Targeting myeloid-derived suppressor cells for cancer immunotherapy

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with an immune suppressive phenotype. They represent a critical component of the immune suppressive niche described in cancer, where they support immune escape and tumor progression through direct effects on both the innate and adaptive immune responses, largely by contributing to maintenance of a high oxidative stress environment. The number of MDSCs positively correlates with protumoral activity, and often diminishes the effectiveness of immunotherapies, which is particularly problematic with the emergence of personalized medicine. Approaches targeting MDSCs showed promising results in preclinical studies and are under active investigation in clinical trials in combination with various immune checkpoint inhibitors. In this review, we discuss MDSC targets and therapeutic approaches targeting MDSC that have the aim of enhancing the existing tumor therapies.

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Phase III study with FOLFIRI + cetuximab versus FOLFIRI + cetuximab followed by cetuximab alone in RAS and BRAF WT mCRC

Future Oncology, Ahead of Print.


https://ift.tt/2LHHGsq

Precise predictive and therapeutic strategy for breast cancer

Future Oncology, Ahead of Print.


https://ift.tt/2xrE4YL

Treatment patterns and medication adherence among patients diagnosed with multiple myeloma and treated with panobinostat

Future Oncology, Ahead of Print.


https://ift.tt/2LMsoTq

The initial development of the Pregnancy-related Anxiety Scale

Publication date: Available online 30 May 2018
Source:Women and Birth
Author(s): Robyn J. Brunton, Rachel Dryer, Anthony Saliba, Jane Kohlhoff
Problem/backgroundPregnancy-related anxiety is a distinct anxiety characterised by pregnancy-specific concerns. This anxiety is consistently associated with adverse birth outcomes, and obstetric and paediatric risk factors, associations generally not seen with other anxieties. The need exists for a psychometrically sound scale for this anxiety type. This study, therefore, reports on the initial development of the Pregnancy-related Anxiety Scale.MethodsThe item pool was developed following a literature review and the formulation of a definition for pregnancy-related anxiety. An Expert Review Panel reviewed the definition, item pool and test specifications. Pregnant women were recruited online (N=671).ResultsUsing a subsample (N=262, M=27.94, SD=4.99), fourteen factors were extracted using Principal Components Analysis accounting for 63.18% of the variance. Further refinement resulted in 11 distinct factors. Confirmatory Factor Analysis further tested the model with a second subsample (N=369, M=26.59, SD=4.76). After additional refinement, the resulting model was a good fit with nine factors (childbirth, appearance, attitudes towards childbirth, motherhood, acceptance, anxiety, medical, avoidance, and baby concerns). Internal consistency reliability was good with the majority of subscales exceeding α=.80.ConclusionsThe Pregnancy-related Anxiety Scale is easy to administer with higher scores indicative of greater pregnancy-related anxiety. The inclusion of reverse-scored items is a potential limitation with poorer reliability evident for these factors. Although still in its development stage, the Pregnancy-related Anxiety Scale will eventually be useful both clinically (affording early intervention) and in research settings.



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Birth Control Pills (Taytulla Physician Sample Packs) Recalled Over Potential Pregnancy Risk

WEDNESDAY, May 30, 2018 -- Almost 170,000 birth control pill packs are being recalled over a manufacturing error that could lead to unplanned pregnancy, maker Allergan says. Taytulla physician sample packs include active capsules and inactive...

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Free choice tasks as random generation tasks: an investigation through working memory manipulations

Abstract

Free choice tasks are tasks in which two or more equally valid response options per stimulus exist from which participants can choose. In investigations of the putative difference between self-generated and externally triggered actions, they are often contrasted with forced choice tasks, in which only one response option is considered correct. Usually, responses in free choice tasks are slower when compared with forced choice task responses, which may point to a qualitative difference in response selection. It was, however, also suggested that free choice tasks are in fact random generation tasks. Here, we tested the prediction that in this case, randomness of the free choice responses depends on working memory (WM) load. In Experiment 1, participants were provided with varying levels of external WM support in the form of displayed previous choices. In Experiment 2, WM load was induced via a concurrent n-back task. The data generally confirm the prediction: in Experiment 1, WM support improved both randomness and speed of responses. In Experiment 2, randomness decreased and responses slowed down with increasing WM load. These results suggest that free choice tasks have much in common with random generation tasks.

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Efficacy of BGJ398, a fibroblast growth factor receptor 1-3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations [Research Articles]

BGJ398, a potent and selective pan-fibroblast growth factor receptor (FGFR) antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.

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Companies Scaling Back IDO1 Inhibitor Trials [News in Depth]

Disappointing results prompted the decisions, but researchers argued that studies should continue.

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Prospective analysis of adoptive TIL therapy in patients with metastatic melanoma: response, impact of anti-CTLA4, and biomarkers to predict clinical outcome

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Experimental Design: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival and progression free survival. Immunologic factors associated with response were also evaluated. Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4 naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA-4 naive patients, but not in anti-CTLA-4 refractory patients. Baseline serum levels of IL-9 predicted response to TIL ACT, while TIL persistence, tumor recognition and mutation burden did not correlate with outcome. Conclusions:This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL-9 levels can potentially serve as a predictive tool to appropriately select sequence for immunotherapies.

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Comprehensive molecular profiling of intra- and extrahepatic cholangiocarcinomas: potential targets for intervention

Purpose: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response. Experimental Design: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher's exact tests were performed to identify associations between clinical characteristics and genetic alterations.

Results: 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma (IHC) were IDH1(30%), ARID1A(23%) BAP1(20%), TP53(20%) and FGFR2gene fusions (14%). A tendency towards mutual exclusivity was seen between multiple genes in IHC including TP53:IDH1, IDH1:KRAS, TP53:BAP1, IDH1:FGFR2. Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker directed therapy or clinical trial enrollment in 16% of patients. Conclusions: Cholangiocarcinoma is a genetically diverse cancer. Alterations in CDKN2A/Band ERBB2are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers.

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Radium-223 dichloride in Combination with Vascular Endothelial Growth Factor-Targeting Therapy in Advanced Renal Cell Carcinoma with Bone Metastases

Purpose: This study investigates the biologic activity of radium-223 with vascular endothelial growth factor (VEGF)-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases. Experimental Design: Fifteen treatment-naïve patients (n=15) received pazopanib 800 mg orally once-daily and 15 previously-treated patients received sorafenib 400 mg orally twice-daily. Radium-223 55 kilobecquerel/kg was administered concurrently every four weeks for up to 6 infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin and bone-specific alkaline phosphatase) compared to baseline. Secondary endpoints included safety, rate of symptomatic-skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use and quality of life. Exploratory analysis of tumor genomic alterations was performed. Results: Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases and 83% had a history of SSE prior to enrolment. No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time. Conclusions: Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in aRCC with skeletal metastases. NCT02406521

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CORL Expression in the Drosophila Central Nervous System Is Regulated by Stage Specific Interactions of Intertwined Activators and Repressors

CORL proteins (SKOR in mice and Fussel in humans) are a subfamily of central nervous system (CNS) specific proteins related to Sno/Ski oncogenes. Their developmental and homeostatic roles are largely unknown. We previously showed that Drosophila CORL (dCORL; fussel in Flybase) functions between the Activin receptor Baboon and Ecdysone Receptor-B1 (EcR-B1) activation in mushroom body neurons of third instar larval brains. To better understand dCORL regulation and function we generated a series of reporter genes. We examined the embryonic and larval CNS and found that dCORL is regulated by stage specific interactions between intertwined activators and repressors spanning numerous reporters. The reporter AH.lacZ, which contains sequences 7-11kb upstream of dCORL exon1, reflects dCORL brain expression at all stages. Surprisingly, AH.lacZ is not present in EcR-B1 expressing mushroom body neurons. In larvae AH.lacZ is coexpressed with Elav and the transcription factor Drifter as well as in dILP2 insulin producing cells of the pars intercerebralis. The presence of dCORL in insulin producing cells suggests that dCORL functions non-autonomously in the regulation of EcR-B1 mushroom body activation via the modulation of insulin signaling. Overall, the high level of sequence conservation seen in all CORL/SKOR/Fussel family members and their common CNS-specificity suggest that similarly complex regulation and a potential function in insulin signaling are associated with SKOR/Fussel proteins in mammals.

