Cancers, Vol. 9, Pages 117: Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients

Cancers, Vol. 9, Pages 117: Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients

Cancers doi: 10.3390/cancers9090117

Authors: Susan Cedra Susanne Wiegand Marlen Kolb Andreas Dietz Gunnar Wichmann

Targeting of αVβ3 and αVβ5 integrins by cilengitide may reduce growth of solid tumors including head and neck squamous cell carcinoma (HNSCC). Preclinical investigations suggest increased activity of cilengitide in combination with other treatment modalities. The only published trial in HNSCC (ADVANTAGE) investigated cisplatin, 5-fluorouracil, and cetuximab (PFE) without or with once (PFE+CIL1W) or twice weekly cilengitide (PFE+CIL2W) in recurrent/metastatic HNSCC. ADVANTAGE showed good tolerability of the cilengitide arms and even lower adverse events (AEs) compared to PFE but not the benefit in overall survival expected based on preclinical data. As we found in the FLAVINO assay, a short-time ex vivo assay for prediction of chemosensitivity, only a subgroup of HNSCC had an increased suppressive effect of cilengitide containing combination therapies on colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatory cytokines, whereas other HNSCC failed to respond. Response to αVβ3 and αVβ5 integrin targeting by cilengitide classifies HNSCC regarding outcome. We present FLAVINO data arguing for further development of cilengitide plus cetuximab in treatment of a subgroup of HNSCC potentially identified by the FLAVINO assay using a set of biomarkers for response evaluation.

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Cancers, Vol. 9, Pages 118: EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients

Cancers, Vol. 9, Pages 118: EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients

Cancers doi: 10.3390/cancers9090118

Authors: Sarah Sabir Sharon Yeoh George Jackson Richard Bayliss

Since the discovery of the fusion between EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase), EML4-ALK, in lung adenocarcinomas in 2007, and the subsequent identification of at least 15 different variants in lung cancers, there has been a revolution in molecular-targeted therapy that has transformed the outlook for these patients. Our recent focus has been on understanding how and why the expression of particular variants can affect biological and molecular properties of cancer cells, as well as identifying the key signalling pathways triggered, as a result. In the clinical setting, this understanding led to the discovery that the type of variant influences the response of patients to ALK therapy. Here, we discuss what we know so far about the EML4-ALK variants in molecular signalling pathways and what questions remain to be answered. In the longer term, this analysis may uncover ways to specifically treat patients for a better outcome.

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Lotus birth, a holistic approach on physiological cord clamping

Publication date: Available online 4 September 2017
Source:Women and Birth
Author(s): Laura A. Zinsser
BackgroundThe positive effects of delayed cord clamping (DCC) has been extensively researched. DCC means: waiting at least one minute after birth before clamping and cutting the cord or till the pulsation has stopped. With physiological clamping and cutting (PCC) the clamping and cutting can happen at the earliest after the pulsation has stopped. With a Lotus birth, no clamping and cutting of the cord is done. A woman called Clair Lotus Day imitated the holistic approach of PCC from an anthropoid ape in 1974. The chimpanzee did not separate the placenta from the newborn.AimThe aim of this case report is to discuss and learn a different approach in the third stage of labour.MethodThree cases of Lotus birth by human beings were observed. All three women gave birth in an out-of-hospital setting and had ambulant postnatal care.FindingsThe placenta was washed, salted and herbs were put on 2–3h post partum. The placenta was wrapped in something that absorbs the moisture. The salting was repeated with a degreasing frequency depending on moistness of the placenta. On life day six all three Lotus babies experiences a natural separation of the cord. All three Lotus birth cases were unproblematic, no special incidence occurred.ConclusionsOne should differentiate between early cord clamping (ECC), delayed cord clamping (DCC) and physiological cord clamping (PCC). Lotus birth might lead to an optimisation of the bonding and attachment. Research is needed in the areas of both PCC and Lotus birth.



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Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study

Abstract

Background

Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients.

Patients and methods

We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan–Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival.

Results

Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64–0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53–0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p < 0.001). Results remained significant in landmark analyses. The onset of any single AE or any combinations of the AEs were all statistically significantly associated with prolonged OS, except for the presence of proteinuria. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting overall survival.

Conclusion

Presence of HTN, proteinuria, or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients.

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Role of Immune Microenvironment in Gastrointestinal Stromal Tumors

Abstract

Introduction

The immune microenvironment is a prognostic factor for various malignancies. The significance of key players of this immune microenvironment including tumor-infiltrating lymphocytes and expression of programmed death-ligand 1 (PD-L1), indoleamine-2,3-dioxygenase (IDO), and tryptophanyl-tRNA synthetase (WARS) in gastrointestinal stromal tumors (GISTs) is largely unknown.

Methods

Tissue microarrays were constructed from pathology files, 1996-2016. Immunohistochemistry for PD-L1, IDO, WARS was correlated with tumor size, mitoses, and outcomes. Tumor infiltrating lymphocytes (TILs) expressing CD3, CD4, CD8, FoxP3, and GBP5 were counted.

Results

129 GISTs were analyzed. Mean patient age was 62.5 years; 52.0% were male. Tumor location included 89 stomach (69.0%), 33 small bowel (25.6%), 7 other (5.4%). Mean tumor size was 5.6 cm; mean mitoses were 7.2/50HPF. Nineteen patients (15.0%) developed disease progression, to abdominal wall (n=8), liver (n=6), and elsewhere (n=5). Median progression-free survival was 56.6 months; 5 patients died of disease. PD-L1 was positive in 87/126 tumor samples (69.0%), 114/127 tumors were IDO-positive (89.8%), and 60/127 were positive for WARS (47.2%). PD-L1 was associated with increased size (p=0.01), necrosis (p=0.018), and mitoses (p=0.006). Disease progression was not associated with PD-L1 (p=0.44), IDO (p=0.14), or WARS (p=0.36) expression. PD-L1-positive GISTs with CD8- or CD3-positive TILs were significantly smaller than tumors with CD8- or CD3-negative TILs.

Conclusions

PD-L1 expression was associated with increased size and mitoses. High CD8- or CD3-positive TIL counts were associated with decreased PD-L1/IDO-positive GIST size. PD-L1 and IDO could be significant in GIST tumor biology and invite consideration of immunotherapy as a potential treatment option.

This article is protected by copyright. All rights reserved.

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A Decision Instrument to Identify Isolated Traumatic Subdural Hematomas at Low Risk of Neurological Deterioration, Surgical Intervention or Radiographic Worsening

Abstract

Background and Objectives

Subdural hematoma (SDH) is the most common form of traumatic intracranial hemorrhage. Severity of disease in patients with SDH varies widely. It was hypothesized that a decision rule could identify patients with SDH who are at very low-risk for neurological decline, neurosurgical intervention or radiographic worsening.

Methods

Retrospective chart review of consecutive patients age ≥ 16 with Glasgow Coma Score (GCS) ≥ 13 and CT-documented isolated SDH presenting to a university affiliated, urban, 100,000-annual-visit ED from 2009-2015. Demographic, historical and physical exam variables were collected. Primary outcome was a composite of neurosurgical intervention, worsening repeat CT and neurological decline. Univariate analysis was performed and statistically important variables were utilized to create a logistic regression model.

Results

644 patients with isolated SDH were reviewed, 340 in the derivation group and 304 in the validation set. Mortality was 2.2%. 15.5% of patients required neurosurgery. A decision instrument was created: patients were low risk if they had none of the following factors: SDH thickness ≥ 5mm, warfarin use, clopidogrel use, GCS < 14 and presence of midline shift. This model had a sensitivity of 98.6% for the composite endpoint, specificity of 37.1% and a negative likelihood ratio of 0.037. In the validation cohort, sensitivity was 96.3%, specificity was 31.5% and negative likelihood ratio was 0.127.

Conclusion

Subdural hematomas are amenable to risk stratification analysis. With prospective validation, this decision instrument may aid in triaging these patients, including reducing the need for transfer to tertiary centers.

This article is protected by copyright. All rights reserved.

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Association between oropharyngeal carriage of Kingella kingae and osteoarticular infection in young children: a case-control study [Research]

BACKGROUND:

Kingella kingae has been increasingly identified in patients with osteoarticular infections. Our main objective was to evaluate the association between carriage of K. kingae in the oropharynx of preschool children and osteoarticular infections.

METHODS:

We conducted this prospective case–control study in 2 tertiary care pediatric hospitals (Canada and Switzerland) between 2014 and 2016. Potential cases were children aged 6 to 48 months with a presumptive diagnosis of osteoarticular infection according to the treating emergency physician. Confirmed cases were those with diagnosis of osteomyelitis or septic arthritis proven by positive findings on technetium-labelled bone scan or magnetic resonance imaging or identification of a microorganism in joint aspirate or blood. For each case, we recruited 4 age-matched controls from among children presenting to the same emergency department for trauma. The independent variable was presence of oropharyngeal K. kingae DNA identified by a specific polymerase chain reaction assay. We determined the association between oropharyngeal carriage of K. kingae and definitive osteoarticular infection.

RESULTS:

The parents of 77 children admitted for suspected osteoarticular infection and 286 controls were invited to participate and provided informed consent. We identified K. kingae in the oropharynx of 46 (71%) of 65 confirmed cases and 17 (6%) of 286 controls; these results yielded an odds ratio of 38.3 (95% confidence interval 18.5–79.1).

INTERPRETATION:

Detection of oropharyngeal K. kingae was strongly associated with osteoarticular infection among children presenting with symptoms suggestive of such infection.

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Kingella kingae: From carriage to infection [Commentary]

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Stopping anticoagulation in a woman with unprovoked venous thromboembolism [Practice]

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Future of health system hinges on collaboration: outgoing CMA pres [News]

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An emerging multidrug-resistant bacteria [Practice]

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Supporting Bill S-206 protects Canadian children from violence [Letters]

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Brown tumours of the spine presenting with acute urine incontinence [Practice]

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Doctors mobilize against tax changes [News]

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Extra rice, please [Humanities]

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Genome analysis of food-processing stressful-resistant probiotic Bifidobacterium animalis subsp. lactis BF052, and its potential application in fermented soymilk

Abstract

In this study, Bifidobacterium animalis subsp. lactis BF052 was demonstrated the growth capability in soymilk and could be thus supplemented as a probiotic starter that employed soymilk as one of its food vehicles. The complete genome sequence of BF052 was therefore determined to understand the genetic basis of BF052 as a technological and functional probiotic starter. The whole genome sequence of BF052 consists of a circular genome of 1938 624 bp with a G+C content of 60.50%. This research highlights relevant genes involving in its adaptive responses to industrial and/or environmental stresses and utilization of α-galacto-oligosaccharides in BF052 strain compared with other representative bifidobacterial genomes.

