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Τρίτη 11 Δεκεμβρίου 2018

Venous Thromboembolism Prophylaxis and Risk in the Inpatient and Outpatient Continuum of Care Among Hospitalized Acutely Ill Patients in the US: A Retrospective Analysis

Abstract

Introduction

Venous thromboembolism (VTE) is a leading cause of preventable morbidity and mortality among hospitalized patients in the US. The objectives of this study were to examine VTE prophylaxis patterns and risk for VTE events during hospitalization and post-discharge among patients hospitalized for acute illnesses in the US.

Methods

Acutely ill hospitalized patients were identified from the MarketScan databases (January 1, 2012–June 30, 2015). Proportions of patients that received inpatient and/or outpatient VTE prophylaxis were determined. VTE rates were calculated for the overall study population and for each subpopulation with each acute illness type. Risk for VTE events after the index admission was determined by Kaplan–Meier analysis.

Results

Of the acutely ill patients (n = 17,895, mean age: 58.4 years), most were hospitalized for infectious diseases (40.6%), followed by respiratory diseases (31.0%), cancer (10.7%), heart failure (10.4%), ischemic stroke (6.4%), and rheumatic diseases (0.9%). Among the entire study population, 59.1% did not receive any VTE prophylaxis, and only 7.1% received both inpatient and outpatient prophylaxis. Among the overall study population, cumulative VTE rate, including during index admission and within 6 months post-discharge, was 4.6%. VTE risk in the inpatient and outpatient continuum of care remained elevated up to 30-40 days after hospital admission, with 60.1% of VTEs occurring within 40 days of hospital admission.

Conclusion

In this retrospective analysis of nearly 18,000 patients hospitalized for acute illnesses, 59.1% did not receive any VTE prophylaxis and only 7.1% received VTE prophylaxis in both the inpatient and outpatient continuum of care, despite significant VTE risk extending from hospitalization into the post-discharge period.

Funding

Portola Pharmaceuticals.



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Shi’s Daoyin Therapy for Neck Pain: A Randomized Controlled Trial

Objective. To compare the immediate and short term effectiveness of Shi's Daoyin therapy (DT) rather than the Melbourne Protocol (MP) in terms of pain, mobility, and isometric strength of cervical muscles in nonacute nonspecific neck pain patients. Material and Methods. A total of 114 nonacute nonspecific neck pain patients aged 20~50 years were recruited and randomly assigned to be treated by either Shi's DT or the MP. 56 cases and 54 cases received treatment for 3 weeks and were evaluated before and after intervention and at 3-week follow-up in Shi's DT group and MP group, respectively. The outcome measures were Chinese version of the Neck Disability Index (NDI), cervical range of motion (ROM), maximal voluntary isometric force (MVIF), and pain intensity (Numeric Pain Rating Scale, NPRS). Results. All outcomes of both groups showed statistically significant improvements after the intervention and at 3-week follow-up (P

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Efficacy of a Chinese Herbal Medicine Compound Zhangpi Ointment against Hydroxyurea-Induced Leg Ulcers: A Prospective, Randomized, Open-Label, Controlled Clinical Trial

Objective. The randomized controlled trial was to evaluate the efficacy of topical Chinese herbal Zhangpi Ointment for hydroxyurea-induced leg ulcers in patients with myeloproliferative neoplasms. Patients and Methods. This single-center, prospective, randomized, open-label, controlled clinical trial conducted at Shanghai Ninth People's Hospital enrolled 54 patients with hydroxyurea-induced leg ulcers. Patients were randomly assigned to the control group (n = 27) treated with chlorhexidine dressing or the intervention group (n = 27) treated with the Zhangpi Ointment. Finally, 26 patients in the control group and 23 patients in the intervention group completed 8 weeks of observation. Results. The rate of complete healing was 100% for the intervention group, which was significantly higher than that of the control group (96.15%) (P

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Cancers, Vol. 10, Pages 510: Management of Typical and Atypical Pulmonary Carcinoids Based on Different Established Guidelines

Cancers, Vol. 10, Pages 510: Management of Typical and Atypical Pulmonary Carcinoids Based on Different Established Guidelines

Cancers doi: 10.3390/cancers10120510

Authors: Rohit Gosain Sarbajit Mukherjee Sai S. Yendamuri Renuka Iyer

Neuroendocrine tumors (NETs) are a group of malignancies that originated from neuroendocrine cells, with the most common sites being lungs and the gastrointestinal tract. Lung NETs comprise 25% of all lung malignancies. Small cell lung cancer is the most common form of lung NETs, and other rare forms include well-differentiated typical carcinoids (TCs) and poorly differentiated atypical carcinoids (ACs). Given the paucity of randomized studies, rational treatment is challenging. Therefore, it is recommended that these decisions be made using a multidisciplinary collaborative approach. Surgery remains the mainstay of treatment, when feasible. Following surgery, various guidelines offer different recommendations in the adjuvant setting. In this paper, we describe the adjuvant management of lung NETs, as recommended by different guidelines, and highlight their differences. In addition to that, we also discuss the management of metastatic lung NETS, including the use of peptide receptor radionucleotide therapy.



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Cancers, Vol. 10, Pages 509: Mitochondrial Hyperactivation and Enhanced ROS Production are Involved in Toxicity Induced by Oncogenic Kinases Over-Signaling

Cancers, Vol. 10, Pages 509: Mitochondrial Hyperactivation and Enhanced ROS Production are Involved in Toxicity Induced by Oncogenic Kinases Over-Signaling

Cancers doi: 10.3390/cancers10120509

Authors: Monica Ceccon Mario Mauri Luca Massimino Giovanni Giudici Rocco Piazza Carlo Gambacorti-Passerini Luca Mologni

Targeted therapy is an effective, rational, and safe approach to solid and hematological tumors treatment. Unfortunately, a significant fraction of patients treated with tyrosine kinase inhibitors (TKI) relapses mainly because of gene amplification, mutations, or other bypass mechanisms. Recently a growing number of papers showed how, in some cases, resistance due to oncogene overexpression may be associated with drug addiction: cells able to proliferate in the presence of high TKI doses become also TKI dependent, undergoing cellular stress, and apoptosis/death upon drug withdrawal. Notably, if a sub-cellular population survives TKI discontinuation it is also partially re-sensitized to the same drug. Thus, it is possible that a subset of patients relapsing upon TKI treatment may benefit from a discontinuous therapeutic schedule. We focused on two different hematologic malignancies, chronic myeloid leukemia (CML) and anaplastic large cell lymphoma (ALCL), both successfully treatable with TKIs. The two models utilized (LAMA and SUP-M2) differed in having oncogene overexpression as the sole cause of drug resistance (CML), or additionally carrying kinase domain mutations (ALCL). In both cases drug withdrawal caused a sudden overload of oncogenic signal, enhanced mitochondria activity, induced the release of a high amount of reactive oxygen species (ROS), and caused genotoxic stress and massive cell death. In LAMA cells (CML) we could rescue the cells from death by partially blocking downstream oncogenic signaling or lowering ROS detrimental effect by adding reduced glutathione.



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Prehospital Double Sequential Defibrillation: A Matched Case‐Control Study

Abstract

Study Objectives

The goal of our study is to determine if prehospital double sequential defibrillation (DSD) is associated with improved survival to hospital admission in the setting of refractory ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT).

Methods

This project is a matched case‐control study derived from prospectively collected Quality Assurance/Quality Improvement (QA/QI) data obtained from the San Antonio Fire Department out‐of‐hospital cardiac arrest database between JAN 2013 and DEC 2015. The cases were defined as out‐of‐hospital cardiac arrest (OHCA) patients with refractory VF/pVT that survived to hospital admission. The control group was defined as OHCA patients with refractory VF/pVT that did not survive to hospital admission. The primary variable in our study was prehospital DSD. The primary outcome of our study was survival to hospital admission.

Results

Of 3469 consecutive OHCA patients during the study period, 205 OHCA patients met the inclusion criterion of refractory VF/pVT. Using a predefined algorithm, two blinded researchers identified sixty‐four unique cases and matched them with sixty‐four unique controls. Survival to hospital admission occurred in 48.0% of DSD patients and 50.5% of the conventional therapy patients (p>0.99) (OR 0.91, 95% CI [0.40,2.1]).

Conclusion

Our matched case‐control study on the prehospital use of double sequential defibrillation for refractory ventricular fibrillation/pulseless ventricular tachycardia found no evidence of associated improvement in survival to hospital admission. Our current protocol of considering prehospital double sequential defibrillation after the third conventional defibrillation in out‐of‐hospital cardiac arrest is ineffective.

This article is protected by copyright. All rights reserved.



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Identification of Long Noncoding RNA MIR22HG as a Novel Biomarker in Thyroid Cancer

Abstract

Thyroid cancer (TC) is the one of the most common endocrine malignancy. However, currently there are no specific and sensitive biomarkers for predicting the prognosis for TC. In this study, we for the first time showed MIR22HG was down-regulated in thyroid cancer by analyzing public datasets, including TCGA, GSE29265, GSE33630, and GSE55091. Furthermore, we observed the lower expression levels of MIR22HG were significantly related to higher age, lymph node metastasis status, residual tumor status, N stage, Grade, and T stage in TC. We also observed higher MIR22HG expression was associated with longer overall and disease-free survival time in TC. In order to explore the potential mechanisms of MIR22HG regulating TC progression, 4 hub gene networks regulated by MIR22HG were constructed in the present study. Bioinformatics analysis showed MIR22HG was associated with apoptotic process, regulation of transcription, mRNA splicing, regulation of cell cycle, and Hippo signaling pathway in TC. These results suggested MIR22HG could serve as a novel biomarker for thyroid cancer.



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Mexico and mitochondrial replacement techniques: what a mess

Abstract
Background
The first live birth following the use of a new reproductive technique, maternal spindle transfer (MST), which is a mitochondrial replacement technique (MRT), was accomplished by dividing the execution of the MST procedure between two countries, the USA and Mexico. This was done in order to avoid US legal restrictions on this technique.
Sources of data
Academic articles, news articles, documents obtained through freedom of information requests, laws, regulations and national reports.
Areas of agreement
MRTs are new reproductive techniques that present novel ethical and legal challenges, since genetic material from three people is employed to create a child.
Areas of controversy
Could the first MST procedure that culminated in a live birth negatively impact reproductive medicine in Mexico?
Growing points
The USA and Mexico need specific and clear legislation on MRTs, in order for such techniques not to be governed by prior existing legislation on assisted reproduction that is inadequate for dealing with the new challenges that these techniques present.
Areas timely for developing research
There is a pressing need for work to be done on the international governance of new reproductive techniques.

