Androgen excess and metabolic disorders in women with PCOS: beyond the body mass index

Abstract

Background

Insulin resistance is a common feature among women with polycystic ovary syndrome (PCOS), especially in those patients with hyperandrogenism and chronic anovulation. PCOS women are at risk for developing metabolic syndrome, impaired glucose tolerance and type II diabetes mellitus (DM II).

Objective

The aim of this review is to explore the existing knowledge of the interplay between androgen excess, pancreatic β-cell function, non-alcoholic fatty liver disease (NAFLD), intra-abdominal and subcutaneous (SC) abdominal adipocytes in PCOS, providing a better comprehension of the molecular mechanisms of diabetologic interest.

Methods

A comprehensive MEDLINE^® search was performed using relevant key terms for PCOS and DM II.

Results

Insulin-induced hyperandrogenism could impair pancreatic β-cell function, the SC abdominal adipocytes' lipid storage capacity, leading to intra-abdominal adipocyte hypertrophy and lipotoxicity, which in turn promotes insulin resistance, and could enhance NAFLD. Fetal hyperandrogenism exposure prompts to metabolic disorders. Treatment with flutamide showed to partially reverse insulin resistance.

Conclusions

Metabolic impairment seems not to be dependent only on the total fat mass content and body weight in women with PCOS and might be ascribed to the androgen excess.

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Effects of an individualized home-based unsupervised aerobic training on body composition and physiological parameters in obese adults are independent of gender

Abstract

Purpose

Evaluation of the effects of an individualized home-based unsupervised aerobic training on body composition, physical and physiological parameters in female and male obese adults.

Methods

Two hundred and twenty obese adults (age 47.9 ± 12.4 years; BMI 38.0 ± 7.2 kg/m²) entered the 4-month training program. Body composition, physiological and functional capacities were assessed pre- and post-intervention. All subjects were requested to perform unsupervised aerobic training with the intensity based on heart rate, walking speed and OMNI-RPE score corresponding to the individual ventilatory threshold for at least 5 days/week.

Results

After 4-month study period, 40% of patients completed the protocol, 24% had high compliance (HC) (exercise ≥ 3 days/week), while 16% had low compliance (LC) to exercise prescription (exercise < than 3 days/week). In HC group, a significant improvement of body composition variables after training was performed. Moreover, oxygen uptake and metabolic equivalent at peak significantly increased after training. Six-minute walking test (6MWT) distance significantly increased while heart rate during 6MWT was significantly lower after training. No significant differences were found in LC group between pre- and post-intervention in all variables. Interestingly, gender does not influence the effects of training.

Conclusions

Our results indicate that subjects, independent of gender, with high compliance to the aerobic training based on a new individualized method can achieve a significant reduction in weight loss and also an improvement in physical and physiological parameters. This innovative personalized prescription could be a valuable tool for exercise physiologist, endocrinologists, and nutritionists to approach and correct life style of obese subjects.

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The epidemiology of osteoporosis in Italian postmenopausal women according to the National Bone Health Alliance (NBHA) diagnostic criteria: a multicenter cohort study

Abstract

Purpose

The study was aimed at evaluating the prevalence of osteoporosis, defined by BMD and the National Bone Health Alliance (NBHA) criteria, and the prevalence of clinical risk factors for fractures in Italian postmenopausal women.

Methods

This is a cross-sectional, multicenter, cohort study evaluating 3247 postmenopausal women aged ≥ 50 and older in different areas of Italy in the period 2012–2014. All the participants were evaluated as far as anthropometrics; questionnaires for FRAX^® and DeFRA calculation were administered and bone mineral density was measured at lumbar spine, femoral neck and total hip by DXA.

Results

The prevalence of osteoporosis, as assessed by BMD and NBHA criteria was 36.6 and 57%, respectively. Mean ± SD values of FRAX^® and DeFRA were: 10.2 ± 7.3 and 11 ± 9.4 for major fractures, and 3.3 ± 4.9 and 3.9 ± 5.9 for hip fractures, respectively. Among clinical risk factors for fracture, the presence of previous fracture, particularly non-spine/non-hip fracture, parental history of hip fracture and current smoking were the most commonly observed.

Conclusions

Our study showed that more that the half of postmenopausal women aged 50 and older in Italy has osteoporosis on the basis of the NBHA criteria. There is a relevant high risk of femur fracture, as assessed by the FRAX^® and DeFRA and previous fracture, parental history of hip fracture and current smoking are the most common risk factors. The data should be considered particularly in relation to the need to increase prevention strategies on modifiable risk factors and therapeutic intervention.

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Interaction between gender and uric acid on hemoglobin A1c in community-dwelling persons

Abstract

Introduction

Higher glycated hemoglobin (Hb) (HbA1c) is significantly associated with an increased risk of cardiovascular disease (CVD). Serum uric acid (SUA) levels are associated with glucose intolerance and type 2 diabetes. Whether gender-specific differences regarding the relationship between SUA levels and HbA1c exist is unknown.

Aim

We recruited 1636 (men, 696 aged of 70 ± 10 years; women, 940 aged of 70 ± 9 years) participants and enrolled in the study during their annual health examination from a single community. We investigated the association between SUA levels and HbA1c within each gender.

Results

Multiple linear regression analysis showed that in men, SUA (β = −0.091, p = 0.014) with prevalence of antidiabetic medication (β = 0.428, p < 0.001) and eGFR (β = 0.112, p = 0.016) were significantly and negatively associated with HbA1c, and in women, SUA (β = 0.101, p = 0.002) with prevalence of antidiabetic medication (β = 0.458, p < 0.001) were significantly and positively associated with HbA1c. Moreover, the interaction between gender and SUA (β = 0.445, p < 0.001) as well as gender (β = −0.465, p < 0.001), prevalence of antidiabetic medication (β = 0.444, p < 0.001), eGFR_CKDEPI (β = 0.074, p = 0.014), and SUA (β = −0.356, p < 0.001) was a significant and independent determinant of HbA1c. A significant interactive effect of gender and SUA on determinants of HbA1c was noted in patients not on antidiabetic medications, regardless of age, HbA1c, and renal function.

Conclusions

The interaction between gender and SUA was associated with HbA1c independent of other metabolic factors in community-dwelling persons.

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Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease

Abstract

Objective

To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer's disease (LOAD) in multiplex families.

Methods

We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci.

Results

A variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040).

Conclusions and Relevance

Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.

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Estimation of causal effect measures with the R -package stdReg

Abstract

Measures of causal effects play a central role in epidemiology. A wide range of measures exist, which are designed to give relevant answers to substantive epidemiological research questions. However, due to mathematical convenience and software limitations most studies only report odds ratios for binary outcomes and hazard ratios for time-to-event outcomes. In this paper we show how logistic regression models and Cox proportional hazards regression models can be used to estimate a wide range of causal effect measures, with the R-package stdReg. For illustration we focus on the attributable fraction, the number needed to treat and the relative excess risk due to interaction. We use two publicly available data sets, so that the reader can easily replicate and elaborate on the analyses. The first dataset includes information on 487 births among 188 women, and the second dataset includes information on 2982 women diagnosed with primary breast cancer.

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The Addition of Platelet-Rich Plasma to Facial Lipofilling

A new study examines the potential benefits of platelet-rich plasma as an additive to facial lipofilling procedures.
Plastic and Reconstructive Surgery

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Heterotopic Ossification: A Late Chemical Burn Complication

A patient who sustained a napalm burn in combat later developed heterotopic ossification. How was this case diagnosed and managed?
ePlasty, Open Access Journal of Plastic Surgery

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Cisplatin suppresses proliferation, migration and invasion of nasopharyngeal carcinoma cells in vitro by repressing the Wnt/β-catenin/Endothelin-1 axis via activating B cell translocation gene 1

Abstract

Purpose

Nasopharyngeal carcinoma (NPC) is one of the most commonly diagnosed cancers worldwide with significantly high prevalence in Southern China. Chemoprevention of cancer with alkylating agent compounds could potentially reverse, suppress, or prevent cancer progression. Cisplatin (CIS) is an antineoplastic or cytotoxic platinum-based drug used for chemotherapy of different types of human cancers such as NPC. Nevertheless, the effects of CIS on the migration and invasion of human NPC cells and the underlying molecular mechanisms have not yet been fully scrutinized.

Methods

In this work, we tested the effect of CIS on the proliferation, migration and invasion of NPC cells. The results exhibited that this drug exerts remarkable inhibitory effects on the proliferation, migration and invasion of NPC cells in a dose-dependent manner. Western blotting and real time RT-PCR were used for expression analyses.

Results

We found that CIS treatment led to a dose-dependent inhibition of Endothelin-1 (ET1) expression, at protein as well as mRNA levels in NPC cells. CIS was also found to activate the expression of BTG1 in NPC cells. Moreover, mechanistic analyses revealed that CIS increased the expression of B cell translocation gene 1 (BTG1) to suppress the expression of ET1. Furthermore, we show that ET1 could not be induced in CIS-resistant cells with suppressed BTG1 expression, and subsequently demote the proliferation, migration and invasion of NPC cells.

Conclusions

These findings provided compelling evidence of the role of CIS in suppressing NPC metastasis and its underlying molecular mechanisms.

