPO study centres and using NICE-defined risk factors for GDM, diagnosing GDM using NICE 2015 criteria had an NMB of £239 902 (relative to no treatment) at a CE threshold of £30 000 per QALY compared with WHO 2013 criteria, which had an NMB of £186 675. NICE 2015 criteria had a 51.5% probability of being cost-effective compared with the WHO 2013 diagnostic criteria, which had a 27.6% probability of being cost-effective (no treatment had a 21.0% probability of being cost-effective). For women without NICE risk factors in this population, the NMBs for NICE 2015 and WHO 2013 criteria were both negative relative to no treatment and no treatment had a 78.1% probability of being cost-effective.

Conclusion

The NICE 2015 diagnostic criteria for GDM can be considered cost-effective relative to the WHO 2013 alternative at a CE threshold of £30 000 per QALY. Universal screening for GDM was not found to be cost-effective relative to screening based on NICE risk factors.

http://ift.tt/2vVGyNg

Facilitation roles and characteristics associated with research use by healthcare professionals: a scoping review

Background

Implementing research findings into practice is a complex process that is not well understood. Facilitation has been described as a key component of getting research findings into practice. The literature on facilitation as a practice innovation is growing. This review aimed to identify facilitator roles and to describe characteristics of facilitation that may be associated with successful research use by healthcare professionals.

Methods

We searched 10 electronic databases up to December 2016 and used predefined criteria to select articles. We included conceptual papers and empirical studies that described facilitator roles, facilitation processes or interventions, and that focused on healthcare professionals and research use. We used content and thematic analysis to summarise data. Rogers' five main attributes of an innovation guided our synthesis of facilitation characteristics.

Results

Of the 38 488 articles identified from our online and manual search, we included 195 predominantly research studies. We identified nine facilitator roles: opinion leaders, coaches, champions, research facilitators, clinical/practice facilitators, outreach facilitators, linking agents, knowledge brokers and external-internal facilitators. Fifteen facilitation characteristics were associated with research use, which we grouped into five categories using Rogers' innovation attributes: relative advantage, compatibility, complexity, trialability and observability.

Conclusions

We found a diverse and broad literature on the concept of facilitation that can expand our current thinking about facilitation as an innovation and its potential to support an integrated, collaborative approach to improving healthcare delivery.

http://ift.tt/2vW9qoP

Comprehensive geriatric assessment in 326 older women with early breast cancer

Comprehensive geriatric assessment in 326 older women with early breast cancer

British Journal of Cancer advance online publication, August 10 2017. doi:10.1038/bjc.2017.257

Authors: D O Okonji, R Sinha, I Phillips, D Fatz & A Ring

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Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy

Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy

British Journal of Cancer advance online publication, August 10 2017. doi:10.1038/bjc.2017.253

Authors: Rebecca Y Tay, Elizabeth Blackley, Catriona McLean, Maggie Moore, Peter Bergin, Sanjeev Gill & Andrew Haydon

http://ift.tt/2uti9OO

One-step nucleic acid amplification assay is an accurate technique for sentinel lymph node biopsy of breast cancer patients: a meta-analysis

One-step nucleic acid amplification assay is an accurate technique for sentinel lymph node biopsy of breast cancer patients: a meta-analysis

British Journal of Cancer advance online publication, August 10 2017. doi:10.1038/bjc.2017.262

Authors: Fang Shi, Qian Zhang, Zhenzhen Liang, Mengmeng Zhang & Xin Liu

http://ift.tt/2uM8uOI

Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A

Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A

British Journal of Cancer advance online publication, August 10 2017. doi:10.1038/bjc.2017.263

Authors: Siti Aminah Abdul Rahim, Anne Dirkse, Anais Oudin, Anne Schuster, Jill Bohler, Vanessa Barthelemy, Arnaud Muller, Laurent Vallar, Bassam Janji, Anna Golebiewska & Simone P Niclou

http://ift.tt/2utJTCV

Cytomegalovirus-related transverse myelitis in an immunocompetent host: a subacute onset of an immune-mediated disease?

We report a case of transverse myelitis in an immunocompetent host with an atypical long onset of symptoms. A 56-year-old man was admitted to the hospital reporting 5 months of progressive ascending lower extremity weakness and numbness, inability to walk, bowel incontinence,urinary retention and several episodes of nausea and vomiting. MRI showed moderate spinal swelling and multiple hyperintense signal changes on cervical levels C2–C5 and thoracic levels T1–T3. Cerebrospinal fluid (CSF) showed pleocytosis and was positive for anti-cytomegalovirus (CMV) IgG intrathecal antibodies, but the CSF PCR for CMV was negative. The diagnosis of immune-mediated CMV-related transverse myelitis was established and the patient was treated with methylprednisolone and valgancyclovir. The patient had poor recovery and remained paraplegic at discharge.