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The role of neutrophils in cancer and Ethics and cloning



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The impact of the General Data Protection Regulation on health research

Abstract
Background
On the May 25, 2018 the General Data Protection Regulation (hereafter the GDPR or the Regulation) came into force, replacing the Data Protection Directive 95/46/EC (upon which the Data Protection Act 1998 is based), and imposing new responsibilities on organizations which process the data of European Union citizens.
Sources of data
This piece examines the impact of the Regulation on health research.
Areas of agreement
The Regulation seeks to harmonize data privacy laws across Europe, to protect and empower all EU citizen's data privacy and to reshape the way that organizations approach data privacy (See the GDPR portal at: https://www.eugdpr.org/ (accessed 8 May 2018). As a Regulation the GDPR is directly applicable in all member states as opposed to a directive which requires national implementing measures (In the UK the Data Protection Act 1998 was the implementing legislation for the Data Protection Directive 95/46/EC.).
Areas of controversy
The Regulation is sector wide, but its impact on organizations us sector specific. In some sectors, the Regulation inhibits the processing of personal data, whilst in others it enables that processing. The Regulation takes the position that the 'processing of data should be designed to serve mankind' (Recital 4). Whilst it does not spell out what exactly is meant by this, it indicates that a proportionate approach will be taken to the protection of personal data, where that data can be processed for common goods such as healthcare. Thus, the protection of personal data is not absolute, but considered in relation to its function in society and balance with other fundamental rights in accordance with the principle of proportionality (Recital 4). Differing interpretations of proportionality can detract from the harmonization objective of the Regulation.
Growing points
Reflecting the commitment to proportionality, scientific research holds a privileged position in the Regulation. Throughout the Regulation provision is made for organizations that process personal data for scientific research purposes to avoid restrictive measures which might impede the increase of knowledge. However, the application of the Regulation differs across health research sectors and across jurisdictions. Transparency and engagement across the health research sector is required to promote alignment.
Areas timely for developing research
Research which focuses on the particular problems which arise in the context of the regulation's application to health research would be welcome. Particularly in the context of the operation of the Regulation alongside the duty of confidentiality and the variation in approaches across Member States.

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Salivary Duct Carcinoma of Parotid Gland: a Rare Tumor



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ALDH1A3 induces mesenchymal differentiation and serves as a predictor for survival in glioblastoma

ALDH1A3 induces mesenchymal differentiation and serves as a predictor for survival in glioblastoma

ALDH1A3 induces mesenchymal differentiation and serves as a predictor for survival in glioblastoma, Published online: 11 December 2018; doi:10.1038/s41419-018-1232-3

ALDH1A3 induces mesenchymal differentiation and serves as a predictor for survival in glioblastoma

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CCN3 and DLL1 co-regulate osteogenic differentiation of mouse embryonic fibroblasts in a Hey1-dependent manner

CCN3 and DLL1 co-regulate osteogenic differentiation of mouse embryonic fibroblasts in a Hey1-dependent manner

CCN3 and DLL1 co-regulate osteogenic differentiation of mouse embryonic fibroblasts in a Hey1-dependent manner, Published online: 11 December 2018; doi:10.1038/s41419-018-1234-1

CCN3 and DLL1 co-regulate osteogenic differentiation of mouse embryonic fibroblasts in a Hey1-dependent manner

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Dysregulated autophagy contributes to caspase-dependent neuronal apoptosis

Dysregulated autophagy contributes to caspase-dependent neuronal apoptosis

Dysregulated autophagy contributes to caspase-dependent neuronal apoptosis, Published online: 11 December 2018; doi:10.1038/s41419-018-1229-y

Dysregulated autophagy contributes to caspase-dependent neuronal apoptosis

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GPx1 is involved in the induction of protective autophagy in pancreatic cancer cells in response to glucose deprivation

GPx1 is involved in the induction of protective autophagy in pancreatic cancer cells in response to glucose deprivation

GPx1 is involved in the induction of protective autophagy in pancreatic cancer cells in response to glucose deprivation, Published online: 11 December 2018; doi:10.1038/s41419-018-1244-z

GPx1 is involved in the induction of protective autophagy in pancreatic cancer cells in response to glucose deprivation

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Therapeutic effect of hepatocyte growth factor-overexpressing bone marrow-derived mesenchymal stem cells on CCl4-induced hepatocirrhosis.

Therapeutic effect of hepatocyte growth factor-overexpressing bone marrow-derived mesenchymal stem cells on CCl4-induced hepatocirrhosis.

Therapeutic effect of hepatocyte growth factor-overexpressing bone marrow-derived mesenchymal stem cells on CCl<sub>4</sub>-induced hepatocirrhosis., Published online: 11 December 2018; doi:10.1038/s41419-018-1239-9

Therapeutic effect of hepatocyte growth factor-overexpressing bone marrow-derived mesenchymal stem cells on CCl4-induced hepatocirrhosis.

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FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1–TYMS axis uncoupling in 5-FU resistance

FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1–TYMS axis uncoupling in 5-FU resistance

FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1–TYMS axis uncoupling in 5-FU resistance, Published online: 11 December 2018; doi:10.1038/s41419-018-1235-0

FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1–TYMS axis uncoupling in 5-FU resistance

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Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib

Abstract

Background

Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce.

Objective

To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib.

Patients and Methods

In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib.

Results

Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number.

Conclusion

EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.



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The oculoauriculofrontonasal syndrome: Further clinical characterization and additional evidence suggesting a nontraditional mode of inheritance

Abstract

The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo‐auriculo‐vertebral spectrum (OAVS)‐associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next‐generation sequencing strategy performed on blood‐derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism.



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Malan syndrome: Extension of genotype and phenotype spectrum

Malan syndrome and Marshall–Smith syndrome (MSS) are allelic disorders caused by mutation in NFIX gene. We report a 3‐year‐ 6 months‐ old female with clinical features suggestive of Malan syndrome with mutation in exon 2 of NFIX gene. NFIX gene, where most of the mutations in Malan syndrome are located. She did not have advanced bone age. The radiographs of long bones showed metaphyseal changes which were not reported previously. This study reports the first mutation proven case from India and highlights the overlap between MSS and Malan syndrome.



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Pathogenicity of Cryptococcus neoformans VNI (ST 32) recovered from environmental and clinical isolates in Nigeria

Abstract

We present the comparative pathogenicity of Nigeria environmental and clinical Cryptococcus neoformans VNI (ST32) strains in an animal model. Isolates previously identified and confirmed in a different study, using matrix-assisted laser desorption ionization–time-of-flight mass spectrometry (MALDI–TOF MS) and multi-locus sequence typing (MLST) techniques, were inoculated into male mice weighing 26 ± 4.0 g. Postinfection survival time, tissue fungal burden, and histopathological changes were observed. Log–rank survival curve comparisons showed that there is a significant difference between clinical and control isolates and between environmental and control isolates. However, when intragroup and intergroup comparisons were made, no significant difference was observed. There was a significant difference when the brain fungal burden of mice infected with environmental isolate was compared with the kidney fungal burden. Tissues of the control group inoculated with PBS showed no evidence of lesions. The mouse group infected with clinical isolates showed a significant difference when the brain fungal burden was compared with the kidney fungal burden. No lesion was produced in the kidneys of mouse groups infected with environmental and positive control isolates. The evaluated pathogenicity indices in this study may suggest that both the environmental and clinical isolates of C. neoformans VNI exhibit similar pathogenicity potential.



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Genotype and phenotype correlations for SHANK3 de novo mutations in neurodevelopmental disorders

Abstract

SHANK3 has been identified as the causative gene of 22q13.3 microdeletion syndrome phenotype. De novo mutations (DNMs) of SHANK3 were subsequently identified in patients with several neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia (SCZ), a Rett syndrome‐like phenotype, and intellectual disability (ID). Although broad developmental phenotypes of these patients have been described in single studies, few studies have reviewed the genotype and phenotype relationships using a relatively large cohort of patients with SHANK3 DNMs. In this study, we identified a de novo splice mutation (NM_033517.1: c.2265+1G>A) that functionally impairs mRNA splicing, produces multiple splice variants, and results in the reduction of the amounts of mRNA. To analyze the genotype and phenotype correlations for SHANK3 DNMs, we reviewed 37 previously published patients with 28 SHANK3 DNMs. Our results revealed that haploinsufficiency of SHANK3 causes a broad spectrum of neurodevelopmental phenotypes with impaired social interaction, repetitive behavior, speech impairment, ID, and regression as the most common observations. Seizures, hypotonia, global development delay, dysmorphic features, and several other features also occurred recurrently. Specific phenotypes are also observed in certain genotypes. Our study provides the frequency of the heterogeneous co‐occurring conditions caused by SHANK3 DNMs, which will be beneficial for diagnosis and clinical management.



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The COX2 effector microsomal PGE2 synthase-1 is a regulator of immunosuppression in cutaneous melanoma

Purpose: Microsomal prostaglandin E2 synthase 1 (mPGES1) was evaluated as an important downstream effector of the cyclooxygenase 2 (COX2) pathway responsible for tumor-mediated immunosuppression in melanoma. Experimental Design: The analysis of a Stage III melanoma tissue microarray (n=91) was performed to assess the association between mPGES1, COX2, CD8, and patient survival. Pharmacological inhibitors and syngeneic mouse models using mPGES1 knockout mouse melanoma cell lines were used to evaluate the mPGES1-mediated immunosuppressive function. Results: We observed correlations in expression and co-localization of COX2 and mPGES1, which are associated with increased expression of immunosuppressive markers in human melanoma. In a syngeneic melanoma mouse model, mPGES1 knockout increased melanoma expression of PD-L1, increased infiltration of CD8a+ T cells and CD8a+ dendritic cells into tumors and suppressed tumor growth. Durable tumor regression was observed in mice bearing mPGES1 knockout tumors that were given anti-PD-1 therapy. Analysis of a stage III melanoma tissue microarray revealed significant associations between high mPGES1 expression and low CD8+ infiltration, which correlated with a shorter patient survival. Conclusions: Our results are the first to illustrate a potential role for mPGES1-inhibition in melanoma immune evasion and selective targeting in supporting the durability of response to PD-1 checkpoint immunotherapy. More research effort in this drug development space is needed to validate the use of mPGES1 inhibitors as safe treatment options.



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Identification and characterization of synthetic viability with ERCC1 deficiency in response to interstrand crosslinks in lung cancer

Purpose:ERCC1/XPF is a DNA endonuclease with variable expression in primary tumor specimens, and has been investigated as a predictive biomarker for efficacy of platinum-based chemotherapy. The failure of clinical trials utilizing ERCC1 expression to predict response to platinum-based chemotherapy suggests additional mechanisms underlying the basic biology of ERCC1 in the response to interstrand crosslinks (ICLs) remain unknown. We aimed to characterize a panel of ERCC1 knockout (D) cell lines where we identified a synthetic viable phenotype in response to ICLs with ERCC1 deficiency. Experimental Design:We utilized the CRISPR-Cas9 system to create a panel of ERCC1D lung cancer cell lines which we characterized. Results:We observe that loss of ERCC1 hypersensitizes cells to cisplatin when wildtype (WT) p53 is retained, while there is only modest sensitivity in cell lines that are p53mutant/null. Additionally, when p53 is disrupted by CRISPR-Cas9 (p53*) in ERCC1D/p53WT cells, there is reduced apoptosis and increased viability after platinum treatment. These results were recapitulated in two patient data sets utilizing p53 mutation analysis and ERCC1 expression to assess Overall Survival. We also show that kinetics of ICL- repair (ICL-R) differ between ERCC1D/p53WT and ERCC1D/p53* cells. Finally, we provide evidence that cisplatin tolerance in the context of ERCC1 deficiency relies on DNA-PKcs and BRCA1 function. Conclusions:Our findings implicate p53 as a potential confounding variable in clinical assessments of ERCC1 as a platinum biomarker via promoting an environment in which error-prone mechanisms of ICL- repair may be able to partially compensate for loss of ERCC1.