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HDR Salvage Brachytherapy: Multiple Hypothesis Testing vs Machine Learning Analysis

Publication date: Available online 13 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Gilmer Valdes, Albert J. Chang, Yannet Interian, Kenton Owen, Shane T. Jensen, Lyle H. Ungar, Adam Cunnan, Timothy D. Solberg, I-Chow Hsu

Teaser

Approximately only 50% of patients benefit from Salvage High Dose Rate Brachytherapy (sHDRB) with the majority of second recurrences occurring distantly. Therefore, a better patient selection before sHDRB is critical. Using Machine learning we found that patients with a Fraction of Positive Cores > 0.35 and a Disease Free Interval < 4.12 years after their initial radiation treatment experienced a higher failure rate after salvage HDRB of 0.75 vs 0.38 for the rest of the population.


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Close margin <2mm is not associated with higher risks of 10-year local recurrence and breast cancer mortality compared to negative margins in women treated with breast-conserving therapy

Publication date: Available online 13 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Susan Tyler, Pauline T. Truong, Mary Lesperance, Alan Nichol, Chris Baliski, Rebecca Warburton, Scott Tyldesley
PurposeThe 2014 SS0/ASTRO consensus suggests "no ink on tumor" is a sufficient surgical margin for invasive breast cancer treated with breast conserving surgery (BCS). Whether close margin <2 mm is associated with inferior outcomes remains controversial. This study evaluates 10-year outcomes by margin status in a population-based cohort treated with BCS and adjuvant radiotherapy (RT).MethodsSubjects were 10,863 women with pT1-T3, any N, M0 invasive cancer referred from 2001-2011, an era in which the institutional policy was to re-excise close or positive margins, except in select cases. All women underwent BCS and whole breast ± boost RT. Local recurrence (LR) and breast cancer-specific survival (BCSS) were examined using competing risk analysis in cohorts with negative (≥2 mm; n=9241, 85%), close (<2 mm; n=1310, 12%), or positive (tumor touching ink; n=312, 3%) margins. Multivariable analysis (MVA) and matched-pair analysis were performed.ResultsMedian follow-up was 8 years. Systemic therapy was used in 87% of patients. Boost RT was used in 34.1%, 76.9% and 79.5% of patients with negative, close, and positive margins, respectively. In the negative, close, and positive margin cohorts, 10-year cumulative incidence of LR were 1.8%, 2.0%, and 1.1%, (p=0.759). Corresponding BCSS estimates were 93.9%, 91.8%, and 87.9%, (p<0.001). On MVA, close margins were not associated with increased LR (HR 1.25, 95% CI 0.79-1.97, p=0.350) or reduced BCSS (HR 1.25, 95% CI 0.98-1.58, p=0.071) relative to negative margins. On matched-pair analysis, close margin cases had similar LR (p=0.114) and BCSS (p=0.100) compared to negative margin controls.ConclusionSelect cases with close or positive margins in this population-based analysis had similar LR and BCSS compared to negative margins. While these findings do not endorse omitting re-excision for all cases, the data support a policy of accepting carefully selected cases with close margins for adjuvant radiation therapy without re-excision.



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Cisplatin suppresses proliferation, migration and invasion of nasopharyngeal carcinoma cells in vitro by repressing the Wnt/β-catenin/Endothelin-1 axis via activating B cell translocation gene 1

Abstract

Purpose

Nasopharyngeal carcinoma (NPC) is one of the most commonly diagnosed cancers worldwide with significantly high prevalence in Southern China. Chemoprevention of cancer with alkylating agent compounds could potentially reverse, suppress, or prevent cancer progression. Cisplatin (CIS) is an antineoplastic or cytotoxic platinum-based drug used for chemotherapy of different types of human cancers such as NPC. Nevertheless, the effects of CIS on the migration and invasion of human NPC cells and the underlying molecular mechanisms have not yet been fully scrutinized.

Methods

In this work, we tested the effect of CIS on the proliferation, migration and invasion of NPC cells. The results exhibited that this drug exerts remarkable inhibitory effects on the proliferation, migration and invasion of NPC cells in a dose-dependent manner. Western blotting and real time RT-PCR were used for expression analyses.

Results

We found that CIS treatment led to a dose-dependent inhibition of Endothelin-1 (ET1) expression, at protein as well as mRNA levels in NPC cells. CIS was also found to activate the expression of BTG1 in NPC cells. Moreover, mechanistic analyses revealed that CIS increased the expression of B cell translocation gene 1 (BTG1) to suppress the expression of ET1. Furthermore, we show that ET1 could not be induced in CIS-resistant cells with suppressed BTG1 expression, and subsequently demote the proliferation, migration and invasion of NPC cells.

Conclusions

These findings provided compelling evidence of the role of CIS in suppressing NPC metastasis and its underlying molecular mechanisms.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pcTRTB

Estimation of causal effect measures with the R -package stdReg

Abstract

Measures of causal effects play a central role in epidemiology. A wide range of measures exist, which are designed to give relevant answers to substantive epidemiological research questions. However, due to mathematical convenience and software limitations most studies only report odds ratios for binary outcomes and hazard ratios for time-to-event outcomes. In this paper we show how logistic regression models and Cox proportional hazards regression models can be used to estimate a wide range of causal effect measures, with the R-package stdReg. For illustration we focus on the attributable fraction, the number needed to treat and the relative excess risk due to interaction. We use two publicly available data sets, so that the reader can easily replicate and elaborate on the analyses. The first dataset includes information on 487 births among 188 women, and the second dataset includes information on 2982 women diagnosed with primary breast cancer.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2tTbY71

Microenvironment of proliferative diabetic retinopathy supports lymphatic neovascularization

Abstract

Proliferative diabetic retinopathy (PDR) is a major diabetic microvascular complication characterized by pathological angiogenesis. Several retinopathy animal models have been developed to study the disease mechanisms and putative targets. However, knowledge on the human proliferative disease remains incomplete, relying on steady-state results from thin histological neovascular tissue sections and vitreous samples. New translational models are thus required to comprehensively understand the disease pathophysiology and develop improved therapeutic interventions. We describe here a clinically relevant model, whereby the native multicellular PDR landscape and neo(fibro)vascular processes can be analyzed ex vivo and related to clinical data. As characterized by 3D whole-mount immunofluorescence and electron microscopy, heterogeneity in patient-derived PDR neovascular tissues included discontinuous capillaries coupled with aberrantly differentiated, lymphatic-like, and tortuous endothelia. Spatially-confined apoptosis and proliferation co-existed with inflammatory cell infiltration and unique vascular islet formation. Ex vivo-cultured explants sustained multicellularity, islet patterning and capillary or fibrotic outgrowth in response to vitreoretinal factors. Strikingly, PDR neovascular tissues, whose matched vitreous enhanced lymphatic endothelial cell sprouting, contained lymphatic-like capillaries in vivo and developed Prox1⁺ capillaries and sprouts with lymphatic endothelial ultrastructures ex vivo. Among elaborate vitreal components, VEGFC was one factor found at lymphatic endothelium activating concentrations. These results indicate that the ischemia- and inflammation-induced human PDR microenvironment supports pathological neolymphvascularization, bringing a new concept to the PDR mechanisms and targeting options.

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Evidence of transcranial direct current stimulation-generated electric fields at subthalamic level in human brain in vivo

Publication date: Available online 13 March 2018
Source:Brain Stimulation
Author(s): Pratik Y. Chhatbar, Steven A. Kautz, Istvan Takacs, Nathan C. Rowland, Gonzalo J. Revuelta, Mark S. George, Marom Bikson, Wuwei Feng
BackgroundTranscranial direct current stimulation (tDCS) is a promising brain modulation technique for several disease conditions. With this technique, some portion of the current penetrates through the scalp to the cortex and modulates cortical excitability, but a recent human cadaver study questions the amount. This insufficient intracerebral penetration of currents may partially explain the inconsistent and mixed results in tDCS studies to date. Experimental validation of a transcranial alternating current stimulation-generated electric field (EF) in vivo has been performed on the cortical (using electrocorticography, ECoG, electrodes), subcortical (using stereo electroencephalography, SEEG, electrodes) and deeper thalamic/subthalamic levels (using DBS electrodes). However, tDCS-generated EF measurements have never been attempted.Objective/Hypothesis: We aimed to demonstrate that tDCS generates biologically relevant EF as deep as the subthalamic level in vivo.MethodsPatients with movement disorders who have implanted deep brain stimulation (DBS) electrodes serve as a natural experimental model for thalamic/subthalamic recordings of tDCS-generated EF. We measured voltage changes from DBS electrodes and body resistance from tDCS electrodes in three subjects while applying direct current to the scalp at 2 mA and 4 mA over two tDCS montages.ResultsVoltage changes at the level of deep nuclei changed proportionally with the level of applied current and varied with different tDCS montages.ConclusionsOur findings suggest that scalp-applied tDCS generates biologically relevant EF. Incorporation of these experimental results may improve finite element analysis (FEA)-based models.