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Isolation of proteolytic bacteria from mealworm ( Tenebrio molitor ) exoskeletons to produce chitinous material

Abstract

The use of insects as a source of protein is becoming an important factor for feeding an increasing population. After protein extraction for food use, the insect exoskeleton may offer the possibility for the production of added value products. Here, the aim was to isolate bacteria from the surface of farmed mealworms (Tenebrio molitor Linnaeus, 1758) for the production of chitinous material from insect exoskeletons using microbial fermentation. Isolates were screened for proteases and acid production that may aid deproteination and demineralisation of insects through fermentation to produce chitin. Selected isolates were used single-step (isolated bacteria only) or two-step fermentations with Lactobacillus plantarum (DSM 20174). Two-step fermentations with isolates from mealworm exoskeletons resulted in a demineralisation of 97.9 and 98.5% from deproteinated mealworm fractions. Attenuated total reflectance-Fourier- transform infrared spectroscopy analysis showed that crude chitin was produced. However, further optimisation is needed before the process can be upscaled. This is, to our knowledge, the first report using microbial fermentation for the extraction of chitin from insects.

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Identification of a new gene yecC involved in threonine export in Escherichia coli

Abstract

Threonine (Thr), an essential amino acid for mammals, has expanded its application to industries with fast-growing market demand. One factor that limits the production of L-threonine by microbial fermentation is the lack of an effective export system. This study proposes a method based on isobaric tags for relative and absolute quantification (iTRAQ) to determine potential Thr excretion proteins. Proteomics analysis revealed that an ABC family transport protein named YecC was upregulated in response to Thr addition. When the yecC gene or yecC-yecS-fliY is overexpressed in Escherichia coli DH5α, a phenotype resistant to inhibitory concentrations of Thr was observed in the strains. In addition, Thr production was increased when the yecC gene and yecC-yecS-fliY were overexpressed in the Thr producers in which rthA or rthBC was deleted separately or in combination. Therefore, YecC protein could facilitate Thr efflux in E. coli and be suitable for application in engineering microbial cells to produce Thr.

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Subcellular localization and function study of a secreted phospholipase C from Nocardia seriolae

Abstract

Fish nocardiosis is a chronic systemic granulomatous disease, and Nocardia seriolae is the main pathogen that causes it. The pathogenesis and virulence factors of N. seriolae are not fully understood. A phospholipase C (PLC), which is likely to be a secreted protein targeting host cell mitochondria, was found by a bioinformatics analysis of the whole genome sequence of N. seriolae. In order to determine the subcellular localization and study the preliminary function of PLC from N. seriolae (NsPLC), in this study gene cloning, secreted protein identification, subcellular localization in host cells and apoptosis detection of NsPLC were carried out. Mass spectrometry analysis of extracellular products from N. seriolae showed that NsPLC was a secreted protein. Subcellular localization of NsPLC–GFP fusion protein in fathead minnow (FHM) cells revealed that the green fluorescence exhibited a punctate distribution near the nucleus and did not co-localize with mitochondria. In addition, an apoptosis assay suggested that apoptosis was induced in FHM cells by the overexpression of NsPLC. This study may lay the foundations for further studies on the function of NsPLC and promote the understanding of the virulence factors and pathogenic mechanism of N. seriolae.

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Vascular, inflammatory, and metabolic factors associated with cognition in aging persons with chronic epilepsy

Summary

We examined cognition in aging persons with chronic epilepsy; characterized targeted vascular, inflammatory, and metabolic risk factors associated with abnormal cognitive aging in the general population; and examined associations between cognition and vascular, inflammatory, and metabolic health. Participants included 40 persons with chronic localization-related epilepsy and 152 controls, aged 54.6 and 55.3, respectively. Participants underwent neuropsychological assessment, clinical examination, and fasting blood evaluation for quantification of vascular status (systolic and diastolic blood pressure, obesity/body mass index [BMI], total and high-density lipoprotein [HDL] cholesterol level, and homocysteine), inflammatory markers (high sensitivity C-reactive protein [hs-CRP], and interleukin-6 [IL-6]), and metabolic status (insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], glucose). Epilepsy participants exhibited impairment across all cognitive factor scores (all p's < 0.0001); abnormalities in BMI (p = 0.049), hs-CRP (p = 0.046), HOMA-IR (p = 0.0040), and fasting glucose (p = 0.03), with significant relationships between higher HOMA-IR with poorer Immediate Memory (p = 0.03) and Visuospatial Ability (0.03); elevated hs-CRP with poorer Visuospatial (p = 0.035) and Verbal Ability (p = 0.06); elevated BMI with poorer Speed/Flexibility (p = 0.04), Visuospatial (p = 0.001) and Verbal Ability (p = 0.02); and lower HDL with poorer Verbal Learning/Delayed Memory (p = 0.01), Speed/Flexibility (p = 0.043), and Working Memory (p = 0.008). Aging persons with chronic epilepsy exhibit multiple abnormalities in metabolic, inflammatory, and vascular health that are associated with poorer cognitive function.

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International Endodontic Journal 50th Anniversary Editorial

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Issue Information

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Advances in Microbiology Vol.7,No.8 (August 2017)

Effect of Inorganic Salts on the Thermotolerance and Probiotic Properties of Lactobacilli Isolated from Curdled Milk Traditionally Produced in Mezam Division, Cameroon
Probiotics Products, Thermotolerance, Bile Tolerance, Calcium, Food Processing
Paper Information Full Paper: PDF (Size:1233KB)
DOI: 10.4236/aim.2017.78046

Cellular Localization of Gold and Mechanisms of Gold Resistance in Rhodobacter sphaeroides
Rhodobacter sphaeroides, Heavy Metal Bioremediation, Inductively Coupled Plasma (ICP), Transmission Electron Microscopy (TEM)
Paper Information Full Paper: PDF (Size:3664KB)
DOI: 10.4236/aim.2017.78047

Soil Urease Activity of Sundarban Mangrove Ecosystem, India
Soil Urease Activity, Soil Ammonia, Deep Forest Region, Rooted Region, Un-Rooted Region, and Sundarban Forest Ecosystem
Paper Information Full Paper: PDF (Size:2082KB)
DOI: 10.4236/aim.2017.78048

Microbial Quality of "Tchachanga", a Barbecued Mutton Sold in Benin
Food Safety, Tchachanga, Street-Vended Food, Microorganisms, Public Health
Paper Information Full Paper: PDF (Size:290KB)
DOI: 10.4236/aim.2017.78049

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Re-irradiation for oligo-recurrence from esophageal cancer with radiotherapy history: a multi-institutional study

Abstract

Background

Neoadjuvant chemoradiotherapy following surgery has recently become a standard therapy. The purpose of the present study was to determine the effectiveness and toxicity of re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy.

Methods

We reviewed retrospectively 248 patients treated with (chemo)radiotherapy for oligo-recurrence in lymph nodes from esophageal cancer in five Japanese high-volume centers between 2000 and 2015. Thirty-three patients in whom re-irradiation was performed were enrolled in this study, and the results for patients in whom re-irradiation was performed were compared with the results for other patients.

Results

Median maximum lymph node diameter was 22 mm. Median total radiation dose was 60 Gy. The median calculated biological effective dose using the LQ model with α/β = 10 Gy (BED10) in patients in whom re-irradiation was performed was significantly lower than the median BED10 in others. There was no different factor except for BED10, histology and irradiation field between patients with a past irradiation history and patients without a past irradiation history. The median observation period in surviving patients in whom re-irradiation was performed was 21.7 months. The 3-year overall survival rate in the 33 patients with a past irradiation history was 17.9%, with a median survival period of 16.0 months. Overall survival rate and local control rate in patients with a past irradiation history were significantly worse than those in patients without a past irradiation history (log-rank test, p = 0.016 and p = 0.0007, respectively). One patient in whom re-irradiation was performed died from treatment-related gastric hemorrhage.

Conclusions

Results in the present study suggested that re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy might be acceptable but unsatisfactory.

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Treatment outcomes for isoniazid-resistant tuberculosis under program conditions in British Columbia, Canada

Every year, over 1 million people develop isoniazid (INH) resistant tuberculosis (TB). Yet, the optimal treatment regimen remains unclear. Given increasing prevalence, the clinical efficacy of regimens used by...

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Children with respiratory tract infections in Swedish primary care; prevalence of antibiotic resistance in common respiratory tract pathogens and relation to antibiotic consumption

The majority of antibiotics consumed in developed countries are prescribed in primary care. However, little is known about resistance levels in the primary care population.

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ERRATUM for Beta-blockers in 2016: Still the safest and most useful drugs for portal hypertension?

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Endoscopic Features and Clinical Outcomes of Colorectal Mucosa-associated Lymphoid Tissue Lymphoma

Colorectal mucosa-associated lymphoid tissue (MALT) lymphoma is a rare disease. The purpose of this study was to investigate the clinical and endoscopic features of colorectal MALT lymphoma.

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Assessing Colon Polypectomy Competency and its Association with Established Quality Metrics

Inadequate polypectomy leads to incomplete resection, interval colorectal cancer, and adverse events. However, polypectomy competency is rarely reported and quality metrics are lacking. The primary aims of this study were to (1) assess polypectomy competency among a cohort of gastroenterologists, and (2) measure the correlation between polypectomy competency and established colonoscopy quality metrics (adenoma detection rate [ADR] and withdrawal time [WT]).

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Cohort study comparing the diagnostic yields of 2 different EUS fine-needle biopsy needles

Two second-generation, flexible EUS fine-needle biopsy (FNB) needles have recently been marketed in the United States. Thus far, there have been no comparative studies of the diagnostic yield of these needles. The aim of this study was to compare the diagnostic yield achieved with FNB using one needle during one time period and the other needle during a second time period.

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Managing ulcerative colitis patients with endoscopically invisible low-grade dysplasia

There is uncertainty regarding the optimal management of endoscopically invisible ("flat") low grade dysplasia in ulcerative colitis. Such a finding does not currently provide an automatic indication for colectomy; however, a recommendation of surveillance instead of surgery is controversial. The aim of this study was to determine the clinical and cost-effectiveness of colonoscopic surveillance versus colectomy for endoscopically invisible low-grade dysplasia of the colon in ulcerative colitis.

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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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Rare finding of a giant ischioanal lipoma

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Transperineal rectocele repair: a systematic review

Background

Transperineal rectocele repairs, either as isolated fascial repair or in combination with mesh augmentation, are hypothesized to reduce the risk of complications compared with alternative techniques.

Aim

The aim of this study was to ascertain long-term success and complication rates following transperineal rectocele repairs.

Method

A literature search of PubMed and Embase was performed using the terms 'transperineal rectocele', 'rectocele', 'transperineal' and 'repair'. Prospective studies, case series and retrospective case note analyses from 1 January 1994 to 1 December 2016 were included. Those that detailed outcomes of the transperineal approach or compared it to transanal/transvaginal approaches were included. The main outcome measures were reported complications and functional outcome scores.

Results

A total of 14 studies were included. Of 566 patients, 333 (58.8%) underwent a transperineal rectocele repair and 220 (41.2%) a transanal repair. Complications were identified in 27 (12.3%) of the 220 transanal repairs and in 41 (12.3%) of the 333 transperineal repairs. A significant complication following transperineal repair was noted in eight studies. There are not enough data to make a reliable comparison between mesh and non-mesh transperineal repairs or to compare biological and synthetic mesh use.

Limitations

Outcome reporting differed between studies, precluding a full meta-analysis.