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Tumor microenvironment remodeling by intratumoral oncolytic vaccinia virus enhances the efficacy of immune checkpoint blockade

Purpose: Cancer immunotherapy is a potent treatment modality, but its clinical benefit depends on the tumor's immune profile. Here, we employed mJX-594 (JX), a targeted and GM-CSF-armed oncolytic vaccinia virus, as a strategy to remodel the tumor microenvironment (TME) and subsequently increase sensitivity to αPD-1 and/or αCTLA-4 immunotherapy. Experimental Design: The remodeling of TME was determined using histologic, flow cytometric, and NanoString immune profiling analyses. JX was intratumorally injected into implanted Renca kidney tumors or MMTV-PyMT transgenic mouse breast cancers with or without αPD-1 and/or αCTLA-4. Various combination regimens were used to evaluate immunotherapeutic anti-cancer responses. Results: Intratumoral injection of JX remodeled the TME through dynamic changes in the immune system, as shown by increased tumor-infiltrating T cells and upregulation of immune-related gene signatures. This remodeling induced conversion of a non-inflamed tumor into an inflamed tumor. JX virotherapy led to enhanced abscopal effects in distant tumors, with increased intratumoral infiltration of CD8+ T cells. A depletion study revealed that GM-CSF is an indispensable regulator of anti-cancer efficacy of JX. Dual-combination therapy with intratumoral JX and systemic αPD-1 or αCTLA-4 further enhanced the anti-cancer immune response, regardless of various treatment schedules. Of note, triple-combination immunotherapy with JX, αPD-1, and αCTLA-4 elicited the most potent anti-cancer immunity and induced complete tumor regression and long-term overall survival. Conclusions: Our results show that intratumoral JX treatment induces dramatic remodeling of TME and more potently suppresses cancer progression with immune checkpoint blockades by overcoming resistance to immunotherapy.



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Coordinately targeting cell cycle checkpoint functions in integrated models of pancreatic cancer

Purpose: Cancer cells often have deficiencies in cell cycle control mechanisms and could be dependent on specific cell cycle checkpoints to maintain viability. Due to the documented role of KRAS in driving replication stress, we targeted the checkpoint governing DNA replication using CHK1 kinase inhibitors in pancreatic ductal adenocarcinoma (PDAC) models and examined mechanisms of resistance. Experimental Design: Single agent efficacy of CHK1 inhibition was investigated in established and primary PDAC lines. Drug screening was performed to identify cooperative agents. In vitro and in vivo studies were employed to interrogate combination treatment efficacy and mechanisms of resistance. Results: Many PDAC models evade single agent inhibition through mechanisms that allow S-phase progression with CHK1 inhibited. Gene expression analysis revealed FOXM1 as a potential marker of CHK1 sensitivity and defined a form of pancreatic cancer with poor prognosis. Drug screen analysis identified WEE1 as a cooperative agent with CHK1 and was effective in cell culture. In vivo experiments validated the combination efficacy; however, resistance could evolve. Resistance was due to selection of a stable sub-clone from the original PDX tumor, which harbored high baseline replication stress. In vitro analysis revealed that gemcitabine could eliminate viability in the resistant models. The triplet regimen of gemcitabine, CHK1 and WEE1 inhibition provided strong disease control in all xenograft models interrogated. Conclusions: These results demonstrate the therapeutic resiliency of pancreatic cancer and indicate that coordinately targeting cell cycle checkpoints in concert with chemotherapy could be particularly efficacious.



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Case Numbers of U.S. Children With Polio-Like Illness Hit Record High

TUESDAY, Dec. 11, 2018 -- There has been a record number of cases of a rare paralyzing illness among children in the United States this year, according to health officials. So far, 158 cases of acute flaccid myelitis (AFM) have been confirmed in 36...

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Consensus Decision Pathway Developed for Tobacco Cessation

TUESDAY, Dec. 11, 2018 -- An expert consensus decision pathway has been developed for tobacco cessation treatment; the report was published online Dec. 5 in the Journal of the American College of Cardiology. Rajat S. Barua, M.D., Ph.D., from the...

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Paid Childbearing Policies Lacking for Residents

TUESDAY, Dec. 11, 2018 -- Policies for paid childbearing or family leave for residents are lacking at top-ranking medical schools and may be exacerbated by lack of direction from specialty boards, according to two research letters published in the...

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Free Flap Breast Reconstruction Safe in Elderly Patients

TUESDAY, Dec. 11, 2018 -- Free flap breast reconstruction is a viable and safe procedure in elderly patients, according to a study published in the December issue of Plastic and Reconstructive Surgery. Radbeh Torabi, M.D., from the Louisiana State...

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Donor-derived hepatocytes in human hematopoietic cell transplant recipients: evidence of fusion

Abstract

Reconstitution of hepatocytes by hematopoietic stem cells—a phenomenon which occurs in rodents under highly selective conditions—results from infrequent fusion between incoming myelomonocytes and host hepatocytes, with subsequent proliferation. Human hematopoietic stem cell transplant recipients have been little studied, with some support for transdifferentiation (direct differentiation). We studied routinely obtained autopsy liver tissue of four female hematopoietic cell transplant recipients with male donors, using a highly specific conjoint immunohistochemistry in situ hybridization light microscopic technique. Hepatocyte nuclei were identified by cytokeratin (Cam5.2) staining and evaluated for X and Y chromosome content. Over 1.6 million hepatocytes were assessed for rare instances of donor origin, revealing a Y chromosome in 67. Mixed tetraploids (XXXY) and their nuclear truncation products (XXY, XY, Y) were directly demonstrated, with no detection of the male tetraploids (XXYY) that may result from transdifferentiation with subsequent tetraploidization, nor their unique truncation products (XYY, YY), implicating fusion as the mechanism. To determine whether it is the sole mechanism, we modeled the chromosome distribution based on the same probability of detection of each X chromosome, deriving parameters of sensitivity and female tetraploidy by best fit. We then hypothesized that the distribution of Y chromosome–containing cells could be predicted by a similar model. After modification to account for "clumpy" Y chromosomes, the observed results were in accord with the predicted results (p = 0.6). These results suggest that all the Y-containing cells, including apparent XY cells, derive from mixed tetraploids, consistent with fusion as the sole mechanism.



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Prophylactic Mesh Implantation Reduces Hernia Formation

TUESDAY, Dec. 11, 2018 -- Prophylactic mesh implantation reduces the incidence of hernia formation among patients undergoing elective open abdominal surgery but increases early postoperative pain and leads to prolonged wound healing of surgical site...

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U.S. Medical Schools See Increase in Diversity

TUESDAY, Dec. 11, 2018 -- After implementation of the Liaison Committee on Medical Education (LCME) diversity accreditation standards, U.S. medical schools saw increasing percentages of female, black, and Hispanic matriculants, according to a...

https://ift.tt/2BdvNpK

CTRC-AACR San Antonio Breast Cancer Symposium, Dec. 4-8

The 41st Annual CTRC-AACR San Antonio Breast Cancer Symposium The annual San Antonio Breast Cancer Symposium was held from Dec. 4 to 8 in San Antonio and attracted more than 7,500 participants from around the world, including medical oncologists,...

https://ift.tt/2UB8S0D

Intellectual Engagement Linked to Cognitive Performance Later

TUESDAY, Dec. 11, 2018 -- Intellectual engagement is associated with level of cognitive performance in later life but does not influence the trajectory of age-related decline in cognitive performance, according to a study published online Dec. 10 in...

https://ift.tt/2Bc3Puz

Visual Registration + Image Fusion Best for Targeted Biopsy

TUESDAY, Dec. 11, 2018 -- The combination of visual registration and image fusion should be used when targeted biopsy is being performed on men with suspected prostate cancer, according to a study published online Dec. 5 in European Urology. Sami...

https://ift.tt/2UCGOtz

Flu Vaccine Linked to Reduced Risk for Death in Heart Failure

TUESDAY, Dec. 11, 2018 -- After extensive adjustment for confounders, influenza vaccination is associated with a reduced risk for all-cause and cardiovascular death among patients with heart failure, according to a study published online Dec. 10 in...

https://ift.tt/2B9jzyt

Reference Infliximab, Biosimilar Equivalent for Crohn's Disease

TUESDAY, Dec. 11, 2018 -- CT-P13, which is a biosimilar of the reference product (RP) infliximab, has equivalent effectiveness for infliximab-naive patients with Crohn's disease (CD), according to a study published online Dec. 11 in the Annals of...

https://ift.tt/2BeAhfJ

Patients May Become Immune to Botulinum Toxin Treatments

TUESDAY, Dec. 11, 2018 -- About 15 percent of patients treated with botulinum toxin type A (BoNT/A) for dystonia or spasticity can develop an immune response to the treatment itself, according to a study published online Nov. 21 in...

https://ift.tt/2UzRDwG

Mail-Based HPV Testing May Increase Access

TUESDAY, Dec. 11, 2018 -- A mail-based human papillomavirus (HPV) self-testing program appears to be a promising approach to screening women in Appalachia, according to a pilot study published online Nov. 19 in Sexually Transmitted Diseases. Paul L....

https://ift.tt/2UzRBF4

Fetal Famine Exposure Tied to Early Menopause

TUESDAY, Dec. 11, 2018 -- Fetal exposure to famine is associated with an increased risk for early menopause, according to a study published online Dec. 3 in Menopause. Nengying Wang, M.D., from the Shengli Clinical Medical College of Fujian Medical...

https://ift.tt/2Bg45bU

Breast CA Detection Rate Up With Digital Mammography in the U.K.

TUESDAY, Dec. 11, 2018 -- Digital mammography (DM) has increased the overall cancer detection rate by 14 percent, with higher detection rates for grade 1 and 2 invasive cancers, according to research published online Dec. 11 in Radiology. Roger G....

https://ift.tt/2UBDEpV.

DNA methylation controls metastasis-suppressive 14q32-encoded miRNAs

Expression of 14q32-encoded miRNA is a favorable prognostic factor in patients with metastatic cancer. In this study, we use genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-2′-deoxycytidine (5-Aza-dC, Decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNA in the 14q32 cluster. DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the Maternally Expressed Gene 3 differentially methylated region (MEG3-DMR), which acts as a cis-regulatory element for 14q32 miRNA expression. 5-Aza-dC activated demethylation of the MEG3-DMR and expression of 14q32 miRNA, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells. Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNA and resistance to 5-Aza-dC-induced suppression of AIM. Expression of methylation-dependent 14q32 miRNA suppressed metastatic colonization in preclinical models of lung and liver metastasis and correlated with improved clinical outcomes in patients with metastatic cancer. These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of Decitabine on the activation of metastasis-suppressive miRNA.

https://ift.tt/2QLAQaH

A Kidney Conundrum: More or Less?