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Bayesian Networks Predict Neuronal Transdifferentiation

We employ the language of Bayesian networks to systematically construct gene-regulation topologies from deep-sequencing single-nucleus RNA-Seq data for human neurons. From the perspective of the cell-state potential landscape, we identify attractors that correspond closely to different neuron subtypes. Attractors are also recovered for cell states from an independent data set confirming our models accurate description of global genetic regulations across differing cell types of the neocortex (not included in the training data). Our model recovers experimentally confirmed genetic regulations and community analysis reveals genetic associations in common pathways. Via a comprehensive scan of all theoretical three-gene perturbations of gene knockout and overexpression, we discover novel neuronal trans-differrentiation recipes (including perturbations of SATB2, GAD1, POU6F2 and ADARB2) for excitatory projection neuron and inhibitory interneuron subtypes.

https://ift.tt/2IWW965

A Collection of Transgenic Medaka Strains for Efficient Site-Directed Transgenesis Mediated by phiC31 Integrase

Genetic analysis is facilitated by the efficient production of transgenic strains expressing a DNA of interest as a single copy at a designated chromosomal location. However, technical progress toward this goal in medaka fish (Oryzias latipes), a vertebrate model organism, has been slow. It is well known that phiC31 integrase enables efficient site-directed transgenesis by catalyzing the recombination of an attP DNA motif in a host genome with an attB motif in a targeting vector. This system was pioneered in medaka using the Sleeping Beauty transposon system, and the attP site was established at three chromosomal locations. However, this number appeared insufficient with regard to genetic linkage between the attP-landing site and a genetically modified locus of interest. Here, to establish a collection of transgenic strains of medaka, we introduced an attP motif into the medaka genome using the Ac/Ds maize transposon system and established 12 independent transgenic strains harboring a single copy of the attP motif in at least 11 of the 24 medaka chromosomes. We designed an attB-targeting vector that was integrated efficiently and precisely into the attP-landing site, and with which the DNA of interest was efficiently transmitted to germline cells. Extraneous sequences in the integrants derived from the bacterial backbone of the attB-targeting vector as well as a transgenic fluorescence marker present in the attP-landing site were removable through flippase-mediated recombination. Further, an advanced targeting vector with a heart-specific recombination marker served as a useful tool for easily screening phiC31 integrase-mediated recombinant G₀ embryos, leading to the efficient establishment of transgenic strains. Thus, our resources advance genetic research in medaka.

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Upregulation of dNTP Levels After Telomerase Inactivation Influences Telomerase-Independent Telomere Maintenance Pathway Choice in Saccharomyces cerevisiae

In 10-15% of cancers, telomere length is maintained by a telomerase-independent, recombination-mediated pathway called alternative lengthening of telomeres (ALT). ALT mechanisms were first seen, and have been best studied, in telomerase-null Saccharomyces cerevisiae cells called "survivors". There are two main types of survivors. Type I survivors amplify Y' subtelomeric elements while type II survivors, similar to the majority of human ALT cells, amplify the terminal telomeric repeats. Both types of survivors require Rad52, a key homologous recombination protein, and Pol32, a non-essential subunit of DNA polymerase . A number of additional proteins have been reported to be important for either type I or type II survivor formation, but it is still unclear how these two pathways maintain telomeres. In this study, we performed a genome-wide screen to identify novel genes that are important for the formation of type II ALT-like survivors. We identified 23 genes that disrupt type II survivor formation when deleted. 17 of these genes had not been previously reported to do so. Several of these genes (DUN1, CCR4, and MOT2) are known to be involved in the regulation of dNTP levels. We find that dNTP levels are elevated early after telomerase inactivation and that this increase favors the formation of type II survivors.

https://ift.tt/2H60wGf

Birth Control Pills Recalled Over Potential Pregnancy Risk

WEDNESDAY, May 30, 2018 -- Almost 170,000 birth control pill packs are being recalled over a manufacturing error that could lead to unplanned pregnancy, maker Allergan says. Taytulla physician sample packs include active capsules and inactive...

https://ift.tt/2srGLnq

ACS Updates Colorectal Cancer Screening to Start at Age 45

WEDNESDAY, May 30, 2018 -- Colorectal cancer (CRC) screening should begin at age 45 for people at average risk, according to updated guidelines from the American Cancer Society published online May 30 in CA: A Cancer Journal for Clinicians. Andrew...

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FDA Approves New Treatment for Ulcerative Colitis

WEDNESDAY, May 30, 2018 -- U.S. Food and Drug Administration approval of Xeljanz (tofacitinib) has been expanded to include adults with active moderate-to-severe ulcerative colitis, the agency said Wednesday. Xeljanz was first approved in 2012 for...

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Older Adults Often Reluctant to Set Up Secure Patient Portal

WEDNESDAY, May 30, 2018 -- About half of older adults report having set up a patient portal, according to survey results from the National Poll on Healthy Aging. A randomly selected group of 2,013 older adults, age 50 to 80 years, completed an...

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Helminth-induced regulatory T cells and suppression of allergic responses

Jayden Logan | Severine Navarro | Alex Loukas | Paul Giacomin

https://ift.tt/2Jk7lcv

Dendritic cells, T cells and lymphatics: dialogues in migration and beyond

Marc Permanyer | Berislav Bošnjak | Reinhold Förster

https://ift.tt/2JjjSwJ

The Antitumor Mechanism of Paeonol on CXCL4/CXCR3-B Signals in Breast Cancer Through Induction of Tumor Cell Apoptosis

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


https://ift.tt/2sjoObe

In vivo and in vitro expression of five genes involved in Corynebacterium pseudotuberculosis virulence

Caseous lymphadenitis (LC) is a chronic contagious disease caused by Corynebacterium pseudotuberculosis, which mainly affects goats and sheep. Vaccination is an effective but not yet well-established method, part...

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Bile acids and FXR in functional gastrointestinal disorders

Functional Gastrointestinal Disorders (FGIDs), such as Irritable Bowel Syndrome (IBS) and Chronic Constipation (CC), are commonly diagnosed conditions in clinical practice which create a substantial global burden. Since the Farnesoid X Receptor (FXR) and bile acids (BAs) are responsible for maintaining homeostasis in the GI tract, any disturbances in the expression of FXR or the composition of BAs may contribute to the development of the GI symptoms. Alterations in the mechanism of action of FXR directly affect the BAs pool and account for increased intestinal permeability and changes in abundance and diversity of gut microbiota leading to intestinal dysmotility.

https://ift.tt/2kDIZN0

Long-term Follow-up in Adults with Coeliac Disease: Predictors and Effect on Health Outcomes

Guidelines recommend regular follow-up in coeliac disease, but effect of this on long-term outcomes remains unclear.

https://ift.tt/2spAY1y

Meta-analysis comparing the efficacy and adverse events of biologics and thiopurines for Crohn's Disease after surgery for ulcerative colitis

Long-term inflammatory complications of IPAA include Crohn's Disease (CD) or "CD-like" (CDL) condition. We performed a meta-analysis to evaluate the efficacy of anti-tumor necrosis factor (anti-TNF) with or without immunomodulator (IM) therapy in this group of patients.

https://ift.tt/2IXSAgf

982 SINGLE-SCOPE TRANSGASTRIC ANTEGRADE CHOLANGIOSCOPY (STAC) AND INTRADUCTAL POLYPECTOMY VIA EUS-GUIDED HEPATICOGASTROSTOMY (HGS) WITH A LUMEN-APPOSING-METAL STENT (LAMS)

Tissue diagnosis and biliary drainage are standard steps in the palliative management of pancreaticobiliary malignancies. These steps are typically undertaken by EUS-FNA and ERCP, respectively. We present a case in which EUS-FNA failed to diagnose polypoid cholangiocarcinoma and ERCP failed to drain the upstream duct. EUS-guided hepaticogastrostomy (HGS) was performed with a lumen-apposing metal stent (LAMS). HGS provided biliary drainage and access for single-scope transgastric antegrade cholangioscopy (STAC).

https://ift.tt/2LKqIK7

Su1448 ENDOSONOGRAPHIC ALTERATIONS OF THE RESECTED SMALL SUBEPITHELIAL LESIONS ON UPPER GASTROINTESTINAL TRACT DURING SURVEILLANCES