Conclusion

Transperineal rectocele repair offers an effective method of symptom improvement and appears to have a similar complication rate as transanal rectocele repair. Concomitant use of synthetic and biological mesh augmentation is becoming more common; however, high-quality comparative data are lacking, so a direct comparison between surgical approaches is not yet possible.

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3,6-Dihydroxyflavone regulates microRNA-34a through DNA methylation

Abstract

Background

Breast cancer is the common cancer in China. In previous study, we determined that 3,6-dihydroxyflavone (3,6-DHF) increases miR-34a significantly in breast carcinogenesis, but the mechanism remains unclear.

Methods

We used qRT-PCR to analyze miR-34a and ten-eleven translocation (TET)1, TET2, TET3 levels in breast cancer cells. With a cellular breast carcinogenesis model and an experimental model of carcinogenesis in rats, TET1 levels were evaluated by western blot analysis and immunofluorescence. TET1 and 5hmC (5-hydroxymethylcytosine) levels were evaluated by immunofluorescence in nude mouse xenografts of MDA-MB-231 cells. Chromatin immunoprecipitation(ChIP) assayed for TET1 on the TET1 promoter, and dot blot analysis of DNA 5hmC was performed in MDA-MB-231 cells. We evaluated the mechanism of 3,6-DHF on the expression of tumor suppressor miR-34a by transfecting them with DNA methyltransferase (DNMT)1 plasmid and TET1 siRNA in breast cancer cells. Methylation-specific PCR detected methylation of the miR-34a promoter.

Results

First, we found that 3,6-DHF promotes the expression of TET1 during carcinogen-induced breast carcinogenesis in MCF10A cells and in rats. 3,6-DHF also increased TET1 and 5hmC levels in MDA-MB-231 cells. Further study indicated that TET1 siRNA and pcDNA3/Myc-DNMT1 inhibited the 3,6-DHF reactivation effect on expression of miR-34a in breast cancer cells. Methylation-specific PCR assays indicated that TET1 siRNA and pcDNA3/Myc-DNMT1 inhibit the effect of 3,6-DHF on the demethylation of the miR-34a promoter.

Conclusions

Our study showed that 3,6-DHF effectively increases TET1 expression by inhibiting DNMT1 and DNA hypermethylation, and consequently up-regulates miR-34a in breast carcinogenesis.

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Programmed cell death ligand 1 cut-point is associated with reduced disease specific survival in resected pancreatic ductal adenocarcinoma

Abstract

Background

Programmed cell death 1 (PD1) inhibitors have recently shown promising anti-cancer effects in a number of solid tumor types. A predictive biomarker to this class of drugs has not been clearly identified; however, overexpression of the PD1 ligand (PD-L1) has shown particular promise in lung adenocarcinoma. In this study, we explore the staining characteristics, prevalence, and clinico-molecular correlates of PD-L1 overexpression in pancreatic ductal adenocarcinoma (PDAC).

Methods

A tissue microarray (TMA) was constructed from cases of resected PDAC. PD-L1 immunohistochemistry (IHC) was performed using the SP142 primary antibody. Immunohistochemical assessment for deficient mismatch repair status (MMRd), CD3 and CD8 were performed. All biomarkers were assessed independently by two anatomical pathologists and consensus achieved on all cases. Survival analysis was performed using three thresholds (> = 1%, >5% and >10%) for tumor cell membrane staining.

Results

Two-hundred fifty-two cases were included in the TMA and evaluable by IHC. Thirty-one (12%), 17 (7%), 12(5%) cases were positive at percentage cut offs of >0, >5, and >10% respectively. Increased PD-L1 expression was associated with inferior prognosis (p = 0.0367). No statistically significant association was identified between PD-L1 status and MMR status or tumor infiltrating lymphocytes.

Conclusions

This data suggests that there is an inverse relationship between PD-L1 expression and disease specific survival times in resected PDAC. Consequently, this association may represent a phenotype where increased PD-L1 expression has an effect on tumor biology and could therefore identify a subgroup where PD1 blockade could have enhanced effectiveness.

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Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination

Abstract

Background

Resistance to adjuvant radiotherapy is a major cause of treatment failure in patients with glioblastoma (GBM). Autophagy inhibitors have been shown to enhance the efficacy of radiotherapy for certain solid tumors. However, current inhibitors do not penetrate the blood-brain-barrier (BBB). Here, we assessed the radiosensitivity effects of the antipsychotic drug trifluoperazine (TFP) on GBM in vitro and in vivo.

Methods

U251 and U87 GBM cell lines as well as GBM cells from a primary human biopsy (P3), were used in vitro and in vivo to evaluate the efficacy of TFP treatment. Viability and cytotoxicity was evaluated by CCK-8 and clonogenic formation assays. Molecular studies using immunohistochemistry, western blots, immunofluorescence and qPCR were used to gain mechanistic insight into the biological activity of TFP. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models.

Results

IC50 values of U251, U87 and P3 cells treated with TFP were 16, 15 and 15.5 μM, respectively. TFP increased the expression of LC3B-II and p62, indicating a potential disruption of autophagy flux. These results were further substantiated by a decreased Lysotracker Red uptake, indicating impaired acidification of the lysosomes. We show that TFP and radiation had an additive effect when combined. This effect was in part due to impaired TFP-induced homologous recombination. Mechanistically we show that down-regulation of cathepsin L might explain the radiosensitivity effect of TFP. Finally, combining TFP and radiation resulted in a significant antitumor effect in orthotopic GBM xenograft models.

Conclusions

This study provides a strong rationale for further clinical studies exploring the combination therapy of TFP and radiation to treat GBM patients.

http://ift.tt/2eEV4SI

Redefining the Positive Margin in Pancreatic Cancer: Impact on Patterns of Failure, Long-Term Survival and Adjuvant Therapy

Abstract

Purpose

There is debate regarding the definition and clinical significance of margin clearance in pancreatic ductal adenocarcinoma (PDA). A comprehensive archival analysis of surgical resection margins was performed to determine the effect on locoregional recurrence and survival, and the impact of adjuvant therapy in PDA.

Methods

We identified 105 patients with resected PDA. Pancreatic, anterior, bile duct, and posterior surgical resection margins (PM; posterior surface, uncinate and vascular groove) were identified. Three pathologists reviewed all archival surgical specimens and recategorized each margin as tumor at ink/transected, <0.5, 0.5–1, >1–2, or >2 mm from the inked surface. The impact of these and other clinical variables was assessed on local control, disease-free survival (DFS), and overall survival (OS).

Results

Among all margins, PM clearance up to 2 mm was prognostic of DFS (p = 0.01) and OS (p = 0.01). Dichotomizing the PM at 2 mm revealed it to be an independent predictor of local recurrence-free survival [hazard ratio HR] 0.20, 95% confidence interval [CI] 0.048–0.881, p = 0.033), DFS (HR 0.46, 95% CI 0.22–0.96, p = 0.03), and OS (HR 0.31, 95% CI 0.14–0.74, p = 0.008). A margin status of >2 mm was also prognostic of OS in patients who received adjuvant chemotherapy (HR 0.31, 95% CI 0.11–0.89, p = 0.03), however this difference was mitigated in patients receiving adjuvant chemoradiotherapy (HR 0.40, 95% CI 0.10–1.58, p = 0.19).

Conclusion

These data highlight the clinical significance of the PM and the lack of significance of other resection margins. Clearance in excess of 2 mm should be considered to improve long-term clinical outcomes. The use of adjuvant radiotherapy should be strongly considered in patients with PMs <2 mm.

http://ift.tt/2x67wSZ

Prognostic Value of the Age-Adjusted Charlson Comorbidity Index (ACCI) on Short- and Long-Term Outcome in Patients with Advanced Primary Epithelial Ovarian Cancer

Abstract

Background

We evaluated the prognostic impact of the age-adjusted Charlson Comorbidity Index (ACCI) on both postoperative morbidity and overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) treated at a tertiary gynecologic cancer center.

Patients and Methods

Exploratory analysis of our prospectively documented tumor registry was performed. Data of all consecutive patients with stage IIIB–IV ovarian cancer who underwent primary cytoreductive surgery (PDS) from January 2000 to June 2016 were analyzed. Patients were divided into three groups, based on their ACCI: low (0–1), intermediate (2–3), and high (≥4), and postoperative surgical complications were graded according to the Clavien–Dindo classification (CDC). The Fisher's exact test, log-rank test, and Cox regression models were used to investigate the predictive value of the ACCI on postoperative complications and OS.

Results

Overall, 793 consecutive patients were identified; 328 (41.4%) patients were categorized as low ACCI, 342 (43.1%) as intermediate ACCI, and 123 (15.5%) as high ACCI. A high ACCI was significantly associated with severe postoperative complications (CDC 3–5; odds ratio 3.27, 95% confidence interval 1.97–5.43, p < 0.001). Median OS for patients with a low, intermediate, or high ACCI was 50, 40, and 23 months, respectively (p < 0.001), and the ACCI remained a significant prognostic factor for OS in multivariate analysis (p = 0.001). The same impact was observed in a sensitivity analysis including only those patients with complete tumor resection.

Conclusion

The ACCI is associated with perioperative morbidity in patients undergoing PDS for EOC, and also has a prognostic impact on OS. The potential role of the ACCI as a selection criteria for different therapy strategies is currently under investigation in the ongoing, prospective, multicenter AGO-OVAR 19 trial.

http://ift.tt/2w0FQK4

Visceral Adiposity and Sarcopenic Visceral Obesity are Associated with Poor Prognosis After Resection of Pancreatic Cancer

Abstract

Background

Visceral fat accumulation and muscle depletion have been identified as poor prognostic factors for various cancers. However, the significance of visceral adiposity and sarcopenic visceral obesity on outcomes after resection of pancreatic cancer remains unclear.

Methods

A retrospective analysis of 301 patients who underwent resection for localized pancreatic cancer between 2004 and 2015 was performed. The extent of visceral adiposity [visceral to subcutaneous adipose tissue area ratio (VSR)] and visceral obesity [visceral fat area (VFA)] were measured on preoperative computed tomography images, together with skeletal muscle index (SMI) and muscle attenuation (MA). The impacts of these body composition parameters on outcomes after pancreatic resection were investigated.

Results

The overall survival (OS) and recurrence-free survival (RFS) rates in patients with high VSR were significantly lower than those in patients with low VSR (P = 0.001, P = 0.007, respectively). There were no differences in OS and RFS between high VFA and low VFA group; however, when analyzed together with sarcopenic factors, OS and RFS rates of the patients with sarcopenic visceral obesity were significantly lower compared with those of the others. Multivariate analyses revealed that high VSR was an independent risk factor for mortality (hazard ratio (HR) 1.58, P = 0.009) and recurrence (HR 1.41, P = 0.026) together with low SMI, low MA, high CA19-9, microvascular invasion, and nodal metastasis.