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Multizentrische Analyse des Nutzerverhaltens von Cochlea-Implantat-Trägern

Laryngo-Rhino-Otol
DOI: 10.1055/a-0574-2569

Zusammenfassung Neuartige Cochlear-Implant-Sprachprozessoren bieten die Möglichkeit der Speicherung von Nutzungsdaten (Datalogging). Mit Hilfe dieser Informationen kann eine gezieltere individuelle Betreuung von Patienten ermöglicht werden. Allerdings fehlen bisher Normdaten in größerem Umfang zum individuellen Nutzungsverhalten. Material und Methoden Im Rahmen einer retrospektiven Studie wurden die Nutzungsdaten von 2687 Patienten ausgewertet. Alle Patienten waren mit dem Nucleus 6-System der Firma Cochlear Ltd. versorgt. Ergebnisse Die Daten ermöglichen für die Nutzungsdauer bzw. Tragedauern von Cochlear-Implant-Sprachprozessoren einen Normalbereich festzulegen. Ebenso ist die Identifikation von auffälligem Nutzungsverhalten möglich.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Exosome-based Detection of EGFR T790M in Plasma from Non-Small Cell Lung Cancer Patients

Purpose: About 60% of non-small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a non-invasive option to detect the mutation, however sensitivity is low as many patients have too few detectable copies in circulation. Here we have developed and validated a novel test that overcomes the limited abundance of the mutation by simultaneously capturing and interrogating exosomal RNA/DNA and cfDNA (exoNA) in a single step followed by a sensitive allele specific qPCR. Experimental design: ExoNA was extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) and T790M-negative (N = 108) samples. The T790M mutation status was determined using an analytically validated allele-specific qPCR assay in a CLIA laboratory. Results: Detection of the T790M mutation on exoNA achieved 92% sensitivity and 89% specificity using tumor biopsy results as gold standard. We also obtained high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), for whom detection by liquid biopsy has been particularly challenging. Conclusions: The combination of exoRNA/DNA and cfDNA for T790M detection has higher sensitivity and specificity compared to historical cohorts using cfDNA alone. This could further help avoid unnecessary tumor biopsies for T790M mutation testing.

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p95HER2 methionine 611 carboxy-terminal fragment is predictive of trastuzumab adjuvant treatment benefit in the FinHer trial

Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial. Experimental Design: In the FinHer trial, 232 HER2-positive early breast cancer patients were randomized to receive chemotherapy plus 9-weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag® assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark® assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure. Results: In the arm receiving chemotherapy only, increasing log10(p95) correlated with shorter DDFS (HR=2.0; P=.02). In the arm receiving chemotherapy plus trastuzumab (N=95), increasing log10(p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P=.01). Conclusions: p95 expression levels were prognostic in the chemotherapy-alone arm and predictive of trastuzumab treatment benefit in FinHer. These results warrant further investigation of p95 as a predictive marker of trastuzumab treatment benefit in the adjuvant setting.

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Endogenous replication stress marks melanomas sensitive to CHK1 inhibitors in vivo

Purpose: CHEK1 inhibitors (CHEK1i) have single agent activity in vitro and in vivo. Here we have investigated the molecular basis of this activity. Experimental Design: We have assessed a panel of melanoma cell lines for their sensitivity to the CHEK1i GNE-323 and GDC-0575 in vitro and in vivo. The effects of these compounds on responses to DNA replication stress were analyzed in the hypersensitive cell lines. Results: A subset of melanoma cell lines are hypersensitive to CHEK1i-induced cell death in vitro, and the drug effectively inhibits tumour growth in vivo. In the hypersensitive cell lines, GNE-323 triggers cell death without cells entering mitosis. CHEK1i treatment triggers strong RPA2 hyper-phosphorylation and increased DNA damage in only hypersensitive cells. The increased replication stress was associated with a defective S phase cell cycle checkpoint. The number and intensity of pRPA2 Ser4/8 foci in untreated tumours appeared to be a marker of elevated replication stress correlated with sensitivity to CHEK1i. Conclusions: CHEK1i have single-agent activity in a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated to increased cell death. The level of endogenous replication is marked by the pRPA2Ser4/8 foci in the untreated tumours, and may be useful marker of replication stress in vivo. 

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TFAP2E Methylation and Expression Status Does Not Predict Response to 5FU-based Chemotherapy in Colorectal Cancer

Purpose:A recent study reported that 5-fluorouracil (5FU)-based chemotherapy is less effective in treating advanced colorectal cancer (CRC) patients demonstrating hypermethylation of TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts. Experimental Design: Two cohorts of 783 CRC patients: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of CRC patients to 5FU-based chemotherapy. DNA methylation status of the TFAP2E gene in CRC patients was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed. Results: Correlation between TFAP2E methylation status and IHC staining was performed in 607 CRC. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by TFAP2E hypermethylation in stage IV patients (HR 1.21; 95% CI 0.79-1.87; log rank p 0.6). In stage II-III cases disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU treated (HR 0.91; 95% CI 0.52-1.59; log rank p 0.9) as well as in non-treated patients (HR 0.88; 95% CI 0.5-1.54; log rank p 0.7). Conclusions: TFAP2E hypermethylation does not correlate with loss of its protein expression. Our large, systematic and comprehensive study indicates that TFAP2E methylation and expression may not play a major role in predicting response to 5FU-based chemotherapy in CRC patients.

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RIP1-HAT1-SirT complex identification and targeting in treatment and prevention of cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis and necroptosis has been attributed to RIP1/3 complexes. Experimental design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis and in vivo studies with different mice models. Results: Here, we show that RIP1 is highly expressed in cancer and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass Spectrometry identified 5 acetylations in the kinase and death domain of RIP1. The novel characterised pan-SirT inhibitor, MC2494, increases RIP1 acetylation at 2 additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumour-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumour-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumour-preventive activity by blocking DMBA-induced mammary gland hyper-proliferation in vivo. Conclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention.

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Report of the 14th International Conference on Malignant Lymphoma (ICML) closed workshop on future design of clinical trials in lymphomas.

The 14th ICML held in Lugano in June 2017 was preceded by a closed workshop (organized in collaboration with the American Association for Cancer Research and the European School of Oncology) where experts in preclinical and clinical research in lymphomas met to discuss the current drug development landscape focusing on critical open questions that need to be addressed in the future in order to permit a more efficient drug development paradigm in lymphoma. Topics discussed included both preclinical models that can be used to test new drugs and drug combinations, as well as the optimal design of clinical trials and the endpoints that should be used to facilitate accelerated progress. This report represents a summary of the workshop.

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A Phase I Clinical Trial of AZD1775 in Combination With Neoadjuvant Weekly Docetaxel and Cisplatin Before Definitive Therapy in Head and Neck Squamous Cell Carcinoma

Purpose: The WEE1 tyrosine kinase regulates G2/M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. There is a need to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel. Experimental Design: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with Stage III/IVB HNSCC with borderline-resectable or unresectable disease, who were candidates for definitive chemoradiation. AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with cisplatin (25mg/m 2) and docetaxel (35mg/m 2) for three weeks. The primary outcome measure was adverse events to establish maximum-tolerated-dose (MTD). Secondary measures included response, pharmacokinetics, pharmacodynamics, and genomic data. Results: The MTD for AZD1775 was established at 150mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histological adjustment revealed 3 additional responders. The only drug-limiting toxicity was Grade-3 diarrhea. The PK C8hr target of 240nM was achieved on Day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk and increases in gH2AX, CC3 and RPA32/RPA2 were noted in responders vs. non-responders. Conclusions:The triplet combination of AZD1775, cisplatin and docetaxel is safe and tolerable. Preliminary results show promising anti-tumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase 2 dose.

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The Paddington International virtual ChromoendoScopy ScOre (PICaSSO) in ulcerative colitis exhibits very good inter-rater agreement after computerized module training: a multicenter study across academic and community practice (with video)

Electronic virtual chromoendoscopy (EVC) can demonstrate ongoing disease activity in ulcerative colitis (UC), even when Mayo subscores suggest healing. However, applicability of EVC technology outside the expert setting has yet to be determined.

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Organelle-derived acetyl-CoA promotes prostate cancer cell survival, migration, and metastasis via activation of calmodulin kinase II

Although emerging evidence suggests a potential role of calcium/calmodulin-dependent kinase II (CaMKII) in prostate cancer (PCa), its role in PCa tumorigenesis is largely unknown. Here we examine whether the acetyl CoA-CaMKII pathway, first described in frog oocytes, promotes PCa tumorigenesis. In human PCa specimens, metastatic PCa expressed higher levels of active CaMKII compared to localized PCa. Correspondingly, basal CaMKII activity was significantly higher in the more tumorigenic PC3 and PC3-mm2 cells relative to the less tumorigenic LNCaP and C4-2B4 cells. Deletion of CaMKII by CRISPR/Cas9 in PC3-mm2 cells abrogated cell survival under low-serum conditions, anchorage-independent growth and cell migration; overexpression of constitutively active CaMKII in C4-2B4 cells promoted these phenotypes. In an animal model of PCa metastasis, genetic ablation of CaMKII reduced PC3-mm2 cell metastasis from the prostate to the lymph nodes. Knockdown of the acetyl-CoA transporter carnitine acetyltransferase (CRAT) abolished CaMKII activation, providing evidence that acetyl-CoA generated from organelles is a major activator of CaMKII. Genetic deletion of the β-oxidation rate-limiting enzyme ACOX family proteins decreased CaMKII activation, while overexpression of ACOXI increased CaMKII activation. Overall, our studies identify active CaMKII as a novel connection between organelle β-oxidation and acetyl-CoA transport with cell survival, migration, and PCa metastasis.