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Portal vein aneurysm in thalassaemia

Arterial aneurysms are more common than visceral venous aneurysms. Portal vein aneurysms being the most common type of visceral venous aneurysms. Here, we present an 18-year-old young woman with thalassaemia major, who presented with headache, palpitation, shortness of breath and a recent increase in blood transfusion rate. On clinical examination, she had hepatosplenomegaly. Ultrasonography revealed hepatosplenomegaly with fusiform dilatation of extrahepatic portal vein, which was confirmed to be portal vein aneurysm on contrast enhanced CT. Though portal vein aneurysms were previously thought to be rare, recently they are increasingly diagnosed with the use of cross-sectional imaging. Recognition of this finding can help to avoid potential confusion with other periportal cystic masses of different aetiologies, especially on sonography.

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Acute myeloid leukaemia masquerading as a primary CNS tumour

In children with newly diagnosed acute myeloid leukaemia (AML), myeloid sarcomas (MS) of the central nervous system (CNS) are rare. Since MS involving the CNS are potentially curable, timely recognition is paramount. Establishing a diagnosis may be problematic as they can easily mimic primary CNS neoplasms. We report the case of a 5-year-old boy with AML with t(8;21)(q22;q22) rearrangement who presented with a massive intracranial MS and rapid clinical deterioration suggestive of a meningioma or a primitive neuroectodermal tumour. The peripheral smear showed blasts with Auer rods. Urgent chemotherapy was started for AML with presumptive CNS MS. The mass resolved with chemotherapy, and treatment was consolidated with radiotherapy. Although exceedingly rare, this case highlights the potential for MS to present similarly to a primary CNS tumour. MS should be part of the differential diagnosis as part of a CNS mass, particularly if the complete blood count is abnormal.

http://ift.tt/2fxjUDU

Transvaginal postpartum manual removal of a prolapsed submucous leiomyoma, initially diagnosed hybrid predominantly intramural

We present a rare case of a large infarcted submucous fibroid removed manually after a normal vaginal delivery. This patient was known to have a large postero-fundal hybrid predominantly intramural uterine fibroid, measuring 11 x 10 cm in diameter and diagnosed 2 years prior to last conception. Thirty-five days postpartum, she presented with severe lower abdominal pain and foul smell per vaginum. Abdominal examination revealed a very tender bulky uterus at 24 weeks size, and vaginal examination revealed a big fleshy smelly mass with friable surface just bulging from a dilated cervix. Examination under anaesthesia revealed a very foul smelly large pedunculated submucous fibroid that was felt through a dilated cervix. It was deliverable vaginally, so the submucous leiomyoma was removed manually, a procedure similar to manual removal of placenta. Histopathology examination confirmed an infarcted massive fibroid.

http://ift.tt/2hQCYho

Anterior cervical osteophytosis as a cause of dyspnoea and stridor

Description

A 77-year-old man with no history of respiratory disease presented with a 12-hour history of dyspnoea, stridor, non-productive cough and rhinorrhoea. He denied other symptoms such as dysphagia and dysphonia. Physical examination showed diminished vesicular breath sounds and stridor, although there were no vocal cord abnormalities in the laryngoscopic evaluation. The laboratory results and the posteroanterior chest radiograph revealed no significant abnormalities.

In order to exclude an airway obstruction, a cervical radiograph was obtained. The exam showed anterior osteophytosis involving the lower segment of the cervical spine (figure 1). A CT scan confirmed the diagnosis, revealing a tracheal narrowing due to anterior osteophytosis between C5 and C7 associated with thickening of adjacent soft tissues (figure 2).

Figure 1

Cervical radiograph showing extensive osteophytosis in the anterior aspects of the lower cervical vertebrae.

Figure 2

Cervical CT scan...

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Insulin-mediated lipohypertrophy: an uncommon cause of diabetic ketoacidosis

Description

A 15-year-old boy with a 3-year history of type 1 diabetes mellitus was referred to endocrinology clinic for the management of uncontrolled blood glucose levels. His present treatment plan comprised subcutaneous basal-bolus insulin regimen. He was taking regular insulin before the three major meals and insulin glargine at the bedtime. His body mass index (BMI) was 14.8 kg/m² and HbA1c level 14.9%, suggesting uncontrolled hyperglycaemia for a long time.

On examination, he was found to have remarkably prominent bilateral lipohypertrophic areas on the lower abdomen (figure 1), large enough to be noticeable even through the clothing.

Figure 1

Showing prominent bulge on either side of the lower abdomen (side view).

His injection practices revealed that he was self-administering insulin over the abdomen with the syringe of needle size 6 mm, apparently leading to intramuscular injection in a thin-built person.1 Furthermore,...

http://ift.tt/2fz55Rz