Conclusions

Visceral adiposity and sarcopenic visceral obesity, as well as low muscle mass and quality, were closely associated with mortality and recurrence after resection of pancreatic cancer.

http://ift.tt/2x5QQei

“Clean and Fresh”: Understanding Women’s use of Vaginal Hygiene Products

Abstract

We explore Canadian women's use of vaginal hygiene products including feminine washes, douches, sprays, deodorants, wipes, and powders. Vaginal hygiene products in North America are part of a two billion dollar industry, which focuses on cleanliness and freshness in their advertising toward women. In interviewing women who were currently using or had previously used vaginal hygiene products, we found that vaginal cleanliness and freshness were also frequently brought up as reasons for using these products. Using an inductive thematic analysis informed by Braun and Clarke (2013) we explore how attaining a clean-and-fresh vagina has become a subjective physical need for the participants in our study. In a society where female genitalia are constructed as unclean, we argue the marketing of vaginal hygiene products contributes to the problematization of women's genitalia by suggesting women need to use these products to attain an ideal (i.e., clean and fresh) vagina. The reliance on vaginal hygiene products reported by participants in attaining sensations of vaginal cleanliness and freshness raises concerns in the context of medical literature suggesting adverse health risks that may result from using some of these products. Potential risks include bacterial vaginosis, pelvic inflammatory disease, and a higher susceptibility to sexually transmitted infections, among others. We believe that companies that advertise these products as beneficial for vaginal health and hygiene can be perceived as not just misinforming women but also profiting from products that are harmful.

http://ift.tt/2vGPaHN

Contribution of transcranial magnetic stimulation to assessment of brain connectivity and networks

The brain operates in networks to carry out its function. At one level, information passes between neurons via synapses, and, at another level, information passes from region to region. Visual information flows from occipital areas to the parietal areas and then to the motor areas to properly move the arm and shape the hand to pick up an object. Olfactory information from the smell of coffee integrates with pleasant limbic memories to drive a decision to have another cup. If we want to understand how the brain works, we need to know its anatomical connectivity and what pathways are utilized in different functional tasks.

http://ift.tt/2gAay7v

Pallidal low β-low γ phase-amplitude coupling inversely correlates with Parkinson disease symptoms

β oscillatory activity (13-30 Hz) throughout the basal ganglia-thalamo-cortical (BGTC) motor network has been suggested to contribute to the pathophysiology and serve as a biomarker of Parkinson disease (PD) (Brittain and Brown, 2014; Brown, 2003; Crowell et al., 2012; Eusebio and Brown, 2007; Hammond et al., 2007; de Hemptinne et al., 2015; Kuhn et al., 2009; Little and Brown, 2014; Oswal et al., 2013; Weinberger et al., 2006). STN β power has been shown to be related to severity of rigidity and bradykinesia symptoms and to decrease in proportion to clinical improvement with treatment (Chen et al., 2010; Eusebio et al., 2011; Levy et al., 2002).

http://ift.tt/2eETVdM

Anatomy of the Transverse Mesocolon Based on Embryology for Laparoscopic Complete Mesocolic Excision of Right-Sided Colon Cancer

Abstract

Background

To treat colon cancer via complete mesocolic excision (CME) with central vascular ligation (CVL), dissection along the embryologic fusion planes is required. However, this surgery is difficult, especially for right-sided colon cancer, because the anatomy and embryology of the transverse mesocolon are not familiar to gastrointestinal surgeons.

Methods

In this video article, the anatomic details of the transverse mesocolon based on embryology are illustrated with a focus on the venous anatomy. Dissection of the transverse mesocolon along the embryologic planes using a cranial approach during laparoscopic right hemicolectomy also is presented.

Results

During the development of the primitive gastrointestinal tract, the transverse mesocolon locates between the terminal portion of the midgut and the beginning of the hindgut. After 270° counterclockwise rotation of the primary intestinal loop, the transverse mesocolon fuses with the frontal surface of the duodenum and pancreas. Simultaneously, the greater omentum hangs down from the greater curvature of the stomach in front of the transverse colon and fuses with the transverse mesocolon. Moreover, the drainage vein of the right colon sometimes joins the right gastroepiploic vein, and the gastrocolic trunk is formed. Anatomic complexity of the transverse mesocolon is caused by rotation and fusion of the gastrointestinal tract during embryologic development.

Conclusions

Knowledge concerning these embryologic peculiarities of the transverse mesocolon should be useful in the performance of laparoscopic CME with CVL for right-sided colon cancer.

http://ift.tt/2vFtwE9

Lethal hypothermia – a sometimes elusive diagnosis

http://ift.tt/2eEJ17F

PMCT images of a motorcycle helmet-associated fracture

http://ift.tt/2gzv4F0

Self-inflicted explosive death by intra-oral detonation of a firecracker: a case report

Abstract

Self-inflicted explosive deaths due to detonation of fireworks are rare. In this case report, a peculiar case of an elderly male who discharged a firecracker inside his mouth, resulting in fatal blast induced craniofacial injuries, is described. There is paucity of published data describing fireworks-related suicidal and/or non-suicidal deaths. Even scantier data is present specifically describing fireworks-related blast induced neurotrauma and the mechanism(s) of injury involved in such cases. This case report emphasizes the severe damage that a commercially available explosive, the so-called "Gorilla Bomb", can cause, and raises questions about the relative ease of its acquisition.

http://ift.tt/2eF4KwB

Clinicopathologic and gene expression analysis of initial biopsies from patients with eosinophilic esophagitis refractory to therapy

Some patients with eosinophilic esophagitis (EoE) do not respond to therapy. The clinicopathologic characteristics, and gene expression profile at time of presentation could help predict response to therapy. Refractory EoE was defined as persistence of symptoms and biopsies with histologic features of EoE after 6months of therapy with proton pump inhibitors and topical corticosteroids. Initial biopsies from refractory EoE patients (n=21), responder to therapy (n=8), patients who relapsed (n=6), and reflux controls (n=24) were studied.

http://ift.tt/2eWWy7O

Neutrophil Infiltration is a Favorable Prognostic Factor in Early Stages of Colon Cancer

The tumor immune response has been proven critical to prognosis in colorectal cancer (CRC), but studies on the prognostic role of neutrophil infiltration have shown contradictory results. The aim of this study was to elucidate the prognostic role of infiltrating neutrophils at different intratumoral subsites and in different molecular subgroups of CRC. The relations between neutrophil infiltration and infiltration of other immune cells (T-cell and macrophage subsets) were also addressed. Expression of the neutrophil marker CD66b was assessed by immunohistochemistry in 448 archival human tumor tissue samples from patients surgically resected for CRC.

http://ift.tt/2gGxfKM

Histone deacetylases inhibition: a potential diagnostic and therapeutic target for cancers

It is a currently well-accepted view that epigenetic alterations in cancers, such as DNA methylation, microRNAs and histone modifications, mainly represent two opposing roles, either behaving as oncogenes or tumor suppressors depending on the specific targets and local microenvironment [1]. Histone hypoacetylation induced by the activity of histone deacetylases (HDACs) is an epigenetic mechanism associated with gene silencing and plays a critical role in carcinogenesis [2]. Though the aberrant recruitment of HDACs to their target gene promoter regions could be a common phenomenon in tumor onset, the expression signatures and functional profiles of different HDACs in a variety of human cancers are still largely elusive.

http://ift.tt/2eWwj11

Net1, a therapeutic potential target for cancer

We read with interest the paper by Zhang et al. [1], reporting that Net1 siRNA may reduce the angiogenesis and tumor growth of in vivo cervical squamous cell carcinoma through VEGF down-regulation. The VEGF pathway may represent anti-angiogenic therapy for most cancer types. Ding et al. [2] found that elevated Gab2 could induce tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels. Zhang et al. [1] found that inhibition of Net1 expression resulted in down-regulation of VEGF expression in SiHa cells.

http://ift.tt/2gGlB2G

Prognostic value of microRNA-9 and microRNA-155 expression in triple-negative breast cancer

MicroRNAs (miRNAs) are involved in regulation of epithelial-mesenchymal transition (EMT) during breast cancer progression. The purpose of this study was to analyze the clinicopathologic significance of expression of EMT-related miRNAs, miR-9 and miR-155, in triple-negative breast cancers (TNBCs). We analyzed relative expression levels of miR-9 and miR-155 in 190 surgically resected TNBC specimens using quantitative real-time polymerase chain reaction. Then we analyzed the relationship between these miRNA expression levels and EMT marker expression (vimentin, smooth muscle actin (SMA), osteonectin, N-cadherin, E-cadherin, CD146, and ZEB1) assessed by immunohistochemistry.

http://ift.tt/2eXaA9m

Tumoral FOXP3 expression is associated with favorable clinicopathological variables and good prognosis in gastric adenocarcinoma; the tumor suppressor function of tumoral FOXP3 is related with the P21 expression in gastric adenocarcinoma

The function and its contribution of tumoral FOXP3 in gastric cancer development remains poorly understood. Thus, we studied the expression of tumoral FOXP3 and its relationship with the well-known tumor suppressor proteins P21 and P53 in gastric adenocarcinoma. The tissue microarray (TMA) was constructed from 182 cases of gastric adenocarcinoma. The immunohistochemistry was performed on 4μm tissue sections from each TMA block. We found that positive tumoral FOXP3 expression was significantly correlated with a lower T category, a lower N category, a lower recurrence rate, and less lymphatic invasion.

http://ift.tt/2gGkz6O

Diagnostic Value of Histone 3 Mutations in Osteoclast-Rich Bone Tumors

Differentiating osteoclast-rich lesions of bone (giant cell tumor of bone [GCTB], chondroblastoma [CBA], and aneurysmal bone cyst [ABC]) can be challenging, especially in small biopsies or fine needle aspirations. Mutations affecting codons 34 and 36 of either H3 Histone Family Member 3A (H3F3A) and/or 3B (H3F3B) are characteristically seen in GCTB and CBAs. We devised a simple assay to identify these mutations and evaluated its applicability for routine clinical diagnosis. 124 tissue specimens from 108 patients (43 GCTBs, 38 CBAs and 27 ABCs) were collected from the archives of the Calgary Laboratory Services/University of Calgary and Vanderbilt University Medical Center.

http://ift.tt/2gGwCRq

Hemophagocytic syndrome: primary forms and predisposing conditions

Fernando E Sepulveda | Geneviève de Saint Basile

http://ift.tt/2eWPo3l

Atopic dermatitis and psoriasis: two different immune diseases or one spectrum?