Gastrointestinal subepithelial lesions may have malignant potentials. Some endosonographic features are suggested to differentiate the lesions and surveillances are recommended if they are not removed. To prove the effectiveness of surveillances, the results of inspection that influence the surgical resections should be reported.

https://ift.tt/2LN1Tgq

Sa1340 COST-EFFECTIVENESS OF EUS-DIRECTED TRANSGASTRIC ERCP (EDGE) COMPARED TO DEVICE-ASSISTED ENTEROSCOPY ERCP AND TRANSGASTRIC ERCP IN PATIENTS WITH ROUX-EN-Y ANATOMY

Roux-en-Y gastric bypass (RYGB) surgery remains the most common weight loss surgery in the United States. RYGB anatomy makes it difficult to access patients' biliary system, a requirement for treating choledocholithiasis and other pancreaticobiliary diseases. Commonly used approaches for transpapillary biliary interventions are either device-assisted enteroscopy (DAE) endoscopic retrograde cholangiopancreatography (ERCP) or transgastric (TG) ERCP. DAE-ERCP is limited by forward-viewing optics and imperfect accessories resulting in relatively low technical success rates.

https://ift.tt/2J5WK1D

Su1384 EUS-GUIDED RADIOFREQUENCY ABLATION (EUS-RFA) FOR PANCREATIC NEUROENDOCRINE TUMORS AND CYSTIC MUCINOUS NEOPLASMS: A PILOT STUDY OF SAFETY, FEASIBILITY AND EFFICACY

Preliminary case-reports deem EUS-RFA as a potential effective therapy for selected patients with pancreatic malignancies unfit for or refusing surgery. Recent development of EUS-RFA catheters opens up a potential, minimally invasive treatment option. However, there are scarce data about their real safety, efficcacy and type of lesions potentially treatables. We aimed to assess the feasibility, efficacy, adverse events and early results of EUS-RFA for pancreatic neuroendocrine tumors (PNET) and cystic mucinous neoplasms (CMN)

https://ift.tt/2xsDJoJ

Sa1276 COMPARISON BETWEEN ENDOSCOPIC SPHINCTEROTOMY VERSUS ENDOSCOPIC SPHINCTEROTOMY ASSOCIATED WITH BALLOON DILATION FOR REMOVAL OF BILE DUCT STONES: A SYSTEMATIC REVIEW AND META-ANALYSIS BASED ON RANDOMIZED CONTROLLED TRIALS.

To compare gallstones removal rate and incidence of bleeding, pancreatitis, use of mechanical lithotripsy, cholangitis and perforation between isolated sphincterotomy versus sphincterotomy associated with balloon dilation of papilla in choledocholithiasis through the meta-analysis of randomized clinical trials.

https://ift.tt/2J5WH5X

771 A NATIONAL US HEALTHCARE SYSTEM WEB-BASED COLONOSCOPY QUALITY REPORT CARD: ACCURATE, USABLE, AND ROBUST

Colonoscopy quality measurement and reporting is problematic and burdensome, especially for large health systems. This is mainly due to variability in documentation and lack of structured data, even in the current electronic healthcare record era. Natural language processing (NLP) has shown promise in extracting quality metrics, but operational, dynamic large scale use has not been demonstrated. We aimed to develop and validate an accurate data source and workflow to measure colonoscopy quality for the largest integrated health care system in the US, and to provide a standardized and automated colonoscopy quality report card at the site and provider level.

https://ift.tt/2LN1L0q

542 DOES INITIAL CONTRAST-ENHANCED CT IMPACT ON CLINICAL OUTCOMES OF PATIENTS WITH COLON DIVERTICULAR BLEEDING?

Although the recommended method of an initial examination of hematochezia is colonoscopy, computed-enhanced CT (CECT) is an appealing diagnostic modality for the same disorder, because it has a superior ability of detecting active bleeding and it is widely available, fast, and minimally invasive. In many centers, CECT has already become an established method for characterizing the location of hematochezia. However, its impact on clinical courses of patients with colon diverticular bleeding is fully known.

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Su1416 EUS-GUIDED CHOLEDOCHODUODENOSTOMY USING A LUMEN APPOSING METAL STENT FOR MALIGNANT DISTAL BILIARY OBSTRUCTION: A RESTROSPECTIVE ANALYSIS OF A SINGLE CENTER EXPERIENCE

Endoscopic ultrasonography guided choledochoduodenostomy(EUS-CD) using a lumen apposing metal stent(LAMS) has been recently reported as an alternative approach in the management of patients with malignant obstructive jaundice and failed endoscopic retrograde cholangiopancreatography(ERCP).

https://ift.tt/2LN1IBM

Su1135 CAP ASSISTED ENDOSCOPIC RESECTION VERSUS MULTIBAND MUCOSECTOMY TECHNIQUE FOR THE MANAGEMENT OF ESOPHAGEAL CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS

Esophageal cancer is the eighth most common cancer worldwide. Endoscopic resection (ER) remains a safe and effective treatment for the management of high-grade intraepithelial neoplasms of the esophagus. Different ER techniques have been described such as cap assisted ER and multiband mucosectomy (MBM). Although cap-assisted ER technique has been widely used for the esophagus, it may be technically demanding and laborious, especially when multiple subsequent resections are required. There are small numbers of studies with limited patient number comparing the efficacy of cap assisted ER versus MBM for the management of esophageal cancer.

https://ift.tt/2LKquTh

Sa1890 ROBOT-ASSISTED ENDOSCOPIC SUBMUCOSAL DISSECTION USING DISPOSABLE TIP-MOUNTED ROBOTIC MODULE: FIRST EX VIVO RESULTS

Endoscopic Submucosal Dissection (ESD) is a nascent endoscopic therapeutic procedure that enables en bloc removal of early-stage gastrointestinal neoplasms. While the prognosis for patients who undergo successful ESD is good, the remote locations of these lesions can require substantial dexterity and appreciable cognitive work load, increasing the possibility of adverse events. To address these technical challenges, we developed a tip-mounted robotic system, EndoMODRA (Endoscopic Module for On-Demand Robotic Assistance), which interfaces with commercially-available endoscopes and provides additional dexterity and feedback via on-board actuators and sensors to improve therapeutic yields and facilitate dissection.

https://ift.tt/2J5WDmJ

Sa1308 ENDOSCOPIC TREATMENT OF SYMPTOMATIC COMMON BILE DUCT STONES IN THE ELDERLY

Regardless of age, in Japan it is recommended that the complete removal of stones be achieved for the management of common bile duct (CBD) stones. However, in many elderly patients stones cannot be safely removed at the initial procedure because of their age and the time required to deal with many and/or large stones. In those patients endoscopic biliary stenting (EBS) is recommended as an alternative.

https://ift.tt/2LN1Elw

Sa1044 MULTIPLE-ADENOMA DETECTION RATE HELPS IDENTIFY ENDOSCOPISTS WITH A HIGHER DIAGNOSTIC YIELD OF ADVANCED ADENOMAS IRRESPECTIVE OF THEIR ADENOMA DETECTION RATE

Although adenoma detection rate has become the most frequently used indicator of an endoscopist quality for screening colonoscopy performance, it is not the only one. Other quality indicators have been proposed, which may provide complimentary information regarding quality of colonoscopy. The correlation and differences in terms of relevant lesion diagnostic yield between adenoma detection rate and multiple-adenoma detection rate has not been exhaustively assessed.

https://ift.tt/2xpPigh

923 ADJUSTED COMPARISON OF COMMERCIAL BOWEL PREPARATIONS BASED ON INADEQUACY OF BOWEL PREPARATION IN OUTPATIENT SETTINGS

Adequate bowel preparation is important for effective colonoscopic examination. Although limited research has identified commercial bowel preparations (CBP) associated with inadequate bowel preparation (IBP) it does not adjust for multiple known risk factors associated with IBP. In this study, after adjusting for many factors previously identified to affect IBP, various commercial bowel preparations are compared with each other.

https://ift.tt/2LKqpir

Sa1916 PROSPECTIVE, RANDOMIZED EX VIVO TRIAL TO ASSESS THE ANTI-REFLUX EFFECT OF ANTI-REFLUX MUCOSECTOMY IN PORCINE.

