Defective levels of both circulating dendritic cells and T-regulatory cells correlate with risk of recurrence in cutaneous melanoma

Abstract

Background

Immune markers in the peripheral blood of melanoma patients provide useful information for clinical management although there is poor consensus on circulating cells which could putatively reflect the disease activity and play a prognostic role. Here, we investigated both dendritic cells (DCs) and T-regulatory cells (Tregs).

Methods

The number of DC subsets as myeloid (m) and plasmacytoid was measured by flowcytometry in 113 melanoma patients in different clinical stages and correlated with the disease activity to evaluate the recurrence free survival (RFS) calculated as difference between baseline and post-surgical values in relation to the criteria for the melanoma staging, as primary tumor removal, sentinel lymph node biopsy and completion of lymph node dissection.

Results

Circulating mDC levels were significantly lower in metastatic melanoma than in other stages and inversely correlated to Treg values while both populations were similarly expressed in inactive disease at stage I-III. Furthermore, the levels of these cells after melanoma removal were apparently related to the disease activity since their persistent defect reflected high risk of recurrence and reduced the RFS.

Conclusions

This work highlighted the role of immune cell measurement for the management of melanoma activity and the identification of patients at potential risk of recurrence based on the mDC ratio.

https://ift.tt/2DRPZ4p

Economic Burden of Renal Cell Carcinoma—Part I: An Updated Review

Abstract

Background

The economic burden of renal cell carcinoma (RCC) had been reported to be significant in a previous review published in 2011.

Objective

The objective of this study was to perform an updated review by synthesizing economic studies related to the treatment of RCC that have been published since the previous review.

Methods

We performed a literature search in PubMed, EMBASE, and the Cochrane Library, covering English-language studies published between June 2010 and August 2018. We categorized these articles by type of analyses [cost-effectiveness analysis (CEA), cost analysis, and cost of illness (COI)] and treatment setting (cancer status and treatment), discussed findings from these articles, and synthesized information from each article in summary tables.

Results

We identified 52 studies from 2317 abstracts/titles deemed relevant from the initial search, including 21 CEA, 23 cost analysis, and 8 COI studies. For localized RCC, costs were found to be positively associated with the aggressiveness of the local treatment. For metastatic RCC (mRCC), pazopanib was reported to be cost effective in the first-line setting. We also found that the economic burden of RCC has increased over time.

Conclusion

RCC continues to impose a substantial economic burden to the healthcare system. Despite the large number of treatment alternatives now available for advanced RCC, the cost effectiveness and budgetary impact of many new agents remain unknown and warrant greater attention in future research.

https://ift.tt/2OYiuyd

Caspase 3 as a Novel Marker to Distinguish Chromophobe Renal Cell Carcinoma from Oncocytoma

Abstract

Despite advances in our understanding of the biology of chromophobe renal cell carcinoma (ChRCC) and renal oncocytoma (RO), the differential diagnosis among these tumors remains one of the most problematic in renal pathology. Today, CK7 is the most recommended marker to distinguish these entities, however it appears insufficiently accurate by itself. This study aimed to find an easily accessible IHC stain that might out-compete CK7 in this field. Expressions of CK7, cyclin D1, p16, survivin, CD138, Ki-67 and caspase 3 (CASP3) were analyzed in a total of 27 cases (20 ROs and 7 ChRCCs). Immunoreactivity was assessed based on a combined score of the extent and intensity of staining. Compared to RO, a higher percentage of the total ChRCCs stained positive for CK7 (67% vs. 22%, respectively) and CASP3 (86% vs. 25%) (P < 0.005). The differences in staining with cyclin D1, p16, survivin, CD138 and Ki-67 turned out to be statistically insignificant in differentiating ChRCC from RO. CASP3 is a promising marker in distinguishing ChRCC from RO and may represent an alternative for CK7. Cyclin D1, p16, survivin, CD138 and Ki-67 cannot be used to distinguish these neoplasms.

https://ift.tt/2zmmK5X

Prospective multicenter real-world RAS mutation comparison between OncoBEAM-based liquid biopsy and tissue analysis in metastatic colorectal cancer

https://ift.tt/2R8QBWq

Trabectedin for reversing platinum resistance and resensitization to platinum in patients with recurrent ovarian cancer

Future Oncology, Ahead of Print.


https://ift.tt/2r2n2u8

Culture- and PCR-based detection of BV associated microbiological profile of the removed IUDs and correlation with the time period of IUD in place and the presence of the symptoms of genital tract infection

The long-term use of intrauterine devices (IUDs) may lead to biofilm formation on the surface. The aim of this study was to perform the culture- and PCR-based detection of bacteria/fungi from the biofilm of th...

https://ift.tt/2qZZFS1

A New Statistical Approach to Describe the Quality of Extra Virgin Olive Oils Using Near Infrared Spectroscopy (NIR) and Traditional Analytical Parameters

Summary

NIR prediction models were developed for the determination of relevant parameters to evaluate olive oil quality such as acidity (FFA), peroxide value (PV), UV‐absorption at 232 nm and at 268/270 nm, p‐anisidine value (AnV), isomeric diacylglycerols (DG), and pyropheophytin A (PPP). In addition a new NIR method to estimate the age of olive oil is presented. The relevant wavenumbers are given for the calculation of the parameters and the precision data are presented in comparison to the chemical reference methods. The calibration and validation of the methods were executed with independent data sets (test in test instead of cross‐validation) to cover the wide range of variability of the analytical parameters including the corresponding accurate analytical results from the reference chemical methods. The correctness and accuracy of the developed NIR methods were verified by analyzing certified materials.

Finally, a simple statistical approach has been developed to describe the quality of olive oils using the parameters FFA, PV, K₂₃₂ and K₂₇₀, DG and PPP. The probability of presence of a sensory defect (100% ≙ 1; 0% ≙ 0) was calculated using the following equation:

Pred (BIN) = 1/(1+exp(‐(‐9+37*FFA‐0.9*PV‐2.9*K232+14*K270+3.7*PPP‐0.27*DG))).

Practical applications: The use of NIR allows the analysis of different parameters relevant for the quality of olive oil in one run in comparison to the individual chemical reference methods. That allows saving time and money, and a skilled operator is not necessary making the method interesting for routine analysis. The use of a simple equation developed from the logistic regression using FFA, PV, K‐values, DG and PPP measured by NIR as variables enables for the first time to describe the sensory quality of olive oils without making sensory testing. This criterion without setting limits for the individual parameters estimates the probability of the presence of sensory defects on basis of chemical parameters. This tool can easily be used to differentiate the two categories extra virgin and virgin olive oils both using the traditional laboratory methods and the corresponding NIR‐methods.

https://ift.tt/2KtMLnW

Report on Tropical Oils Meeting: why do we need them?

Abstract

One‐day meeting on Tropical Oils – Production, Applications, Nutritional and Health Aspects was organised by the SCI's Lipids Group in collaboration with Benelux Lipid Network and supported by Euro Fed Lipid on Friday, 22 June 2018 at Thagaste, Augustinian Monastery, Ghent, Belgium. Delegates from five countries attended the meeting which was aimed at highlighting the importance of tropical oils in various applications considering their specific physical and chemical characteristics as well as nutritional and health aspects. Dr Parkash Kochhar, in his welcoming address, emphasised the importance of tropical oils as feedstock for various applications in food and non‐food sectors.

https://ift.tt/2BrHEC0

Evaluation of the oxidative stability of cold‐pressed rapeseed oil by Rancimat and Pressure Differential Scanning Calorimetry measurement

Abstract

Cold‐pressed market rapeseed oils were evaluated for oxidative stability using two accelerated methods: Rancimat and Pressure Differential Scanning Calorimetry. In the study, oils were also determined to their acid, peroxide and p‐anisidine value, fatty acid composition, antioxidants capacity and phenolic compounds content. Obtained results of oxidative stability have been correlated to determine the possibility of using interchangeably tested methods. To examine the impact of individual quality factors on oil oxidative stability the Principal Components Analysis was applied. Analysed oils were characterised by good quality, had a typical fatty acid composition and oxidative stability. Rapeseed oils induction time were determined by Rancimat measurement at 100 ^°C and Pressure Differential Scanning Calorimetry test at a temperature of 120 ^°C. The induction times obtained using these two methods were strongly correlated (r= 0.96). A high value of correlation coefficient might be caused by too little differentiation; thus the possibility of using these methods interchangeably may be applied only to results range between 12.96–14.03 h for a Rancimat method and 60.28–67.05 min for PDSC measurements. Principal Components Analysis analysis showed that the greatest influence on rapeseed oil induction time .in Rancimat and PDSC methods have peroxide value (r= ‐0.73 and r= ‐0.80, respectively), Totox indicator (r= ‐0.67 and r= ‐0.75, respectively) and total polyphenols content (r= 0.67 and r= 0.78, respectively). There was no correlation between the monounsaturated fatty acid content and the antioxidant capacity. Moreover, the induction time was poorly correlated with saturated, polyunsaturated fatty acids and pigments content.

Practical applications: The results show that Rancimat and pressure differential scanning calorimetry (PDSC) methods might be used interchangeably (r= 0.96) for assessing the oxidation stability of cold‐pressed rapeseed oil, for a given set of data. PDSC can be recommended as an appropriate objective method for evaluating the oxidative stability of cold‐pressed rapeseed oils. Results of the Principal Component Analysis (PCA) proved that its primary oxidation state had a high influence on cold‐pressed rapeseed oil oxidative stability. Differences in rapeseed oil oxidation stability do not depend on its fatty acid composition.

https://ift.tt/2KvcFIk

Diversity assessment of Algerian wild and cultivated olive (Olea europeae L.) by molecular, morphological and chemical traits

Abstract

Algeria has several genetic resources on olive trees, mainly made up of small indigenous cultivars, and a very important wild heritage.

We characterized 20 olive samples including eight cultivars and twelve wild trees from the province of Bejaia (Algeria), by combining molecular data (13 SSRs), fruit and pit morphological traits, fatty acids composition and phenolic compounds of the EVOOs. The genetic results based on PCoA, UPGMA and AMOVA analysis demonstrated that olive cultivars and wild trees are mixed suggesting kinship relationships between cultivated and wild olive trees and even the presence of cases of synonymy between some cultivars. PCA analysis on morphological traits showed a good separation of the two olive botanical varieties, the wild olive trees producing smaller fruits than those of the cultivated ones. Significant differences were also found in terms of fatty acids and phenol compounds composition of the EVOOs. Wild olive oils showed the highest contents on phenolic compounds mainly oleocanthal, as well as a considerable richness on oleic acid. The comparison of pairwise distances between olive trees obtained by genetic, morphological, fatty acids and phenolic compounds contents data using Mantel's test indicated a significant correlation among morphological characteristics, DNA polymorphism and phenolic compounds.

The results obtained in the present work contribute to reveal the diversity existing in the cultivated and wild olive trees of the region of Bejaia, shedding some light on the importance of Algerian olives germplasm.