Emma Guttman-Yassky | James G Krueger

http://ift.tt/2gGkrEm

Check point inhibitors as therapies for infectious diseases

Maureen A Cox | Robert Nechanitzky | Tak W Mak

http://ift.tt/2eWHze3

Microbes participated in macrophyte leaf litters decomposition in freshwater habitat

Abstract

Knowledge of aquatic microbes involved in macrophyte leaf litter decomposition is still scarce in freshwater lakes. In situ experiments (150 days) were conducted to study the decomposition processes of macrophyte leaf litters: Zizania latifolia (Zl), Hydrilla verticillata (Hv), and Nymphoides peltata (Np). The decomposition of Np leaf litter was fastest whereas Zl was slowest. The alpha diversity of both bacterial and fungal communities significantly increased, and their community structures showed significant variations over time. For bacteria, the relative abundance of Gammaproteobacteria decreased, whereas that of Firmicutes, Betaproteobacteria, Deltaproteobacteria, and Alphaproteobacteria increased. The dominant fungal phylum Cryptomycota increased significantly in all of the three macrophytes. Both bacteria and fungi were significantly correlated with the dynamics of total phosphorous in the water and the carbon content of the leaf litters. The dynamics of nitrogen content, phosphorous content, as well as N/P ratio of the leaf litters have more influences on fungal communities than on bacteria. In addition, cellulase and xylanase activities were significantly correlated with bacterial and fungal communities, respectively, thereby reflecting the niches differentiation and cooperation between bacteria and fungi on litter decomposition. This work contributes to the understanding of microbially involved carbon and nutrient cycling in macrophyte-dominated freshwater ecosystems.

http://ift.tt/2iVBbYR

Orthodontic braces come back to bite: a novel presentation of a small bowel volvulus

Talia Shepherd<br />Aug 7, 2017; 2017:bcr-2017-221152-bcr-2017-221152<br />other

http://ift.tt/2ez5uiR

Influence of a device intravaginal to synchronization/induction of estrus and its reuse in sheep vaginal flora

Abstract

The objective of this study was to characterize the vaginal bacterial flora and their antibiotic susceptibility in vitro after, application, and the reuse of an intravaginal progesterone device (CIDR) in controlling the estrous cycle in sheep. Thirty Texel ewe lambs were used, after carefully assessed on their health and body condition. Experimental groups were formed by new CIDR (CIDRn, n = 15) and CIDR reused (CIDRu, n = 15). Treatment with progesterone lasted 6 days. Sterile swabs were used for vaginal sample collection, a procedure performed previously of CIDR insertion and on the moment of CIDR removing. The predominant flora prior to insertion of intravaginal devices proved to be 93.3% (14/15) and 80.0% (12/15) of gram-positive agents, especially of the genera Bacillus sp. and Staphylococcus sp. in CIDRn CIDRu groups, respectively. Upon removal of the devices, however, it was observed that the emergence of gram-negative agents in 100% of the samples CIDRn, most of them belonging to the Enterobacteriaceae genus. In CIDRu group, there was a balance between negative- and gram-positive agents on the removal of the devices. Regarding to susceptibility, our findings revelated some degree of resistance in all samples. Therefore, our conclusions pointed out that intravaginal devices (CIDR), when employed in the first use, or reuse, for a period of 6 days, promote a change in vaginal flora of sheep, highlighting the predominance of gram-negative agents during its removal.

http://ift.tt/2gGxK7D

Mediastinitis by Actinomyces meyeri after oesophageal stent placement

Diogo Ferreira Branquinho<br />Jun 5, 2014; 2014:bcr2014204499-bcr2014204499<br />case-report

http://ift.tt/2ezf8C1

Mycoplasma pneumonia-associated mucositis

Cyril Varghese<br />Mar 13, 2014; 2014:bcr2014203795-bcr2014203795<br />case-report

http://ift.tt/2iYx7Hs

Iatrogenic takotsubo cardiomyopathy induced by locally applied epinephrine and cocaine

Jens Sundbøll
Feb 19, 2014; 2014:bcr2013202401-bcr2013202401
case-report

http://ift.tt/2eX4MN6

Vocal cord paralysis associated with Ramsay Hunt syndrome: looking back 50 years

Eva Rye Rasmussen<br />Feb 6, 2014; 2014:bcr2013201038-bcr2013201038<br />case-report

http://ift.tt/2gFFqXE

Fatal hypertriglyceridaemia, acute pancreatitis and diabetic ketoacidosis possibly induced by quetiapine

Kristian Roerbaek Madsen<br />Jan 8, 2014; 2014:bcr2013202039-bcr2013202039<br />case-report

http://ift.tt/2eWxduy

Compression neuropathy of the common peroneal nerve by the fabella

Amit Patel<br />Nov 29, 2013; 2013:bcr2013202154-bcr2013202154<br />case-report

http://ift.tt/2gGeE1A

Postpartum spontaneous pneumomediastinum 'Hamman's syndrome'

Sami Kouki<br />Sep 3, 2013; 2013:bcr2013010354-bcr2013010354<br />case-report

http://ift.tt/2eXcXsC

Clarithromycin-induced haemorrhagic colitis

Ryosuke Miyauchi<br />Aug 20, 2013; 2013:bcr2013009984-bcr2013009984<br />case-report

http://ift.tt/2gHwfG8

Peripheral osteoma of the body of mandible

B S Manjunatha<br />Aug 8, 2013; 2013:bcr2013009857-bcr2013009857<br />case-report

http://ift.tt/2eWCsKT

Brain abscess associated with persistent left superior vena cava in a 58-year-old man

Thomas Barba<br />Mar 18, 2013; 2013:bcr2013009017-bcr2013009017<br />case-report

http://ift.tt/2gF5Gl8

Short Sleep Duration is Associated with Abnormal Serum Aminotransferase Activities and Nonalcoholic Fatty Liver Disease

http://ift.tt/2ez1qPT

Timing of endoscopy in acute nonvariceal gastrointestinal bleeding: still looking for the answer

http://ift.tt/2iWyTIX

Microspheres in gall bladder

http://ift.tt/2gA2jrU

Italian Society of Digestive Endoscopy (SIED) Position Paper on the Non-Anaesthesiologist Administration of Propofol for Gastrointestinal Endoscopy

Propofol sedation by non-anesthesiologists in GI endoscopy, despite generally considered a safe procedure, is still a matter of debate. Benefits of propofol sedation include rapid onset of action, greater patient comfort and fast recovery with prompt discharge from the endoscopy unit.The use of propofol for sedation in GI endoscopy, preceded by dedicated training courses, has been approved by several Anaesthesiologist and Gastroenterologist societies but an Italian Position Paper taking into account the Italian law is lacking.

http://ift.tt/2eEFB4Z

Investigating the effect of re-irradiation or systemic therapy in patients with GBM after tumor progression: a secondary analysis of NRG Oncology RTOG 0525

Optimal treatment for glioblastoma patients who progress after standard chemo-radiotherapy remains unknown. We analyzed data from Trial XXXX to investigate the effect of re-irradiation or systemic treatment on survival after progression. Salvage treatment options were found to be highly variable. Patients who received no salvage treatment had significantly shorter survival than those treated after progression. There was no significant survival difference among patients receiving systemic therapy (alone or with radiation) or radiation alone.

http://ift.tt/2wCjukb

Long-term clinical safety of high-dose proton radiotherapy delivered with pencil beam scanning technique for extracranial chordomas and chondrosarcomas in adult patients: Clinical evidence of spinal cord tolerance

Limited clinical data to define the radiotherapy tolerance of the spinal cord are available to clinicians. To add further clarity, we retrospectively evaluated our patients treated with proton therapy only for spinal chordomas and chondrosarcomas, who received a spinal cord dose in excess of 45 Gy(RBE) with special regard to neurotoxicity. Radiation doses reaching 64 Gy(RBE) to the surface of the spinal cord were associated with limited toxicity, defining this cut-off dose level as a safe threshold for appropriate clinical use.

http://ift.tt/2vGo57D

Cost-Effectiveness of Thoracic Radiotherapy for Extensive Stage Small Cell Lung Cancer Using Evidence from the CREST Trial

Using the Chest Radiotherapy Extensive Stage Small Cell Lung Cancer Trial (CREST) results, a partitioned survival model was developed to evaluate the cost-effectiveness of adding thoracic radiotherapy (TRT) to the standard treatment (ST) of chemotherapy and prophylactic cranial irradiation for extensive-stage small cell lung cancer patients. We found TRT to strongly dominate ST over the actual follow up interval of the CREST. The TRT incremental cost-effectiveness ratio became less favorable over a lifetime horizon.

http://ift.tt/2wCjpgn

Serum microRNA Signature Predicts Response to High-dose Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer

Escalation of radiation dose has not been beneficial in unselected patients with locally-advanced non-small-cell lung cancer. We hypothesized that a subset of patients may derive benefit and sought to identify a dose-response biomarker by analyzing patients treated with varying doses of radiotherapy on four institutional clinical trials. We identified a micro-RNA signature that, when combined with clinical factors, identified a subset of patients who exhibited an overall survival benefit following high-dose radiotherapy.

http://ift.tt/2vGbilK

Brachytherapy for Intermediate Risk Prostate Cancer, Androgen Deprivation and the Risk of Death

Androgen Deprivation Therapy added to radiation for high risk prostate cancer increases survival according to randomized studies. However population studies have shown that it may decrease survival in those with a low risk of prostate cancer death. We investigated its use in 3155 men treated with brachytherapy of whom 47% received ADT. The men with intermediate risk prostate cancer, who were older and had more cardiac comorbidity, had an increased risk of cardiac death and decreased overall survival. This was not observed in those with lower risk cancer, who were younger and healthier. ADT should only be used where randomized data has shown survival advantages.

http://ift.tt/2wCjikX

Inflammatory Response Occurs in Veins of Broiler Chickens Treated with a Selenium Deficiency Diet

Abstract

Selenium (Se) has been indicated to prevent chronic diseases including cancer, cardiovascular disease, and type 2 diabetes. However, a few studies have indicated that Se deficiency can induce vascular diseases. Thus, in the present study, we investigated the effect of Se deficiency on vascular pathology. A total of 60 male broiler chickens were randomly divided into 2 groups (n = 30). The control group (C group) was fed a basic diet, and the Se-deficient group (L group) was fed a Se-deficient, corn-soy-based diet. Changes in messenger RNA (mRNA) and protein levels of inflammatory factors and inflammation-related cytokines were examined by both RT-PCR and Western blot analysis. Our results indicate that the mRNA and protein levels of inflammatory factors and inflammation-related cytokines in the L group were significantly changed in the vein. In addition, principal component analysis (PCA) was used to define the most important parameters that could be used as key factors. The in vitro experiments also demonstrated that Se can enhance the anti-inflammatory ability of vein endothelial cells. In conclusion, Se deficiency induces an inflammatory response by modulating inflammatory factors and inflammation-related cytokines.

http://ift.tt/2ez41JG

Annals for Educators - 5 September 2017

http://ift.tt/2iVZcyW

Effect of Access to an Electronic Medical Resource on Performance Characteristics of a Certification Examination A Randomized Controlled Trial

Background:

Electronic resources are increasingly used in medical practice. Their use during high-stakes certification examinations has been advocated by many experts, but whether doing so would affect the capacity to differentiate between high and low abilities is unknown.

Objective:

To determine the effect of electronic resources on examination performance characteristics.

Design:

Randomized controlled trial.

Setting:

Medical certification program.

Participants:

825 physicians initially certified by the American Board of Internal Medicine (ABIM) who passed the Internal Medicine Certification examination or sat for the Internal Medicine Maintenance of Certification (IM-MOC) examination in 2012 to 2015.

Intervention:

Participants were randomly assigned to 1 of 4 conditions: closed book using typical or additional time, or open book (that is, UpToDate [Wolters Kluwer]) using typical or additional time. All participants took the same modified version of the IM-MOC examination.