Both long-term proton pump inhibitor (PPI) use and surgical fundoplication have potential drawbacks as treatments for chronic gastroesophageal reflux disease (GERD). Our aim was to investigate the safe and efficacy of anti-reflux mucosectomy (ARMS) in porcine and determine the optimal circumference of resection in relation to gastroesophageal junction (GEJ).

https://ift.tt/2J38PV8

Sa1232 DOES INVISIBLE INTRAEPITHELIAL NEOPLASIA OF THE STOMACH EXIST?

Gastric cancer is the third leading cause of cancer death worldwide. Gastric dysplasia is considered a precancerous lesion. While early identification and management of these lesions are important for prevention of gastric cancer, the accuracy of diagnosis of low grade intraepithelial neoplasia (LGIN) in the stomach and its optimal management remain controversial. Some classification systems either do not include the term dysplasia or fail to differentiate between high grade intraepithelial neoplasia (HGIN) and LGIN in their classifications.

https://ift.tt/2LKqliH

Su1683 ENDOSCOPIC FINDINGS ARE USEFUL AS PREDICTORS OF EFFICACY OF ANTI-TNFα THERAPY FOR CROHN'S DISEASE

Although anti-TNFα therapy is effective for treating Crohn's disease, recently there have been cases of primary and secondary failure. There are few reports with regard to usefulness of endoscopic findings in estimating the efficacy of anti-TNFα therapy for Crohn's disease. We explored the kinds of endoscopic findings to evaluate them in terms of their usefulness as predictors of anti-TNFα therapy efficacy for Crohn's disease.

https://ift.tt/2xvgfiE

British Society for Gene and Cell Therapy Annual Conference; Friday 27th April 2018; Regent's Conference Centre, London, UK; www.bsgct.org

Human Gene Therapy, Ahead of Print.


https://ift.tt/2JiQ0QY

Author Index

Human Gene Therapy, Ahead of Print.


https://ift.tt/2L4D9zl

Paraquat induced acute kidney injury and lung fibrosis: a case report from Bangladesh

Since Bangladesh government issued a ban on the use of highly toxic WHO Class I pesticides, annual consumption of herbicides like Paraquat have been sharply increasing in the markets. Paraquat poisoning is an ...

https://ift.tt/2H6WflR

Some coagulase negative Staphylococcus spp. isolated from buffalo can be misidentified as Staphylococcus aureus by phenotypic and Sa442 PCR methods

Staphylococcus aureus is a commonly reported cause of buffalo mastitis. However, its prevalence may be overestimated. The aim of this study was to compare S. aureus identification by conventional phenotypic and g...

https://ift.tt/2kCsDEn

Compliance to iron and folic acid supplementation in pregnancy, Northwest Ethiopia

Strict compliance to iron and folic acid supplementation is vital for prevention of anemia in pregnancy. However, data are scarce in Ethiopia. So, we conducted this study to assess the level of compliance to i...

https://ift.tt/2spjF0H

Does Higher Protein Intake Up Heart Failure Risk in Men?

WEDNESDAY, May 30, 2018 -- Higher dietary protein intake is associated with a trend toward increased heart failure risk among middle-aged men, according to a study published online May 29 in Circulation: Heart Failure. Heli E.K. Virtanen, from the...

https://ift.tt/2kAFRBf

Tighter Alcohol Policies Cut Alcohol-Related Crash Deaths

WEDNESDAY, May 30, 2018 -- Strengthening state alcohol policies can reduce alcohol-related crash fatalities, according to a study published online May 29 in JAMA Internal Medicine. Timothy S. Naimi, M.D., M.P.H., from Boston University, and...

https://ift.tt/2smIk5K

Genomic Medicine Will Help Shift Cardio Care to Proactive Approach

WEDNESDAY, May 30, 2018 -- Genomic medicine is likely to help clinical care shift from a reactive to a proactive approach, especially in the field of cardiovascular medicine, according to a scientific statement from the American Heart Association...

https://ift.tt/2kDMSkW

Children Typically Have 14 Simple Infections by Age 3 Years

WEDNESDAY, May 30, 2018 -- Children experience a median of 14 infections during their first three years of life, though there is large variation in incidence, according to a study published online May 24 in Pediatrics. Nadja Hawwa Vissing, M.D.,...

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Mini-Dose Glucagon May Halt Post-Exercise Hypoglycemia

TUESDAY, May 29, 2018 -- Mini-dose glucagon (MDG) is an effective approach for preventing exercise-induced hypoglycemia in patients with type 1 diabetes, according to a study published online May 18 in Diabetes Care. Michael R. Rickels, M.D., from...

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Hypofractionated Radiotherapy Best in Anaplastic Thyroid Cancer

TUESDAY, May 29, 2018 -- In an orthotopic anaplastic thyroid cancer (ATC) model, hypofractionated radiotherapy (RT) is superior to conventionally fractionated RT, according to a study published online May 18 in Thyroid. Ayman Oweida, Ph.D., from the...

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Prediction Tool Helps Tailor Lung Cancer Screening to Patients

TUESDAY, May 29, 2018 -- Personalizing the harm-benefit assessment of low-dose computed tomography (LDCT) screening for lung cancer can inform patient-centered screening decisions, according to a study published online May 29 in the Annals of...

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Babies of Adolescents in CPS Care More Likely to Be Taken Into Care

TUESDAY, May 29, 2018 -- Teen mothers who are in the care of child protection services (CPS) when they gave birth have more than a seven times higher likelihood that their child will be taken into care before age 2 years, compared to teen mothers...

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Insomnia Found to Be Common but Mild in Older Adults

TUESDAY, May 29, 2018 -- Insomnia is common in older community-dwelling adults, but usually mild, according to a study published online May 21 in the Journal of the American Geriatrics Society. Brienne Miner, M.D., from Yale University in New Haven,...

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Gaps in Care Post Discharge for Mild Traumatic Brain Injury

TUESDAY, May 29, 2018 -- There are considerable gaps in follow-up care for patients with mild traumatic brain injury (mTBI) who have been discharged from the hospital, according to a study published online May 25 in JAMA Network Open. Seth A....

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Senior CA Patients Also Benefit From Palliative Radiotherapy

WEDNESDAY, May 30, 2018 -- All patients with painful bone metastasis should be referred for palliative radiotherapy to relieve the pain, regardless of age, according to a study published online May 23 in the Journal of Medical Imaging and Radiation...

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Most Premature Infants Receive Early Antibiotics

TUESDAY, May 29, 2018 -- Most premature infants receive empirical antibiotic therapy, according to a study published online May 25 in JAMA Network Open. Dustin D. Flannery, D.O., from the Children's Hospital of Philadelphia, and colleagues examined...

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Reduced-Dose Anticoagulants Feasible for Extended VTE Tx

TUESDAY, May 29, 2018 -- For an extended duration, reduced-dose direct oral anticoagulants (DOACs) may be as effective as full-dose treatment for preventing recurrent venous thromboembolism (VTE), according to a review published online May 17 in the...

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Worse Survival for BRCA Germline Mutation Carriers in Pancreatic CA

WEDNESDAY, May 30, 2018 -- BRCA1/BRCA2 germline mutation carriers with pancreatic ductal adenocarcinoma (PDAC) have worse survival after resection, according to a study published in the April issue of the Journal of the American College of...

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New Hypertension Guideline Discussed for Older Adults

TUESDAY, May 29, 2018 -- Clinicians caring for older adults with hypertension should be mindful of the specific blood pressure (BP) goals proven to reduce cardiovascular disease events, while adopting the new 2017 American College of...

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Recommendations Developed for Improving Women's Health Care

WEDNESDAY, May 30, 2018 -- Women face unique health challenges across their lifetimes, and policies should be implemented to improve their health outcomes, according to a position paper published online May 29 in the Annals of Internal...

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Parents Have Concerns Over Food Allergy Precautions at Schools

WEDNESDAY, May 30, 2018 -- A substantial portion of parents whose children have food allergies have concerns over the safety of their child at school, according to a study published online May 12 in BMC Pediatrics. S. Shahzad Mustafa, M.D., from the...

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CDC: Outpatient Rehab Rates Suboptimal for Stroke Survivors

WEDNESDAY, May 30, 2018 -- In 2015, 35.5 percent of adult stroke survivors used outpatient rehabilitation, up from 31.2 percent in 2013, according to research published in the May 25 issue of the U.S. Centers for Disease Control and Prevention's...