Practical applications: Cultivated and wild olive diversity were assessed by genetic, morphological, fatty acids and phenolic composition. SSR marker analysis demonstrated the presence of a high genetic variations between the analyzed samples

A significant correlation of morphological characteristics with DNA polymorphism and phenolic compounds was foundA significant diversity in the wild and cultivated olive trees was observed.

https://ift.tt/2Bs65zi

Potential of Nuclear Magnetic Resonance for a discriminant characterization of PDO VOOs

Abstract

Interest in virgin olive oil (VOO) is growing among consumers and industry due to its well‐received sensorial attributes and to its higher oxidative stability, as well as to its healthy effects. Furthermore, attention is being increasingly paid to other quality attributes of VOO, such as sustainability and geographical origin. For these reasons, this oil has an important added value and is exposed to fraudulent practices. In order to guarantee its origin, the European Union (EU) has developed the Protected Designation of Origin (PDO) quality scheme that links the characteristics of a VOO to its geographical origin. In recent years attempts to develop tools that enable the authentication of PDO‐labeled VOOs have been carried out. In this regard, studies using Nuclear Magnetic Resonance (NMR) to this aim are here reviewed.

Practical applications: Due to the added value of PDO VOOs, their authentication is of great importance for administration, consumers and producers. The studies in which NMR spectroscopy has been used to this aim are analyzed here. In this context, this review provides a view of the state of the art that can be of practical interest not only for the researchers of the subject but also for the aforementioned groups.

https://ift.tt/2KruBU6

Development and validation of a TaqMan RT-PCR method for identification of mayonnaise spoilage yeast Pichia kudriavzevii

Food spoilage and its contamination with yeast and mold is a serious problem of food industry. Despite the high fat content, mayonnaise is an attractive substrate for food spoilage microorganisms. The aim of t...

https://ift.tt/2DFbX9W

Expression and regulation of phenol-soluble modulins and enterotoxins in foodborne Staphylococcus aureus

Although high levels of staphylococcal phenol-soluble modulins (PSMs) in clinical methicillin-resistant Staphylococcus aureus (MRSA) has been shown to correlate with bacterial virulence, the PSMs expression in fo...

https://ift.tt/2QdJ0s5

Somatic experiencing® for patients with low back pain and comorbid posttraumatic stress disorder – protocol of a randomized controlled trial

Research has almost exclusively focused on the neck in order to explain the mechanisms of persistent pain after motor vehicle collisions (MVC). However, studies have shown that low back pain after MVC is as co...

https://ift.tt/2DHxsXo

Lack of association between single-nucleotide polymorphisms of pro- and anti-inflammatory cytokines and HTLV-1-associated myelopathy / tropical spastic paraparesis development in patients from Rio de Janeiro, Brazil

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive neurological and inflammatory disease, associated with HTLV-1 infection. HAM/TSP neurological disease is a consequence of an...

https://ift.tt/2R1QnQG

The geographic variation and spatiotemporal distribution of hepatitis C virus infection in Libya: 2007–2016

Hepatitis C Virus infection has been considered an important hidden pandemic in developing countries, particularly in Africa. It varies greatly from one region to another and even within districts of the same ...

https://ift.tt/2PKwssS

Differential distribution of IgA-protease genotypes in mucosal and invasive isolates of Haemophilus influenzae in Sweden

Several different IgA-proteases exist in Haemophilus influenzae. The variants have been suggested to play differential roles in pathogenesis, but there is limited information on their distribution in clinical iso...

https://ift.tt/2R5CssX

Growing Human Parathyroids in a Microphysiological System: A Novel Approach to Understanding and Developing New Treatments for Hyperparathyroidism

We developed a novel model for studying hyperparathyroidism by growing ex vivo 3-dimensional human parathyroids as part of a microphysiological system (MPS) that mimics human physiology. The purpose of this study was to validate the parathyroid portion of the MPS. We prospectively collected parathyroid tissue from 46 patients with hyperparathyroidism for growth into pseudoglands. We evaluated pseudogland architecture and calcium responsiveness. Following 2 weeks in culture, dispersed cells successfully coalesced into pseudoglands ∼500–700 µm in diameter that mimicked the appearance of normal parathyroid glands. Functionally, they also appeared similar to intact parathyroids in terms of organization and calcium-sensing receptor expression. Immunohistochemical staining for calcium-sensing receptor revealed 240–450/cell units of mean fluorescence intensity within the pseudoglands. Finally, the pseudoglands showed varying levels of calcium responsiveness, indicated by changes in parathyroid hormone (PTH) levels. In summary, we successfully piloted the development of a novel MPS for studying the effects of hyperparathyroidism on human organ systems. We are currently evaluating the effect of PTH on adverse remodeling of tissue engineered cardiac, skeletal, and bone tissue within the MPS.
Cells Tissues Organs

https://ift.tt/2PNKCK2

The Many Faces of Peroxisomal Disorders: Lessons from A Large Arab Cohort

Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease‐causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30,000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend towards genotype/phenotype correlation in terms of long‐term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond one year of age. Most unusual among the long‐term survivors was a multiplex family in which the affected members presented as adults with nonspecific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl‐CoA reductase 1 disorder as well as CRSPW syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" VLCFA assay, which highlights the value of a genomics‐first approach in these cases.

This article is protected by copyright. All rights reserved.

https://ift.tt/2zkfwiM

Genetic Risk Score modifies the effect of APOE on risk and age onset of Alzheimer’s disease

Single nucleotide polymorphism (SNP)‐based genetic risk score (GRS) and APOE genotype are both important in risk prediction of Alzheimer's disease (AD); however, the interaction between GRS and APOE has not been extensively investigated. Our objective was to determine whether GRS modifies the APOE effect on AD risk and age at onset (AAO). The study included 774 AD cases and 767 controls of European descent. Population standardized GRS was calculated based on 17 previously implicated AD risk‐associated SNPs. Association was analyzed using logistic regression, Cox proportional hazards model and Kaplan–Meier curve. We found that GRS was significantly associated with AD risk and the association was stronger among APOE ε4 carriers. Compared to ε4 non‐carriers, the Odds Ratio (OR) for AD was 8.09 (95% Confidence Interval [CI]: 4.98‐13.63) for ε4 carriers with high‐GRS (≥1.5). In contrast, the OR was 2.55 (95% CI: 1.46‐4.49) for ε4 carriers with low‐GRS (<0.6). In conclusion, these results suggest SNP‐based GRS may supplement APOE for better assessment of inherited risk and age of onset of AD.

This article is protected by copyright. All rights reserved.

https://ift.tt/2OZ2WdR

A novel mutation in MYORG causes primary familial brain calcification with central neuropathic pain

https://ift.tt/2zoDoBU

A novel nonsense homozygous variant in the NLGN1 gene found in a pair of monozygotic twin brothers with intellectual disability and autism

https://ift.tt/2OXyj8E

Genetics meets dna methylation in rare diseases

Alterations in epigenetic landscapes are hallmarks of many complex human diseases, yet, it is often challenging to assess the underlying mechanisms and causal link with clinical manifestations. In this regard, monogenic diseases that affect actors of the epigenetic machinery are of considerable interest to learn more about the etiology of complex traits. Spectacular breakthroughs in medical genetics are largely the result of advances in genome‐wide approaches to identify genomic and epigenomic alterations in patients. These approaches have enabled the identification of an ever‐increasing number of hereditary disorders caused by defects in the establishment of epigenetic marks early during development or in the perpetuation of such marks at later stages. We focus our review on particular cases where DNA methylation landscapes are altered at the genome scale, whether it is a direct consequence of mutations in DNA methyltransferases (DNMT) or that it reflects initial alterations of chromatin states or guiding factors caused by mutations in chromatin modifiers or transcription factors. Collectively, increased knowledge of these rare diseases will add to our understanding of the genetic determinants of DNA methylation in humans. Moreover, investigating how perturbations to these determinants affect genome function has far‐reaching potential to understand various complex human diseases.

This article is protected by copyright. All rights reserved.

https://ift.tt/2zmtxN4

Improving redox sensitivity of roGFP1 by incorporation of selenocysteine at position 147

Redox-sensitive green fluorescent protein (roGFP) is a genetically-encoded redox-sensitive protein used to detect cellular oxidative stress associated with reactive oxygen species production. Here we replaced ...

https://ift.tt/2TABoyW

Soluble transferrin receptor and soluble transferrin receptor/log ferritin index in diagnosis of iron deficiency anemia in pediatric inflammatory bowel disease

There is no single reliable marker of iron homeostasis in inflammatory bowel disease.

https://ift.tt/2r901G5

Liver Abscesses: blame it on the chicken bone

https://ift.tt/2FF8Dhx

Bruno’s Score

Many of our experiences in hospice and palliative care medicine are challenging. We support dying patients and their families as they struggle with the transition from life to death, and continue to support those in mourning. Many times, in America, it is difficult to even appreciate a glimmer of spiritual grace as our patients die. We easily remain stuck in the material, and distance ourselves from the spiritual. Some exits are quite graceful, however. I present the case of an exceptional person, who enjoyed an exceptional life and had an exceptionally graceful dying process and death, in hopes that his story may encourage other healers as much as he inspired me.

https://ift.tt/2FAi2H2

Multicenter Study of the psychometric properties of the new Demoralization Scale (DS-II) in Spanish-speaking advanced cancer patients

Demoralization is a state of existential distress in patients with advanced illness, typically with coping difficulties, feelings of loss of sense and purpose in life and despair, among other things. The DS-II is an evaluation tool for this syndrome, which has recently been reformulated on a shorter scale.

https://ift.tt/2qZXEoJ

Pre-treatment psychoneurological symptoms and their association with longitudinal cognitive function and quality of life in older breast cancer survivors

Symptoms affect quality of life (QOL), functional status, and cognitive function in cancer survivors, but older survivors are understudied.

https://ift.tt/2FzoWwp

FAmily CEntered (FACE) Advance Care Planning among African-American and non-African-American Adults Living with HIV in Washington, DC: A Randomized Controlled Trial to Increase Documentation & Health Equity

No prospective studies address disease-specific Advance Care Planning (ACP) for adults living with HIV/AIDS.

https://ift.tt/2r28BGi

Development of a Simulation-Based Mastery Learning Curriculum for Breaking Bad News

Physician communication impacts patient outcomes. However, communication skills, especially around difficult conversations, remain suboptimal and there is no clear way to determine the validity of entrustment decisions. The aims of this study are to (a) describe the development of a simulation-based mastery learning (SBML) curriculum for breaking bad news (BBN) conversation skills; and (b) set a defensible minimum passing standard (MPS) to ensure uniform skill acquisition among learners.

https://ift.tt/2r2X8q9

Correlating structure with visual function in patients with multiple sclerosis: where is this leading?

Visual loss, particularly from optic neuritis (ON), is a major cause of disability in multiple sclerosis (MS). Determining the precise cause of the visual loss, what can be done to treat it and, indeed, what can be done to prevent it are major priorities in current clinical research. Over the last few decades, our understanding of the pathology in MS has shifted from a purely inflammation-based disease of axons in the white matter of the brain to a disorder which causes progressive degeneration of cells in the grey matter of the brain and in the ganglion cell layer of the retina.

https://ift.tt/2FDRFjE

Dynamic Cerebral Autoregulation: A Marker of Post-Operative Delirium?