Measurements:

Primary outcomes included item difficulty (how easy or difficult the question was), item discrimination (how well the question differentiated between high and low abilities), and average question response time. Secondary outcomes included examination dimensionality (that is, the number of factors measured) and test-taking strategy. Item response theory was used to calculate question characteristics. Analysis of variance compared differences among conditions.

Results:

Closed-book conditions took significantly less time than open-book conditions (mean, 79.2 seconds [95% CI, 78.5 to 79.9 seconds] vs. 110.3 seconds [CI, 109.2 to 111.4 seconds] per question). Mean discrimination was statistically significantly higher for open-book conditions (0.34 [CI, 0.32 to 0.35] vs. 0.39 [CI, 0.37 to 0.41] per question). A strong single dimension showed that the examination measured the same factor with or without the resource.

Limitation:

Only 1 electronic resource was evaluated.

Conclusion:

Inclusion of an electronic resource with time constraints did not adversely affect test performance and did not change the specific skill or factor targeted by the examination. Further study on the effect of resource inclusion on other examinations is warranted.

Primary Funding Source:

ABIM Foundation.

http://ift.tt/2w7q7N4

Enhancing the Role of Internists in the Transition From Pediatric to Adult Health Care

http://ift.tt/2iWDlri

Expansion of Treatment for Hepatitis C Virus Infection by Task Shifting to Community-Based Nonspecialist Providers A Nonrandomized Clinical Trial

Background:

Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection has resulted in high rates of disease cure; however, not enough specialists currently are available to provide care.

Objective:

To determine the efficacy of HCV treatment independently provided by nurse practitioners (NPs), primary care physicians (PCPs), or specialist physicians using DAA therapy.

Design:

Nonrandomized, open-label clinical trial initiated in 2015. (ClinicalTrials.gov: NCT02339038)

Setting:

13 urban, federally qualified health centers (FQHCs) in the District of Columbia.

Patients:

A referred sample of 600 patients, of whom 96% were black, 69% were male, 82% were treatment naive, and 20% had cirrhosis. Seventy-two percent of the patients had HCV genotype 1a infection. The baseline characteristics of patients seen by each provider type were similar.

Intervention:

Patients were assigned in a nonrandomized but specified manner to receive treatment from 1 of 5 NPs, 5 PCPs, or 6 specialists. All providers underwent an identical 3-hour training session based on guidelines. Patients received treatment with ledipasvir–sofosbuvir, which was provided on site, according to U.S. Food and Drug Administration labeling requirements.

Measurements:

Sustained virologic response (SVR).

Results:

516 patients achieved SVR, a response rate of 86% (95% CI, 83.0% to 88.7%), with no major safety signals. Response rates were consistent across the 3 provider types: NPs, 89.3% (CI, 83.3% to 93.8%); PCPs, 86.9% (CI, 80.6% to 91.7%); and specialists, 83.8% (CI, 79.0% to 87.8%). Patient loss to follow-up was the major cause of non-SVR.

Limitation:

Nonrandomized patient distribution; possible referral bias.

Conclusion:

In a real-world cohort of patients at urban FQHCs, HCV treatment administered by nonspecialist providers was as safe and effective as that provided by specialists. Nurse practitioners and PCPs with compact didactic training could substantially expand the availability of community-based providers to escalate HCV therapy, bridging existing gaps in the continuum of care for patients with HCV infection.

Primary Funding Source:

National Institutes of Health and Gilead Sciences.

http://ift.tt/2uArzTY

Polygenic Risk for Hypertriglyceridemia Can Mimic a Major Monogenic Mutation

http://ift.tt/2urjfck

The Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms A Systematic Review

Background:

Cannabis is increasingly available for the treatment of chronic pain, yet its efficacy remains uncertain.

Purpose:

To review the benefits of plant-based cannabis preparations for treating chronic pain in adults and the harms of cannabis use in chronic pain and general adult populations.

Data Sources:

MEDLINE, Cochrane Database of Systematic Reviews, and several other sources from database inception to March 2017.

Study Selection:

Intervention trials and observational studies, published in English, involving adults using plant-based cannabis preparations that reported pain, quality of life, or adverse effect outcomes.

Data Extraction:

Two investigators independently abstracted study characteristics and assessed study quality, and the investigator group graded the overall strength of evidence using standard criteria.

Data Synthesis:

From 27 chronic pain trials, there is low-strength evidence that cannabis alleviates neuropathic pain but insufficient evidence in other pain populations. According to 11 systematic reviews and 32 primary studies, harms in general population studies include increased risk for motor vehicle accidents, psychotic symptoms, and short-term cognitive impairment. Although adverse pulmonary effects were not seen in younger populations, evidence on most other long-term physical harms, in heavy or long-term cannabis users, or in older populations is insufficient.

Limitation:

Few methodologically rigorous trials; the cannabis formulations studied may not reflect commercially available products; and limited applicability to older, chronically ill populations and patients who use cannabis heavily.

Conclusion:

Limited evidence suggests that cannabis may alleviate neuropathic pain in some patients, but insufficient evidence exists for other types of chronic pain. Among general populations, limited evidence suggests that cannabis is associated with an increased risk for adverse mental health effects.

Primary Funding Source:

U.S. Department of Veterans Affairs. (PROSPERO: CRD42016033623)

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Let me stop when it is done

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Benefits and Harms of Plant-Based Cannabis for Posttraumatic Stress Disorder A Systematic Review

Background:

Cannabis is available from medical dispensaries for treating posttraumatic stress disorder (PTSD) in many states of the union, yet its efficacy in treating PTSD symptoms remains uncertain.

Purpose:

To identify ongoing studies and review existing evidence regarding the benefits and harms of plant-based cannabis preparations in treating PTSD in adults.

Data Sources:

MEDLINE, the Cochrane Library, and other sources from database inception to March 2017.

Study Selection:

English-language systematic reviews, trials, and observational studies with a control group that reported PTSD symptoms and adverse effects of plant-based cannabis use in adults with PTSD.

Data Extraction:

Study data extracted by 1 investigator was checked by a second reviewer; 2 reviewers independently assessed study quality, and the investigator group graded the overall strength of evidence by using standard criteria.

Data Synthesis:

Two systematic reviews, 3 observational studies, and no randomized trials were found. The systematic reviews reported insufficient evidence to draw conclusions about benefits and harms. The observational studies found that compared with nonuse, cannabis did not reduce PTSD symptoms. Studies had medium and high risk of bias, and overall evidence was judged insufficient. Two randomized trials and 6 other studies examining outcomes of cannabis use in patients with PTSD are ongoing and are expected to be completed within 3 years.

Limitation:

Very scant evidence with medium to high risk of bias.

Conclusion:

Evidence is insufficient to draw conclusions about the benefits and harms of plant-based cannabis preparations in patients with PTSD, but several ongoing studies may soon provide important results.

Primary Funding Source:

U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. (PROSPERO: CRD42016033623)

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Annals Graphic Medicine - Dear Doctor I

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Bone Health and Bone-Targeted Therapies for Nonmetastatic Prostate Cancer A Systematic Review and Meta-analysis

Background:

Bone health is a significant concern in men with prostate cancer.

Purpose:

To evaluate the effectiveness of drug, supplement, and lifestyle interventions aimed at preventing fracture, improving bone mineral density (BMD), or preventing or delaying osteoporosis in men with nonmetastatic prostate cancer.

Data Sources:

Ovid MEDLINE (1946 to 19 January 2017), EMBASE (1980 to 18 January 2017), and the Cochrane Database of Systematic Reviews (19 January 2017).

Study Selection:

Randomized trials and systematic reviews of trials that were published in English; involved men with nonmetastatic prostate cancer; and compared bone-targeted therapies with placebo, usual care, or other active treatments.

Data Extraction:

Two reviewers independently extracted study characteristics and assessed study risk of bias for each outcome.

Data Synthesis:

Two systematic reviews and 28 reports of 27 trials met inclusion criteria. All trials focused on men with nonmetastatic prostate cancer who were initiating or continuing androgen deprivation therapy (ADT). Bisphosphonates were effective in increasing BMD, but no trial was sufficiently powered to detect reduction in fractures. Denosumab improved BMD and reduced the incidence of new radiographic vertebral fractures in 1 high-quality trial. No trials compared calcium or vitamin D versus placebo. Three lifestyle intervention trials did not show a statistically significant difference in change in BMD between exercise and usual care.

Limitations:

Most trials were of moderate quality. Only 2 randomized controlled trials were designed to examine fracture outcomes. Potential harms of treatments were not evaluated.

Conclusion:

Both bisphosphonates and denosumab improve BMD in men with nonmetastatic prostate cancer who are receiving ADT. Denosumab also reduces risk for radiographic vertebral fractures, based on 1 trial. More trials studying fracture outcomes are needed in this population.

Primary Funding Source:

Program in Evidence-Based Care.

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Prescription Opioid Use, Misuse, and Use Disorders in U.S. Adults: 2015 National Survey on Drug Use and Health

Background:

Despite the continuing epidemic of opioid misuse, data on the prevalence of prescription opioid use, misuse, and use disorders are limited.

Objective:

To estimate the prevalence of prescription opioid use, misuse, and use disorders and motivations for misuse among U.S. adults.

Design:

Survey.

Setting:

The 2015 National Survey on Drug Use and Health (NSDUH).

Participants:

72 600 eligible civilian, noninstitutionalized adults were selected for NSDUH, and 51 200 completed the survey interview.

Measurements:

Prescription opioid use, misuse, and use disorders.

Results:

Weighted NSDUH estimates suggested that, in 2015, 91.8 million (37.8%) U.S. civilian, noninstitutionalized adults used prescription opioids; 11.5 million (4.7%) misused them; and 1.9 million (0.8%) had a use disorder. Among adults with prescription opioid use, 12.5% reported misuse; of these, 16.7% reported a prescription opioid use disorder. The most commonly reported motivation for misuse was to relieve physical pain (63.4%). Misuse and use disorders were most commonly reported in adults who were uninsured, were unemployed, had low income, or had behavioral health problems. Among adults with misuse, 59.9% reported using opioids without a prescription, and 40.8% obtained prescription opioids for free from friends or relatives for their most recent episode of misuse.

Limitation:

Cross-sectional, self-reported data.

Conclusion:

More than one third of U.S. civilian, noninstitutionalized adults reported prescription opioid use in 2015, with substantial numbers reporting misuse and use disorders. Relief from physical pain was the most commonly reported motivation for misuse. Economic disadvantage and behavioral health problems may be associated with prescription opioid misuse. The results suggest a need to improve access to evidence-based pain management and to decrease excessive prescribing that may leave unused opioids available for potential misuse.

Primary Funding Source:

U.S. Department of Health and Human Services.

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Prescription Opioid Use Among U.S. Adults: Our Brave New World

Han and colleagues present striking results from an analysis of the 2015 National Survey on Drug Use and Health. Although improved access to evidence-based pain management and a decrease in excessive prescribing are needed, the editorialist discusses why the way out of the opioid crisis requires a much broader policy approach that alleviates social contributors to poor health.