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Elevated HbA1c Usually Leads to Prompt Tx Start, Intensification

WEDNESDAY, May 30, 2018 -- Most patients are newly initiated on antidiabetic therapy or have antidiabetic therapy intensified within six months of hemoglobin A1c (HbA1c) elevation, according to a study published online May 24 in Diabetes...

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One in Six Women Regret Freezing Their Eggs

TUESDAY, May 29, 2018 -- Certain identifiable factors are associated with decision regret following elective oocyte cryopreservation (EOC), according to a study published online May 25 in Fertility and Sterility. Eleni A. Greenwood, M.D., from the...

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Social media posts and online search behaviour as early-warning system for MRSA outbreaks

Despite many preventive measures, outbreaks with multi-drug resistant micro-organisms (MDROs) still occur. Moreover, current alert systems from healthcare organizations have shortcomings due to delayed or inco...

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The tigecycline evaluation and surveillance trial; assessment of the activity of tigecycline and other selected antibiotics against gram-positive and gram-negative pathogens from France collected between 2004 and 2016

A high level of antibiotic consumption in France means antimicrobial resistance requires rigorous monitoring. The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) is a global surveillance study that mo...

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The MPLEx Protocol for Multi-omic Analyses of Soil Samples

A protocol is presented for simultaneously extracting metabolites, proteins, and lipids from a single soil sample, allowing reduced sample preparation times and enabling multi-omic mass spectrometry analyses of samples with limited quantities.

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Hindering the formation and promoting the dispersion of medical biofilms: non-lethal effects of seagrass extracts

Biofilms have great significance in healthcare-associated infections owing to their inherent tolerance and resistance to antimicrobial therapies. New approaches to prevent and treat unwanted biofilms are urgen...

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In vitro antibacterial effects of Tanreqing injection combined with vancomycin or linezolid against methicillin-resistant Staphylococcus aureus

Combining conventional drugs and traditional medicine may represent a useful approach to combating antibiotic resistance, which has become a serious threat to global public health. This study aimed to evaluate...

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Malignant adnexal tumors of the skin: a single institution experience

Abstract

Background

Malignant adnexal tumors of the skin (MATS) are rare. We aimed to measure the survival of patients with MATS and identify predictors of improved survival.

Methods

A retrospective review of MATS treated at our institution from 1990 to 2012.

Results

There were 50 patients within the time period. Median age was 59.5 years (range 22–95); primary site was the head and neck (52%); most common histologic subtypes were skin appendage carcinoma (20%) and eccrine adenocarcinoma (20%); and the vast majority were T1 (44%). Most patients (98%) underwent surgical treatment. Chemotherapy and radiation were administered to 8 and 14% of patients, respectively. Recurrence rate was 12%. Median OS was 158 months (95% CI, 52–255). OS and recurrence-free survival at 5 years were 62.4 and 47.4% and at 10 years 56.7 and 41.5%, respectively. Five-year and 10-year disease-specific survival (DSS) was 62.9%. Age > 60 years was an unfavorable predictor of OS (HR 12.9, P < .0008) and recurrence-free survival (RFS) (HR 12.53, P < .0003). Nodal metastasis was a negative predictor of RFS (HR 2.37, P < 0.04) and DSS (HR 7.2, P < 0.03) while treatment with chemotherapy was predictive of poor DSS (HR 14.21, P < 0.03).

Conclusions

Younger patients had better OS and RFS. Absence of nodal metastasis translated to better RFS and DSS. Lymph node basin staging is worth considering in the workup and treatment.

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Using Laser Doppler Imaging and Monitoring to Analyze Spinal Cord Microcirculation in Rat

Here we present a combination of laser Doppler perfusion imaging (LDPI) and laser Doppler perfusion monitoring (LDPM) to measure spinal cord local blood flows and oxygen saturation (SO2), as well as a standardized procedure for introducing spinal cord trauma on rat.

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Summary results of the 2014-2015 DARPA Chikungunya challenge

Background: Emerging pathogens such as Zika, chikungunya, Ebola, and dengue viruses are serious threats to national and global health security. Accurate forecasts of emerging epidemics and their severity are crit...

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Faecal colonization of E. coli and Klebsiella spp. producing extended-spectrum beta-lactamases and plasmid-mediated AmpC in Mozambican university students

In recent years, the world has seen a surge in Enterobacteriaceae resistant to broad-spectrum beta-lactam antibiotics due to the production of extended-spectrum beta-lactamases (ESBLs) or plasmid-mediated AmpC...

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Genetic and epidemiological analysis of norovirus from children with gastroenteritis in Botswana, 2013–2015

Norovirus is a leading cause of viral gastroenteritis worldwide with a peak of disease seen in children. The epidemiological analysis regarding the virus strains in Africa is limited. The first report of norov...

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Remote Memory and Cortical Synaptic Plasticity Require Neuronal CCCTC-Binding Factor (CTCF)

The molecular mechanism of long-term memory has been extensively studied in the context of the hippocampus-dependent recent memory examined within several days. However, months-old remote memory maintained in the cortex for long-term has not been investigated much at the molecular level yet. Various epigenetic mechanisms are known to be important for long-term memory, but how the 3D chromatin architecture and its regulator molecules contribute to neuronal plasticity and systems consolidation is still largely unknown. CCCTC-binding factor (CTCF) is an 11-zinc finger protein well known for its role as a genome architecture molecule. Male conditional knock-out mice in which CTCF is lost in excitatory neurons during adulthood showed normal recent memory in the contextual fear conditioning and spatial water maze tasks. However, they showed remarkable impairments in remote memory in both tasks. Underlying the remote memory-specific phenotypes, we observed that female CTCF conditional knock-out mice exhibit disrupted cortical LTP, but not hippocampal LTP. Similarly, we observed that CTCF deletion in inhibitory neurons caused partial impairment of remote memory. Through RNA sequencing, we observed that CTCF knockdown in cortical neuron culture caused altered expression of genes that are highly involved in cell adhesion, synaptic plasticity, and memory. These results suggest that remote memory storage in the cortex requires CTCF-mediated gene regulation in neurons, whereas recent memory formation in the hippocampus does not.

SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a well-known 3D genome architectural protein that regulates gene expression. Here, we use two different CTCF conditional knock-out mouse lines and reveal, for the first time, that CTCF is critically involved in the regulation of remote memory. We also show that CTCF is necessary for appropriate expression of genes, many of which we found to be involved in the learning- and memory-related processes. Our study provides behavioral and physiological evidence for the involvement of CTCF-mediated gene regulation in the remote long-term memory and elucidates our understanding of systems consolidation mechanisms.

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R-Ras1 and R-Ras2 Are Essential for Oligodendrocyte Differentiation and Survival for Correct Myelination in the Central Nervous System

Rapid and effective neural transmission of information requires correct axonal myelination. Modifications in myelination alter axonal capacity to transmit electric impulses and enable pathological conditions. In the CNS, oligodendrocytes (OLs) myelinate axons, a complex process involving various cellular interactions. However, we know little about the mechanisms that orchestrate correct myelination. Here, we demonstrate that OLs express R-Ras1 and R-Ras2. Using female and male mutant mice to delete these proteins, we found that activation of the PI3K/Akt and Erk1/2-MAPK pathways was weaker in mice lacking one or both of these GTPases, suggesting that both proteins coordinate the activity of these two pathways. Loss of R-Ras1 and/or R-Ras2 diminishes the number of OLs in major myelinated CNS tracts and increases the proportion of immature OLs. In R-Ras1^–/– and R-Ras2^–/–-null mice, OLs show aberrant morphologies and fail to differentiate correctly into myelin-forming phenotypes. The smaller OL population and abnormal OL maturation induce severe hypomyelination, with shorter nodes of Ranvier in R-Ras1^–/– and/or R-Ras2^–/– mice. These defects explain the slower conduction velocity of myelinated axons that we observed in the absence of R-Ras1 and R-Ras2. Together, these results suggest that R-Ras1 and R-Ras2 are upstream elements that regulate the survival and differentiation of progenitors into OLs through the PI3K/Akt and Erk1/2-MAPK pathways for proper myelination.