We investigated the potential association of cerebral autoregulation (CA) with postoperative delirium (PD), a common complication of cardiac surgery with cardiopulmonary bypass (CPB).

https://ift.tt/2r0Wdqj

Widening the phenotypical spectrum of EGR2-related CMT: unusual phenotype for R409W mutation

Mutations in EGR2 are associated with a wide spectrum of inherited neuropathies: congenital hypomyelinating (MIM 605253)/Dejerine-Sottas (MIM 1459000) syndromes, Charcot-Marie-Tooth type 1 D (CMT1D) (MIM 607678) with variable onset and severity (Shiga et al. 2012), CMT1 with susceptibility to vincristine (Nakamura et al. 2012), and mild adult-onset axonal CMT (Sevilla et al. 2015). Herein, we report a 46-year-old man who had presented, since his late thirties, a slowly progressive symmetric distal limb weakness and atrophy, associated with mild distal sensory loss.

https://ift.tt/2FzkYDN

Clinical utility of cervical vestibular-evoked myogenic potentials in predicting residual dizziness after benign paroxysmal positional vertigo

Benign paroxysmal positional vertigo (BPPV) is one of the most common vestibular disorders with a lifetime prevalence of approximately 2.4% in the general population (von Brevern et al., 2007). Otoconial particles, which have fallen from otolith organs into semicircular canals, induce BPPV (Bhattacharyya et al., 2008). BPPV can be cured through appropriate canalith repositioning maneuvers (Fife et al., 2008; Helminski et al., 2010). However, despite clear pathogenesis and treatment, some patients still experience an imbalance after successful repositioning maneuvers.

https://ift.tt/2r8Z7cF

Filtering and other methodological issues of auditory N100 gating studies

As shown in my recent meta-analysis, the deficit of patients with schizophrenia in auditory N100 gating is characterized by a reduced N100 amplitude to the initial stimulus, as compared to controls, whereas the N100 amplitudes to repeated stimuli show little variation between patients and controls (Rosburg, 2018). In their comment to this study, Hsieh and Liu (2018) draw attention to three important methodological aspects, when conducting research on N100 gating.

https://ift.tt/2FDYKkp

Lymphoid hyperplasia with atypical dendritic/Langerhans cell proliferation mimicking Hodgkin lymphoma

Abstract

Classical Hodgkin lymphoma (CHL) is characterized by an inflammatory background and Hodgkin/Reed‐Sternberg (HRS) cells. The HRS cells exhibit abundant amphophilic cytoplasm, large nuclei, vesicular chromatin and prominent inclusion like nucleoli. Disorders other than CHL may contain HRS – like cells. The HRS cells express CD30 in 90‐96% and CD15 in 75 – 85% of the cases. Pan B cell markers are expressed variably, the most consistent being PAX5.¹ The variability in the morphology and immunophenotype poses diagnostic difficulty and other disorders may be mistaken for CHL.

This article is protected by copyright. All rights reserved.

https://ift.tt/2zk7Ahu

Somatic genetic alterations in synchronous and metachronous low‐grade serous tumours and high‐grade carcinomas of the adnexa

Abstract

Aims

Low‐grade serous carcinomas (LGSCs) and their precursor serous borderline tumours (SBTs) characteristically harbour mutations in BRAF, KRAS and NRAS but rarely in TP53, whereas high‐grade serous carcinomas (HGSCs) are characterised by frequent TP53 mutations but rare BRAF, KRAS and NRAS mutations. In a small subset of cases, LGSCs and/or SBTs develop high‐grade tumours including HGSCs and poorly differentiated carcinomas (PDCs). Here we sought to define the repertoire of somatic genetic alterations in low‐grade serous tumours and synchronous or metachronous high‐grade adnexal carcinomas.

Methods and Results

DNA extracted from five SBTs/LGSCs and synchronous or metachronous HGSCs/PDCs and matched normal tissue was subjected to massively‐parallel sequencing targeting all exons and selected non‐coding regions of 341 cancer‐related genes. The low‐grade and high‐grade tumours from a given case were related, and shared mutations and copy number alterations. Progression from low‐grade to high‐grade lesions was observed, and involved acquisition of additional mutations and copy number alterations or shifts from subclonal to clonal mutations. Only two (a HGSC and a PDC) of the five high‐grade tumours investigated harboured TP53 mutations, whereas NRAS and KRAS hotspot mutations were seen in two and one HGSCs, respectively.

Conclusions

Our results suggest that progression from SBT to HGSC may take place in a subset of cases, and that at least some of the rare HGSCs lacking TP53 mutations may be derived from a low‐grade serous precursor.

This article is protected by copyright. All rights reserved.

https://ift.tt/2P0mrTg

MUC5B, CA9 and CLDN18 are potential theranostic markers of gallbladder carcinoma

Abstract

Background

Gallbladder cancer (GBC) is an aggressive tumor usually diagnosed at advanced stages and characterized by a poor prognosis. Using public data of normal human tissues, we found that mRNA and protein levels of MUC5B and CA9 genes are highly enriched in gallbladder tissues. In addition, previous evidence showed that CLDN18 protein expression is higher in GBC. In this study we performed an analysis of these cell surface proteins along the histological progression of GBC in order to identify their theranostic potential.

Methods

Expression of MUC5B, CA9 and CLDN18 was examined by immunohistochemistry in a series of 179 chronic cholecystitis (including 16 metaplastic tissues), 15 dysplasias and 217 GBC samples using tissue microarray analysis. A composite staining score was calculated considering staining intensity and percentage of positive cells.

Results

Immunohistochemistry analysis showed a high expression of MUC5B and CA9 among normal epithelium, metaplastic and dysplastic tissues. However, expression of both proteins was observed in about 50% of GBC samples. By contrast, CLDN18 was absent in normal epithelium, but its expression was higher in metaplastic cells. Among GBC cases, approximately half presented high expression of CLDN18. No associations were found between the expression of MUC5B, CA9 and CLDN18 with any clinicopathological features.

Conclusions

CLDN18 is a new metaplasia marker in gallbladder tissues and is conserved in roughly half of GBC cases. MUC5B and CA9 are highly conserved along GBC histological progression. The three markers are potential theranostic markers, in particular CA9 and CLDN18, for which there are already targeted therapies available.

This article is protected by copyright. All rights reserved.

https://ift.tt/2zwdoVp

Reviewers List

https://ift.tt/2P0w58B

A further change of the guard

https://ift.tt/2zwdkVF

Issue Information

https://ift.tt/2OSK5RD

Biphasic pathologic pattern in transformed mycosis fungoides not associated with DUSP22‐IRF4 translocation

Abstract

Large‐cell transformation in mycosis fungoides (MF) is usually encountered in tumors and is associated with prognosis worsening. It is defined by the onset of more than 25% of lymphocytes, usually expressing CD30, exceeding 4 times the size of normal lymphocytes, either diffuse or organized in sheets in the dermal infiltrate. Recently, an unusual biphasic pathologic pattern was reported in lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (ALCL) which was constantly associated with DUSP22‐IRF4 gene rearrangement ^(1)(2)(3) . We report a case of transformed mycosis fungoides (TMF) with a biphasic infiltrate not associated with DUSP22 gene rearrangement.

This article is protected by copyright. All rights reserved.

https://ift.tt/2zmswob

Alterations in the Gut Microbiota and Metabolite Profiles of Thyroid Carcinoma Patients

The aim of this study was to investigate the relationship among the gut microbiota community, metabolite profiles and thyroid carcinoma (TC). First, 30 TC patients and 35 healthy controls (HCs) fecal samples were applied to characterize the gut microbial community using 16S rRNA gene sequencing. Differential microbiota compositions were observed, with significant enrichment of 19 and depletion of 8 genera in TC samples compared with those in HCs (Q value < 0.05), and some genera were correlated with various clinical parameters, such as lipoprotein a and apolipoprotein B. Furthermore, 6 different genera distinguished TC patients from HCs with the AUC of 0.94. The PICRUSt analysis showed 12 remarkably different metabolic pathways (Q value < 0.05). Subsequently, we systematically analyzed the gut microbiota and metabolites in the same TC patients (n = 15) and HCs (n = 15). The characteristics of the gut microbiota community were mostly consistent with the above results (30 TC patients and 35 HCs), and liquid chromatography mass spectrometry analysis was performed to characterize the metabolite profiles. In total, 21 different genera (Q value < 0.05) and 72 significantly changed metabolites (VIP > 1.0 and p < 0.05) were observed and correlated to each other. Eight metabolites combined with 5 genera were more effective in distinguishing TC patients from HCs (AUC = 0.97). In conclusion, this study presents a comprehensive landscape of the gut microbiota and metabolites in TC patients, and provides a research direction of the mechanism of interaction between gut microbiota alteration and TC pathogenesis.

This article is protected by copyright. All rights reserved.

https://ift.tt/2PM35GF

Amputation neuroma of the vagal nerve simulating celiac lymph node enlargement: diagnosis with EUS-FNA

https://ift.tt/2S8scA5

An uncommon diagnosis done by colonoscopy

https://ift.tt/2DSTcR9

An effective dendritic cell‐based vaccine containing glioma stem‐like cell lysate and CpG adjuvant for an orthotopic mouse model of glioma

Owing to the limited therapeutic efficacy of glioma vaccines, new strategies are required to improve cancer vaccines. This study aimed to assess the therapeutic efficacy of a glioma vaccine called STDENVANT. This vaccine, comprising glioma stem‐like cell (GSC) lysate, dendritic cells (DCs), and Toll‐like receptor (TLR) 9 agonist CpG motif‐containing oligodeoxynucleotides (CpG ODNs), was assessed using a GL261‐C57BL/6 orthotopic mouse model of glioma. STDENVANT markedly improved survival and tumor regression by enhancing anti‐tumor immune function. Moreover, STDENVANT upregulated programmed death 1 (PD‐1) and its ligand PD‐L1 on effector T cells, DCs, and glioma tissues, resulting in the accumulation of regulatory T (Treg) cells in the brain and lymph nodes. Combinatorial administration of anti‐PD‐L1 antibody and STDENVANT conferred a greater survival advantage and decreased the Treg cell population in the brain. The present results indicate that PD‐L1 blockade can promote tumor regression via STDENVANT in a mouse model of glioma, and combinatorial administration of anti‐PD‐L1 antibody and STDENVANT increases the therapeutic anti‐tumor efficacy of treatment.

This article is protected by copyright. All rights reserved.

https://ift.tt/2R22lJX

Relationship of DNA methylation to mutational changes and transcriptional organization in fusion‐positive and fusion‐negative rhabdomyosarcoma

Our previous study of DNA methylation in the pediatric soft tissue tumor rhabdomyosarcoma (RMS) demonstrated that fusion‐positive (FP) and fusion‐negative (FN) RMS tumors exhibit distinct DNA methylation patterns. To further examine the significance of DNA methylation differences in RMS, we investigated genome‐wide DNA methylation profiles in discovery and validation cohorts. Unsupervised analysis of DNA methylation data identified novel distinct subsets associated with the specific fusion subtype in FP RMS and with RAS mutation status in FN RMS. Furthermore, the methylation pattern in normal muscle is most similar to the FN subset with wild‐type RAS mutation status. Several biologically relevant genes were identified with methylation and expression differences between the two fusion subtypes of FP RMS or between the RAS wild‐type and mutant subsets of FN RMS. Genomic localization studies showed that promoter and intergenic regions were hypomethylated and the 3' untranslated regions were hypermethylated in FP compared to FN tumors. There was also a significant difference in the distribution of PAX3‐FOXO1 binding sites between genes with and without differential methylation. Moreover, genes with PAX3‐FOXO1 binding sites and promoter hypomethylation exhibited the highest frequency of overexpression in FP tumors. Finally, a comparison of RMS model systems revealed that patient‐derived xenografts most closely recapitulate the DNA methylation patterns found in human RMS tumors compared with cell lines and cell line‐derived xenografts. In conclusion, these findings highlight the interaction of epigenetic changes with mutational alterations and transcriptional organization in RMS tumors, and contribute to improved molecular categorization of these tumors.