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Inhibin is a novel paracrine factor for tumor angiogenesis and metastasis

Inhibin is a heterodimeric TGF-β family ligand that is expressed in many cancers and is a selective biomarker for ovarian cancers, however its tumor-specific functions remain unknown. Here we demonstrate that the α subunit of Inhibin (INHA), which is critical for the functionality of dimeric Inhibin A/B, correlates with microvessel density (MVD) in human ovarian tissues and xenografts and is predictive of poor clinical outcomes in multiple cancers. We demonstrate that Inhibin regulated angiogenesis is necessary for metastasis. While Inhibin had no direct impact on tumor cell signaling, both tumor cell-derived and recombinant Inhibin elicit a strong paracrine response from endothelial cells by triggering SMAD1/5 activation and angiogenesis in vitro and in vivo. Inhibin-induced angiogenesis was abrogated via anti-Inhibinα antibodies. The endothelial-specific TGF-β receptor complex comprising ALK1 and endoglin were crucial mediators of Inhibin signaling, offering a molecular mechanism for Inhibin-mediated angiogenesis. These results are the first to define a role for Inhibin in tumor metastasis and vascularization and offer an antibody-based approach for targeting Inhibin therapeutically

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Visualization of breast cancer metabolism using multimodal non-linear optical microscopy of cellular lipids and redox state

Label-free non-linear optical microscopy (NLOM) based on two-photon excited fluorescence (TPEF) from cofactors Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FAD+) is widely used for high-resolution cellular redox imaging. In this work, we combined three, label-free NLOM imaging methods to quantitatively characterize breast cancer cells and their relative invasive potential: 1) TPEF optical redox ratio (ORR = FAD+/NADH + FAD+), 2) coherent Raman scattering (CRS) of cellular lipids, and 3) second harmonic generation (SHG) of extracellular matrix (ECM) collagen. 3D spheroid models of primary mammary epithelial cells (PME) and breast cancer cell lines (T47D and MDA-MB-231) were characterized based on their unique ORR and lipid volume fraction signatures. Treatment with 17β-estradiol (E2) increased glycolysis in both PME and T47D ER+ breast cancer cells. However, PME cells displayed increased lipid content with no ECM effect, while T47D cells had decreased lipid storage (p<0.001) and significant reorganization of collagen. By measuring deuterated lipids synthesized from exogenously administered deuterium-labeled glucose, treatment of T47D cells with E2 increased both lipid synthesis and consumption rates. These results confirm that glucose is a significant source for the cellular synthesis of lipid in glycolytic breast cancer cells and that the combination of cellular redox and lipid fraction imaging endpoints is a powerful approach with new and complementary information content.

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Effects of nasal septum perforation repair on nasal airflow: An analysis using computational fluid dynamics on preoperative and postoperative three-dimensional models

The purpose of this research is to examine the changes in nasal airflow dynamics before and after the nasal perforation repair.

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Clinical features of nasal and sinonasal inverted papilloma associated with malignancy

Nasal and sinonasal inverted papilloma (IP) are rare benign tumors and have the potential to exhibit malignancy in approximately 10% of cases. This study aimed to analyze the clinical features of IP associated with malignancy. Furthermore, we reviewed our therapeutic strategy and the clinical course of malignant IP.

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Clinical predictors of bevacizumab-associated intestinal perforation in non-small cell lung cancer

Summary

Background Bevacizumab (Bev) is generally well-tolerated, and Bev-associated intestinal perforation (BAP) is a rare albeit serious side effect in cases of non-small cell lung cancer (NSCLC). Therefore, the present study aimed to identify clinical predictors of BAP to help predict and manage the development of life-threatening intestinal complications among patients receiving Bev. Methods This retrospective study evaluated demographic, clinical, and treatment factors for patients with NSCLC who were treated with Bev between February 2010 and August 2015 at our center. Results We identified 314 regimens (208 patients; median age: 65 years; 115 women) for analysis, which included 119 first-line regimens, 74 s-line regimens, and 121 third-line or later regimens. BAP occurred in 7 cases (2.23% among all regimens and 3.37% among all patients), which generally occurred during first- or second-line treatment and was caused by ulcerative colitis (1 case), colon diverticulitis (1 case), and idiopathic perforations (5 cases). Univariate analyses revealed that BAP was significantly associated with deteriorating PS during the first cycle of chemotherapy (odd ratio [OR]: 11.07, 95% confidence interval [CI]: 2.37–51.63, p = 0.0022), grade ≥ 3 diarrhea (OR: 11.37, 95% CI: 2.37–54.50, p = 0.0024), febrile neutropenia (OR: 9.16, 95% CI: 1.98–42.49, p = 0.0047), and stomatitis (OR: 4.60, 95% CI: 1.01–21.04, p = 0.0492). Conclusions Among patients with NSCLC, BAP was associated with deteriorating PS during the first cycle of chemotherapy, grade ≥ 3 diarrhea, febrile neutropenia, and stomatitis. Therefore, careful observation is needed for patients with NSCLC who receive Bev in any line of treatment, especially if they develop serious side effects that affect their PS or mucous membrane.

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Cover Image

The cover image, by G. Haymerle et al., is based on the Correspondence The effect of adjuvant radiotherapy on radial forearm free flap volume after soft palate reconstruction in 13 patients, DOI 10.1111/coa.13042.

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Author Guidelines

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Issue Information

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Prevalence of C-shaped canal system in mandibular first and second molars in a Saudi population assessed via cone beam computed tomography: a retrospective study

Abstract

Objectives

The purpose of this study was to determine the prevalence of the C-shaped root canal configuration, location of the longitudinal groove, sex differences, and unilateral/bilateral presence in mandibular first and second molars in a Saudi population using cone beam computed tomography (CBCT).

Materials and methods

CBCT images for the mandibular first and second molars of 487 patients (a total of 529 first molars and 681 s molars) were evaluated. The teeth were assessed for the presence of C-shaped root canals according to Fan criteria. Subdivisions were also made according to sex, direction of the longitudinal groove, and unilateral/bilateral presence.

Results

Only one C-shaped mandibular first molar was observed (0.19%), whereas 62 second molars (9.1%) exhibited C-shaped anatomy. Unilateral presence of the C-shaped root canal system was more common (53.85%). Female patients had a higher prevalence than males. Longitudinal grooves were most commonly found on the root lingual surface (58.1%).

Conclusions

The prevalence of the C-shaped canal configuration in a Saudi Arabian population was 0.19% in the mandibular first molar and 9.1% in the mandibular second molar. Longitudinal groove prevalence was highest on the lingual surface. Women had a significantly higher prevalence of the C-shaped canal configuration than men. Patients with unilateral presence of the C-shaped canal configuration were more common than those with bilateral presence.

Clinical relevance

Tooth type, patient sex, and ethnicity can help clinicians predict the prevalence of the C-shaped canal system in mandibular molars.

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Thyroid Disease Around the World

Thyroid disease is one of the most common pathologies in the world, with two of the most clinically important subgroups being iodine deficiency and thyroid goiter, and thyroid cancer. This review looks at the current state of thyroid disease in the world and evaluates the future direction in terms of thyroid disease treatment and prevention. Several of the most impactful epidemiologic studies are presented and analyzed, as well as a brief overview of the current socioeconomic burden of disease.

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A turning point in therapy for ameloblastomas

Ameloblastoma is a benign but locally aggressive odontogenic neoplasm in the jaw and maxilla [1,2]. If untreated, these lesions can reach enormous sizes and sometimes pose an airway risk. Although most are nonmetastasizing, they frequently recur if not adequately resected [3]. The current standard therapy for ameloblastoma is complete bone resection (radical intervention) with an adequate margin of safety, which is classified as marginal or segmental osteotomy for the mandible, and partial or total maxillectomy for the maxilla [1,4].

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Cervicofacial actinomycosis can obscure a malignancy: A case report

A 72-year-old male presented with a diffuse growth on his left lower jaw region. The lesion started 1 year back as a small ulcer on his left cheek and gradually progressed to a diffuse growth involving most of his left lower jaw. The patient had a 50-year history of tobacco chewing. Intraoral examination revealed an ulcero-proliferative growth in the left buccal mucosa extending into the gingivobuccal sulcus. Multiple pus discharging sinuses were noted on the surface of the extra-oral lesion. Provisional diagnosis was Cervicofacial Actinomycosis.

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Asthma-Related Mortality in the United States of America, 1999-2015: A Multiple Causes of Death Analysis

Asthma mortality based on the underlying cause of death (UCOD) underestimates disease burden.

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A turning point in therapy for ameloblastomas

Ameloblastoma is a benign but locally aggressive odontogenic neoplasm in the jaw and maxilla [1,2]. If untreated, these lesions can reach enormous sizes and sometimes pose an airway risk. Although most are nonmetastasizing, they frequently recur if not adequately resected [3]. The current standard therapy for ameloblastoma is complete bone resection (radical intervention) with an adequate margin of safety, which is classified as marginal or segmental osteotomy for the mandible, and partial or total maxillectomy for the maxilla [1,4].

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Cervicofacial actinomycosis can obscure a malignancy: A case report

A 72-year-old male presented with a diffuse growth on his left lower jaw region. The lesion started 1 year back as a small ulcer on his left cheek and gradually progressed to a diffuse growth involving most of his left lower jaw. The patient had a 50-year history of tobacco chewing. Intraoral examination revealed an ulcero-proliferative growth in the left buccal mucosa extending into the gingivobuccal sulcus. Multiple pus discharging sinuses were noted on the surface of the extra-oral lesion. Provisional diagnosis was Cervicofacial Actinomycosis.

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Prevalence of C-shaped canal system in mandibular first and second molars in a Saudi population assessed via cone beam computed tomography: a retrospective study

Abstract

Objectives

The purpose of this study was to determine the prevalence of the C-shaped root canal configuration, location of the longitudinal groove, sex differences, and unilateral/bilateral presence in mandibular first and second molars in a Saudi population using cone beam computed tomography (CBCT).