A 66-year-old ex-smoker presented with metastatic renal cell cancer with lytic lesions in the left femur, T8, and a 1.5-cm lesion in the right lung. A biopsy from the femur confirmed clear cell renal cell cancer; the lung lesion could not be biopsied safely. The patient underwent a radical nephrectomy (pathologically staged as pT3a). He commenced sunitinib, which was stopped owing to severe hypertension, followed by everolimus, stopped after 8 cycles owing to muscle cramping. Repeat imaging demonstrated resolution of the lung nodule but progression in the left femur, T8, and new disease in the anterior right 10th rib and left humerus.

https://ift.tt/2B9UDHi

In Regard to Keall et al

We read with interest the review by Keall et al of real-time 3-dimensional (3D) image guided radiation therapy (IGRT) on standard-equipped radiation therapy systems.1 All clinically implemented techniques were based on markers, and the authors noted that although markerless tracking is preferable, it is challenging, especially in the abdominal-pelvic region. However, there are sites where it is possible.

https://ift.tt/2QrKhN9

Tet2-dependent hydroxymethylome plasticity reduces melanoma initiation and progression

Although numerous epigenetic aberrancies accumulate in melanoma, their contribution to initiation and progression remain unclear. The epigenetic mark 5-hydroxymethylcytosine (5hmC), generated through TET-mediated DNA modification, is now referred to as the sixth base of DNA and has recently been reported as a potential biomarker for multiple types of cancer. Loss of 5hmC is an epigenetic hallmark of melanoma, but whether a decrease in 5hmc levels contributes directly to pathogenesis or whether it merely results from disease-progression-associated epigenetic remodelling remains to be established. Here we show that NRAS-driven melanomagenesis in mice is accompanied by an overall decrease in 5hmC and specific 5hmC gains in selected gene bodies. Strikingly, genetic ablation of Tet2 in mice cooperated with oncogenic NRASQ61K to promote melanoma initiation while suppressing specific gains in 5hmC. We conclude that Tet2 acts as a barrier to melanoma initiation and progression, partly by promoting 5hmC gains in specific gene bodies.

https://ift.tt/2SFScDh

Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins

Chromosomal rearrangements involving receptor tyrosine kinases (RTK) are a clinically relevant oncogenic mechanism in human cancers. These chimeric oncoproteins often contain the C-terminal kinase domain of the RTK joined in cis to various N-terminal, non-kinase fusion partners. The functional role of the N-terminal fusion partner in RTK fusion oncoproteins is poorly understood. Here we show that distinct N-terminal fusion partners drive differential subcellular localization, which imparts distinct cell signaling and oncogenic properties of different, clinically-relevant ROS1 RTK fusion oncoproteins. SDC4-ROS1 and SLC34A2-ROS1 fusion oncoproteins resided on endosomes and activated the MAPK pathway. CD74-ROS1 variants that localized instead to the endoplasmic reticulum (ER) showed compromised activation of MAPK. Forced re-localization of CD74-ROS1 from the ER to endosomes restored MAPK signaling. ROS1 fusion oncoproteins that better activate MAPK formed more aggressive tumors. Thus, differential subcellular localization controlled by the N-terminal fusion partner regulates the oncogenic mechanisms and output of certain RTK fusion oncoproteins.

https://ift.tt/2QPSom0

Meetings

December 7-8, 2018

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Mastectomy May Be an Inferior Oncologic Approach Compared With Breast Preservation

To the Editor: In our recent publication in this journal we suggested that it may be important to parameterize the residual breast tissue (RBT) in patients undergoing various forms of mastectomy.1 We identified RBT in 66% and 83%, respectively, of therapeutic and prophylactic nipple-sparing mastectomies (Tables 1 and 2). Because of the characteristics of our sample, we were unable to formally analyze the relationship between these findings and oncologic outcomes, even though most of our patients had not received postoperative radiation therapy.

https://ift.tt/2Qou0Zw

Safeguarding Autonomy of Patients With Bladder Cancer

In the world of cancer care, Halstedian paradigms for radical surgery have evolved toward organ preservation strategies without compromising the probability of cure. As such, clinicians have increasingly turned their focus toward minimizing the stigmata of treatment, with patient-centered outcomes having greater influence on decision making. Today, patients are typically able to preserve much of their functional anatomy and cosmesis. For example, selected patients with head and neck cancers are routinely offered a strategy of larynx preservation with upfront radiation therapy and chemotherapy, reserving a more morbid total laryngectomy for the minority who relapse (1).

https://ift.tt/2RTaDEq

In Reply to Daugherty and Lawrence

Thanks to Daugherty and Lawrence for the thoughtful review and comments1. We agree with your perspective. Margin assessment remains an integral component in evaluating local recurrence risk in patients managed with breast-conserving therapy. We share your concerns that caution is needed, particularly in dealing with patients in whom adjuvant radiation therapy is omitted, including the elderly populations. Clinical trials evaluating outcomes in patients treated without breast radiation therapy require strict adherence to margin clearance.

https://ift.tt/2Qob797

Erratum to: Hao Y, Ran Y, Lu B, et al. Therapeutic Effects of Human Umbilical Cord—derived Mesenchymal Stem Cells on Canine Radiation-Induced Lung Injury. Int J Radiat Oncol Biol Phys 2018;102:407-416.

In the original paper, there was an error in the part of "Reprint requests to". The corrected expression shall appear as below.

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In Reply to Dahele and Verbakel

The authors' letter and translational research work support the question posed in the review1,2: Are we at the tipping point for the era of real-time radiation therapy? The research by Dahele and Verbakel adds additional clinical evidence that real-time 3-dimensional image guided radiation therapy (3D IGRT) can be performed on standard-equipped cancer radiation therapy (RT) systems. Indeed, had it been published or known to us before we wrote the review, their clinical translation of markerless spine tracking3 would have been included as a fourth real-time 3D IGRT implementation on standard-equipped systems.

https://ift.tt/2RNM2B3

Mastectomy May Be an Inferior Oncologic Approach Compared to Breast Preservation

Multiple randomized studies have demonstrated that breast-conserving therapy (partial mastectomy plus whole breast radiation) can yield survival outcomes equivalent to those of mastectomy (1). However, newer population-based data suggest that breast cancer–specific survival and overall survival with breast-conserving therapy may actually be better than those with mastectomy (2-8). How is this possible? How can removal of the breast yield outcomes inferior to those of a therapy that leaves most of the breast intact and where in-breast failures are reported to occur in approximately 5% to 10% of patients at 10 years posttreatment in historical series (1) (albeit with lower rates over time (9), especially in favorable patients (10))?

https://ift.tt/2Qpj127

Larry Emanuel Kun, March 10, 1946-May 27, 2018

Larry Kun was a mentor and friend to all who knew him. He was born in Philadelphia on March 10, 1946. His father was a mechanical engineer, and his mother was a homemaker. He entered Penn State, and after 1 year, he entered a unique program at Penn State through Jefferson Medical College that combined both college and medical school as an integrated degree. He received his MD degree in year 5. He completed residency in radiation therapy at Penrose Hospital, Colorado Springs, Colorado, with Juan del Regato.

https://ift.tt/2RSGiGh

In Regard to Tyler et al

To the Editor: The article by Tyler et al on tumor-free margin is an excellent and extensive study on its impact on local recurrence and on breast cancer–specific survival1 Both in the conclusion and in the discussion, authors report a lack of significant difference among negative, close, or positive margins regarding the aforementioned outcomes. It is important to note that entire the patient population (>10,000 patients) had postoperative whole breast radiation.

https://ift.tt/2QsV3Ti

Putting Women on the Escalator: How to Address the Ongoing Leadership Disparity in Radiation Oncology

"Do you ever look at the front of the room and worry that you're on the stairs to nowhere?" remarked one radiation oncologist to a colleague at a large committee meeting. She went on: "That's the escalator—the positions that lead directly to the Board—aren't you appalled that there isn't a single woman on there? How can that still be?" The paucity of women in leadership positions in the field of radiation oncology has long been the subject of concern. Although women comprise about 25% to 30% of radiation oncology trainees and attendings—a proportion that has remained relatively constant over the last 3 decades (1, 2)—only 1 nominee for the prominent American Society for Radiation Oncology (ASTRO) board of directors was female this year, and no new female members were elected (3).

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Issue Highlights

FitzGerald et al

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Embolize, Resect, Irradiate

Given the high-grade epidural spinal cord compression, we would recommend urgent surgical decompression (1). Separation surgery for metastatic renal cell carcinoma is challenging given its highly vascular nature. As such, provided that the patient is not acutely symptomatic from spinal cord compression or overt mechanical instability, we would perform preoperative embolization of the segmental arterial feeders to improve hemostasis and visualization of the neural elements during the operation. Surgery would include a right costotransverse approach to tumor resection with likely sacrifice of the right T7 and possibly T8 nerve roots, with posterior instrumented fusion from T5 to T10.

https://ift.tt/2RT8okK

Erratum to: Käsmann L, Manapov F. Immune Checkpoint Inhibition Combined With Intracranial Stereotactic Radiation Therapy in Non-Small Cell Lung Cancer: Is There an Increased Rate of Radionecrosis or Not? Int J Radiat Oncol Biol Phys 2018;102:465.

During the production of this paper, an error appeared in the title. The title should be, "Immune Checkpoint Inhibition Combined With Intracranial Stereotactic Radiation Therapy in Non-Small Cell Lung Cancer: Is There an Increasing Rate of Radionecrosis or Not? In Regards to Schapira et al, Huppeling et al and Colaco et al."

https://ift.tt/2QnwjvM

Precision Medicine for Localized Prostate Cancer: Time to Move Beyond NCCN Risk Stratification?

Prostate cancer is the leading cause of cancer treatment–related years lived with disability for men worldwide.1 This has driven a disruptive change in management of favorable-risk prostate cancer such that nearly all National Comprehensive Cancer Network (NCCN) very low-risk patients are recommended conservative management rather than radical therapy.2 Simultaneously, at the other end of the risk spectrum, treatment intensification with more potent systemic therapies has been the subject of recent trials for men with higher-risk disease (eg, NCT02772588).

https://ift.tt/2RUaSiz

Erratum to: Olsen JR, Murphy JD, Huguet F, et al. Oncology Scan: Gastrointestinal Cancers – Carving Out the Optimal Local Therapies in the Gastrointestinal Tract. Int J Radiat Oncol Biol Phys 2018;102:233-242.