This article is protected by copyright. All rights reserved.

https://ift.tt/2RbR9ed

Overweight in midlife and risk of cancer in late life: a nationwide Swedish twin study

This study examined whether midlife overweight (body mass index [BMI] ≥25) is associated with late‐life cancer risk and explored the role of genetic and early‐life environmental factors in this association. The study included 14,766 individuals from the Swedish Twin Registry, whose midlife (30–50 years) height and weight were recorded. Information on cancer diagnoses in late life (>65 years) was derived from the National Patient Registry and Cancer Registry. Generalized estimating equation (GEE) models were used to analyze unmatched case‐control data (controlled for the clustering of twins within a pair). A co‐twin matched case‐control analysis used conditional logistic regression to compare cancer‐discordant twins. Of all participants, 3,968 (26.9%) were overweight and 4,253 (28.8%) had cancer. In multi‐adjusted GEE models using normal‐weight (BMI 18.5–24.9) participants as the reference group, overweight was related to higher risk of colon cancer (OR 1.36, 95% CI: 1.00‐1.84, P=0.049), liver cancer (OR 2.00, 95% CI: 1.11‐3.62), cervix uteri cancer (OR 2.86, 95% CI: 1.19‐6.91), and corpus uteri cancer (OR 1.78, 95% CI: 1.14‐2.78) but lower risk of non‐melanoma skin cancer (OR 0.77, 95% CI: 0.66‐0.90). In conditional logistic regression analysis, these associations were attenuated becoming non‐significance. The difference in ORs from the unmatched and matched analyses was not significant. In conclusion, midlife overweight is associated with increased risk of late‐life colon, liver, and uterine cancer but reduced risk of late‐life non‐melanoma skin cancer. Further investigations are warranted to explore the role of genetic and early‐life environmental factors in these associations.

This article is protected by copyright. All rights reserved.

https://ift.tt/2PNIYYQ

Management of HPV‐Positive Women in Cervical Screening Using Results from Two Consecutive Screening Rounds

We studied whether triage of human papillomavirus (HPV)‐positive women participating in an HPV‐based screening programme can be improved by including the HPV result at the previous screen in the triage algorithm.

We analyzed data of a subgroup of 366 women from the POBASCAM trial, screened by cytology and HPV co‐testing. Women were included if they tested HPV‐positive in the second HPV‐based screening round. We evaluated the clinical performance of sixteen strategies, consisting of cytology, HPV genotyping, and/or previous screen HPV result. The clinical endpoint was cervical precancer or cancer (CIN3+).

The current Dutch triage testing policy for HPV‐positive women is to refer women for colposcopy if they have abnormal cytology at baseline or after 6‐18 months. In the second HPV‐based screening round, this strategy yielded a negative predictive value (NPV) of 95.8% (95% confidence interval: 91.9‐98.2) and colposcopy referral rate of 37.6% (32.3‐43.2%). Replacing repeat cytology by the previous screen HPV result yielded a similar NPV (96.9%, 93.3‐98.9) and colposcopy referral rate (38.8%, 33.4‐44.4). A higher NPV (99.2%, 96.3‐100%) at the cost of a higher colposcopy referral rate (49.2%, 43.6‐54.8) was achieved when cytology was combined with HPV16/18 genotyping. The other 13 triage strategies yielded a lower NPV, a higher colposcopy referral rate or performed similarly but required additional testing.

HPV‐positive women in the second HPV‐based screening round can be suitably managed by cytology, HPV16/18 genotyping and the HPV result at the previous screen, obviating the need for repeat testing of HPV‐positive, cytology negative women.

https://ift.tt/2R7iGxg

Introducing national healthcare safety investigation bodies

https://ift.tt/2AduNSg

Scientific surgery

https://ift.tt/2TzwQJ7

Reducing gender bias in surgery

https://ift.tt/2AejzN3

Issue information

https://ift.tt/2TxMjJP

Snapshot quiz

https://ift.tt/2AaunM8

Spanish translation section

https://ift.tt/2TE8EFF

Sex differences in faecal occult blood test screening for colorectal cancer

Background

This analysis of patients in a randomized population‐based health services study was done to determine the effects of faecal occult blood test (FOBT) screening of colorectal cancer (CRC) in outcomes beyond mortality, and to obtain explanations for potential sex differences in screening effectiveness.

Methods

In the Finnish FOBT screening programme (2004–2011), people aged 60–69 years were randomized into the screening and control arms. Differences in incidence, symptoms, tumour location, TNM categories, non‐vital outcomes and survival in the screening and control arms were analysed.

Results

From 321 311 individuals randomized, 743 patients with screening‐detected tumours and 617 control patients with CRC were analysed. CRC was less common in women than in men (0·34 versus 0·50 per cent; risk ratio (RR) 0·82, 95 per cent c.i. 0·74 to 0·91) and women were less often asymptomatic (16·7 versus 22·0 per cent; RR 0·76, 0·61 to 0·93). Women more often had right‐sided tumours (32·0 versus 21·3 per cent; RR 1·51, 1·26 to 1·80). Among men with left‐sided tumours, those in the screening arm had lower N (RR 1·23, 1·02 to 1·48) and M (RR 1·57, 1·14 to 2·17) categories, as well as a higher overall survival rate than those in the control arm. Furthermore among men with left‐sided tumours, non‐radical resections (26·2 versus 15·7 per cent; RR 1·67, 1·22 to 2·30) and postoperative chemotherapy sessions (61·6 versus 48·2 per cent; RR 1·28, 1·10 to 1·48) were more frequent in the control arm. Similar benefits of screening were not detected in men with right‐sided tumours or in women.

Conclusion

Biennial FOBT screening seems to be effective in terms of improving several different outcomes in men, but not in women. Differences in incidence, symptoms and tumour location may explain the differences in screening efficacy between sexes.

https://ift.tt/2AhpZeo

Development and performance of a novel vasopressor-driven mortality prediction model in septic shock

Vasoactive medications are essential in septic shock, but are not fully incorporated into current mortality prediction risk scores. We sought to develop a novel mortality prediction model for septic shock inco...

https://ift.tt/2S4ZrED

Increased NAD(H) pool promotes colon cancer progression by suppressing ROS level

Abstract

Nicotinamide adenine dinucleotide (NAD) exists in a reduced form (NADH) and an oxidized form (NAD+). NAD+ plays crucial roles in cancer metabolism, including in cellular signaling, energy production and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD⁺ and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD⁺/NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD⁺ salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two‐photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)‐induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive ROS levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT‐mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.

This article is protected by copyright. All rights reserved.

https://ift.tt/2PShyBa

CD47 agonist peptide pkhb1 induces immunogenic cell death in T‐cell acute lymphoblastic leukemia cells

Abstract

T‐cell acute lymphoblastic leukemia (T‐ALL) has a poor prognosis derived from its genetic heterogeneity, which translates to a high chemoresistance. Recently, our workgroup designed TSP1‐derived CD47 agonist peptides and demonstrated their ability to induce cell death in chronic lymphocytic leukemia. Encouraged by these promising results, we evaluated cell death induced by PKHB1 (the first‐described serum‐stable CD47‐agonist peptide) on CEM and MOLT‐4 human cell lines (T‐ALL) and on one T‐murine tumor lymphoblast cell‐line (L5178Y‐R), also assessing caspase and calcium dependency and mitochondrial membrane potential. Additionally, we evaluated selectivity for cancer cell lines by analyzing cell death and viability of human and murine non‐tumor cells after CD47 activation. In vivo, we determined that PKHB1‐treatment in mice bearing L5178Y‐R cell line, increased leukocyte cell count in peripheral blood and lymphoid organs while recruiting leukocytes to the tumor site. To analyze if CD47 activation induced immunogenic cell death (ICD), we evaluated damage‐associated molecular patterns (DAMPs) exposure (Calreticulin, CRT) and release (ATP, HSP70, HSP90, HMGB1, CRT). Furthermore, we administered a prophylactic antitumor vaccination, determining immunologic memory. Our data indicate that PKHB1 induces caspase‐independent and calcium‐dependent cell death in leukemic cells while sparing non‐tumor murine and human cells. Moreover, our results show that PKHB1 can induce ICD in leukemic cells as it induces CRT exposure and DAMPs release in vitro, and prophylactic vaccinations inhibit tumor establishment in vivo. Altogether our results improve the knowledge of CD47 agonist peptides potential as therapeutic tools to treat leukemia.

This article is protected by copyright. All rights reserved.

https://ift.tt/2R6gXs3

Presence and diagnostic value of circulating tsncRNA for ovarian tumor

Abstract

tRNA-derived small non-coding RNAs (tsncRNAs), a class of newly defined small non-coding RNA, have been considered to be involved in various cellular biological processes through regulating gene expression at both transcriptional and post-transcriptional level. However, the presence of circulating tsncRNAs and their diagnostic potential is largely unclear. In this study, we investigate the serum-derived public transcriptome data from ovarian tumor patients and non-cancer controls, and find that circulating tsncRNAs cover a high proportion of total small RNA and are non-random degradation products in serum (ranging from 2.5–29.4%), which are enriched in several specific types of related tRNA (e.g., Gly-tRNA). Particularly, four tsncRNAs are differentially expressed in serum from cancer patients compared to those from healthy controls, and can predict abnormal cell proliferation with high accuracy. Our results reveal the ubiquitous presence of circulating tsncRNAs in serum, and diagnostic potential of specific tsncRNAs for ovarian tumor.

https://ift.tt/2POUByw

BRD4 and Cancer: going beyond transcriptional regulation

Abstract

BRD4, member of the Bromodomain and Extraterminal (BET) protein family, is largely acknowledged in cancer for its role in super-enhancers (SEs) organization and oncogenes expression regulation. Inhibition of BRD4 shortcuts the communication between SEs and target promoters with a subsequent cell-specific repression of oncogenes to which cancer cells are addicted and cell death. To date, this is the most credited mechanism of action of BET inhibitors, a class of small molecules targeting BET proteins which are currently in clinical trials in several cancer settings.

However, recent evidence indicates that BRD4 relevance in cancer goes beyond its role in transcription regulation and identifies this protein as a keeper of genome stability.