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Enhancing the Role of Internists in the Transition From Pediatric to Adult Health Care

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Opening the Book on Maintenance of Certification

In recent years, the Maintenance of Certification (MOC) program of the American Board of Internal Medicine has generated substantial controversy. Lipner and colleagues' study demonstrates that allowing access to a single informational resource did not adversely affect the performance of the examination. The editorialist discusses the findings and the need for continuing modifications to make the MOC process more relevant, more valuable, less burdensome, and less time-consuming.

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connecting flight to Rochester, MN

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Cannabis for Pain and Posttraumatic Stress Disorder: More Consensus Than Controversy or Vice Versa?

Interest in scientific evidence for medical cannabis use is increasing. This issue includes systematic reviews evaluating the evidence for cannabis in the treatment of pain and posttraumatic stress disorder. The editorialist discusses the lack of high-quality data from which to draw firm conclusions about the efficacy of cannabis for these conditions, for which it is both sanctioned and commonly used.

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Influenza

Influenza is an acute viral respiratory disease that affects persons of all ages and is associated with millions of medical visits, hundreds of thousands of hospitalizations, and thousands of deaths during annual winter epidemics of variable severity in the United States. Elderly persons have the highest influenza-associated hospitalization and mortality rates. The primary method of prevention is annual vaccination. Early antiviral treatment has the greatest clinical benefit; otherwise, management includes adherence to recommended infection prevention and control measures as well as supportive care of complications.

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Maintaining Bone Health During Hormonal Therapy for Prostate Cancer

Alibhai and colleagues report a systematic review of therapies to maintain bone health in patients receiving hormonal therapy for prostate cancer. The editorialists discuss the findings and the need for comparative effectiveness studies of the available agents to better define benefits and harms.

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Prescription Opioid Use, Misuse, and Use Disorders in U.S. Adults

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Shared Humanity

It all feels cold. I do not yet have the clinical experience but cannot escape the feeling that Robert deserves a more human touch.

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Proposed U.S. Funding Cuts Threaten Progress on Antimicrobial Resistance

Increasing resistance to antimicrobial agents has led to international pledges to increase funding for public health initiatives as well as for research and development to combat this grave threat. The authors discuss their views of the probable effect of proposals by the Trump administration on these efforts and on the leadership role of the United States in antimicrobial stewardship.

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Diagnostic Accuracy of Novel and Traditional Rapid Tests for Influenza Infection Compared With Reverse Transcriptase Polymerase Chain Reaction A Systematic Review and Meta-analysis

Background:

Rapid and accurate influenza diagnostics can improve patient care.

Purpose:

To summarize and compare accuracy of traditional rapid influenza diagnostic tests (RIDTs), digital immunoassays (DIAs), and rapid nucleic acid amplification tests (NAATs) in children and adults with suspected influenza.

Data Sources:

6 databases from their inception through May 2017.

Study Selection:

Studies in English, French, or Spanish comparing commercialized rapid tests (that is, providing results in <30 minutes) with reverse transcriptase polymerase chain reaction reference standard for influenza diagnosis.

Data Extraction:

Data were extracted using a standardized form; quality was assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) criteria.

Data Synthesis:

162 studies were included (130 of RIDTs, 19 of DIAs, and 13 of NAATs). Pooled sensitivities for detecting influenza A from Bayesian bivariate random-effects models were 54.4% (95% credible interval [CrI], 48.9% to 59.8%) for RIDTs, 80.0% (CrI, 73.4% to 85.6%) for DIAs, and 91.6% (CrI, 84.9% to 95.9%) for NAATs. Those for detecting influenza B were 53.2% (CrI, 41.7% to 64.4%) for RIDTs, 76.8% (CrI, 65.4% to 85.4%) for DIAs, and 95.4% (CrI, 87.3% to 98.7%) for NAATs. Pooled specificities were uniformly high (>98%). Forty-six influenza A and 24 influenza B studies presented pediatric-specific data; 35 influenza A and 16 influenza B studies presented adult-specific data. Pooled sensitivities were higher in children by 12.1 to 31.8 percentage points, except for influenza A by rapid NAATs (2.7 percentage points). Pooled sensitivities favored industry-sponsored studies by 6.2 to 34.0 percentage points. Incomplete reporting frequently led to unclear risk of bias.

Limitations:

Underreporting of clinical variables limited exploration of heterogeneity. Few NAAT studies reported adult-specific data, and none evaluated point-of-care testing. Many studies had unclear risk of bias.

Conclusion:

Novel DIAs and rapid NAATs had markedly higher sensitivities for influenza A and B in both children and adults than did traditional RIDTs, with equally high specificities.

Primary Funding Source:

Québec Health Research Fund and BD Diagnostic Systems.

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Contemporary Influenza Diagnostics: Renewed Focus on Testing Patients

Testing for influenza infection with traditional reverse transcriptase polymerase chain reaction (RT-PCR) is complex, slow, and costly. Two newer technologies, digital immunoassays that use automated immunochromatographic antigen detection and rapid nucleic acid amplification tests, are available but infrequently used. A systematic review and meta-analysis compares the diagnostic accuracy of novel and traditional rapid tests for influenza with that of RT-PCR. The editorialist believes that this review should prompt revision of guidelines to encourage use of the newer tests.

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Reconciling the Effects of Screening on Prostate Cancer Mortality in the ERSPC and PLCO Trials

Background:

The ERSPC (European Randomized Study of Screening for Prostate Cancer) found that screening reduced prostate cancer mortality, but the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) found no reduction.

Objective:

To evaluate whether effects of screening on prostate cancer mortality relative to no screening differed between the ERSPC and PLCO.

Design:

Cox regression of prostate cancer death in each trial group, adjusted for age and trial. Extended analyses accounted for increased incidence due to screening and diagnostic work-up in each group via mean lead times (MLTs), which were estimated empirically and using analytic or microsimulation models.

Setting:

Randomized controlled trials in Europe and the United States.

Participants:

Men aged 55 to 69 (ERSPC) or 55 to 74 (PLCO) years at randomization.

Intervention:

Prostate cancer screening.

Measurements:

Prostate cancer incidence and survival from randomization; prostate cancer incidence in the United States before screening began.

Results:

Estimated MLTs were similar in the ERSPC and PLCO intervention groups but were longer in the PLCO control group than the ERSPC control group. Extended analyses found no evidence that effects of screening differed between trials (P = 0.37 to 0.47 [range across MLT estimation approaches]) but strong evidence that benefit increased with MLT (P = 0.0027 to 0.0032). Screening was estimated to confer a 7% to 9% reduction in the risk for prostate cancer death per year of MLT. This translated into estimates of 25% to 31% and 27% to 32% lower risk for prostate cancer death with screening as performed in the ERSPC and PLCO intervention groups, respectively, compared with no screening.

Limitation:

The MLT is a simple metric of screening and diagnostic work-up.

Conclusion:

After differences in implementation and settings are accounted for, the ERSPC and PLCO provide compatible evidence that screening reduces prostate cancer mortality.

Primary Funding Source:

National Cancer Institute.

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Different Effects of Screening on Prostate Cancer Death in Two Trials

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Prostate Cancer Screening: Time to Question How to Optimize the Ratio of Benefits and Harms

Tsodikov and colleagues apply a mathematical framework to the results of 2 large prostate cancer screening trials and conclude that the effects of screening on prostate cancer mortality were similar in both trials after differences in the studies were accounted for. The editorialist discusses the findings and advocates for a shift in focus from whether screening with prostate-specific antigen testing provides benefit to how to implement screening so that the benefits outweigh the harms.

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Effects of Intensive Systolic Blood Pressure Control on Kidney and Cardiovascular Outcomes in Persons Without Kidney Disease A Secondary Analysis of a Randomized Trial

Background:

The public health significance of the reported higher incidence of chronic kidney disease (CKD) with intensive systolic blood pressure (SBP) lowering is unclear.

Objective:

To examine the effects of intensive SBP lowering on kidney and cardiovascular outcomes and contrast its apparent beneficial and adverse effects.

Design:

Subgroup analyses of SPRINT (Systolic Blood Pressure Intervention Trial). (ClinicalTrials.gov: NCT01206062)

Setting:

Adults with high blood pressure and elevated cardiovascular risk.

Participants:

6662 participants with a baseline estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m².

Intervention:

Random assignment to an intensive or standard SBP goal (120 or 140 mm Hg, respectively).

Measurements:

Differences in mean eGFR during follow-up (estimated with a linear mixed-effects model), prespecified incident CKD (defined as a >30% decrease in eGFR to a value <60 mL/min/1.73 m²), and a composite of all-cause death or cardiovascular event, with surveillance every 3 months.

Results:

The difference in adjusted mean eGFR between the intensive and standard groups was −3.32 mL/min/1.73 m² (95% CI, −3.90 to −2.74 mL/min/1.73 m²) at 6 months, was −4.50 mL/min/1.73 m² (CI, −5.16 to −3.85 mL/min/1.73 m²) at 18 months, and remained relatively stable thereafter. An incident CKD event occurred in 3.7% of participants in the intensive group and 1.0% in the standard group at 3-year follow-up, with a hazard ratio of 3.54 (CI, 2.50 to 5.02). The corresponding percentages for the composite of death or cardiovascular event were 4.9% and 7.1% at 3-year follow-up, with a hazard ratio of 0.71 (CI, 0.59 to 0.86).

Limitation:

Long-term data were lacking.

Conclusion:

Intensive SBP lowering increased risk for incident CKD events, but this was outweighed by cardiovascular and all-cause mortality benefits.

Primary Funding Source:

National Institutes of Health.

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Survival After Fulminant Myocarditis Induced by Immune-Checkpoint Inhibitors

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Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model

This protocol demonstrates the induction of cerebral cavernous malformation disease in a mouse model and uses contrast enhanced micro computed tomography to measure lesion burden. This method enhances the value of established mouse models to study the molecular basis and potential therapies for cerebral cavernous malformation and other cerebrovascular diseases.

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Anti-tumor Effects of Eribulin Depend on the Modulation of Tumor Microenvironment by Vascular Remodeling in Mouse Models

Summary

We previously reported that eribulin mesylate (eribulin), a tubulin-binding drug (TBD), could remodel tumor vasculature (i.e., increased tumor vessels and perfusion) in human breast cancer xenograft models; however, a role of this vascular remodeling in anti-tumor effects is not fully understood. Here, we investigated the effects of eribulin-induced vascular remodeling on anti-tumor activities in multiple human cancer xenograft models. Microvessel densities (MVDs) were evaluated by immunohistochemistry (CD31 staining), and anti-tumor effects were examined in 10 human cancer xenograft models. Eribulin significantly increased MVDs compared to the controls in 6 out of 10 models with a correlation between enhanced MVD levels and anti-tumor effects (R²=0.54). Because of increased MVDs, we next utilized radiolabeled liposomes to examine if eribulin treatment would result in increased tumoral accumulation levels of these macromolecules, and indeed, we found that eribulin, unlike vinorelbine (another TBD) enhanced them. Since eribulin increased accumulation of radiolabeled liposomes, we postulated that this treatment might enhance anti-tumor effect of Doxil (a liposomal anti-cancer agent) and facilitate the recruitment of immune cells into the tumor. As expected, eribulin enhanced anti-tumor activity of Doxil in post-erlotinib treatment H1650 (PE-H1650) xenograft model. Furthermore, infiltrating CD11b-positive immune cells were significantly increased in multiple eribulin-treated xenografted tumors, and natural killer (NK) cell depletion reduced anti-tumor effects of eribulin. These findings suggested a contribution of the immune cells for anti-tumor activities of eribulin. Taken together, our results suggested vascular remodeling induced by eribulin would act as a microenvironment modulator, and consequently, this alteration enhanced anti-tumor effects of eribulin.