SIGNIFICANCE STATEMENT In this study, we show that R-Ras1 and R-Ras2 play essential roles in regulating myelination in vivo and control fundamental aspects of oligodendrocyte (OL) survival and differentiation through synergistic activation of PI3K/Akt and Erk1/2-MAPK signaling. Mice lacking R-Ras1 and/or R-Ras2 show a diminished OL population with a higher proportion of immature OLs, explaining the observed hypomyelination in main CNS tracts. In vivo electrophysiology recordings demonstrate a slower conduction velocity of nerve impulses in the absence of R-Ras1 and R-Ras2. Therefore, R-Ras1 and R-Ras2 are essential for proper axonal myelination and accurate neural transmission.

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Conditional Bistability, a Generic Cellular Mnemonic Mechanism for Robust and Flexible Working Memory Computations

Persistent neural activity, the substrate of working memory, is thought to emerge from synaptic reverberation within recurrent networks. However, reverberation models do not robustly explain the fundamental dynamics of persistent activity, including high-spiking irregularity, large intertrial variability, and state transitions. While cellular bistability may contribute to persistent activity, its rigidity appears incompatible with persistent activity labile characteristics. Here, we unravel in a cellular model a form of spike-mediated conditional bistability that is robust and generic. and provides a rich repertoire of mnemonic computations. Under asynchronous synaptic inputs of the awakened state, conditional bistability generates spiking/bursting episodes, accounting for the irregularity, variability, and state transitions characterizing persistent activity. This mechanism has likely been overlooked because of the subthreshold input it requires, and we predict how to assess it experimentally. Our results suggest a reexamination of the role of intrinsic properties in the collective network dynamics responsible for flexible working memory.

SIGNIFICANCE STATEMENT This study unravels a novel form of intrinsic neuronal property: conditional bistability. We show that, thanks to its conditional character, conditional bistability favors the emergence of flexible and robust forms of persistent activity in PFC neural networks, in opposition to previously studied classical forms of absolute bistability. Specifically, we demonstrate for the first time that conditional bistability (1) is a generic biophysical spike-dependent mechanism of layer V pyramidal neurons in the PFC and that (2) it accounts for essential neurodynamical features for the organization and flexibility of PFC persistent activity (the large irregularity and intertrial variability of the discharge and its organization under discrete stable states), which remain unexplained in a robust fashion by current models.

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Here and Now: A New Clinical Practice Section

He who studies medicine without books sails an uncharted sea, but he who studies medicine without patients does not go to sea at all.-William Osler

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Issue Highlights

Celiac disease has been historically considered to be important in the Western hemisphere, but recent data suggests a global emergence of this disease. In this issue of the journal, Singh et al1 present a comprehensive meta-analysis of the worldwide prevalence of celiac disease. They identified 96 relevant studies published between 1991 and 2016 containing data from 6 continents. Among 275,818 individuals, the pooled global seroprevalence of celiac disease was 1.4% (positive anti-tissue transglutaminase or anti-endomysial antibodies).

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Editorial Board

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Treatment Failure With Over-the-Scope Clip in High-Risk Gastrointestinal Bleeding: What Were the Causes?

We read with great interest the article by Brandler et al1 investigating the efficacy of over-the-scope clip (OTSC) as primary or rescue therapy for patients with bleeding lesions that are at high risk of adverse outcome (HR-AO). In this retrospective study, the authors identified 67 patients with gastrointestinal bleeding (Rockall score was 6.9 ± 1.4) arising from lesions that had HR-AO features and OTSC was successful in preventing rebleeding in 81.3% of cases. They defined HR-AO features as bleeding lesions (1) located in the territory of major arteries (duodenum, lesser curve, lower rectum); (2) presence of a large-caliber artery (>2 mm); (3) deep penetrating, excavated, and fibrotic ulcer with high-risk stigmata; and (4) high-risk of complications with standard endoscopic therapy.

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Endocuff to Improve Adenoma Detection: Supported by Low-Quality Evidence or Not Supported by High-Quality Evidence?

We read with great interest the network meta-analysis by Facciorusso et al1 that compared the efficacy of add-on devices with each other or with standard colonoscopy. Facciorusso et al1 are to be commended for their excellent work on investigating the effect of add-on devices on colonoscopy performance. Among the add-on devices, it has been reported that Endocuff (ARC Medical Design, Leeds, UK) is safe, effective, easy to handle, and may improve both the adenoma detection rate (ADR) and control of the tip of the colonoscope, and might reduce colorectal interval carcinomas.

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Correction

Mindikoglu AL, Pappas SC. New developments in hepatorenal syndrome. Clin Gastroenterol Hepatol 2018;16:162–177.

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Quality Assessment of Trials Comparing Add-On Devices With Standard Colonoscopy

We appreciate the interest shown by Zhang et al1 for our study and we thank them for their letter, which points out some aspects in our paper that evidently need further explanation. They are absolutely right in highlighting the substantial difference in quality assessment between studies published only as abstracts and those published as full-text papers, but this issue is widely addressed in Supplementary Figure 1 of our meta-analysis where conference abstracts were rated at high risk of "other bias" (seventh item of the Cochrane tool for assessing the risk of bias).

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Cover

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Reply

We appreciate the thoughtful comments and questions that Asokkumar et al1 raised after reading our article about investigating the efficacy of over-the-scope clip (OTSC) as primary or rescue therapy for patients with bleeding lesions that are at high risk of adverse outcome.2 As a standard practice, all OTSC placements are checked for adequate peritarget tissue and target vessel entrapment. Appropriate additional thermal, mechanical, or occlusive approaches are taken to address the concerns raised by Asokkumar et al.

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Contents

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Elsewhere in The AGA Journals

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Information for Authors and Readers

Clinical Gastroenterology and Hepatology is the go-to resource on a broad spectrum of themes in clinical gastroenterology and hepatology. The official clinical practice journal of the AGA Institute brings you the best original research in the field with a unique combination of reviews, editorials, podcasts, video abstracts, and outcomes research—all supporting clinical practice. Articles on education, policy, and practice management highlight issues pertinent to clinicians.

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Schaffer Collateral Inputs to CA1 Excitatory and Inhibitory Neurons Follow Different Connectivity Rules

Neural circuits, governed by a complex interplay between excitatory and inhibitory neurons, are the substrate for information processing, and the organization of synaptic connectivity in neural network is an important determinant of circuit function. Here, we analyzed the fine structure of connectivity in hippocampal CA1 excitatory and inhibitory neurons innervated by Schaffer collaterals (SCs) using mGRASP in male mice. Our previous study revealed spatially structured synaptic connectivity between CA3 and CA1 pyramidal cells (PCs). Surprisingly, parvalbumin-positive interneurons (PVs) showed a significantly more random pattern spatial structure. Notably, application of Peters' rule for synapse prediction by random overlap between axons and dendrites enhanced structured connectivity in PCs, but, by contrast, made the connectivity pattern in PVs more random. In addition, PCs in a deep sublayer of striatum pyramidale appeared more highly structured than PCs in superficial layers, and little or no sublayer specificity was found in PVs. Our results show that CA1 excitatory PCs and inhibitory PVs innervated by the same SC inputs follow different connectivity rules. The different organizations of fine scale structured connectivity in hippocampal excitatory and inhibitory neurons provide important insights into the development and functions of neural networks.

SIGNIFICANCE STATEMENT Understanding how neural circuits generate behavior is one of the central goals of neuroscience. An important component of this endeavor is the mapping of fine-scale connection patterns that underlie, and help us infer, signal processing in the brain. Here, using our recently developed synapse detection technology (mGRASP and neuTube), we provide detailed profiles of synaptic connectivity in excitatory (CA1 pyramidal) and inhibitory (CA1 parvalbumin-positive) neurons innervated by the same presynaptic inputs (CA3 Schaffer collaterals). Our results reveal that these two types of CA1 neurons follow different connectivity patterns. Our new evidence for differently structured connectivity at a fine scale in hippocampal excitatory and inhibitory neurons provides a better understanding of hippocampal networks and will guide theoretical and experimental studies.