Indeed, a non-transcriptional role of BRD4 in controlling DNA damage checkpoint activation and repair as well as telomere maintenance has been proposed, throwing new lights into the multiple functions of this protein and opening new perspectives on the use of BETi in cancer. Here we discuss the current available information on non-canonical, non-transcriptional functions of BRD4 and on their implications in cancer biology. Integrating this information with the already known BRD4 role in gene expression regulation, we propose a "common" model to explain BRD4 genomic function. Furthermore, in light of the transversal function of BRD4, we provide new interpretation for the cytotoxic activity of BETi and we discuss new possibilities for a wide and focused employment of these drugs in clinical settings.

https://ift.tt/2R4vPXR

Long-term efficacy of crizotinib in a metastatic papillary renal carcinoma with MET amplification: a case report and literature review

Abstract

Background

Papillary renal cell carcinoma (pRCC) is the 2nd most frequent histological type of kidney cancer and accounts for approximately 15% of all renal cell carcinoma. It has a poorer prognosis than clear cell RCC (ccRCC) with a lack of standard treatments.

Case presentation

We report the case of a 51 year old man with a metastatic pRCC (hepatic dome and left colonic peritoneal carcinomatosis) progressive after sunitinib, with a MET amplification. The patient was enrolled in the UNICANCER-sponsored AcSé crizotinib trial (NCT02034981), designed to give an access to crizotinib for patients with tumors harboring a genomic alteration on one of the biological targets of the drug. With 2nd line crizotinib (250 mg twice/day), the patient had a very good tolerance, a partial response in the target lesions using RECIST 1.1, and a 19 months' clinical efficacy.

Conclusions

In metastatic pRCC with a MET amplification, crizotinib maybe a potential met-inhibitory therapeutic option.

https://ift.tt/2qZLVGI

Off-Label Use of Phakic Intraocular Lens with a “Piggyback” Technique

Purpose: We report a case of a highly myopic pseudophakic patient who received off-label placement of a phakic intraocular lens (pIOL) via a "piggyback" technique, allowing the placement of an intraocular lens (IOL) in his fellow eye, resulting in improved visual acuity and emmetropia. Case Report: A 66-year-old, highly myopic, pseudophakic male with an IOL implant in his left eye was referred for second opinion for surgical options for his phakic right eye. Given the severe myopic status of both eyes, he received off-label placement of a posterior chamber pIOL with a piggyback technique for the pseudophakic left eye followed by standard cataract surgery and intraocular lens implantation in the right eye. For the left eye, uncorrected best visual acuity improved from 20/70 to 20/25. Conclusion: This case demonstrates the successful off-label use of a phakic IOL in a pseudophakic, highly myopic patient with a piggyback technique, resulting in improved visual acuity and ultimately allowing IOL placement in the fellow eye for emmetropia. This off-label use of pIOL can offer ophthalmologists an alternative option for pseudophakic patents with severe refractive error.
Case Rep Ophthalmol 2018;9:465–472

https://ift.tt/2TynU6I

The morphology and metabolic potential of the Chloroflexi in full-scale activated sludge wastewater treatment plants

Abstract

Filamentous bacteria belonging to the phylum Chloroflexi have received considerable attention in wastewater treatment systems for their suggested role in the operational problem of impaired sludge settleability known as bulking. Their consistently high abundance in full-scale systems, even in the absence of bulking, indicates that they make a substantial contribution to the nutrient transformations during wastewater treatment. In this study, extensive 16S rRNA amplicon surveys of Danish wastewater treatment plants (WWTPs) with nutrient removal were screened to identify numerically important Chloroflexi genera. Fluorescence in situ hybridization probes were designed for their in situ characterization. All abundant Chloroflexi phylotypes were putatively identified as facultative anaerobic chemoorganotrophs involved in sugar fermentation. They were all filamentous but differed in their morphology and spatial arrangement. 'Candidatus Villigracilis' was predominantly located within the activated sludge flocs, where they possibly have structural importance, and their abundance was relatively stable. Conversely, the abundance of 'Candidatus Amarolinea' was highly dynamic, relative to other genera, sometimes reaching abundances in excess of 30% of the biovolume, suggesting their likely role in bulking episodes. This study gives an important insight into the role of Chloroflexi in WWTPs, thus contributing to the broader goal of understanding the ecology of these biotechnologically important systems.

https://ift.tt/2r0sn5h

Helicobacter pylori CagA promotes epithelial mesenchymal transition in gastric carcinogenesis via triggering oncogenic YAP pathway

Abstract

Background

Helicobacter pylori (H. pylori) delivers oncoprotein CagA into gastric epithelial cells via the T4SS and drives activation of multiple oncogenic signalling pathways. YAP, a core effector of the Hippo tumour suppressor pathway, is frequently overexpressed in human cancers, suggesting its potential tumor-promoting role. Although CagA is a casual factor in H. pylori induced gastric carcinogenesis, the link between CagA and YAP pathway has not been identified. In this work, we investigated the regulation of oncogenic YAP pathway by H. pylori CagA.

Methods

Expression of YAP and E-cadherin protein in human gastric biopsies were assessed by immunohistochemistry. H. pylori PMSS1 cagA⁻ isogenic mutant strains were generated. Gastric epithelial cells were co-cultured with H. pylori wild-type cagA⁺ strains or isogenic mutants and were also treated by recombinant CagA expression. Immunofluorescence was performed for YAP localization. Immunoblot and quantitative PCR were performed for examining levels of YAP, downstream effectors and markers of epithelial-mesenchymal transition. Verteporfin and siRNA silencing were used to inhibit YAP activity.

Results

YAP is significantly upregulated in human gastric carcinogenesis. We generated PMSS1 CagA isogenic mutant strains with chloramphenicol resistance successfully. Our analysis indicated that H. pylori infection induced YAP and downstream effectors in gastric epithelial cells. Importantly, knockout of CagA in 7.13 and PMSS1 strains reduced the expression of YAP by H. pylori infection. Moreover, Inhibition of YAP suppressed H. pylori infection-induced Epithelial-mesenchymal transition (EMT).

Conclusion

Our results indicated that H. pylori CagA as a pathogenic protein promotes oncogenic YAP pathway, which contributes to EMT and gastric tumorigenesis. This study provided a novel mechanistic insight into why cagA⁺H. pylori infection is associated with a higher risk for the development of gastric cancer.

https://ift.tt/2DDCILR

Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA)

Abstract

Introduction

Low-dose methoxyflurane, administered via a hand-held inhaler, has been used for short-term pain relief in emergency medicine in Australia and New Zealand for over 40 years, and was recently approved in Europe for the rapid relief of moderate-to-severe trauma-related pain in adults. There is currently a lack of data for methoxyflurane versus active comparators, therefore this trial will investigate the efficacy and safety of inhaled methoxyflurane compared with standard of care (SoC) in the treatment of acute trauma-related pain in pre-hospital and ED settings in Italy.

Methods

MEDITA (Methoxyflurane in Emergency Department in ITAly) is a Phase IIIb, prospective, randomised, active-controlled, parallel-group, open-label, multicentre trial. A total of 272 adult patients with moderate-to-severe pain [score ≥ 4 on the Numerical Rating Scale (NRS)] due to limb trauma will be randomised 1:1 to receive 3 mL methoxyflurane (self-administered by the patient via inhalation under supervision of a trained person) or medications that currently comprise the SoC in Italy [intravenous (IV) morphine for severe pain (NRS ≥ 7); IV paracetamol or ketoprofen for moderate pain (NRS 4–6)], administered as soon as possible after randomisation.

Planned Outcomes

Pain intensity will be measured using a 100-mm visual analogue scale (VAS) at baseline (time of randomisation) and at intervals up to 30 min. Time of onset of pain relief as reported by the patient and use of rescue medication will be recorded. The patient will rate the efficacy and the healthcare professional will rate the practicality of study treatment at 30 min after randomisation using a 5-point Likert scale. Adverse events will be recorded until safety follow-up at 14 ± 2 days. Vital signs will be measured at baseline, 10 and 30 min. The primary aim is to demonstrate non-inferiority of methoxyflurane versus SoC for the change in VAS pain intensity from baseline (randomisation) to 3, 5 and 10 min.

Trial Registration

EudraCT number: 2017-001565-25. Clinicaltrials.gov identifier: NCT03585374.

Funding

Mundipharma Pharmaceuticals srl.

https://ift.tt/2KtWif6

Optimal Axis for Lumbosacral Interbody Fusion: Prospective Finite Element Analysis and Retrospective 3D‐CT Measurement

Introduction

A feasible and optimal axis of biomechanical and anatomic significance in axial lumbosacral interbody fusion (AxiaLIF) was designed.

Materials and Methods

Using the image data set of an adult volunteer, two groups of finite element models of the AxiaLIF, lumbosacral anterior column fixation (ACF) models and middle column fixation (MCF) models with different bone graft fusion degrees, were prospectively established, and their biomechanical differences were comparatively predicted. In addition, 3D reconstruction was performed by retrospectively collecting CT data from pelvises in 60 adult cases. Their anatomic parameters relating to two groups of models were digitally measured and statistically compared.

Results

Numerical analysis revealed that the load and the maximum stress on the screw as well as the maximum stress difference between the screw and peripheral tissues in the MCF model were reduced compared with the ACF model. These indices of both models all decreased markedly in response to the increase in the disc fusion degree. Statistical analysis revealed that the effective fixed length of the sacrum in the MCF model was increased compared with the ACF model (P<0.05). The surgical dissection distance of presacral vessels and nerves from the axis to sacrum of the MCF model was reduced compared with the ACF model (P<0.05).

Conclusions

The feasible and optimal axis of biomechanical and anatomic significance of the AxiaLIF is similar to the axis of the MCF model. Disc bone graft fusions plus axial screw fixations of middle column could strengthen the biomechanical stability of the AxiaLIF model.

This article is protected by copyright. All rights reserved.

https://ift.tt/2zmAv4p

Successful treatment of a BRAF V600E-mutant extracranial metastatic anaplastic oligoastrocytoma with vemurafenib and everolimus

.


https://ift.tt/2S4HI03

Dual-target MDM2/MDMX inhibitor increases the sensitization of doxorubicin and inhibits migration and invasion abilities of triple-negative breast cancer cells through activation of TAB1/TAK1/p38 MAPK pathway

.


https://ift.tt/2DTTXcR

Crosstalk between TF/FVIIa and EGFR signaling in colorectal cancer cells

.


https://ift.tt/2DRKNxh

Long non-coding RNA MEG3 suppresses the development of bladder urothelial carcinoma by regulating miR-96 and TPM1

.


https://ift.tt/2S7YOKy

List of reviewers 2017–2018

https://ift.tt/2R5Gn9f

Improving post-operative patient reported benefits and satisfaction following spinal fusion with a single pre-operative education session.

Publication date: Available online 22 November 2018

Source: The Spine Journal

Author(s): Donna Eastwood, Neil Manson, Erin Bigney, Mariah Darling, Eden Richardson, Richard Paixao, Tracy Underwood, Kate Ellis, Edward Abraham

Background Context

Patient expectations have been demonstrated to influence recovery following spine surgery. Addressing patient expectations specifically in regards to pain and post-surgical healing is an important factor in improving recovery patterns. Pre-surgical education can potentially help manage patient expectations.

Purpose

The primary objective was to determine if participation in a single preoperative multidisciplinary educational session would result in reduced patient dissatisfaction with surgical expectations. A secondary objective was to determine if participation resulted in improvements in post-surgical pain, disability, and reductions in emergency room visits following surgery.

Study Design

A retrospective cohort study utilizing data from the Canadian Spine Outcomes and Research Network (CSORN) registry and hospital electronic medical records.

Patient Sample

Participants were patients receiving elective spinal fusion for 2-5 levels (N = 206).