In the above referenced article, portions of the text and table reading "CALGB 80801" should have read "CALGB 80101," to correctly reflect the referenced Fuchs CS et al. publication and CALGB study. The authors regret the error.

https://ift.tt/2Qt2wC6

Late Presentation of Chronic-Organised Biloma Masquerading as Gallbladder Fossa Mass Years After Cholecystectomy: a Diagnostic Enigma



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Hyperthermic Intrathoracic Chemotherapy (HITHOC) for Pleural Malignancies—Experience from Indian Centers

Abstract

Hyperthermic intrathoracic chemotherapy (HITHOC) has been used in addition to radical surgery for primary and secondary pleural malignancies to improve local control, prolong survival, and improve the quality of life. This study was performed to study the indications, methodology, perioperative outcomes, and survival in patients undergoing HITHOC at Indian centers. A retrospective analysis of prospectively collected demographic and clinical data, perioperative and survival data of patients undergoing surgery with or without HITHOC was performed. From January 2011 to May 2018, seven patients underwent pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) with HITHOC and four had P/D or EPP alone at three Indian centers. P/D was performed in two and EPP in nine patients. The primary tumor was pleural mesothelioma in eight, metastases from thymoma in one, germ cell tumor in one, and solitary fibrous tumor of the pleura in one. HITHOC was performed using cisplatin. Grade 3–4 complications were seen in one patient in the HITHOC group and none in the non-HITHOC group, and one patient in the non-HITHOC group died of complications. At a median follow-up of 9 months, five patients of the HITHOC group were alive, four without recurrence, and one with recurrence. One patient in the non-HITHOC group was alive and disease-free at 24 months, and two died of progression at 18 and 36 months. HITHOC can be performed without increasing the morbidity of P/D or EPP. Most of these patients require multimodality treatment and are best managed by multidisciplinary teams.



https://ift.tt/2PuOtGM

Lipometabolism and Glycometabolism in Liver Diseases

The liver is the mainly metabolic organ in the body especially in lipometabolism and glycometabolism. Carbohydrates and fats disorders can result in insulin resistance in the liver. Metabolic imbalance can even lead to life-threatening conditions. Therefore, it is essential to maintain the normal metabolic function of the liver. When the liver is in a pathological state, liver metabolism homeostasis is damaged, and metabolic disorders will further aggravate liver disease. Consequently, it is essential to determine the relationship between liver diseases and metabolic disorders. Here we review a lot of evidence that liver diseases are closely related to lipometabolism and glycometabolism. Although the disorder of the liver metabolism is caused by different liver diseases, the break of metabolic balance is determined by changes in the state of the liver. We discuss the relationship between liver disease and metabolic changes, outline the process of how metabolic changes are regulated by liver diseases, and describe the role which metabolic changes play in the process and prognosis of liver disease.

https://ift.tt/2LaCBJh

Low Diagnostic Accuracy of Body Mass Index-Based and Waist Circumference-Based References of Childhood Overweight and Obesity in Identifying Overfat among Chinese Children and Adolescents

This study aimed to investigate the diagnostic accuracy of body mass index- (BMI-) based and waist circumference- (WC-) based references for childhood overweight and obesity in screening overfat individuals among 2134 Chinese children and adolescents. In this study, overfat status was defined as over 25% body fat for boys and over 30% for girls. Childhood obesity or overweight was defined by four BMI-based references and two WC-based references. All BMI-based references for obesity showed low sensitivity (SE) (0.128–0.473) but high specificity (SP) (0.971–0.998) in detecting overfat individuals in the current population. SE values increased from 0.493 to 0.881 when BMI- and WC-based references for overweight were used to detect overfat individuals. All references for overweight showed high SP rates (0.816–0.966). To improve diagnostic accuracy for childhood obesity, further studies may define a cut-off value for childhood obesity specific for a local population and ethnicity by using health-related overfat data.

https://ift.tt/2C4MUMi

Potential of Zeolite and Algae in Biomass Immobilization

The interest in utilizing algae for wastewater treatment has been increased due to many advantages. Algae-wastewater treatment system offers a cost-efficient and environmentally friendly alternative to conventional treatment processes such as electrocoagulation and flocculation. In this biosystem, algae can assimilate nutrients in the wastewater for their growth and simultaneously capture the carbon dioxide from the atmosphere during photosynthesis resulting in a decrease in the greenhouse gaseousness. Furthermore, the algal biomass obtained from the treatment process could be further converted to produce high value-added products. However, the recovery of free suspended algae from the treated effluent is one of the most important challenges during the treatment process as the current methods such as centrifugation and filtration are faced with the high cost. Immobilization of algae is a suitable approach to overcome the harvesting issue. However, there are some drawbacks with the common immobilization carriers such as alginate and polyacrylamide related to low stability and toxicity, respectively. Hence, it is necessary to apply a new carrier without the mentioned problems. One of the carriers that can be a suitable candidate for the immobilization is zeolite. To date, various types of zeolite have been used for the immobilization of cells of bacteria and yeast. If there is any possibility to apply them for the immobilization of algae, it needs to be considered in further studies. This article reviews cell immobilization technique, biomass immobilization onto zeolites, and algal immobilization with their applications. Furthermore, the potential application of zeolite as an ideal carrier for algal immobilization has been discussed.

https://ift.tt/2LaCygz

Relationships between Financial Toxicity and Symptom Burden in Cancer Survivors: A Systematic Review

Financial toxicity (FT) is used to describe the financial distress/hardship associated with cancer and its treatment.

https://ift.tt/2C6gGQM

A scoping review to map empirical evidence regarding key domains and questions in the clinical pathway of delirium in palliative care

Based on the clinical care pathway of delirium in palliative care (PC), a published analytic framework (AF) formulated research questions in key domains and recommended a scoping review to identify evidence gaps.

https://ift.tt/2LaCrSb

Transport-exclusion pharmacology to localize lactate dehydrogenase activity within cells

Abstract

Background

Recent in vitro and in vivo work has shown that lactate provides an important source of carbon for metabolic reactions in cancer cell mitochondria. An interesting question is whether lactate is oxidized by lactate dehydrogenase (LDH) in the cytosol and/or in mitochondria. Since metabolic processes in the cytosol and mitochondria are affected by redox balance, the location of LDH may have important regulatory implications in cancer metabolism.

Methods

Within most mammalian cells, metabolic processes are physically separated by membrane-bound compartments. Our general understanding of this spatial organization and its role in cellular function, however, suffers from the limited number of techniques to localize enzymatic activities within a cell. Here, we describe an approach to assess metabolic compartmentalization by monitoring the activity of pharmacological inhibitors that cannot be transported into specific cellular compartments.

Results

Oxamate, which chemically resembles pyruvate, is transported into mitochondria and inhibits LDH activity in purified mitochondria. GSK-2837808A, in contrast, is a competitive inhibitor of NAD, which cannot cross the inner mitochondrial membrane. GSK-2837808A did not inhibit the LDH activity of intact mitochondria, but GSK-2837808A did inhibit LDH activity after the inner mitochondrial membrane was disrupted.

Conclusions

Our results are consistent with some mitochondrial LDH that is accessible to oxamate, but inaccessible to GSK-2837808A until mitochondria are homogenized. This strategy of using inhibitors with selective access to subcellular compartments, which we refer to as transport-exclusion pharmacology, is broadly applicable to localize other metabolic reactions within cells.



https://ift.tt/2C7oYrH

Correction



https://ift.tt/2QRQIbI

Current Status of Theranostics in Jordan

Abstract

Exploring the unknown is one of the key factors that lead to great discoveries in mankind history. With the advances in medicine and the development of new approaches towards patient care, like next-generation sequencing and patient-centered care, the need for treatments tailored to patient through personalized medicine has become more compelling. Theranostics has been introduced as a combination of a diagnostic tool and a therapeutic tool on the same vector for a specific disease, to facilitate personalized medicine. Nuclear medicine has shown the capability of providing a strong platform for this new approach through its arms, molecular imaging, and targeted molecular therapies. Though the prototype of theranostics has been practiced in Jordan since decades in the field of diagnosis and treatment of well-differentiated thyroid cancer, recently, the King Hussein Cancer Center (KHCC), a leading and comprehensive cancer center in Jordan and in the Middle East, has leaped forward to introduce the new approaches of theranostics through the nuclear medicine applications. This paper sheds the light on the most important aspects of this new theranostics practice in Jordan such as peptide receptor radionuclide therapy (PRRT) and prostate-specific membrane antigen (PSMA)–based theranostics.



https://ift.tt/2LcYtUm

Interfering with bromodomain epigenome readers as therapeutic option in mucoepidermoid carcinoma

Abstract

Purpose

Emerging evidence indicates that bromodomains comprise a conserved class of epigenome readers involved in cancer development and inflammation. Bromodomains are associated with epigenetic modifications of gene transcription through interactions with lysine residues of histone tails. Particularly, the bromodomain and extra-terminal domain (BET) family member BRD4 has been found to be involved in the control over oncogenes, including c-MYC, and in the maintenance of downstream inflammatory processes. The objective of this study was to evaluate the effect of pharmacologically displacing BRD4 in mucoepidermoid carcinoma (MEC) cells.

Methods

We assessed the presence of BRD4 levels in a panel of human MEC tissue samples in conjunction with histological grading and clinical information. In vitro studies were carried out using human MEC-derived cell lines. The BET inhibitor iBET762 was administered to MEC cells to assess the impact of disrupted BRD4 signaling on colony forming capacities and cell cycle status. The activation of cellular senescence induced by iBET762 was determined by immunohistochemical staining for p16ink4. Flow cytometry was used to identify populations of cancer stem cells in MEC-derived cell lines.

Results

We found that primary human MECs and MEC-derived cell lines are endowed with high BRD4 expression levels compared to those in normal salivary glands. We also found that, by displacing BRD4 from chromatin using the BET inhibitor iBET762, MEC cells lose their colony forming capacities and undergo G1 cell cycle arrest and senescence. Finally, we found that targeted displacement of BRD4 from chromatin results in depletion of cancer stem cells from the overall MEC cell populations.

Conclusions

Our findings indicate that bromodomain-mediated gene regulation constitutes an epigenetic mechanism that is deregulated in MEC cells and that the use of BET inhibitors may serve as a feasible therapeutic strategy to manage MECs.



https://ift.tt/2Qrrth1

A technique to rapidly generate synthetic CT for MRI-guided online adaptive re-planning: an exploratory study

A method to quickly create synthetic CT (sCT) by transferring rED from patient's own CT based on deformable registration of CT and MRI with special consideration of bone and air regions has been developed. The sCT generated is more accurate than that from the commonly-used bulk density assignment but without the need for multiple MR sequences. The method can be fully automated, thus, applicable for online adaptive replanning.

https://ift.tt/2GaN1K5

Safety of endoscopy in cancer patients with thrombocytopenia and neutropenia

Cancer patients are prone to thrombocytopenia and neutropenia, which increase the risk of bleeding and infection. We assessed the safety of endoscopic procedures in cancer patients with thrombocytopenia and/or neutropenia.

https://ift.tt/2Gf5UM3

Is Low-Dose Ketamine an Effective Alternative to Opioids for Acute Pain?