Materials and methods

CBCT images for the mandibular first and second molars of 487 patients (a total of 529 first molars and 681 s molars) were evaluated. The teeth were assessed for the presence of C-shaped root canals according to Fan criteria. Subdivisions were also made according to sex, direction of the longitudinal groove, and unilateral/bilateral presence.

Results

Only one C-shaped mandibular first molar was observed (0.19%), whereas 62 second molars (9.1%) exhibited C-shaped anatomy. Unilateral presence of the C-shaped root canal system was more common (53.85%). Female patients had a higher prevalence than males. Longitudinal grooves were most commonly found on the root lingual surface (58.1%).

Conclusions

The prevalence of the C-shaped canal configuration in a Saudi Arabian population was 0.19% in the mandibular first molar and 9.1% in the mandibular second molar. Longitudinal groove prevalence was highest on the lingual surface. Women had a significantly higher prevalence of the C-shaped canal configuration than men. Patients with unilateral presence of the C-shaped canal configuration were more common than those with bilateral presence.

Clinical relevance

Tooth type, patient sex, and ethnicity can help clinicians predict the prevalence of the C-shaped canal system in mandibular molars.

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Effects of stimulus response compatibility on covert imitation of vowels

Abstract

When we observe someone else speaking, we tend to automatically activate the corresponding speech motor patterns. When listening, we therefore covertly imitate the observed speech. Simulation theories of speech perception propose that covert imitation of speech motor patterns supports speech perception. Covert imitation of speech has been studied with interference paradigms, including the stimulus–response compatibility paradigm (SRC). The SRC paradigm measures covert imitation by comparing articulation of a prompt following exposure to a distracter. Responses tend to be faster for congruent than for incongruent distracters; thus, showing evidence of covert imitation. Simulation accounts propose a key role for covert imitation in speech perception. However, covert imitation has thus far only been demonstrated for a select class of speech sounds, namely consonants, and it is unclear whether covert imitation extends to vowels. We aimed to demonstrate that covert imitation effects as measured with the SRC paradigm extend to vowels, in two experiments. We examined whether covert imitation occurs for vowels in a consonant–vowel–consonant context in visual, audio, and audiovisual modalities. We presented the prompt at four time points to examine how covert imitation varied over the distracter's duration. The results of both experiments clearly demonstrated covert imitation effects for vowels, thus supporting simulation theories of speech perception. Covert imitation was not affected by stimulus modality and was maximal for later time points.

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Impact of database quality in knowledge-based treatment planning for prostate cancer

Publication date: Available online 13 March 2018
Source:Practical Radiation Oncology
Author(s): Phillip D.H. Wall, Robert L. Carver, Jonas D. Fontenot
PurposeInvestigate dose-volume prediction improvements in a common knowledge-based planning (KBP) method using a Pareto plan database compared to using a conventional, clinical plan database.MethodsTwo plan databases were created using retrospective, anonymized data of 124 VMAT prostate cancer patients. The clinical plan database (CPD) contained planning data from each patient's clinically-treated VMAT plan, which were manually optimized by various planners. The multi-criteria optimization database (MCOD) contained Pareto-optimal plan data from VMAT plans created using a standardized multi-criteria optimization protocol. Overlap volume histograms, incorporating fractional OAR volumes only within the treatment fields, were computed for each patient and used to match new patient anatomy to similar database patients. For each database patient, CPD and MCOD KBP predictions were generated for D10, D30, D50, D65, and D80 of the bladder and rectum in a leave-one-out manner. Prediction achievability was evaluated through a re-planning study on a subset of 31 randomly selected database patients using the best KBP predictions, regardless of plan database origin, as planning goals.ResultsMCOD predictions were significantly lower than CPD predictions for all five bladder dose-volumes and rectum D50 (p=0.004) and D65 (p<0.001), while CPD predictions for rectum D10 (p=0.005) and D30 (p<0.001) were significantly less than MCOD predictions. KBP predictions were statistically achievable in the re-plans for all predicted dose-volumes, excluding D10 of bladder (p=0.03) and rectum (p=0.04). Compared to clinical plans, re-plans showed significant average reductions in Dmean for bladder (7.8Gy; p<0.001) and rectum (9.4Gy; p<0.001), while maintaining statistically similar PTV, femoral head, and penile bulb dose.ConclusionKBP dose-volume predictions derived from Pareto plans were more optimal overall than those resulting from manually optimized clinical plans, which significantly improved KBP-assisted plan quality.



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Unilateral Cleft Lip Rhinoplasty

Publication date: Available online 13 March 2018
Source:Operative Techniques in Otolaryngology-Head and Neck Surgery
Author(s): Phillip Montague, Mark Armeni
Cleft lip rhinoplasty is a challenging procedure both in terms of obtaining desirable appearance and function, but also in achieving consistency across one's patient population. Classically, formal nasal surgery was delayed until the patient had completed nasal and mid-facial growth, however, this paradigm is changing, and more rhinoplasty is being performed at the time of the lip repair which has revolutionized patient outcomes. The three options for repair in terms of timing are designated as primary, intermediate, and secondary (defined later in this text). At our institution, the majority of cases are either primary or secondary, with intermediate rhinoplasty reserved for only special circumstances. This article aims to describe the relevant anatomy and its aberrancy as well as discuss the surgical techniques to repair the cleft nasal deformity.



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Training Students to Evaluate Preterm Infant Feeding Safety Using a Video-Recorded Patient Simulation Approach

Purpose

The purpose of this study was to determine if brief video-recorded patient simulation training increased students' ability to assess feeding skills in preterm infants.

Method

Baccalaureate-level nursing students (N = 52) and graduate-level speech-language pathology students (N = 42) were randomized to 1 of 2 groups: didactic training (N = 51) or didactic training plus video simulation (N = 43). Outcome measures included knowledge test scores, calculated clinical judgment scores, and clinical marker documentation accuracy.

Results

Students' knowledge increased as the result of training, without differences in test scores between the 2 types of training. Students who received video simulation training interpreted simulated feeding behaviors of preterm infants more accurately than students who received didactic training. Infant distress signs were also documented with higher accuracy for students who received video simulation training. After training and regardless of method, participants correctly attributed distress behaviors during bottle-feeding to increased risk for feeding difficulty.

Conclusions

In the current educational environment, training opportunities with high-risk preterm infants are constrained by access to health care settings specializing in care for this population and availability of clinical supervisors with expertise in this area of practice. Patient simulators are expensive; however, video simulation offers inexpensive opportunities for students to effectively gain knowledge and skills for assessing feeding in preterm infants. With video simulation, students effectively apply principles of preterm infant feeding to cases and practice critical thinking skills before entering related clinical practicum placements.

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Examination of Prosody and Timbre Perception in Adults With Cochlear Implants Comparing Different Fine Structure Coding Strategies

Purpose

This study aimed to investigate whether adults with cochlear implants benefit from a change of fine structure (FS) coding strategies regarding the discrimination of prosodic speech cues, timbre cues, and the identification of natural instruments. The FS processing (FSP) coding strategy was compared to 2 settings of the FS4 strategy.

Method

A longitudinal crossover, double-blinded study was conducted. This study consisted of 2 parts, with 14 participants in the first part and 12 participants in the second part. Each part lasted 3 months, in which participants were alternately fitted with either the established FSP strategy or 1 of the 2 newly developed FS4 settings. Participants had to complete an intonation identification test; a timbre discrimination test in which 1 of 2 isolated cues changed, either the spectral centroid or the spectral irregularity; and an instrument identification test.

Results

A significant effect was seen in the discrimination of spectral irregularity with 1 of the 2 FS4 settings. The improvement was seen in the FS4 setting in which the upper envelope channels had a low stimulation rate. This improvement was not seen with the FS4 setting that had a higher stimulation rate on the envelope channels.

Conclusions

In general, the FSP strategy and the 2 settings of the FS4 strategy provided similar levels in the perception of prosody and timbre cues, as well as in the identification of instruments.

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Patient Acceptance of Invasive Treatments for Tinnitus

Purpose

The field of neuromodulation is currently seeking to treat a wide range of disorders with various types of invasive devices. In recent years, several preclinical trials and case reports in humans have been published on their potential for chronic tinnitus. However, studies to obtain insight into patients' willingness to undergo these treatments are scarce. The aim of this survey study was to find out whether tinnitus patients are willing to undergo invasive neuromodulation when taking its risks, costs, and potential benefits into account.

Method

A Visual Analog Scale (VAS, 0–10) was used to measure the outcome. Spearman's rank-order correlation coefficients were computed to determine the correlation between patient characteristics and acceptance rates.

Results

Around one fifth of the patients were reasonably willing to undergo invasive treatment (VAS 5–7), and around one fifth were fully willing to do so (VAS 8–10). Hearing aids, used as a control, were accepted most, followed by cochlear implantation, deep brain stimulation, and cortical stimulation. Acceptance rates were slightly higher when the chance of cure was higher. Patients with a history of attempted treatments were more eager than others to find a new treatment for tinnitus.

Conclusions

A considerable proportion of patients with tinnitus would accept a variety of invasive treatments despite the associated risks or costs. When clinical neuromodulatory studies for tinnitus are to be performed, particular attention should be given to obtaining informed consent, including explaining the potential risks and providing a realistic outcome expectation.