This article is protected by copyright. All rights reserved.

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Japanese genome-wide association study identifies a significant colorectal cancer susceptibility locus at chromosome 10p14

Summary

Genome wide association studies are a powerful tool for searching for disease susceptibility loci. Several studies identifying SNPs connected intimately to the onset of colorectal cancer (CRC) have been published, but there are few reports of genome-wide association studies in Japan. To identify genetic variants that modify the risk of CRC oncogenesis, especially in the Japanese population, we performed a multi-stage genome wide association study using a large number of samples: 1,846 CRC cases and 2,675 controls. We identified four SNPs (rs7912831, rs4749812, rs7898455, and rs10905453) in chromosome region 10p14 associated with CRC; however, there are no coding or non-coding genes within this region of fairly extensive linkage disequilibrium (a 500 kb block) on 10p14. Our study revealed that the 10p14 locus is a significant CRC susceptibility region in the Japanese population, in accordance with multiple studies beyond this race.

This article is protected by copyright. All rights reserved.

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Acquired Hemophilia A in an advanced age patient of hispanic origin: a case report

Acquired Hemophilia A (AHA) is a rare hematological disorder that exhibits an incidence of approximately 1.5 cases per million patients a year. It is characterized by the development of autoantibodies against ...

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Microfluidic Dry-spinning and Characterization of Regenerated Silk Fibroin Fibers

A protocol for the microfluidic spinning and microstructure characterization of regenerated silk fibroin monofilament is presented.

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Role of intraoperative radiotherapy in the treatment of sacral chordoma

Publication date: Available online 4 September 2017
Source:The Spine Journal
Author(s): A.C. Jullien-Petrelli, J.M. Asencio, M.I. Orue-Echebarria, P. Lozano, A. Álvarez, J. Serrano, F.M. Calvo, J.A. Calvo-Haro, J.M. Lasso, J.L. García-Sabrido
Background contextSacral chordoma is a rare entity with high local recurrence rates when complete resection is not achieved. Till date, there are not any series available in literature combining surgery and intraoperative radiotherapy (IORT).PurposeTo report the experience of our Centre in the management of sacral chordoma combining radical resection with both external radiotherapy and intraoperative radiotherapy (IORT).Study DesignRetrospective case series.Patients sample15 patients with sacral chordoma resected in our centre from 1998 to 2015.Outcome measuresOverall survival (OS), Disease free survival and rates of local and distant recurrence.MethodsWe retrospectively revised the records of all the patients with sacral chordoma resected in our centre from 1998 to December 2015. Overall survival (OS), Disease free survival and rates of local and distant recurrence were calculated. Results between patients treated with or without IORT were compared.ResultsA total of 15 patients were identified: 8 males and 7 females. Median age was 59 years (range 28-77). IORT was applied in 9 patients and 6 were treated with surgical resection without IORT. In 13 patients we performed the treatment of the primary tumor and in 2 patients we performed the treatment of recurrence disease. A posterior approach was used in 4 patients. Wide surgical margins (R0) were achieved in 6 patients, marginal margins (R1) in 7 patients and there were not any patient with intralesional (R2) margins. At a median follow up of 38 months (range 11-209 months), the 5 years OS in the IORT group was 100% versus 53% in the group of non-IORT (p=0.05). The median DFS in the IORT group was 85 months versus 41 months in the non-IORT group. In the group without IORT, two patients died and nobody died during the follow up in the group treated with IORT. High sacrectomy treated patients had a median survival of 41 months versus 90 months in low sacrectomy treated patients. DFS in patients without gluteal involvement was 100% at 5 years, and 40% in patients with gluteal involvement (fig 8). All patients with a recurrence in our study had gluteal involvement.ConclusionsMultidisciplinary management of sacral chordoma seems to improve local control. The use of IORT, in our experience, is associated with an increase in overall survival and disease-free survival. The level of resection and gluteal involvement seems to affect survival. The posterior approach is useful in selected cases. Multicenter studies should be performed in order to confirm the utility of IORT.



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Expedited Radiation Biodosimetry by Automated Dicentric Chromosome Identification (ADCI) and Dose Estimation

The cytogenetic dicentric chromosome (DC) assay quantifies exposure to ionizing radiation. The Automated Dicentric Chromosome Identifier and Dose Estimator software accurately and rapidly estimates biological dose from DCs in metaphase cells. It distinguishes monocentric chromosomes and other objects from DCs, and estimates biological radiation dose from the frequency of DCs.

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Measuring Synaptic Vesicle Endocytosis in Cultured Hippocampal Neurons

Synaptic vesicle endocytosis is detected by light microscopy of pHluorin fused with synaptic vesicle protein and by electron microscopy of vesicle uptake.

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Immune profiling of melanoma tumors reflecting aggressiveness in a preclinical model

Abstract

Melanoma, like most solid tumors, is highly heterogeneous in terms of invasive, proliferative, and tumor-initiating potential. This heterogeneity is the outcome of differential gene expression resulting from conditions in the tumor microenvironment and the selective pressure of the immune system. To investigate possible signatures combining immune-related gene expression and lymphocyte infiltration, we established a preclinical model using B16.F1-derived clones, in the context of melanoma aggressiveness. Combinatorial analyses revealed that tumors concomitantly expressing low levels of Tnf-a, Pd-1, Il-10, Il-1ra, Ccl5, Ido, high Il-9, and with low infiltration by CD45⁺, CD3⁺, CD4⁺ and CD8⁺ cells and a high CD4⁺:CD8⁺ T cell ratio exhibited the most aggressive growth characteristics. Overall, these results support the notion that the intratumoral immunologic network molds aggressive melanoma phenotypes.

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Ill. electric company equips 240 trucks with AEDs

According to the American Heart Association, people who go into cardiac arrest while at work have only a 5-7 percent chance of surviving when an AED is not present

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Immune profiling of melanoma tumors reflecting aggressiveness in a preclinical model

Abstract

Melanoma, like most solid tumors, is highly heterogeneous in terms of invasive, proliferative, and tumor-initiating potential. This heterogeneity is the outcome of differential gene expression resulting from conditions in the tumor microenvironment and the selective pressure of the immune system. To investigate possible signatures combining immune-related gene expression and lymphocyte infiltration, we established a preclinical model using B16.F1-derived clones, in the context of melanoma aggressiveness. Combinatorial analyses revealed that tumors concomitantly expressing low levels of Tnf-a, Pd-1, Il-10, Il-1ra, Ccl5, Ido, high Il-9, and with low infiltration by CD45⁺, CD3⁺, CD4⁺ and CD8⁺ cells and a high CD4⁺:CD8⁺ T cell ratio exhibited the most aggressive growth characteristics. Overall, these results support the notion that the intratumoral immunologic network molds aggressive melanoma phenotypes.

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Reply: MMP-9 as a biomarker of PML development in MS patients receiving Natalizumab

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On establishing a grant pre-review process for new investigators

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Alcohol improves cerebellar-learning deficit in myoclonus-dystonia - a clinical and electrophysiological investigation

Abstract

Objectives: To characterize neurophysiological subcortical abnormalities in myoclonus-dystonia and their modulation by alcohol administration.

Methods: Cerebellar associative learning and basal ganglia-brainstem interaction were investigated in 17 myoclonus-dystonia patients with epsilon-sarcoglycan (SGCE) gene mutation and 21 age- and sex-matched healthy controls by means of classical eyeblink conditioning and blink reflex recovery cycle before and after alcohol intake resulting in a breath alcohol concentration of 0.08% (0.8 g/l). The alcohol responsiveness of clinical symptoms was evaluated by three blinded raters with a standardized video protocol and clinical rating scales including the Unified Myoclonus Rating Scale (UMRS) and the Burke Fahn Marsden Dystonia Rating Scale (BFMDRS).

Results: Patients showed a significantly reduced number of conditioned eyeblink responses before alcohol administration compared to controls. While the conditioning response rate decreased under alcohol intake in controls, it increased in patients (ANOVA: alcohol state x Group p = 0.004). Blink reflex recovery cycle before and after alcohol intake did not differ between groups. Myoclonus improved significantly after alcohol intake (p = 0.016). The severity of action myoclonus at baseline correlated negatively with the conditioning response in classical eyeblink conditioning in patients.

Interpretation: The combination of findings with reduced baseline acquisition of conditioned eyeblink responses and normal blink reflex recovery cycle in patients that improved significantly by alcohol intake suggests a crucial role of cerebellar networks in the generation of symptoms in these patients. This article is protected by copyright. All rights reserved.

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MMP-9 as a biomarker of PML development in MS patients receiving Natalizumab

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Internal Grant Review to Increase Grant Funding for Junior Investigators

Abstract

Decreasing biomedical research support over the past decade has driven many talented young scientists to seek careers outside academia. In 2011, the Department of Neurology at Johns Hopkins University School of Medicine developed an internal grant review program (IGRP) to systematically review career development awards (CDAs) and research grants (e.g., R01s) for junior investigators prior to NIH submission. With IGRP implementation, we observed significant increases in the number of CDAs and R-grants awarded to junior investigators. Thus, internal grant review is an effective means for supporting junior faculty and help them retain their research roles within academia. This article is protected by copyright. All rights reserved.

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Concussion in adolescence and risk of multiple sclerosis

Abstract

Objective: To assess whether concussion in childhood or adolescence is associated with subsequent multiple sclerosis risk. Previous research suggests an association but methodological limitations included retrospective data collection and small study populations.

Methods: The national Swedish Patient (hospital diagnoses) and Multiple Sclerosis registers were used to identify all MS diagnoses up to 2012 among people born from 1964, when the Patient Register was established. The 7292 patients with multiple sclerosis were matched individually with 10 people without MS by sex, year of birth, age/vital status at multiple sclerosis diagnosis, and region of residence (county), resulting in a study population of 80212. Diagnoses of concussion and control diagnoses of broken limb bones were identified using the Patient Register from birth to age 10 years or from ages 11 to 20 years. Conditional logistic regression was used to examine associations with multiple sclerosis.

Results: Concussion in adolescence was associated with a raised risk of multiple sclerosis, producing adjusted odds ratios (and 95% confidence intervals) of 1.22 (1.05-1.42, p=0.008) and 2.33 (1.35-4.04, p=0.002) for one diagnosis of concussion, or more than one diagnosis of concussion, respectively, compared with none. No notable association with multiple sclerosis was observed for concussion in childhood, or broken limb bones in childhood and adolescence.

Interpretation: Head trauma in adolescence, particularly if repeated, is associated with a raised risk of future multiple sclerosis, possibly due to initiation of an autoimmune process in the central nervous system. This further emphasises the importance of protecting young people from head injuries. This article is protected by copyright. All rights reserved.

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