Cohort 1 included patients who participated in preoperative multidisciplinary education (n= 103). Cohort 2 included patients who opted out of the educational session (n= 103).

Outcome Measures

Outcomes measured included the Oswestry Disability Index (ODI), NRS scales for back and leg pain (NRS-B/NRS-L), CSORN questions pertaining to patient satisfaction with surgery and whether or not the surgery met expectations. Electronic chart review quantified emergency room visits following surgery.

Methods

Spinal fusion patients are encouraged to attend a one time, two-hour education session 3-6 weeks prior to their surgery. The education session includes interactive discussions with nursing, physiotherapy and occupational therapy staff concentrating on what patients should expect, how to best prepare for surgery and proper care post-surgery. A one-way ANOVA was conducted for continuous variables of interest (age, number of levels operated on, ASA score and number of visits to the emergency room following surgery). Chi-squared analysis was conducted for categorical variables of interest (pathology, gender, patient satisfaction, and patient expectations). A 2 (Cohort; education: no education) x 2 (Time; baseline: follow-up) repeated measure ANOVA was conducted for NRS-B, NRS-L, and ODI. Significance was set at p<0.05.

Results

Patients (n=103) who took part in the pre-surgical education sessions were significantly more satisfied with their surgery compared to the control cohort (p = 0.014). Patients (n=103) who did not participate in the education session failed to have their expectations met in terms of improvement in daily activities (p = 0.03), improvement in walking capacity (p = 0.03) and their expectation of back pain reduction (p = .001). There was a statistically significant effect of participation in the educational session reducing postoperative back pain (p = 0.03), although this improvement did not reach a minimally clinically important difference. Number of visits to the emergency room in the 12 weeks following spine surgery was significantly lower (p = 0.04) for patients in the education cohort.

Conclusions

Reduced emergency room utilization, improved patient satisfaction, achievement of expected improvements and alleviation of back pain were documented with greater success following participation in a single 2-hour educational session prior to surgery. A single education session is a viable tool for improving patient outcomes due to its low administrative burden.

https://ift.tt/2PMWvzS

RNA-based analysis of ALK fusions in non-small cell lung cancer cases showing IHC/FISH discordance

Abstract

Background

Rearrangements of the anaplastic lymphoma kinase (ALK) belong to the promising targets in the therapy of advanced non-small cell lung cancer (NSCLC) and are predominantly detected by immunohistochemistry (IHC) and/or fluorescence in-situ hybridization (FISH). However, both methods occasionally produce discordant results, especially in so-called borderline (BL) cases, showing ALK FISH-positive signals in 10–20% of the tumor nuclei around the cutoff (15%). This leads to a diagnostic and thus to a therapeutic dilemma.

Methods

We selected 18 unequivocal (12 ALK IHC/FISH-negative; 6 ALK IHC/FISH-positive) and 15 equivocal samples with discordant results between FISH (Abbott, Vysis LSI ALK Dual Color) and IHC (Ventana, D5F3), including cases with FISH-BL results, for further RNA based-analysis. To detect ALK rearrangement at the transcriptional level, RNA was analyzed using a targeted multiplex-PCR panel followed by IonTorrent sequencing and by direct transcript counting using a digital probe-based assay (NanoString). Sensitivity of both methods was defined using RNA obtained from an ALK-positive cell line dilution series.

Results

Cases with unequivocal IHC/FISH results showed concordant data with both RNA-based methods, whereas the three IHC-negative/FISH-positive samples were negative. The four IHC-negative/FISH-BL-negative cases, as well as the five IHC-negative/FISH-BL-positive samples showed negative results by massive parallel sequencing (MPS) and digital probe-based assay. The two IHC-positive/FISH-BL-positive cases were both positive on the RNA-level, whereas a tumor with questionable IHC and FISH-BL-positive status displayed no ALK fusion transcript.

Conclusions

The comparison of methods for the confirmation of ALK rearrangements revealed that the detection of ALK protein by IHC and ALK fusion transcripts on transcriptional level by MPS and the probe-based assay leads to concordant results. Only a small proportion of clearly ALK FISH-positive cases are unable to express the ALK protein and ALK fusion transcript which might explain a non-responding to ALK inhibitors. Therefore, our findings led us to conclude that ALK testing should initially be based on IHC and/or RNA-based methods.

https://ift.tt/2PMMaDV

Health-related quality of life in long-term survivors of colorectal cancer and its association with all-cause mortality: a German cohort study

Abstract

Background

The group of colorectal cancer (CRC) survivors continues to grow worldwide. Understanding health-related quality of life (HRQOL) determinants and consequences of HRQOL impairments in long-term CRC survivors may help to individualize survivorship care plans. We aimed to i) examine the HRQOL status of CRC long-term survivors, ii) identify cross-sectional sociodemographic and clinical correlates of HRQOL, and iii) investigate the prospective association of HRQOL after CRC diagnosis with all-cause mortality.

Methods

We assessed HRQOL within a Northern German cohort of 1294 CRC survivors at a median of 6 years after CRC diagnosis using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Cross-sectional correlates of different HRQOL dimensions were analyzed using multivariable-adjusted logistic regression models with HRQOL as a binary variable. With multivariable-adjusted Cox proportional hazards regression models, hazard ratios (HR) of all-cause mortality were estimated per 10-point-increments of an HRQOL summary score, a global quality of life scale, and HRQOL functioning and symptom domains.

Results

The median HRQOL summary score was 87 (interquartile range: 75–94). Sex, age, education, tumor location, metastases, other cancers, type of therapy, and current stoma were identified as correlates of different HRQOL scales. After a median follow-up time of 7 years after HRQOL assessment, 175 participants had died. Nearly all HRQOL domains, except for cognitive functioning and diarrhea, were significantly associated with all-cause mortality. A 10-point-increment in the summary score decreased the risk of death by 24% (HR: 0.76; 95% CI: 0.70–0.82).

Conclusions

HRQOL in CRC survivors appeared to be relatively high in the long term. Various clinical and sociodemographic factors were cross-sectionally associated with HRQOL in long-term CRC survivors. Lower HRQOL was associated with increased all-cause mortality. Individualized healthcare programs for CRC survivors (including psychosocial screening and interventions) are needed to detect decreased HRQOL and to further improve long-term HRQOL and survival.

https://ift.tt/2R5F2iJ

Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells

Abstract

Background

Glycosylation plays a critical role in the aggressiveness of pancreatic cancer (PC). Emerging evidences indicate significant involvement of cancer stem cells (CSCs) in PC aggressiveness. However, the importance of glycosylation in pancreatic cancer stem cells (PCSCs) is yet to be addressed. Hence, we evaluated the potential role of glycosylation in maintenance of stemness of PCSCs.

Methods

Effect of glycosylation specific inhibitors on growth and PCSCs of PC cells was assessed by MTT assay and Side Population (SP) analysis. Isolated PCSCs/SP were characterized using molecular and functional assays. Expression of tumor-associated carbohydrate antigens (TACAs) was analyzed in PCSCs by western blotting. Effect of tunicamycin on PCSCs was analyzed by tumorsphere, clonogenicity, migration assay and immunoblotting for CSCs markers. The differential expression of glycogenes in PCSCs compared to non-CSCs were determined by RT-qPCR, immunoblotting and immunofluorescence. Co-expression of GALNT3 and B3GNT3 with CD44v6 was assessed in progression stages of Kras^G12D; Pdx-1-Cre (KC) and Kras^G12D; p53^R172H; Pdx-1-Cre (KPC) tumors by immunofluorescence. Transient and CRISPR/Cas9 silencing of GALNT3 and B3GNT3 was performed to examine their effect on CSCs maintenance.

Results

Inhibition of glycosylation decreased growth and CSCs/SP in PC cells. PCSCs overexpressed CSC markers (CD44v6, ESA, SOX2, SOX9 and ABCG2), exhibited global expressional variation of TACAs and showed higher self-renewal potential. Specifically, N-glycosylation inhibition, significantly decreased tumorsphere formation, migration, and clonogenicity of PCSCs, as well as hypo-glycosylated CD44v6 and ESA. Of note, glycosyltransferases (GFs), GALNT3 and B3GNT3, were significantly overexpressed in PCSCs and co-expressed with CD44v6 at advanced PDAC stages in KC and KPC tumors. Further, GALNT3 and B3GNT3 knockdown led to a decrease in the expression of cell surface markers (CD44v6 and ESA) and self-renewal markers (SOX2 and OCT3/4) in PCSCs. Interestingly, CD44v6 was modified with sialyl Lewis a in PCSCs. Finally, CRISPR/Cas9-mediated GALNT3 KO significantly decreased self-renewal, clonogenicity, and migratory capacity in PCSCs.

Conclusions

Taken together, for the first time, our study showed the importance of glycosylation in mediating growth, stemness, and maintenance of PCSCs. These results indicate that elevated GALNT3 and B3GNT3 expression in PCSCs regulate stemness through modulating CSC markers.

https://ift.tt/2PKrYCw

The effect of cold tetracaine on the severity of burning sensation upon instillation

https://ift.tt/2r1pvFa

Normative developmental trajectories of actigraphic sleep variables during the preschool period: A three‐wave longitudinal study

Abstract

Important changes in sleep are believed to occur in the preschool years, but studies that have documented these changes were generally cross‐sectional or based on subjective sleep measures. The current longitudinal study modeled the developmental trajectories followed by five sleep variables objectively assessed during the preschool period. Children (N = 128) wore an actigraph over 3 days at 2, 3, and 4 years of age and change in sleep variables was assessed with growth curves. The results showed a linear decrease of daytime, total, and nighttime sleep duration, and a linear increase of sleep efficiency and proportion of nighttime to total sleep. For all sleep variables, the rhythm of change was relatively uniform across children, but there was significant inter‐individual variation around the initial status for most variables. To our knowledge, this study is the first to model the developmental trajectories followed by several sleep variables during the preschool period.

https://ift.tt/2R2kdVa

Experience with hypofractionated stereotactic radiosurgery in a series of patients with skull base tumors

Abstract

Introduction and objective

Although the effectiveness of single-fraction brain stereotactic radiosurgery has been extensively demonstrated, recent evidence is suggesting that when skull base lesions are the targets, radiation near critical structures (e.g., optic nerves, and brainstem) should be reduced to avoid radiotoxic effects, with the risk of treatment inefficacy. Hence, in these tumors, hypofractionated stereotactic radiosurgery (HSRS) would offer a therapeutical opportunity. Here, we present our experience with this modality in the management of patients with skull base tumors.

Methods

A series of patients with skull base tumors was retrospectively analyzed to evaluate the treatment with HSRS. The primary endpoint was tumor control in post-treatment imaging. Age, sex, tumor histology, tumor volume, type of radiation protocol, pre-treatment Karnofsky performance status (KPS), previous neurosurgery, and prior radiotherapy were analyzed.

Results

A total of 84 patients were treated between January/2009 to January/2017. Median age: 51.5 years. Female gender: 53.6%. There was 92.7% of non-progression after HSRS, with a median f/u of 36 months. Main tumors treated were pituitary adenomas, acoustic schwannomas, and skull base meningioma. Most of the patients were treated with a 5-day fraction scheme of a 25 Gy total dose. No late radiotoxicity was observed. In multivariate analysis, a high KPS was associated with non-progression.