The search identified 237 unique citations, and 3 trials (N=261) met the inclusion criteria of the review. All studies reported mean numeric rating scale score and used a single dose of morphine at 0.1 mg/kg as the control. One study evaluated ketamine at 0.5 mg/kg in patients with long bone fractures. The other 2 trials used ketamine at 0.3 mg/kg and included patients with abdominal, flank, or musculoskeletal pain. Two trials reported mean pain scores at multiple points, up to 120 minutes, but only the results for the primary outcome of pain reduction at 10 minutes were pooled.

https://ift.tt/2Puy2dy

Sonic Hedgehog Protein is Frequently Up-Regulated in Pancreatic Cancer Compared to Colorectal Cancer

Abstract

Sonic hedgehog (SHH) is a secreted protein which functions in autocrine or paracrine fashion on target cells to activate hedgehog (HH) signalling cascade responsible for growth and proliferation. This study is an attempt to understand the expression dynamics of SHH protein in colon, rectal and pancreatic cancers. Protein expression of SHH was studied by Western Blotting in the histologically confirmed colon, rectum and pancreatic cancer tissue samples along with their adjacent normal tissues. Only 31.4% (11 of 35) and 26.9% (7 of 26) of colon and rectal cancer cases respectively showed an increase in SHH expression in tumours compared to 72.7% (24 of 33) of the pancreatic cancer cases when compared with their adjacent normal tissues. Our results suggest that SHH may have a strong role in the predisposition of Pancreatic cancer and could possibly be used as a diagnostic or prognostic biomarker.



https://ift.tt/2SEL5ek

ASO Author Reflections: The Role of Robotic Surgery in Liver Resection



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Abnormal Iodine Nutrition-Induced ER Stress Upregulates MCP-1 Expression Through P38/MAPK Signaling Pathway in Thyroid Cells

Abstract

Iodine is an important chemical for thyroid hormone synthesis. The association between iodine nutrition status and the risk of disease present U-shaped curve, as either low or high iodine nutrition status will increase the risk of thyroid diseases. Endoplasmic reticulum stress (ER stress), which can induce over expressions of inflammation factors, like monocyte chemo-attractant protein-1 (MCP-1), is related to the pathogenesis of thyroid disease. However, the correlations among iodine, MCP-1 and ER stress are not entirely clear during the pathogenesis of thyroid diseases. Present study aims to investigate how iodine nutrition status influences MCP-1 expression through P38/MAPK pathway as well as the roles of ER stress in this process. Human thyroid cells (Nthy-ori-3-1) was used as a cell model in this study. The expressions of p-P38, PERK, IRE1, ATF6, and MCP-1 were detected after the cells were treated with iodine at different concentrations with or without ER stress inhibitor (4-PBA) or P38/MAPK blocker (SB203580). The expressions of p-P38, PERK, IRE1, ATF6, and MCP-1 in Nthy-ori-3-1 cells treated with iodine at abnormal concentrations were all significantly higher than those in cells treated with iodine at normal concentration. However, addition of ER stress blocker, 4-PBA in the abnormal-iodine treated cells, decreased the expressions of p-P38, PERK, IRE1, ATF6, and MCP-1. Similarly, P38/MAPK activity inhibitor, SB203580, also decreased the expressions of p-P38 and MCP-1. Abnormal iodine nutrition status triggered ER stress and upregulated MCP-1 expression through P38/MAPK signaling pathway in thyrocyte.



https://ift.tt/2Eh5FxD

Desperately seeking…Models to find the right partner and the best use for checkpoint inhibitors

Desperately seeking…Models to find the right partner and the best use for checkpoint inhibitors

Desperately seeking…Models to find the right partner and the best use for checkpoint inhibitors, Published online: 11 December 2018; doi:10.1038/s41416-018-0353-x

Desperately seeking…Models to find the right partner and the best use for checkpoint inhibitors

https://ift.tt/2C67w6P

Data on whole genome sequencing of the oomycete Pythium insidiosum strain CBS 101555 from a horse with pythiosis in Brazil

The oomycete Pythium insidiosum infects humans and animals worldwide, and causes the life-threatening condition, called pythosis. Most patients lose infected organs or die from the disease. Comparative genomic an...

https://ift.tt/2GdLp2l

Anaemia requiring red blood cell transfusion is associated with unfavourable 90-day survival in surgical patients with sepsis

The mortality associated with sepsis remains unacceptably high, despite modern high-quality intensive care. Based on the results from previous studies, anaemia and its management in patients with sepsis appear...

https://ift.tt/2ryYeu1

Lyme neuroborreliosis‐ clinical outcomes, controversy, pathogenesis, and polymicrobial infections

ABSTRACT

Lyme Borreliosis is the object of numerous misconceptions. In this review, we revisit the fundamental manifestations of neuroborreliosis (meningitis and cranial and radiculoneuritis) as these have withstood the test of time. We also discuss other manifestations that are less frequent. Stroke, as a manifestation of Lyme neuroborreliosis, is considered in the context of other infections. The summary of the literature regarding clinical outcomes of neuroborreliosis leads to its controversies. We also include new information on pathogenesis, and on the polymicrobial nature of tick‐borne diseases. In this way, we update the review that we wrote in this journal in 1995.

This article is protected by copyright. All rights reserved.



https://ift.tt/2EpHQEG

Functional Evaluation of Olfactory Pathways in Living Xenopus Tadpoles

58028fig1.jpg

Xenopus tadpoles offer a unique platform to investigate the function of the nervous system in vivo. We describe methodologies to evaluate the processing of olfactory information in living Xenopus larvae in normal rearing conditions or after injury.

https://ift.tt/2Pud7Hy

Pancreaticoduodenectomy with Mesocaval Shunt for Locally Advanced Pancreatic Adenocarcinoma

Abstract

Introduction

Patients with locally advanced pancreatic cancer (LAPC) represent a challenging group to treat, given the involvement of major vascular structures. In selected patients with favorable biology, temporary mesocaval shunt can facilitate the resection and allow for a safer procedure with enhanced exposure to the superior mesenteric vessels.

Methods

We present a video of a pancreaticoduodenectomy (PD) with temporary mesocaval shunt with left internal jugular (LIJ) vein conduit.

Results

A 65-year-old woman presented with LAPC in the uncinate, causing total occlusion of the superior mesenteric vein (SMV) and encasement of the first jejunal artery. After neoadjuvant therapy and evidence of disease stability, a decision was made to perform a PD with a temporary mesocaval shunt to divert mesenteric flow to reduce blood loss and prevent bowel ischemia. During the procedure, the main mesenteric collateral (ileocolic vein) was divided to create the shunt to the inferior vena cava (IVC) with LIJ interposition. The remaining mesenteric tributaries involved by the tumor were divided. The uncinate dissection was performed using a superior mesenteric artery-first approach. Once the resection was completed, the shunt was stapled from the IVC and the graft transposed to the upper SMV. Standard reconstruction was performed. Total operative time was 536 min, and estimated blood loss was 250 cc without transfusions. No perioperative complications occurred.

Conclusion

In selected patients with LAPC, PD with temporary mesocaval shunt can facilitate resection and venous reconstruction in patients with complete portal vein/SMV occlusion.



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ASO Author Reflections: Use of the Survival Recurrent Network for Prediction of Overall Survival in Patients with Gastric Cancer



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Biomarkers of Bad Biology: Curse or a Blessing?



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Laterally Extended Pelvic Resection for Gynaecological Malignancies: A Multicentric Experience with Out - of - the - Box Surgery

Abstract

Purpose

To evaluate morbidity and oncological outcome in a multicentre series of women with gynaecological malignancies infiltrating pelvic side wall (PSW) that received laterally extended pelvic resection (LEPR).

Methods

Patients operated between 2007 and 2017 at three institutions were included. LEPR was defined as an en bloc lateral resection of a pelvic tumour involving sidewall muscle, and/or bone, and/or major nerve, and/or major vascular structure. Postsurgical complications and survivals were evaluated.

Results

Sixty-three women with gynaecological tumours involving PSW were treated with LEPR. Five women underwent primary LEPR, whereas 58 (92%) patients needed LEPR because of recurrence. Twenty-four women (38%) received previous radiation therapy before the surgery. R0 resection was achieved in 54 patients (85.7%), whereas the pathologic margins were microscopically and macroscopically positive in 8 (12.7%) patients and 1 (1.6%) patient, respectively. There was one perioperative death, whereas major postoperative complications occurred in 17 patients (27.7%). Thirty (47.5%) women experienced recurrences: 24/54 (44.4%) were in the R0 group, and 6/9 (66.6%) were in the R1 group, with a median PFS of 15 months and 7 months, respectively (p = 0.024). In total, 11 of 54 (20.3%) patients died of disease in the R0 group and 5 of 9 (55.5%) in the R1 group; a median OS was not reached and was 32 months for R0 and R1 groups, respectively (p = 0.033).

Conclusions

Involvement of the PSW should not prevent obtaining R0 resection. Although the LEPR is associated with considerable morbidity (≈ 30%), a long-term survival seems to be achieved in those women with complete resection.



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Sites of Recurrence After Complete Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Patients with Peritoneal Carcinomatosis from Colorectal and Appendiceal Adenocarcinoma: A Tertiary Center Experience

Abstract

Background

This report describes patterns of disease recurrence after optimal cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC) of colorectal (CRC) and appendiceal adenocarcinoma (AC) origin.

Methods

Patients undergoing optimal CRS/HIPEC (2007–2016) at the authors' institution were retrospectively reviewed from a prospectively maintained database. Data regarding disease recurrence were analyzed.

Results

Of 74 patients who underwent CRS/HIPEC for PC from CRC (n = 46) or AC (n = 28), 49 (66%) had recurrence during a median follow-up period of 39.5 months. The sites of recurrence were peritoneal-only (n = 34, 69%), hematogenous-only (n = 6, 12%), and combined peritoneal and hematogenous (n = 9, 19%) sites. No patients with AC had hematogenous-only recurrence. The median disease-free survival (DFS) time for all the patients was 15 months (95% confidence interval [CI] 12.5–17.5 months). The recurrence rate after CRS/HIPEC was 41% at 1 year, 73% at 3 years, and 76% at 5 years. All the patients with hematogenous-only metastases experienced recurrence within 12 months after CRS/HIPEC. Mucinous or signet ring features predicted peritoneal recurrence (p = 0.041), whereas a complete cytoreduction of 1 was a predictor of early recurrence (p = 0.040). Patients who underwent repeat cytoreduction survived longer than those who received systemic chemotherapy alone. The median survival time after peritoneal-only recurrence was 33 months (95% CI 27.8–38.9 months).

Conclusion

Recurrence for patients with PC is common, even after optimal CRS/HIPEC. Hematogenous-only recurrence occurs early after CRS/HIPEC, suggesting occult disease at the time of treatment and highlighting the need for methods to identify micro-metastases and improve patient selection. Patients experiencing peritoneal-only recurrence had long survival period after CRS/HIPEC, suggesting its effectiveness at controlling peritoneal disease for a time.



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Actual 5-Year Survivors After Surgical Resection of Hilar Cholangiocarcinoma

Abstract

Background

The prevalence and characteristics of actual 5-year survivors after surgical treatment of hilar cholangiocarcinoma (HC) have not been described previously.

Methods

Patients who underwent resection for HC from 2000 to 2015 were analyzed through a multi-institutional registry from 10 U.S. academic medical centers. The clinicopathologic characteristics and both the perioperative and long-term outcomes for actual 5-year survivors were compared with those for non-survivors (patients who died within 5 years after surgery). Patients alive at last encounter who had a follow-up period shorter than 5 years were excluded from the study.

Results

The study identified 257 patients with HC who underwent curative-intent resection with an actuarial 5-year survival of 19%. Of 194 patients with a follow-up period longer than 5 years, 23 (12%) were 5-year survivors. Compared with non-survivors, the 5-year survivors had a lower median pretreatment CA 19-9 level (116 vs. 34 U/L; P = 0.008) and a lower rate of lymph node involvement (42% vs. 15%; P = 0.027) and R1 margins (39% vs. 17%; P = 0.042). However, the sole presence of these factors did not preclude a 5-year survival after surgery. The frequencies of bile duct resection alone, major hepatectomy, caudate lobe resection, portal vein or hepatic artery resection, preoperative biliary sepsis, intraoperative blood transfusion, serious postoperative complications, and receipt of adjuvant chemotherapy were comparable between the two groups.

Conclusions

One in eight patients with HC reaches the 5-year survival milestone after resection. A 5-year survival can be achieved even in the presence of traditionally unfavorable clinicopathologic factors (elevated CA 19-9, nodal metastasis, and R1 margins).



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Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis

Abstract

Introduction

Improvement in overall survival (OS) by locoregional treatment (LRT) of the primary tumor in de novo metastatic breast cancer (MBC) patients remains controversial.