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Clinical Strategies for Sampling Word Recognition Performance

Purpose

Computer simulation was used to estimate the statistical properties of searches for maximum word recognition ability (PB max). These involve presenting multiple lists and discarding all scores but that of the 1 list that produced the highest score. The simulations, which model limitations inherent in the precision of word recognition scores, were done to inform clinical protocols. A secondary consideration was a derivation of 95% confidence intervals for significant changes in score from phonemic scoring of a 50-word list.

Method

The PB max simulations were conducted on a "client" with flat performance intensity functions. The client's performance was assumed to be 60% initially and 40% for a second assessment. Thousands of estimates were obtained to examine the precision of (a) single lists and (b) multiple lists using a PB max procedure. This method permitted summarizing the precision for assessing a 20% drop in performance.

Results

A single 25-word list could identify only 58.4% of the cases in which performance fell from 60% to 40%. A single 125-word list identified 99.8% of the declines correctly. Presenting 3 or 5 lists to find PB max produced an undesirable finding: an increase in the word recognition score.

Conclusions

A 25-word list produces unacceptably low precision for making clinical decisions. This finding holds in both single and multiple 25-word lists, as in a search for PB max. A table is provided, giving estimates of 95% critical ranges for successive presentations of a 50-word list analyzed by the number of phonemes correctly identified.

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Psychophysical Boundary for Categorization of Voiced–Voiceless Stop Consonants in Native Japanese Speakers

Purpose

The purpose of this study was to investigate the psychophysical boundary used for categorization of voiced–voiceless stop consonants in native Japanese speakers.

Method

Twelve native Japanese speakers participated in the experiment. The stimuli were synthetic stop consonant–vowel stimuli varying in voice onset time (VOT) with manipulation of the amplitude of the initial noise portion and the first formant (F1) frequency of the periodic portion. There were 3 tasks, namely, speech identification to either /d/ or /t/, detection of the noise portion, and simultaneity judgment of onsets of the noise and periodic portions.

Results

The VOT boundaries of /d/–/t/ were close to the shortest VOT values that allowed for detection of the noise portion but not to those for perceived nonsimultaneity of the noise and periodic portions. The slopes of noise detection functions along VOT were as sharp as those of voiced–voiceless identification functions. In addition, the effects of manipulating the amplitude of the noise portion and the F1 frequency of the periodic portion on the detection of the noise portion were similar to those on voiced–voiceless identification.

Conclusion

The psychophysical boundary of perception of the initial noise portion masked by the following periodic portion may be used for voiced–voiceless categorization by Japanese speakers.

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Relation between globus pharyngeus and OSA in patients examined simultaneously by PSG and pH monitor: A cross sectional study

Publication date: Available online 12 March 2018
Source:Auris Nasus Larynx
Author(s): Ayako Fukui, Meiho Nakayama, Naoko Sakamoto, Sachie Arima, Shintaro Sato, Motohiko Suzuki, Shingo Murakami
ObjectiveThis was a first cross-sectional single-center study to research the relation between globus pharyngeus, OSA and GERD. Since previous clinical studies have demonstrated a relationship between globus phayrngeus and GERD, however, no reported study on the relation between globus pharyngeus, sleep disorders including OSA, and GERD.MethodsSeventeen patients underwent general and otorhinolaryngological examinations and responded to several questionnaires (ESS, PSQI, HADS, and Globus pharyngeus VAS score) at their first visit, and underwent a gastroesophageal test for 24-h pH monitoring and in-laboratory PSG one to two months later.ResultsNo significant differences were seen in ESS, PSQI, or HADS scores between the groups. The acid exposure time was not significantly different among the groups. The percentage of esophageal reflux time was higher than the percentage of laryngopharyngeal reflux time through the total time as well as the supine period. This indicated that GERD occurred more frequently than laryngopharyngeal reflux. The entire results showed concurrent OSA in 10 cases (59%) and concurrent GERD in 7 cases (41%). The cases with OSA were treated by CPAP or oral appliance, and those treatments were effective for globus pharyngeus.ConclusionAlthough the relation between OSA and globus phayngeus is still controversial, these findings suggest that OSA may be a previously undetected cause of globus pharyngeus. By improving OSA, it may offer an additional option of treatment for those globus pharyngeus cases combined with OSA.



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Blood Epstein–Barr virus DNA does not predict outcome in advanced HIV-associated Hodgkin lymphoma

Abstract

In HIV-seronegative patients with advanced Hodgkin lymphoma (HL), Epstein–Barr virus (EBV) viraemia at diagnosis predicts a worse progression-free survival (PFS), independent of the International Prognostic Score. However, its role in HIV-associated HL is uncharacterised. We collected clinico-pathologic and treatment data from a prospective series of 44 HIV-associated HLs from 2000 to 2016. We evaluated circulating EBV DNA as a prognostic factor on uni- and multivariable analyses in relationship to the International Prognostic Index criteria. In 44 patients with HIV-associated HL, EBV was detected by in situ hybridisation in all diagnostic biopsies. Blood EBV DNA was detectable in 26 patients (59%) with a median of 600 copies/mL (range 0–161,000). EBV DNA was independent of CD4 cell count (p = 0.9) or HIV viral load (p = 0.6) and did not predict PFS (HR 1.6, 95% CI 0.39–6.7, p = 0.49). EBV DNA is not a prognostic trait in HIV-associated HL. Prognostication in HIV-associated HL should be solely based on the International Prognostic Index criteria.

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Acquired Non-malignant Cervical Trachea-Esophageal Fistula: A Case Series

Abstract

Acquired non-malignant trachea-esophageal fistula (TEF) of cervical oesophagus is rare. Surgical closure of fistula is the standard treatment of choice. Our experience in management of such cases is presented. Five cases of acquired cervical TEF of varying etiology were retrospectively analysed. Two patients had history of migrated endoluminal stent. All the patients were treated by trans-cervical repair with muscle interposition. Tracheal Stenosis in two patients was managed concurrently. Successful repair was achieved in four cases. One patient with chronic obstructive pulmonary disease and active leprosy has residual fistula. Of the two patients with tracheal stenosis correction one was decannulated 6 month later and second has stent in situ. Post-operative vocal cord palsy occurred in one patient. Transcervical repair with muscle interposition is treatment of choice in cases of acquired nonmalignant cervical tracheoesophageal fistulas. Endoluminal stents have high tendency to migrate and are not recommended.

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MCM-2 expression differentiates potentially malignant verrucous lesions from oral carcinomas

Publication date: Available online 13 March 2018
Source:Annals of Diagnostic Pathology
Author(s): Kochli Channappa Niranjan, Niharika Abhay Sarathy, Devendra Alrani
BackgroundMcm-2 is a biomarker belonging to Mcm family of proteins which has rarely been used in oral potentially malignant and malignant lesions of the verrucous type. The objective of this study is to assess the expression of Mcm-2 in Normal Oral Mucosa (NM), Verrucous Hyperplasia (VH), Verrucous Carcinoma (VC) and Oral Squamous Cell Carcinoma (OSCC) and compare it with the clinicopathological characteristics.MethodologyA total of 70 formalin fixed paraffin embedded tissue samples (10 cases of Normal Mucosa NM- Group A, 10 cases of Verrucous Hyperplasia- VH without Dysplasia- Group B, 10 cases of Verrucous Hyperplasia- VH with Dysplasia- Group C, 20 cases of Verrucous Carcinoma VC-Group D, 20 cases of Oral Squamous Cell Carcinoma OSCC- Group E) were subjected to immunohistochemistry with Mcm-2 antibody. Statistical analysis was carried out with various tests like ANOVA, Tukey HSD, Chi-Square and Shapiro-Wilk test by using the SPSS software.ResultsThere was a significant difference in Mcm-2 expression with quantitative analysis among all the groups (p < 0.05). There was a significant progressive increase in nuclear Labelling Indices (nLI) from NM (49.08%), VC (60.45%), VH with Dysplasia (64.10%), and OSCC (89.22%).ConclusionThe findings suggest that Mcm-2 may be a sensitive proliferation marker in oral potentially malignant and malignant lesions which may be useful for differentiating between VH with/ without dysplasia, VC and OSCC.



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Clinicopathological and prognostic features of Epstein-Barr virus infection, microsatellite instability, and PD-L1 expression in gastric cancer

Background and Objectives

Gastric cancer (GC) has recently been categorized in molecular subtypes, which include Epstein-Barr (EBV)-positive and microsatellite instability (MSI) tumors. This distinction may provide prognostic information and identifies therapeutic targets. The aim of this study was to evaluate EBV, MSI, and PD-L1 immunoexpression in GC and its relationship with clinicopathological characteristics and patient's prognosis.

Methods

We evaluated 287 GC patients who underwent D2-gastrectomy through immunohistochemistry for DNA mismatch repair proteins and PD-L1, and in situ hybridization for EBV detection utilizing tissue microarray.

Results

EBV-positive and MSI were identified in 10.5% and 27% of the GCs, respectively. EBV positivity was associated to male gender (P = 0.032), proximal location (P < 0.001), undetermined Lauren type (P < 0.001), poorly differentiated histology (P = 0.043) and severe inflammatory infiltrate (P < 0.001). MSI-tumors were associated to older age (P = 0.002), subtotal gastrectomy (P = 0.004), pN0 (P = 0.024) and earlier TNM stage (P = 0.020). PD-L1-positive was seen in 8.8% of cases, with predominant expression in EBV-positive GC (P < 0.001). MSI was associated to better survival outcomes.

Conclusion

EBV-positive GCs had increased PD-L1 expression, while MSI GC had better survival outcome. EBV and MSI subgroups are distinct GC entities, their recognition is feasible by conventional techniques, and it may help individualize follow-up and guide adjuvant therapy.