Conclusions

In our series of patients, the high incidence of non-progression of tumors indicated that HSRS could be a therapeutic option in some cases of skull base lesions, mainly residuals or tumoral recurrences of pituitary adenomas, schwannomas, and meningiomas.

https://ift.tt/2R5WGTc

Long non‐coding RNA expression profiling in cancer: challenges and opportunities

Abstract

In recent years, technological advances in transcriptome profiling revealed that the repertoire of human RNA molecules is more diverse and extended than originally thought. This diversity and complexity mainly derives from a large ensemble of non‐coding RNAs. Because of their key roles in cellular processes important for normal development and physiology, disruption of non‐coding RNA expression is intrinsically linked to human disease, including cancer. Therefore, studying the non‐coding portion of the transcriptome offers the prospect of identifying novel therapeutic and diagnostic targets. While evidence of the relevance of non‐coding RNAs in cancer is accumulating, we still face many challenges when it comes to accurately profiling their expression levels. Some of these challenges are inherent to the technologies employed, while others are associated with characteristics of the non‐coding RNAs themselves. In this review, we discuss the challenges related to long non‐coding RNA expression profiling, highlight how cancer long non‐coding RNAs provide new opportunities for cancer diagnosis and treatment, and reflect on future developments.

This article is protected by copyright. All rights reserved.

https://ift.tt/2DTL573

Dosimetric comparison of different radiation techniques (IMRT vs. 3-dimensional) of the “true” (deep) ano-inguinal lymphatic drainage of anal cancer patients

Abstract

Introduction

The ano-inguinal lymphatic drainage (AILD) is located in the subcutaneous adipose tissue of the proximal medial thigh. Currently, there are no recommendations for an inclusion of the 'true' AILD in the clinical target volume (CTV) of definitive chemoradiation for anal cancer patients. To estimate the relevance of inguinal recurrence, we compared the incidental dose to the AILD in anal cancer (AC) patients who were treated either with Volumetric Arc Therapy – Intensity Modulated Radiation Therapy (VMAT-IMRT) or conventional 3D-radiation technique.

Methods

One VMAT-IMRT-plans and one 3D-plans were calculated on the same target volumes and identical dose prescription in ten patients. We defined the volume of the AILD on the planning CT-scans based on the information of new fluorescence methods. Furthermore, we defined several anatomical subvolumes of interest inside the AILD. We examined and compared absolute and relative dosimetric parameters of the AILD and different anatomical subunits.

Results

The Dmean of the AILD was 40 Gy in the 3D-group and 38 Gy in the IMRT-group. Dmean and Dmedian as well as the V30Gy of the AILD and all subvolumes of the caudal AILD were significant higher using 3D-RT compared to IMRT. Even though the absolute differences were small, in the caudal aspect of the ano-inguinal lymphatic drainage the V30Gy could be more than 10% less with VMAT-IMRT.

Conclusions

3D-RT was slightly superior to IMRT in terms of dose coverage of the AILD. However, the absolute differences were very small. Some relevant caudal parts of the AILD received an insufficient dose for treating potential micrometastases. Particularly in high-risk situations, this may lead to inguinal recurrence and therefore the true deep AILD should be included into the target volume in high risk patients.

https://ift.tt/2TzvbmS

Comparison of different treatment planning approaches for intensity-modulated proton therapy with simultaneous integrated boost for pancreatic cancer

Abstract

Background

Neoadjuvant radio(chemo)therapy of non-metastasized, borderline resectable or unresectable locally advanced pancreatic cancer is complex and prone to cause side-effects, e.g., in gastrointestinal organs. Intensity-modulated proton therapy (IMPT) enables a high conformity to the targets while simultaneously sparing the normal tissue such that dose-escalation strategies come within reach. In this in silico feasibility study, we compared four IMPT planning strategies including robust multi-field optimization (rMFO) and a simultaneous integrated boost (SIB) for dose-escalation in pancreatic cancer patients.

Methods

For six pancreatic cancer patients referred for adjuvant or primary radiochemotherapy, four rMFO-IMPT-SIB treatment plans each, consisting of two or three (non-)coplanar beam arrangements, were optimized. Dose values for both targets, i.e., the elective clinical target volume [CTV, prescribed dose D_pres = 51Gy(RBE)] and the boost target [D_pres = 66Gy(RBE)], for the organs at risk as well as target conformity and homogeneity indexes, derived from the dose volume histograms, were statistically compared.

Results

All treatment plans of each strategy fulfilled the prescribed doses to the targets (D_{pres(GTV,CTV)} = 100%, D_{95%,(GTV,CTV)} ≥ 95%, D_2%,(GTV,CTV) ≤ 107%). No significant differences for the conformity index were found (p > 0.05), however, treatment plans with a three non-coplanar beam strategy were most homogenous to both targets (p < 0.045). The median value of all dosimetric results of the large and small bowel as well as for the liver and the spinal cord met the dose constraints with all beam arrangements. Irrespective of the planning strategies, the dose constraint for the duodenum and stomach were not met. Using the three-beam arrangements, the dose to the left kidney could be significant decreased when compared to a two-beam strategy (p < 0.045).

Conclusion

Based on our findings we recommend a three-beam configuration with at least one non-coplanar beam for dose-escalated SIB with rMFO-IMPT in advanced pancreatic cancer patients achieving a homogeneous dose distribution in the target while simultaneously minimizing the dose to the organs at risk. Further treatment planning studies on aspects of breathing and organ motion need to be performed.

https://ift.tt/2AfloJX

Small-Cell Lung Cancer Comorbid with Pulmonary Mycobacterium avium Infection: A Case Report

Background: Small-cell lung cancer (SCLC) rarely coexists with pulmonary Mycobacterium avium intracellular complex (MAC) infection. The key drug for SCLC treatment is etoposide, which is metabolized by cytochrome P-450 (CYP) 3A4. Meanwhile, the key drugs for pulmonary MAC infection are clarithromycin (CAM) and rifampicin (RFP), and their metabolism influences CYP3A4. Therefore, treatment of concurrent SCLC and pulmonary MAC infection is difficult, and to the best of our knowledge, no report of treatments for concurrent SCLC and pulmonary MAC infection has been published. Patient Concerns and Diagnoses: A 65-year-old man presented to our hospital with abnormal findings of chest computed tomography: (1) a hilar region nodule in the left lung and mediastinal lymphadenopathy and (2) a thick-walled cavity lesion in the right upper lobe of the lung. After further examinations, the former lesions were diagnosed as SCLC, cT4N3M0, stage IIIC and the latter as pulmonary MAC infection, fibrocavitary disease. Interventions and Outcomes: Concurrent treatment was conducted with discontinuation of CAM and RFP before and after etoposide administration. Specifically, intravenous cisplatin and etoposide were administered on day 1 and days 1–3, respectively, and CAM, RFP, and ethambutol (EB) were administered orally on days 6–22 every 4 weeks. Concurrent radiotherapy was added to the drug administration on days 1–27 of the first cycle. The chemotherapy was continued for 4 cycles, followed by continuation of CAM and RFP administration. EB was discontinued because of optic nerve disorder. The treatments were conducted completely and safely, and both of the SCLC lesions and the MAC lesion were improved. Conclusions: Treatments for concurrent SCLC and pulmonary MAC infection may be successfully conducted with discontinuation of CAM and RFP before and after etoposide administration.
Chemotherapy 2018;63:257–261

https://ift.tt/2TFHbmW

A systematic review of non-standard dosing of oral anticancer therapies

Abstract

Background

The use of oral systemic anticancer therapies (SACT) has increased and led to improved cancer survival outcomes, particularly with the introduction of small molecule targeted agents and immunomodulators. Oral targeted SACT are, however, associated with toxicities, which might result in reduced quality of life and non-adherence. To reduce treatment-related toxicity, the practice of non-standard dosing is increasing; however guidance to govern this practice is limited. A systematic review was conducted to identify evidence of, and outcomes from, non-standard dosing of oral SACT in oncology and malignant haematology.

Methods

A comprehensive search of 78 oral SACT was conducted in the following databases: MEDLINE®, EMBASE®, Cochrane Library©, and Cumulative Index to Nursing and Allied Health Literature (CINAHL©). Studies were selected based on predefined inclusion/exclusion criteria, and were critically appraised. Extracted data were tabulated to summarise key findings. Due to diversity of study designs and heterogeneity of reported outcomes, studies were categorised and evidence was synthesised in three main themes: dose interruption; dose reduction; and other dosing strategies.

Results

Thirty-four studies were eligible for inclusion: four clinical trials, fifteen cohort studies and fifteen case reports. Evidence for non-standard dosing was reported for eleven oral SACT. Dose interruptions were the most commonly reported strategy (14 studies); nine studies reported dose reductions; and eleven reported other dosing strategies. Eight retrospective cohort studies reported dose interruption of sunitinib in renal cell carcinoma and showed either similar or improved responses and survival outcomes, and fewer or equivalent high grade toxicities, compared to the standard schedule. Four cohort studies retrospectively evaluated dose reductions of imatinib, gefitinib or erlotinib, for chronic myeloid leukaemia and non-small cell lung cancer, respectively. Other dosing strategies included alternate-day dosing. The quality of the evidence was limited by the small sample size in many studies, retrospective study designs, and lack of reported toxicity and/or QoL outcomes.

Conclusions

This review identified limited evidence to support current non-standard dosing strategies, but some of findings, e.g. dose interruption of sunitinib, warrant further investigation in large-scale prospective clinical trials.

https://ift.tt/2An8x8D

Prevalence of drug-drug interactions in oncology patients enrolled on National Clinical Trials Network oncology clinical trials

Abstract

Background

Drug-drug interactions (DDIs) in subjects enrolling in clinical trials can impact not only safety of the patient but also study drug outcomes and data validity. This makes it critical to adequately screen and manage DDIs. The study objective was to determine the prevalence of DDIs involving study medications in subjects enrolling in National Clinical Trials Network (NCTN) clinical trials at a single institution. DDIs were evaluated based on study protocol recommendations for concomitant medication use (i.e. exclude, avoid or use caution), screening via DDI tool, and pharmacist review.

Methods

Subjects enrolled in NCTN trials of commercially available agents between January 2013 and August 2017 were included if a complete medication list was available. Complete medication lists were collected from the date of enrollment or the next available date then screened utilizing protocol guidance and the DDI screening tool, Lexicomp® Drug Interactions (Wolters Kluwer, Hudson, OH). Interactions were reviewed for clinical relevance: defined as a DDI that would require a medication change to ensure study agent safety and efficacy at enrollment.

Results

One hundred and twenty-eight subjects enrolled in 35 clinical trials were included. Protocol guidance detected 15 unique DDI pairs that should be avoided or used with caution in 10.2% (13/128) of subjects. The majority of these subjects did not have a clinically relevant DDI (69.2%, 9/13) based on pharmacist review. Lexicomp® detected moderate to major DDIs in 24.2% (31/128) of subjects, with 9.4% (12/128) having a clinically relevant DDI.