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Short-Term Plasticity Combines with Excitation-Inhibition Balance to Expand Cerebellar Purkinje Cell Dynamic Range

The balance between excitation (E) and inhibition (I) in neuronal networks controls the firing rate of principal cells through simple network organization, such as feedforward inhibitory circuits. Here, we demonstrate in male mice, that at the granule cell (GrC)-molecular layer interneuron (MLI)-Purkinje cell (PC) pathway of the cerebellar cortex, E/I balance is dynamically controlled by short-term dynamics during bursts of stimuli, shaping cerebellar output. Using a combination of electrophysiological recordings, optogenetic stimulation, and modeling, we describe the wide range of bidirectional changes in PC discharge triggered by GrC bursts, from robust excitation to complete inhibition. At high frequency (200 Hz), increasing the number of pulses in a burst (from 3 to 7) can switch a net inhibition of PC to a net excitation. Measurements of EPSCs and IPSCs during bursts and modeling showed that this feature can be explained by the interplay between short-term dynamics of the GrC-MLI-PC pathway and E/I balance impinging on PC. Our findings demonstrate that PC firing rate is highly sensitive to the duration of GrC bursts, which may define a temporal-to-rate code transformation in the cerebellar cortex.

SIGNIFICANCE STATEMENT Sensorimotor information processing in the cerebellar cortex leads to the occurrence of a sequence of synaptic excitation and inhibition in Purkinje cells. Granule cells convey direct excitatory inputs and indirect inhibitory inputs to the Purkinje cells, through molecular layer interneurons, forming a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we found that presynaptic short-term dynamics affect the balance between synaptic excitation and inhibition on Purkinje cells during high-frequency bursts and can reverse the sign of granule cell influence on Purkinje cell discharge when burst duration increases. We conclude that short-term dynamics may play an important role in transforming the duration of sensory inputs arriving on cerebellar granule cells into cerebellar cortical output firing rate.

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Genetic Activation, Inactivation, and Deletion Reveal a Limited And Nuanced Role for Somatostatin-Containing Basal Forebrain Neurons in Behavioral State Control

Recent studies have identified an especially important role for basal forebrain GABAergic (BF^VGAT) neurons in the regulation of behavioral waking and fast cortical rhythms associated with cognition. However, BF^VGAT neurons comprise several neurochemically and anatomically distinct subpopulations, including parvalbumin-containing BF^VGAT neurons and somatostatin-containing BF^VGAT neurons (BF^SOM neurons), and it was recently reported that optogenetic activation of BF^SOM neurons increases the probability of a wakefulness to non-rapid-eye movement (NREM) sleep transition when stimulated during the rest period of the animal. This finding was unexpected given that most BF^SOM neurons are not NREM sleep active and that central administration of the synthetic somatostatin analog, octreotide, suppresses NREM sleep or increases REM sleep. Here we used a combination of genetically driven chemogenetic and optogenetic activation, chemogenetic inhibition, and ablation approaches to further explore the in vivo role of BF^SOM neurons in arousal control. Our findings indicate that acute activation or inhibition of BF^SOM neurons is neither wakefulness nor NREM sleep promoting and is without significant effect on the EEG, and that chronic loss of these neurons is without effect on total 24 h sleep amounts, although a small but significant increase in waking was observed in the lesioned mice during the early active period. Our in vitro cell recordings further reveal electrophysiological heterogeneity in BF^SOM neurons, specifically suggesting at least two distinct subpopulations. Together, our data support the more nuanced view that BF^SOM neurons are electrically heterogeneous and are not NREM sleep or wake promoting per se, but may exert, in particular during the early active period, a modest inhibitory influence on arousal circuitry.

SIGNIFICANCE STATEMENT The cellular basal forebrain (BF) is a highly complex area of the brain that is implicated in a wide range of higher-level neurobiological processes, including regulating and maintaining normal levels of electrocortical and behavioral arousal. The respective in vivo roles of BF cell populations and their neurotransmitter systems in the regulation of electrocortical and behavioral arousal remains incompletely understood. Here we seek to define the neurobiological contribution of GABAergic somatostatin-containing BF neurons to arousal control. Understanding the respective contribution of BF cell populations to arousal control may provide critical insight into the pathogenesis of a host of neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, and the cognitive impairments of normal aging.

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Time-Restricted Feeding Prevents Ablation of Diurnal Rhythms in Gastric Vagal Afferent Mechanosensitivity Observed in High-Fat Diet-Induced Obese Mice

Mechanosensitive gastric vagal afferents (GVAs) are involved in the regulation of food intake. GVAs exhibit diurnal rhythmicity in their response to food-related stimuli, allowing time of day-specific satiety signaling. This diurnal rhythmicity is ablated in high-fat-diet (HFD)-induced obesity. Time-restricted feeding (TRF) has a strong influence on peripheral clocks. This study aimed to determine whether diurnal patterns in GVA mechanosensitivity are entrained by TRF. Eight-week-old male C57BL/6 mice (N = 256) were fed a standard laboratory diet (SLD) or HFD for 12 weeks. After 4 weeks of diet acclimatization, the mice were fed either ad libitum or only during the light phase [Zeitgeber time (ZT) 0–12] or dark phase (ZT12–24) for 8 weeks. A subgroup of mice from all conditions (n = 8/condition) were placed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at ZT0. HFD mice gained more weight than SLD mice. TRF did not affect weight gain in the SLD mice, but decreased weight gain in the HFD mice regardless of the TRF period. In SLD mice, diurnal rhythms in food intake were inversely associated with diurnal rhythmicity of GVA mechanosensitivity. These diurnal rhythms were entrained by the timing of food intake. In HFD mice, diurnal rhythms in food intake and diurnal rhythmicity of GVA mechanosensitivity were dampened. Loss of diurnal rhythmicity in HFD mice was abrogated by TRF. In conclusion, diurnal rhythmicity in GVA responses to food-related stimuli can be entrained by food intake. TRF prevents the loss of diurnal rhythmicity that occurs in HFD-induced obesity.

SIGNIFICANCE STATEMENT Diurnal control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong diurnal changes in food intake. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and exhibit diurnal fluctuations in mechanosensitivity. These diurnal fluctuations in vagal afferent mechanosensitivity are lost in diet-induced obesity. This study provides evidence that time-restricted feeding entrains diurnal rhythmicity in vagal afferent mechanosensitivity in lean and high-fat-diet (HFD)-induced obese mice and, more importantly, prevents the loss of rhythmicity in HFD-induced obesity. These data have important implications for the development of strategies to treat obesity.

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Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohns disease

Objective

Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn's disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy.

Design

Mucosal and blood cells were isolated from patients with Crohn's disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS.

Results

Responders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4β7, and exhibited increased expression of IFN-, T-bet, IL-17A and RORt compared with TNFR2+IL23R– cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23.

Conclusions

Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn's disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn's disease refractory to anti-TNF therapy.

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Carotid and femoral Doppler do not allow the assessment of passive leg raising effects

The hemodynamic effects of the passive leg raising (PLR) test must be assessed through a direct measurement of cardiac index (CI). We tested whether changes in Doppler common carotid blood flow (CBF) and commo...

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Will Palliative Care Ever Be Cool?

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FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel for Neoadjuvant Treatment of Resectable and Borderline Resectable Pancreatic Head Adenocarcinoma

Abstract

Background

Both FOLFIRINOX and gemcitabine/nab-paclitaxel (G-nP) are used increasingly in the neoadjuvant treatment (NAT) of pancreatic ductal adenocarcinoma (PDA). This study aimed to compare neoadjuvant FOLFIRINOX and G-nP in the treatment of resectable (R) and borderline resectable (BR) head PDA.

Methods

A single-institution retrospective review of R and BR patients undergoing pancreaticoduodenectomy after NAT with FOLFIRINOX or G-nP was performed. Comparative analysis was performed using inverse-probability-weighted (IPW) estimators. The end points of the study were overall survival (OS) and an 80% reduction in CA19-9 with NAT.

Results

In this study, 193 patients were analyzed, with 73 patients receiving FOLFIRINOX and 120 patients receiving G-nP. The median OS was 38.7 months for FOLFIRINOX versus 28.6 months for G-nP (p = 0.214). The patients who received FOLFIRINOX were younger and had fewer comorbidities, more BR disease, and larger tumors than those treated with G-nP (all p < 0.05). The two regimens were equally effective in achieving an 80% decline in CA19-9 (p = 0.8). The R0 resection rates were similar (80%), but FOLFIRINOX was associated with a reduction in pN1 disease (56% vs. 72%; p = 0.028). The receipt of adjuvant therapy was similar (74 vs. 75%; p = 0.79). In the Cox regression analysis with adjustment for baseline and treatment-related variables (FOLFIRINOX vs. G-nP, age, gender, computed tomography (CT) tumor size, BR vs. R, pre-NAT CA19-9), regimen type was not associated with a survival benefit. In the IPW analysis of 166 patients, however, the average treatment effect of FOLFIRINOX was to increase OS by 4.9 months compared with G-nP (p = 0.012).