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Editorial Board

Publication date: April 2018
Source:Critical Reviews in Oncology/Hematology, Volume 124





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Analysis of characteristics and outcomes by growth hormone treatment duration in adult patients in the Italian cohort of the Hypopituitary Control and Complications Study (HypoCCS)

Abstract

Purpose

To examine differences in effects according to growth hormone (GH) treatment duration in adult GH-deficient patients.

Methods

In the Italian cohort of the observational Hypopituitary Control and Complications Study, GH-treated adults with GH deficiency (GHD) were grouped by duration of treatment; ≤ 2 years (n = 451), > 2 to ≤ 6 years (n = 387) and > 6 years (n = 395). Between-group differences in demographics, medical history, physical characteristics, insulin-like growth factor-I standard deviation score (IGF-I SDS) and lipid profile at baseline, last study visit and changes from baseline to last study visit were assessed overall, for adult- and childhood-onset GHD and by gender using ANOVA for continuous variables and Chi-squared test for categorical variables.

Results

At baseline, treatment duration groups did not differ significantly for age, gender, body mass index, GHD onset, IGF-I SDS, lipid profile, and quality of life. Mean initial GH dose did not differ significantly according to treatment duration group in any subgroup, except female patients, with highest mean dose seen in the longest duration group. In the longest duration group for patients overall, adult-onset patients and male patients, there were significant decreases in GH dose from baseline to last visit, and in total and low-density lipoprotein (LDL)-cholesterol concentrations. IGF-I SDS increased, to a greater extent, in the longest duration group for patients overall and female patients.

Conclusions

The results show that long-term GH treatment is associated with decreasing GH dose, increased IGF-I, decreased LDL-cholesterol and the presence of surrogate markers that help to give confidence in a diagnosis of GHD.

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Validation conform ISO-15189 of assays in the field of autoimmunity: Joint efforts in The Netherlands

Publication date: Available online 13 March 2018
Source:Autoimmunity Reviews
Author(s): Leontine Mulder, Renate van der Molen, Carin Koelman, Ester van Leeuwen, Anja Roos, Jan Damoiseaux
ISO 15189:2012 requires validation of methods used in the medical laboratory, and lists a series of performance parameters for consideration to include. Although these performance parameters are feasible for clinical chemistry analytes, application in the validation of autoimmunity tests is a challenge. Lack of gold standards or reference methods in combination with the scarcity of well-defined diagnostic samples of patients with rare diseases make validation of new assays difficult. The present manuscript describes the initiative of Dutch medical immunology laboratory specialists to combine efforts and perform multi-center validation studies of new assays in the field of autoimmunity. Validation data and reports are made available to interested Dutch laboratory specialists.



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Head and neck squamous cell cancers in the United States are rare and the risk now is higher among white individuals compared with black individuals

BACKGROUND

The increasing incidence of oropharyngeal squamous cell cancer (OPSCC) is well established. However, up-to-date incidence estimates and trends for head and neck squamous cell cancers (HNSCCs) overall, including major anatomic sites, and nonoropharyngeal (non-OP) HNSCCs by sex, race, and age in the United States are not well described.

METHODS

A retrospective analysis of incident HNSCCs during 1992 through 2014 using the Surveillance, Epidemiology, and End Results database was performed to evaluate the incidence of HNSCCs overall, OPSCC, and non-OP HNSCC (those of the larynx, oral cavity, hypopharynx, nasopharynx, and nasal cavity). Incidence rates were calculated overall and by subgroups of interest, and incidence rate ratios were used to compare rates between groups. The incidence rates presented were per 100,000 population and were age adjusted to the 2000 US standard population (19 age groups; Census P25-1130). The annual percent change (APC) was modeled with and without joinpoints.

RESULTS

The incidence of HNSCC overall declined (average APC [aAPC], -0.8; P<.001) despite significant increases in the incidence of OPSCCs, most notably between 2000 and 2014 (APC, 2.1; P<.001). Significant declines in incidence were observed for all non-OP HNSCC sites for both women and men (P<.001 each). Among women, the risk of OPSCC also significantly decreased (aAPC, -0.8; P = .002), whereas the risk among men was stable during 1992 through 2001 (APC, 0.4; P = .42) and then significantly increased from 2001 to 2014 (APC, 2.7; P<.001). Decreases in the risk of non-OP HNSCC were especially large for black women (aAPC, -2.6; P<.001) and men (aAPC, -3.0; P<.001). Although the incidence of HNSCC previously was highest among black individuals, since 2009 its incidence has been higher among white compared with black individuals.

CONCLUSIONS

The incidence of HNSCC is declining, especially for non-OP HNSCC and among black individuals. Cancer 2018. © 2018 American Cancer Society.

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Efficacy and safety results of depatuxizumab mafodotin (ABT-414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

BACKGROUND

Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific.

METHODS

This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD.

RESULTS

Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional.

CONCLUSIONS

Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Analysis of characteristics and outcomes by growth hormone treatment duration in adult patients in the Italian cohort of the Hypopituitary Control and Complications Study (HypoCCS)

Abstract

Purpose

To examine differences in effects according to growth hormone (GH) treatment duration in adult GH-deficient patients.

Methods

In the Italian cohort of the observational Hypopituitary Control and Complications Study, GH-treated adults with GH deficiency (GHD) were grouped by duration of treatment; ≤ 2 years (n = 451), > 2 to ≤ 6 years (n = 387) and > 6 years (n = 395). Between-group differences in demographics, medical history, physical characteristics, insulin-like growth factor-I standard deviation score (IGF-I SDS) and lipid profile at baseline, last study visit and changes from baseline to last study visit were assessed overall, for adult- and childhood-onset GHD and by gender using ANOVA for continuous variables and Chi-squared test for categorical variables.

Results

At baseline, treatment duration groups did not differ significantly for age, gender, body mass index, GHD onset, IGF-I SDS, lipid profile, and quality of life. Mean initial GH dose did not differ significantly according to treatment duration group in any subgroup, except female patients, with highest mean dose seen in the longest duration group. In the longest duration group for patients overall, adult-onset patients and male patients, there were significant decreases in GH dose from baseline to last visit, and in total and low-density lipoprotein (LDL)-cholesterol concentrations. IGF-I SDS increased, to a greater extent, in the longest duration group for patients overall and female patients.

Conclusions

The results show that long-term GH treatment is associated with decreasing GH dose, increased IGF-I, decreased LDL-cholesterol and the presence of surrogate markers that help to give confidence in a diagnosis of GHD.

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Malignant triton tumor of the duodenum: report of a case

Abstract

We report a case of malignant triton tumor of the duodenum, which is extremely rare. A submucosal malignant tumor was detected in the duodenum of a 49-year-old woman. The tumor was completely resected by performing pancreaticoduodenectomy. Pathological examination revealed that the lesion was a malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation, i.e., a malignant triton tumor. Long-term survival has been achieved with no recurrence at 8.5 years after surgery.

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Head shadow enhancement with low-frequency beamforming improves sound localization and speech perception for simulated bimodal listeners

Publication date: Available online 12 March 2018
Source:Hearing Research
Author(s): Benjamin Dieudonné, Tom Francart
Many hearing-impaired listeners struggle to localize sounds due to poor availability of binaural cues. Listeners with a cochlear implant and a contralateral hearing aid – so-called bimodal listeners – are amongst the worst performers, as both interaural time and level differences are poorly transmitted. We present a new method to enhance head shadow in the low frequencies. Head shadow enhancement is achieved with a fixed beamformer with contralateral attenuation in each ear. The method results in interaural level differences which vary monotonically with angle. It also improves low-frequency signal-to-noise ratios in conditions with spatially separated speech and noise. We validated the method in two experiments with acoustic simulations of bimodal listening. In the localization experiment, performance improved from 50.5∘ to 26.8∘ root-mean-square error compared with standard omni-directional microphones. In the speech-in-noise experiment, speech was presented from the frontal direction. Speech reception thresholds improved by 15.7 dB SNR when the noise was presented from the cochlear implant side, improved by 7.6 dB SNR when the noise was presented from the hearing aid side, and was not affected when noise was presented from all directions. Apart from bimodal listeners, the method might also be promising for bilateral cochlear implant or hearing aid users. Its low computational complexity makes the method suitable for application in current clinical devices.

Graphical abstract

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The Frequency of Metabolic Syndrome and Serum Osteopontin Levels in Survivors of Childhood Acute Lymphoblastic Leukemia

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


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Head shadow enhancement with low-frequency beamforming improves sound localization and speech perception for simulated bimodal listeners

Publication date: Available online 12 March 2018
Source:Hearing Research
Author(s): Benjamin Dieudonné, Tom Francart
Many hearing-impaired listeners struggle to localize sounds due to poor availability of binaural cues. Listeners with a cochlear implant and a contralateral hearing aid – so-called bimodal listeners – are amongst the worst performers, as both interaural time and level differences are poorly transmitted. We present a new method to enhance head shadow in the low frequencies. Head shadow enhancement is achieved with a fixed beamformer with contralateral attenuation in each ear. The method results in interaural level differences which vary monotonically with angle. It also improves low-frequency signal-to-noise ratios in conditions with spatially separated speech and noise. We validated the method in two experiments with acoustic simulations of bimodal listening. In the localization experiment, performance improved from 50.5∘ to 26.8∘ root-mean-square error compared with standard omni-directional microphones. In the speech-in-noise experiment, speech was presented from the frontal direction. Speech reception thresholds improved by 15.7 dB SNR when the noise was presented from the cochlear implant side, improved by 7.6 dB SNR when the noise was presented from the hearing aid side, and was not affected when noise was presented from all directions. Apart from bimodal listeners, the method might also be promising for bilateral cochlear implant or hearing aid users. Its low computational complexity makes the method suitable for application in current clinical devices.