Objective

The aim of our study was to evaluate the impact of LRT on OS in a large retrospective cohort of de novo MBC patients, with regard to immunohistochemical characteristics and pattern of metastatic dissemination.

Methods

We conducted a multicentric retrospective study of patients diagnosed with de novo MBC selected from the French Epidemiological Strategy and Medical Economics MBC database (NCT03275311) between 2008 and 2014. Overall, 4276 women were included in the study. LRT comprised either radiotherapy, surgery, or both.

Results

LRT was used in 40% of patients. Compared with no LRT, patients who received LRT were younger (p < 0.0001) and were more likely to have only one metastatic site (p < 0.0001) or bone-only metastases (p < 0.0001). LRT was associated with a significantly better OS based on landmark multivariate analysis at 1-year (hazard ratio 0.65, 95% confidence interval 0.55–0.76, p < 0.001). Similar results were observed in all sensitivity analyses, including propensity score matching. In subgroup analysis, LRT was associated with better OS in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (61.6 vs. 45.9 months, p < 0.001) and HER2-positive tumors (77.2 vs. 52.6 months, p = 0.008), but not in triple-negative tumors (19 vs. 18.6 months, p = 0.54), and was also associated with a reduction in the risk of death in visceral metastatic patients (p < 0.001).

Conclusions

LRT was associated with a significantly better OS in de novo MBC patients, including patients with visceral involvement at diagnosis; however, LRT did not impact OS in triple-negative MBC.



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Improving Outcomes After Distal Pancreatectomy with Celiac Axis Resection (DP-CAR): As Always, it is All About Patient Selection



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Faecal immunochemical tests (FIT) versus colonoscopy for surveillance after screening and polypectomy: a diagnostic accuracy and cost-effectiveness study

Objective

The English Bowel Cancer Screening Programme (BCSP) recommends 3 yearly colonoscopy surveillance for patients at intermediate risk of colorectal cancer (CRC) postpolypectomy (those with three to four small adenomas or one ≥10 mm). We investigated whether faecal immunochemical tests (FITs) could reduce surveillance burden on patients and endoscopy services.

Design

Intermediate-risk patients (60–72 years) recommended 3 yearly surveillance were recruited within the BCSP (January 2012–December 2013). FITs were offered at 1, 2 and 3 years postpolypectomy. Invitees consenting and returning a year 1 FIT were included. Participants testing positive (haemoglobin ≥40 µg/g) at years one or two were offered colonoscopy early; all others were offered colonoscopy at 3 years. Diagnostic accuracy for CRC and advanced adenomas (AAs) was estimated considering multiple tests and thresholds. We calculated incremental costs per additional AA and CRC detected by colonoscopy versus FIT surveillance.

Results

74% (5938/8009) of invitees were included in our study having participated at year 1. Of these, 97% returned FITs at years 2 and 3. Three-year cumulative positivity was 13% at the 40 µg/g haemoglobin threshold and 29% at 10 µg/g. 29 participants were diagnosed with CRC and 446 with AAs. Three-year programme sensitivities for CRC and AAs were, respectively, 59% and 33% at 40 µg/g, and 72% and 57% at 10 µg/g. Incremental costs per additional AA and CRC detected by colonoscopy versus FIT (40 µg/g) surveillance were £7354 and £180 778, respectively.

Conclusions

Replacing 3 yearly colonoscopy surveillance in intermediate-risk patients with annual FIT could reduce colonoscopies by 71%, significantly cut costs but could miss 30%–40% of CRCs and 40%–70% of AAs.

Trial registration number

ISRCTN18040196; Results.



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https://ift.tt/2SI6gvV

Desperately seeking…Models to find the right partner and the best use for checkpoint inhibitors



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Use of Micronized Purified Flavonoid Fraction Together with Rivaroxaban Improves Clinical and Ultrasound Outcomes in Femoropopliteal Venous Thrombosis: Results of a Pilot Clinical Trial

Abstract

Introduction

The aim of this study was to assess the impact of adding long-term micronized purified flavonoid fraction (MPFF) to standard treatment of femoropopliteal deep vein thrombosis (DVT).

Methods

This pilot, comparative, open-label study with blinded outcome assessor enrolled patients with a first episode of femoropopliteal DVT confirmed by duplex ultrasound scanning (DUS). All participants were randomly allocated to one of two treatment groups: (1) control that received a standard treatment with oral rivaroxaban, and (2) experimental that involved additional treatment with MPFF 1000 mg/day. Both drugs were used for 6 months. Patients were followed for the whole treatment period and underwent DUS every 2 months to determine the degree of recanalization by popliteal (PV), femoral vein (FV), and common femoral vein (CFV) compressibility. Thrombi extension were assessed by the modified Marder score. At the end of the follow-up period, patients were assessed with Villalta and venous clinical severity scales (VCSS). Patients with a Villalta score ≥ 5 were diagnosed with post-thrombotic syndrome (PTS).

Results

Sixty patients were randomized to the control or MPFF groups (n = 30 in each group). There were 40 men and 20 women with a mean age ± SD of 56.3 ± 13.4 years. Clinically unprovoked DVT was recognized in 65% of cases and left side localization in 45%. The mean baseline Marder score was 15.0 ± 4.8 and 11.1 ± 4.3 in the experimental and control groups, respectively (p = 0.002). At 6 months, the mean Villalta score in the MPFF group was significantly lower compared with control (2.9 ± 2.7 versus 5.8 ± 3.0; p < 0.0001). PTS was diagnosed in six patients (20%) and 17 patients (57%) in the experimental and control groups respectively (p = 0.007). A significant difference between the groups was also observed for the VCSS value (2.3 ± 1.9 versus 4.9 ± 1.9; p < 0001). After 6 months of treatment the Marder score decreased to 0.8 ± 1.6 and 2.8 ± 3.5 in the experimental and control groups, respectively (p = 0.006). In the MPFF group, there was a greater reduction in the Marder score (p < 0.0001) and more rapid rate of recanalization for the FV (p < 0.0001), with a non-significant trend for the CFV (p = 0.130) and PV (p = 0.204) compared with the control group. Full recanalization of the PV at 6 months was observed in 24 patients (80%) who had received MPFF, and only 17 patients (57%) in the control group (p = 0.095).

Conclusion

The addition of MPFF to standard therapy for DVT in the form of oral rivaroxaban can reduce the incidence of PTS at 6 months in patients with proximal DVT and increase the speed of deep vein recanalization.

Funding

Les Laboratoires Servier funded the article processing fees, editorial assistance, and open access fee for this manuscript.



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The first Entamoeba moshkovskii molecular detection in Egypt

Abstract

Amebiasis infection is caused by Entamoeba histolytica. The nonpathogenic Entamoeba species, E. moshkovskii and E. dispar, are distinct but morphologically indifferentiable from E. histolytica, which led us to use of multiplex PCR to detect and molecularly differentiate Entamoeba species in fecal samples of a cohort of 504 diarrheic/dysenteric Egyptians attending outpatient clinics of the Beni-Suef University Hospital. E. moshkovskii was detected for the first time in Egypt, added to already reported E. histolytica and E. dispar. Molecular prevalence of all Entamoeba species was 10%. E. histolytica (1.4%) was the least prevalent Entamoeba, 6 times less than nonpathogenic amoebae (7.9%), E. dispar (4.6%), and E. moshkovskii (3.3%). Entamoeba coinfection was found in 0.8% of cases. Coproscopy had a limited diagnostic performance for the diagnosis of E. histolytica, giving false-positive and false-negative results. Use of molecular assays, a laboratory non-coproscopic method, is preferable as it differentiates amoeba infections and monitors the E. histolytica true prevalence for better treatment and effective control.



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Trastuzumab-Based Combination Chemotherapy in Patients with Human Epidermal Growth Factor Receptor-2-Positive Metastatic Carcinoma ex Pleomorphic Adenoma

Background: Carcinoma ex pleomorphic adenoma (CXPA) is a rare histologic subtype of lacrimal gland and submandibular gland cancer. Currently, there is no standard treatment for metastatic CXPA, although some case reports have explored the role of targeted agents in chemotherapy. A few histopathologic analyses have shown that some of these tumors overexpress human epidermal growth factor receptor-2 (HER2), suggesting a potential role for HER2-based therapy. We report here two cases of metastatic CXPA that were treated with trastuzumab-based chemotherapy (IRB approved) with rapid and significant responses. Case Report 1: A 66-year-old male was diagnosed as HER2-positive CXPA of the right lacrimal gland with multiple bone and lymph node metastases. Combination chemotherapy with trastuzumab (Tmab) and nanoparticle albumin-bound paclitaxel (nabPTX) was initiated. A rapid response was confirmed, and after seven cycles of treatment, CR(complete response) was achieved. Case Report 2: A 67-year-old female was diagnosed with HER2 positive CXPA of the right submandibular gland. Multiple pulmonary metastatic lesions were detected after surgery, and combination chemotherapy with Tmab and nab-PTX was initiated. A rapid partial response (PR) was confirmed, and she eventually became disease-free. Conclusion: In the absence of definitive clinical trials, which are unlikely to be performed due to the rarity of HER2-positive CXPA, therapeutic information must be obtained from case reports. Some reports, such as this one, have suggested a potential utility of trastuzumab-based chemotherapy.
Case Rep Oncol 2018;11:835–841

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Invasive Pulmonary Adenocarcinoma with Lepidic Growth Pattern in a Pregnant Patient

Among the differential diagnoses that should be considered in acute respiratory failure (ARF) are infectious processes, autoimmune diseases, interstitial pulmonary fibrosis, and pulmonary neoplasia. Timely diagnosis of lung neoplasia is complicated in the early stages. An opportune diagnosis, as well as the specific treatment, decrease mortality. ARF occurs 1 in 500 pregnancies and is most common during the postpartum period. Among the specific etiologies that cause ARF during pregnancy that must be considered are: (1) preeclampsia; (2) embolism of amniotic fluid; (3) peripartum cardiomyopathy; and (4) trophoblastic embolism. The case of a 36-year-old patient with a 33-week pregnancy and ARF is presented. The patient presented dyspnea while exerting moderate effort that progressed to orthopnea and type 1 respiratory insufficiency. Imaging studies showed bilateral alveolar infiltrates and predominantly right areas of consolidation. Blood cultures, a galactomannan assay and IgG antibodies against mycoplasma pneumoniae, were reported as negative. Autoimmune etiology was ruled out through an immunoassay. A percutaneous pulmonary biopsy was performed and an invasive pulmonary adenocarcinoma with lepidic growth pattern (i.e. lepidic pulmonary adenocarcinoma, LPA) result was reported. This etiology is rare and very difficult to recognize in acute respiratory failure cases. After infectious, autoimmune and interstitial lung fibrosis have been excluded the clinician must suspect of lung cancer in a patient with acute respiratory failure and chest imaging compatible with the presence of ground-glass nodular opacities, a solitary nodule or mass with bronchogram, and lung consolidation. In the presence of acute respiratory failure, the suspicion of pulmonary neoplasia in an adult of reproductive age must be timely. Failure to recognize this etiology can lead to fatal results.
Case Rep Oncol 2018;11:822–834

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N6-methyladenosine RNA methylation is involved in virulence of the rice blast fungus Pyricularia oryzae (syn. Magnaporthe oryzae)

Abstract
N6-methyladenosine (m6A) RNA methylation is a conserved modification of RNA in eukaryotes. Pyricularia oryzae, a filamentous phytopathogenic fungus, is the cause of a destructive rice blast disease that can lead to significant declines in rice production. Here, we characterized the function of m6A RNA methylation in the development and virulence of P. oryzae by studying four genes with functional genomics. We found that PoIme4 is an N6-adenosine-methyltransferase, and deletion of PoIME4 led to decreased levels of m6A RNA methylation. PoYth1 and PoYth2 are two m6A-binding proteins and deletion of PoYTH2 led to reduced conidiation. Co-localization experiments showed that PoAlkb1 (an mRNA:m6A demethylase) and PoYth1 were co-localized with PoDcp1 in the processing bodies involved in mRNA decay. Virulence tests showed that PoIME4, PoALKB1, PoYTH1 and PoYTH2 were involved in virulence on rice in P. oryzae. Therefore, these experimental evidences provide new and important information about the roles of m6A RNA methylation in fungal asexual reproduction and pathogenicity.