Conclusions

This study confirms a high prevalence of DDIs present in subjects enrolling in oncology clinical trials. Further efforts should be made to improve methods to detect and manage DDIs in patients enrolling on clinical trials to ensure patient safety and trial data validity.

https://ift.tt/2TzIYtx

Fecal microbiota transplantation in cancer management: Current status and perspectives

The human gut is home to a large and diverse microbial community, comprising about 1000 bacterial species. The gut microbiota exists in a symbiotic relationship with its host, playing a decisive role in the host's nutrition, immunity, and metabolism. Accumulating studies have revealed the associations between gut dysbiosis or some special bacteria and various cancers. Emerging data suggest that gut microbiota can modulate the effectiveness of cancer therapies, especially immunotherapy. Manipulating the microbial populations with therapeutic intent has become a hot topic of cancer research, and the most dramatic manipulation of gut microbiota refers to fecal microbiota transplantation (FMT) from healthy individuals to patients. FMT has demonstrated remarkable clinical efficacy against Clostridium difficile infection (CDI) and it is highly recommended for the treatment of recurrent or refractory CDI. Lately, interest is growing in the therapeutic potential of FMT for other diseases, including cancers. We briefly reviewed the current researches about gut microbiota and its link to cancer, and then summarized the recent pre‐clinical and clinical evidence to indicate the potential of FMT in cancer management as well as cancer‐treatment associated complications. We also presented the rationale of FMT for cancer management such as reconstruction of intestinal microbiota, amelioration of bile acid metabolism, and modulation of immunotherapy efficacy. This article would help to better understand this new therapeutic approach for cancer patients by targeting gut microbiota.

This article is protected by copyright. All rights reserved.

https://ift.tt/2AgtSjF

Cancers, Vol. 10, Pages 465: mTOR Activation in Liver Tumors Is Associated with Metabolic Syndrome and Non-Alcoholic Steatohepatitis in Both Mouse Models and Humans

Cancers, Vol. 10, Pages 465: mTOR Activation in Liver Tumors Is Associated with Metabolic Syndrome and Non-Alcoholic Steatohepatitis in Both Mouse Models and Humans

Cancers doi: 10.3390/cancers10120465

Authors: Takahiro Okuno Anna Kakehashi Naomi Ishii Masaki Fujioka Min Gi Hideki Wanibuchi

Non-alcoholic steatohepatitis (NASH) can cause liver fibrosis and cirrhosis, with final progression to hepatocellular carcinoma (HCC) in some cases. Various factors have been suggested to be involved in the development of NASH. Considering the many possible contributing factors, we postulated that mechanisms of progression from NASH to HCC could differ depending on the risk factors. In the present study, we applied two mouse models of NASH&ndash;HCC and performed histopathological and proteome analyses of mouse liver tumors. Furthermore, to compare the mechanisms of NASH&ndash;HCC progression in mice and humans, we investigated HCCs in humans with a background of metabolic syndrome and NASH, as well as HCCs associated with hepatitis virus infection by immunohistochemistry. It was demonstrated that upstream regulators associated with the mammalian target of rapamycin (mTOR) pathway were altered in liver tumors of mice with metabolic syndrome characteristics (TSOD mice) using proteome analysis. Immunohistochemical analysis showed that mTOR was characteristically phosphorylated in liver tumors of TSOD mice and HCCs from metabolic syndrome cases in humans. These results indicated that the mTOR pathway is characteristically activated in liver tumors with metabolic syndrome and NASH, unlike liver tumors with other etiologies.

https://ift.tt/2Q8XjOT

The utility of combined mutation analysis and microRNA classification in reclassifying cancer risk of cytologically indeterminate thyroid nodules

Abstract

Objectives

Real‐world clinical results of (1) Bethesda categorization, (2) mutation analysis, and (3) a microRNA classifier were correlated to show the utility of molecular analysis in assessing malignancy risk of indeterminate thyroid nodules.

Methods

Cytology and molecular results of clinically tested thyroid nodules were compared. An additional microRNA threshold was determined based on nodules with known disease status, establishing a 3‐tiered microRNA approach to clinical risk assessments. Expected rate of malignancy given mutation panel and 3‐tiered microRNA approach was validated in an independent cohort of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) and follicular neoplasm or suspicious for follicular neoplasm (FN/SFN) nodules with surgically derived outcomes.

Results

In 2685 patients clinically tested, PIK3CA, PAX8/PPARγ, and RET/PTC mutations occurred in less than 1%. Of note, 2% had BRAFV600E mutation and 82% lacked mutations. The maximum expected risk of malignancy in nodules lacking mutations was 9% and 17% for AUS/FLUS and FN/SFN nodules, respectively. Positive microRNA status further increased risk, with the most worrisome status (level‐3) elevating risk to 36% and 54%, respectively. RAS mutations occurred in 15% of nodules tested clinically, including in 8% of those that were cytologically benign. The maximum expected risk of malignancy in nodules with RAS or PAX8/PPARγ mutations was 49% and 65% for AUS/FLUS and FN/SFN nodules, respectively. Positive microRNA status further increased risk, with the most worrisome microRNA status (level‐3) elevating risk to 85% and 91%, respectively.

Conclusions

Mutation panels alone do not sufficiently risk stratify thyroid nodular disease. microRNA classification complements cytology and mutation analysis with the capacity to better differentiate nodules at high risk of malignancy.

https://ift.tt/2DAMpL4

The diagnostic value of parathyroid hormone washout in primary hyperparathyroidism patients with negative or equivocal 99 m Tc‐MIBI results

Background and objectives

The accurate identification of hyper functioning parathyroid gland is needed for definitive surgical treatment in primary hyperparathyroidism. Ultrasonography and 99mTechnetium sestamibi scintigraphy are the two most used methods with varying sensitivities. This study aimed to assess the value of parathyroid hormone (PTH) assay in preoperative ultrasound guided fine needle aspiration (FNA)‐PTH washout fluid to verify the correct localisation of lesions with negative or inconclusive scintigraphy results.

Methods

We evaluated data of 28 lesions in 21 patients who underwent US‐guided parathyroid fine‐needle aspiration (FNA) with PTH washout, retrospectively. The PTH washout results and the reports of parathyroid surgery and imaging studies were reviewed.

Results

Of operated 28 lesions 23 had positive and 5 had negative washout results. The median FNA‐PTH washout was 2315.5 pg/ ml (min–max: 12.3‐6978 pg/ ml). The calculated sensitivity of FNA‐PTH washout was 85.7% and the specifity was 28.6%. The positive and negative predictive values were 78.3% and 40.0%, respectively.

Conclusions

FNA‐PTH can be used to establish the nature of the lesion, discriminate parathyroid gland from thyroid lesions or cervical lymph nodes, improving the surgical outcomes. It can be used to localise parathyroid lesions preoperatively when negative or discordant ultrasound and scintigraphy findings are obtained.

https://ift.tt/2Qc1E3F

Smear cytological features of large cell neuroendocrine carcinoma of the uterine cervix in pregnancy: A case report and review of the literature

Large‐cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is a rare aggressive tumor. The examination of a cervicovaginal smear from a 31‐year‐old patient diagnosed with LCNEC after a cervical polypectomy during the 32nd week of pregnancy was carried out. The observed atypical cells had large cytoplasm, increased nucleus: cytoplasm ratio with the nucleus containing coarse, dispersed chromatin, and were arranged in a pseudorosette formation, which all confirmed the diagnosis. In addition, adenocarcinoma in situ (AIS) was determined in the histopathological examination of the subsequent hysterectomy material. Given the rarity of this condition, we present and discuss the case herein.

https://ift.tt/2DDWEhK

Galactocele of adult male breast: A cytopathologist's perspective

Galactocele, although a common cytological diagnosis in females, is not previously reported as a cause of breast enlargement in adult males. Hyperprolactinemia is the principal cause of galactocele in male breast. Besides drug induced hyperprolactinemia, other anatomical lesions of hypothalamo‐pituitary region and different medical conditions like cirrhosis and chronic kidney disease are to be considered along with a full evaluation of features revealing hypogonadism in case of galactocele. Aspirated milk from the male breast is the primary clue for this detailed investigation process. Here we are presenting the first case of galactocele of the male breast due to hypogonadotropic hypogonadism with idiopathic hyperprolactinemia.

https://ift.tt/2QfVcst

Prevalence of high‐risk human papilloma virus in liquid‐based cervical samples from Turkish women with normal and abnormal cytology

Abstract

Background

The aim of this study was to investigate the prevalence of human papilloma virus (HPV) infection from Turkish women with normal and abnormal cytology.

Methods

Our study population consisted of 1252 women with normal and abnormal cytology. In our clinic, cervical cancer screening was performed by liquid‐based cytology testing (ThinPrep Pap Test). Reflex high‐risk (HR) HPV testing (Cervista HPV HR and HPV 16/18) was performed in cases with abnormal cytology (n = 330). HR HPV testing was performed to 922 cases with normal cytology.

Results

HR HPV was detected in 18.7% of negative for intraepithelial lesion or malignancy (NILM) samples, and in 79.7% of abnormal cytology cases. HPV types 16 and/or 18 were found in 18.6% and 35.3% of normal cytology cases and abnormal cytology cases, respectively. Of all 435 HR HPV‐positive samples, HPV type 16 and/or 18 prevalence was significantly higher in cases with more severe cytological abnormalities.

Conclusions

The HPV prevalence among Turkish women with normal and abnormal cytology identified in this study largely concurs with those in other studies throughout the world. HPV types 16 and/or 18 were detected significantly in normal cytology cases in our study. We also found that, as has been previously demonstrated, certain HPV genotypes (16/18) are associated with more severe pathologies. However, larger epidemiological studies in different regions of Turkey are needed to evaluate the accurate prevalence of HPV infection throughout the country.

https://ift.tt/2DAlhvw

Advantage of Z‐stacking for teleconsultation between the USA and Colombia

Abstract

Introduction

There is an emerging need for telecytology in Colombia as the demand for cytopathology has increased. However, due to economic and technological constraints telecytology services are limited. Our aim was to evaluate the diagnostic feasibility of using whole slide imaging with and without Z‐stacking for telecytology in Colombia, South America.

Methods

Archival glass slides from 17 fine needle aspiration smears were digitized employing whole slide imaging (WSI) (Nanozoomer 2.0 HT, Hamamatsu) in one Z‐plane at 40x, and panoramic digital imaging (Panoptiq system, ViewsIQ) combining low‐magnification digital maps with embedded 40x Z‐stacks of representative regions of interest. Fourteen Colombian pathologists reviewed both sets of digital images. Diagnostic concordance, time to diagnosis, image quality (scale 1–10), usefulness of Z‐stacking, and technical difficulties were recorded.

Results

Image quality scored by pathologists was on average 8.3 for WSI and 8.7 for panoramic images with Z‐stacks (P = .03). However, diagnostic concordance was not impacted by image quality ranking. In the majority of cases (72.4%) pathologists deemed Z‐stacking to be diagnostically helpful. Technical issues related to Z‐stack video performance constituted only a minor proportion of technical problems reported. Slow downloads and crashing of files while viewing were mostly experienced with larger WSI files.

Conclusion

This study demonstrated that international telecytology for diagnostic purposes is feasible. Panoramic images had to be acquired manually, but were of suitable diagnostic quality and generated smaller image files associated with fewer technical errors. Z‐stacking proved to be useful in the majority of cases and is thus recommended for telecytology.

https://ift.tt/2QeQhYT