Graphical abstract

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Minimally symptomatic cerebral amyloid angiopathy-related inflammation: three descriptive case reports

Introduction

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an unusual cause of encephalopathy, seizures and focal neurological deficits.1 2 We report three cases of CAA-ri with minimal symptoms but striking and dynamically evolving brain MRI findings.

Case 1

A 62-year-old man presented with a moderately severe non-radiating frontal headache. Brain MRI 9 months later showed multiple discrete regions of abnormal signal and mild swelling involving white matter and overlying cortex. Susceptibility-weighted imaging (SWI) demonstrated numerous cortical lobar microbleeds throughout both cerebral hemispheres. Repeat MRI another 9 months later showed resolution of many of the parenchymal abnormalities, but with several new regions containing more peripheral microbleeds. Amyloid-PET (using ¹⁸F-florbetapir) demonstrated moderate widespread amyloid deposition; CSF analysis showed reduced amyloid-beta 1–42 and high-normal total tau. Formal neuropsychological testing suggested mild compromise in frontal functioning only. The patient was treated with 5 days of intravenous methylprednisolone (1 g daily), followed by an...

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Intensive inpatient rehabilitation for persons with Parkinsons disease: last resort or pre-emptive strike?

We discuss the tremendous challenges to reliably demonstrate the benefits of multidisciplinary inpatient care for patients with Parkinson's disease and sketch important areas for future research

Parkinson's disease (PD) is a complex neurodegenerative disorder with a wide variety of motor and non-motor symptoms. Optimal management involves a multidisciplinary approach, combining pharmacotherapy and non-pharmacological interventions. Evidence for several non-pharmacological interventions, such as physiotherapy, is growing fast.1 However, it is unclear whether combining these monodisciplinary interventions into a bundled multidisciplinary team approach offers additional benefits and at what costs. Even less is known about how such multidisciplinary care should be organised, for example, on an outpatient basis (perhaps in the community) or using intensive inpatient rehabilitation. In their JNNP paper, Ferrazzoli and colleagues2 describe their experience with the latter approach.

Specifically, using a single-blind randomised controlled trial, they evaluated whether an intensive 4-week multidisciplinary and inpatient rehabilitation programme improved quality of life...

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Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice

Abstract

Objectives: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here we report the neuro-reparative effects of myeloablative allogeneic bone marrow transplantation in a humanised murine model of the disease.

Methods: Mice received a transplant of fluorescently-tagged sex mis-matched bone marrow cells expressing wild-type frataxin and were assessed at monthly intervals using a range of behavioural motor performance tests. At six months post-transplant, mice were sacrificed for protein and histological analysis. In an attempt to augment numbers of bone marrow-derived cells integrating within the nervous system and improve therapeutic efficacy, a sub-group of transplanted mice also received monthly subcutaneous infusions of cytokines granulocyte-colony stimulating factor and stem cell factor.

Results: Transplantation caused improvements in several indicators of motor coordination and locomotor activity. Elevations in frataxin levels and anti-oxidant defences were detected. Abrogation of disease pathology throughout the nervous system was apparent, together with extensive integration of bone marrow-derived cells in areas of nervous tissue injury that contributed genetic material to mature neurons, satellite-like cells and myelinating Schwann cells by processes including cell fusion. Elevations in circulating bone marrow-derived cell numbers were detected post-cytokine administration and were associated with increased frequencies of Purkinje cell fusion and bone marrow-derived dorsal root ganglion satellite-like cells. Further improvements in motor coordination and activity were evident.

Interpretation: Our data provide proof-of-concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation. This article is protected by copyright. All rights reserved.

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Getting the best outcomes from epilepsy surgery

Abstract

Neurosurgery is an under-utilised treatment that can potentially cure drug-refractory epilepsy. Careful, multidisciplinary pre-surgical evaluation is vital for selecting patients and ensure optimal outcomes. Advances in neuroimaging have improved diagnosis and guide surgical intervention. Invasive electroencephalography allows the evaluation of complex patients who would otherwise not be candidates for neurosurgery. We review the current state of the assessment and selection of patients and consider established and novel surgical procedures, and associated outcome data. We aim to dispel myths that may inhibit physicians from referring and patients from considering neurosurgical intervention for drug-refractory focal epilepsies. This article is protected by copyright. All rights reserved.

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The reality of “ghosts” in authorship of clinical trials in multiple sclerosis

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De Novo Hotspot Variants in CYFIP2 Cause Early-Onset Epileptic Encephalopathy

ABSTRACT

Objective: The cytoplasmic fragile X mental retardation 1 interacting proteins 2 (CYFIP2) is a component of the WAVE regulatory complex, which is involved in actin dynamics. An obvious association of CYFIP2 variants with human neurological disorders has never been reported. Here, we identified de novo hotspot CYFIP2 variants in neurodevelopmental disorders and explore the possible involvement of the CYFIP2 mutants in the WAVE signaling pathway.

Methods: We performed trio-based whole exome sequencing (WES) in 210 families and case-only WES in 489 individuals with epileptic encephalopathies. The functional effect of CYFIP2 variants on WAVE signaling was evaluated by computational structural analysis and in vitro transfection experiments.

Results: We identified three de novo CYFIP2 variants at the Arg87 residue in four unrelated individuals with early-onset epileptic encephalopathy. Structural analysis indicated that the Arg87 residue is buried at an interface between CYFIP2 and WAVE1, and the Arg87 variant may disrupt hydrogen bonding, leading to structural instability and aberrant activation of the WAVE regulatory complex. All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild type CYFIP2. Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2.

Interpretation: Our findings suggest that de novo Arg87 variants in CYFIP2 have gain-of-function effects on the WAVE signaling pathway, and are associated with severe neurological disorders. This article is protected by copyright. All rights reserved.

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Cancers, Vol. 10, Pages 70: Any Place for Immunohistochemistry within the Predictive Biomarkers of Treatment in Lung Cancer Patients?

Cancers, Vol. 10, Pages 70: Any Place for Immunohistochemistry within the Predictive Biomarkers of Treatment in Lung Cancer Patients?

Cancers doi: 10.3390/cancers10030070

Authors: Véronique Hofman Sandra Lassalle Coraline Bence Elodie Long-Mira Sacha Nahon-Estève Simon Heeke Virginie Lespinet-Fabre Catherine Butori Marius Ilié Paul Hofman

The identification of certain genomic alterations (EGFR, ALK, ROS1, BRAF) or immunological markers (PD-L1) in tissues or cells has led to targeted treatment for patients presenting with late stage or metastatic lung cancer. These biomarkers can be detected by immunohistochemistry (IHC) and/or by molecular biology (MB) techniques. These approaches are often complementary but depending on, the quantity and quality of the biological material, the urgency to get the results, the access to technological platforms, the financial resources and the expertise of the team, the choice of the approach can be questioned. The possibility of detecting simultaneously several molecular targets, and of analyzing the degree of tumor mutation burden and of the micro-satellite instability, as well as the recent requirement to quantify the expression of PD-L1 in tumor cells, has led to case by case development of algorithms and international recommendations, which depend on the quality and quantity of biological samples. This review will highlight the different predictive biomarkers detected by IHC for treatment of lung cancer as well as the present advantages and limitations of this approach. A number of perspectives will be considered.

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Collagenous Enteritis is Unlikely a Form of Aggressive Celiac Disease Despite Sharing HLA-DQ2/DQ8 Genotypes

Collagenous enteritis is an uncommon small intestinal injury pattern with unclear pathogenesis. While it has been speculated that collagenous enteritis represents a form of refractory celiac disease, recent clinical studies suggest a potential link to exposure to the antihypertensive medication olmesartan. Here we hypothesized that the pathogenesis of collagenous enteritis involves both genetic and environmental factors. All subjects with biopsy-proven collagenous enteritis diagnosed between 2002 and 2015 were identified from 2 tertiary care medical centers. Human leukocyte antigen (HLA)-DQ genotyping was performed by polymerase chain reaction on archived tissue. Celiac disease serology, past medical history, medications, smoking history, demographics, histology, clinical management, and follow-up were recorded. A total of 32 subjects were included. In contrast to celiac disease, subjects with collagenous enteritis were mostly elderly (median age at diagnosis, 69 y; range, 33 to 84 y). Seventy percent of collagenous enteritis subjects harbored celiac disease susceptibility alleles HLA-DQ2/DQ8; however, only 1 subject had elevated serum levels of celiac disease-associated autoantibodies while on a gluten-containing diet. Furthermore, 56% of subjects were taking nonsteroidal anti-inflammatory drugs, 36% proton-pump inhibitors, 28% statins, and 32% olmesartan at the time of diagnosis. Discontinuation of olmesartan and treatments with steroids and/or gluten-free diet resulted in symptomatic and histologic improvement. Neither lymphoma nor collagenous enteritis–related death was seen in this cohort. Therefore, while collagenous enteritis shares similar HLA genotypes with celiac disease, the difference in demographics, the lack of celiac disease-associated autoantibodies, and potential link to medications as environmental triggers suggest the 2 entities are likely distinct in pathogenesis.

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