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Cancers, Vol. 10, Pages 508: Erratum: Shibata S.; et al. Proton Beam Therapy without Fiducial Markers Using Four-Dimensional CT Planning for Large Hepatocellular Carcinomas. Cancers 2018, 10, 71

Cancers, Vol. 10, Pages 508: Erratum: Shibata S.; et al. Proton Beam Therapy without Fiducial Markers Using Four-Dimensional CT Planning for Large Hepatocellular Carcinomas. Cancers 2018, 10, 71

Cancers doi: 10.3390/cancers10120508

Authors: Satoshi Shibata Shigeyuki Takamatsu Kazutaka Yamamoto Miu Mizuhata Sayuri Bou Yoshitaka Sato Mariko Kawamura Satoko Asahi Yuji Tameshige Yoshikazu Maeda Makoto Sasaki Tomoyasu Kumano Satoshi Kobayashi Hiroyasu Tamamura Toshifumi Gabata

The authors wish to make the following corrections to this paper [...]



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Cancers, Vol. 10, Pages 507: The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin β4 in Breast Cancer

Cancers, Vol. 10, Pages 507: The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin β4 in Breast Cancer

Cancers doi: 10.3390/cancers10120507

Authors: Young Hwa Soung Shane Ford Cecilia Yan Jun Chung

Despite the established role of integrin &beta;4 (ITG &beta;4) in breast cancer progression, the importance of endocytic recycling of ITG &beta;4 and its regulatory mechanism are poorly understood. Here, we found that a sub-population of ITG &beta;4 is sorted into early endosomes, recycled back to the plasma membrane, and secreted in the form of extracellular vesicles (EVs) upon EGF treatment in triple negative breast cancer (TNBC) cells. A metastasis suppressor, ARRDC3 (arrestin domain-containing 3) prevents EGF-driven endocytic recycling of ITG &beta;4 by inducing NEDD4-dependent ubiquitination of ITG &beta;4 and targeting endosomal ITG &beta;4 into lysosomes. Endocytic recycling of ITG &beta;4 is linked to sorting of ITG &beta;4 into EVs (ITG &beta;4+ EVs). ITG &beta;4+ EVs are mainly detectable from supernatants of TNBC cells and their production is inhibited by ARRDC3 expression. ARRDC3 reduces the metastatic potentials of breast cancer cell-derived EVs by reducing ITG &beta;4 levels in EVs. Overall, current studies provide novel mechanistic insights on the regulatory mechanism of ITG &beta;4 recycling, and its importance in invasive potentials of TNBC EVs, thus providing the basis for therapeutic targeting of the ARRDC3/ITG &beta;4 pathway in TNBC.



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Novel features for capturing temporal variations of rhythmic limb movement to distinguish convulsive epileptic and psychogenic nonepileptic seizures

Summary

Objective

To investigate the characteristics of motor manifestation during convulsive epileptic and psychogenic nonepileptic seizures (PNES), captured using a wrist‐worn accelerometer (ACM) device. The main goal was to find quantitative ACM features that can differentiate between convulsive epileptic and convulsive PNES.

Methods

In this study, motor data were recorded using wrist‐worn ACM‐based devices. A total of 83 clinical events were recorded: 39 generalized tonic–clonic seizures (GTCS) from 12 patients with epilepsy, and 44 convulsive PNES from 7 patients (one patient had both GTCS and PNES). The temporal variations in the ACM traces corresponding to 39 GTCS and 44 convulsive PNES events were extracted using Poincaré maps. Two new indices—tonic index (TI) and dispersion decay index (DDI)—were used to quantify the Poincaré‐derived temporal variations for every GTCS and convulsive PNES event.

Results

The TI and DDI of Poincaré‐derived temporal variations for GTCS events were higher in comparison to convulsive PNES events (P < 0.001). The onset and the subsiding patterns captured by TI and DDI differentiated between epileptic and convulsive nonepileptic seizures. An automated classifier built using TI and DDI of Poincaré‐derived temporal variations could correctly differentiate 42 (sensitivity: 95.45%) of 44 convulsive PNES events and 37 (specificity: 94.87%) of 39 GTCS events. A blinded review of the Poincaré‐derived temporal variations in GTCS and convulsive PNES by epileptologists differentiated 26 (sensitivity: 70.27%) of 44 PNES events and 33 (specificity: 86.84%) of 39 GTCS events correctly.

Significance

In addition to quantifying the motor manifestation mechanism of GTCS and convulsive PNES, the proposed approach also has diagnostic significance. The new ACM features incorporate clinical characteristics of GTCS and PNES, thus providing an accurate, low‐cost, and practical alternative to differential diagnosis of PNES.



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Seizures as presenting symptom in patients with glioblastoma

Summary

Objective

The clinical course and underlying molecular causes in patients with glioblastoma presenting with seizures are poorly understood. Here we investigated clinical features and carrier systems as well as a transaminase relevant in glutamate homeostasis in patients with glioblastoma.

Methods

We performed a retrospective analysis of our clinical glioma database for clinical data during a 2‐year period. Patients with glioblastoma were divided into 2 groups: symptomatic and asymptomatic for seizures. Magnetic resonance imaging (MRI) scans and tissue samples from both groups were investigated. A Cox regression analysis was performed for survival and clinical and molecular features.

Results

One hundred three patients diagnosed with glioblastoma in this period were identified. Twenty‐three patients were symptomatic with seizures (22.3%). All were IDH‐1/2 wild‐type. We found no significant difference in the tumor localization between the groups. Patients with seizures from glioblastoma had significantly smaller tumors, which caused less edema compared to nonepileptogenic tumors. A significantly increased up‐regulation of glutamate carrier systems was evident in symptomatic tumors compared to asymptomatic tumors. Moreover, there seems to be an oversupply of glutamate in symptomatic tumors due to dysregulation in glutamate synthesis.

Significance

Glioblastoma presenting with seizures is morphologically different from asymptomatic tumors. Furthermore, we were able to show that the molecular profile of these tumors, particularly glutamate homeostasis controlling systems, is significantly different.



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Ocular Complications from Retained Intraocular Ointment Discovered 33 Months after Cataract Surgery

Topical antibiotic and steroid ointments are sometimes used topically at the conclusion of intraocular surgery, and inadvertent entry into the eye has been reported. Dispersed ointment droplets or consolidated globules in the anterior chamber (AC) can sometimes be visualized on exam. Occasionally, intraocular ointment is found incidentally without apparent toxic effect, but retained ointment usually presents with early or delayed intraocular inflammation, pressure rise, macular edema, or corneal edema. The usual treatment for toxicity from retained ointment is removal of the ointment. While the complication of ointment-induced cystoid macular edema has been reported, there is paucity of literature on the anatomical response and eventual visual outcome of patients who have been treated for long-standing edema from retained ointment. We present a case of a patient who presented with history of poor vision since the time of cataract surgery 33 months prior, who had cystoid macular edema, reduced endothelial cell count, and apparent Maxitrol ointment (neomycin, polymyxin B sulfate, and dexamethasone in paraffin vehicle; Novartis Pharmaceuticals UK) floating in the AC. The patient was treated with AC washout and sub-Tenon injection of triamcinolone. His vision, retinal architecture by optical coherence tomography, endothelial cell count, and pachymetry has been followed for 9 months following this treatment.
Case Rep Ophthalmol 2018;9:493–498

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Biology of Nodal Spread in Colon Cancer: Insights from Molecular and Genetic Studies

Colorectal cancer (CRC) lymph node metastases are common but their genetics and the mechanism whereby these metastases occur are not well understood. Here we present recent data regarding genetic heterogeneity in primary CRCs and their metastasis. In addition, we explain the different potential models describing the mechanisms of metastasis and the data supporting them. Multiple studies have also revealed a variety of prognostic molecular markers that are associated with lymph node metastasis in CRC. A better understanding of genetic heterogeneity and the mechanisms of metastasis is critical to predicting clinical response and resistance to targeted therapy.
Eur Surg Res 2018;59:361–370

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GLP1 Receptor Agonist Liraglutide Is an Effective Therapeutic Option for Perioperative Glycemic Control in Type 2 Diabetes within Enhanced Recovery After Surgery (ERAS) Protocols

Background: Enhanced Recovery After Surgery (ERAS) protocols are multimodal perioperative care pathways designed to achieve early recovery after surgical procedures by maintaining preoperative organ function and reducing profound stress responses following surgery [Wilmore and Kehlet: BMJ 2001; 322(7284): 473–6]. Glucagon-like peptide-1 receptor agonists (GLP-1RAgs), such as liraglutide, have recently been widely used as antidiabetic agents in patients with type 2 diabetes (T2D) because they maintain blood glucose at an ideal level throughout the day, including during postprandial periods, thereby improving hypoglycemia and body weight more than insulin therapies. Additionally, the administration of liraglutide may exert cardiovascular, renal, and cerebral protective effects in T2D patients. The use of GLP-1RAgs for perioperative glycemic control is sometimes considered to be controversial. Methods: The efficacy and safety of liraglutide therapy during perioperative glycemic control in elective surgery patients within ERAS protocols were compared with those of insulin therapy. Ninety adult T2D patients scheduled to undergo elective surgery within ERAS protocols were randomized and analyzed. Forty-nine subjects were prescribed liraglutide and 41 insulin therapy. Procedures comprised orthopedic, thoracic, urological, otolaryngological, hepatic resection, and gynecological breast surgeries. Results: Liraglutide was shown to be a more effective option than insulin therapy because (1) glycemic levels were more stable; (2) the number of patients requiring additional insulin according to the insulin sliding scale was significantly smaller (Fisher's exact test, p = 0.005); (3) the insulin dosage required on the day of surgery was significantly smaller (Fisher's exact, p = 0.004); (4) the additional insulin volume required was significantly less for patients throughout the perioperative period (Fisher's exact test, p = 0.001); and (5) while lean body mass remained the same, body fat measurements, particularly visceral fat, tended to decrease. Conclusions: Based on the results of the present study and a recent large-scale clinical study showing cardiovascular and renal protective effects in T2D patients, we consider the administration of liraglutide within ERAS protocols for T2D patients to represent a more comprehensive suite of patient protection measures as a perioperative non-insulin agent, particularly in patients with limited exercise ability and those at risk of hypoglycemia.
Eur Surg Res 2018;59:349–360

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