Conclusions

Both FOLFIRINOX and G-nP are viable options for neoadjuvant treatment of PDA. In this study, neoadjuvant FOLFIRINOX was associated with a 4.9-month improvement in survival compared with G-nP after adjustment for covariates.

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Most Breast Cancer Patients with T1-2 Tumors and One to Three Positive Lymph Nodes Do Not Need Postmastectomy Radiotherapy

Abstract

Background/Objective

Guidelines concur that postmastectomy radiation therapy (PMRT) in T1-2 tumors with one to three positive (+) lymph nodes (LNs) decreases locoregional recurrence (LRR) but advise limiting PMRT to patients at highest risk to balance against potential harms. In this study, we identify the risks of LRR after mastectomy in patients with T1-2N1 disease, treated with modern chemotherapy, and identify predictors of LRR when omitting PMRT.

Methods

Patients with T1-2N1 breast cancer undergoing mastectomy between 1995 and 2006 were categorized by receipt of PMRT. The Chi square test compared the clinicopathologic features between both groups, and Kaplan–Meier and Cox regression analysis was used to determine the rates of LRR, recurrence-free survival (RFS), and overall survival (OS).

Results

Overall, 1087 patients (924 no PMRT, 163 PMRT) were included in the study, with a median follow-up of 10.8 years (range 0–21). We identified 63 LRRs (56 no PMRT, 7 PMRT), and 10-year rates of LRR with and without PMRT were 4.0% and 7.0%, respectively. Patients receiving PMRT were younger (p = 0.019), had larger tumors (p = 0.0013), higher histologic grade (p = 0.029), more positive LNs (p < 0.0001), lymphovascular invasion (LVI) (p < 0.0001), extracapsular nodal extension (p < 0.0001), and macroscopic LN metastases (p < 0.0001). There was no difference in LRR, RFS, or OS between groups. On multivariate analysis, age < 40 years (p < 0.0001) and LVI (p < 0.0001) were associated with LRR in those not receiving PMRT.

Conclusion

Consistent with the guidelines, 85% of patients with T1-2N1 were spared PMRT at our center, while maintaining low LRR. Age < 40 years and the presence of LVI are significantly associated with LRR in those not receiving PMRT.

https://ift.tt/2H2tg2E

Treatment of Isolated Peritoneal Recurrences in Patients with Colorectal Peritoneal Metastases Previously Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

Abstract

Background

Colorectal peritoneal carcinomatosis (PC) is preferably treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Peritoneal recurrence of disease after treatment can occur without distant metastases, with a variety of treatment options.

Objective

This study aimed to evaluate the management of isolated peritoneal recurrence after primary CRS-HIPEC.

Methods

In two tertiary referral centers, all patients who underwent CRS-HIPEC for colorectal PC between 2004 and 2015 and who developed isolated peritoneal recurrences were retrospectively evaluated. Location, treatment of peritoneal recurrences, and curative or palliative treatment intent were reported, and univariable and multivariable Cox regression analysis and survival analyses were performed.

Results

Of 414 patients treated with CRS-HIPEC for colorectal PC, 106 patients (26%) developed isolated peritoneal recurrence. Forty-three patients (41%) were treated with curative intent and 63 (59%) were treated with palliative intent. Median overall survival (OS) in the patients treated with curative intent was 24.7 months (interquartile range [IQR] 12.1–61.7), compared with 7.6 months (IQR 2.5–15.9) in those treated with palliative intent (p < 0.001). In the patients treated with curative CRS (n = 17) and curative second CRS-HIPEC (n = 15), median OS was 51.7 months (IQR 14.4–NA) and 29.0 months (IQR 18.1–63.0), respectively (p = 0.620). The latter group had a significantly higher region count (median 1 vs. 3; p < 0.001). Postoperative complications and hospital stay did not significantly differ between first and second CRS-HIPEC.

Conclusion

After CRS-HIPEC for colorectal cancer, approximately one of four patients will develop isolated peritoneal recurrences. A substantial amount of these patients can be safely treated with curative intent yielding long-term survival.

https://ift.tt/2IV9Dzn

The Effect of Temperature and Perfusion Time on Response, Toxicity, and Survival in Patients with In-transit Melanoma Metastases Treated with Isolated Limb Perfusion

Abstract

Background

Isolated limb perfusion (ILP) is used to treat in-transit metastases of melanoma of the extremities when surgical excision is not possible. The optimal setting concerning temperature and perfusion time is unknown. The purpose of this study was to analyze these factors concerning their effects on response, toxicity, and survival.

Methods

A retrospective analysis of 284 consecutive stage III melanoma patients treated with melphalan ILP for the first time in our institution, during a 31-year period (July 1986–May 2017), was performed. Our series was divided in four time periods, according to perfusion temperature and duration. Demographical data, stage, number, and size of lesions were retrieved from our prospective database.

Results

Overall response (OR) rate 83% and a complete response (CR) rate of 59%. Significant predictive factors for CR in multivariate analysis were non-bulky tumor, fewer metastases, and a perfusion time of 120 min. Predictive factors for increased local toxicity were femoral ILP and higher perfusion temperatures. The median overall survival was 30 months, and the independent negative prognostic factors were lymph-node status, bulky tumors, response, upper limb perfusion, and 120 min perfusion at 39–40 °C.

Conclusions

Modern ILP uses diminished perfusion time and lower temperature, leading to a decrease in toxicity. However, our data also show a decrease in response, which indicates that optimal perfusion time and temperature regimen remain to be determined.

https://ift.tt/2H4irNA

Is the 8th Edition of the AJCC TNM Staging System Sufficiently Reasonable for All Patients with Noncardia Gastric Cancer? A 12,549-Patient International Database Study

Abstract

Background

The aim of this work is to compare the prognostic ability between the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) tumor–node–metastasis (TNM) classification for gastric cancer (GC).

Methods

A total of 10,194 noncardia GC patients were identified from the Surveillance, Epidemiology, and End Results database from 1988 to 2008. Concordance index (C-index), bayesian information criterion (BIC), and time-dependent receiver operating characteristic (t-ROC) analyses were used. External validation was performed using a dataset (n = 2355) derived from Fujian Medical University Union Hospital.

Results

Overall survival for all five AJCC N categories differed significantly when patients were subgrouped into ≤ 15 versus >15 examined lymph nodes (eLNs). The prognostic ability of the 8th edition (C-index 0.716) was not improved over the 7th edition (C-index 0.716). Subgroup analysis showed superior performance of the 8th over the 7th edition in patients with > 15 eLNs (C-index 0.742 vs. 0.735); however, the two editions showed similar performance for patients with ≤ 15 eLNs (C-index 0.713 vs. 0.713). The BIC and t-ROC analyses were consistent. To better predict the prognosis of patients with ≤ 15 eLNs, we established a novel prognostic model based on independent prognostic factors (C-index 0.735). BIC analysis showed that this new model was better than the 7th and 8th editions. Similar results were obtained from the validation set.

Conclusions

The 8th edition of the AJCC TNM classification shows better prognostic ability than the 7th edition in noncardia GC patients with > 15 eLNs, but no improvement was found in patients with ≤ 15 eLNs; therefore, a novel prognostic model is proposed.

https://ift.tt/2IXZp10

What is the Incidence of Malignancy in Resected IPMN? An Analysis of Over 100 U.S. Institutions in a Single Year

https://ift.tt/2H0vNdL

Predictors of Residual Disease After Breast Conservation Surgery

Abstract

Introduction

Breast-conserving therapy is the standard of care for early-stage breast cancer. In the era of multimodality therapy, the debate on the value of revision surgery for compromised margins continues, and high re-excision rates persist despite updated guidelines. Our study sought to identify the local re-excision rate for compromised margins after lumpectomy, and identify predictors of residual disease at re-excision.

Methods

This population-based retrospective cohort study included women with breast cancer who underwent a lumpectomy between 2009 and 2012 in Manitoba, with close (≤ 2 mm) or positive margins that led to re-excision. Patient demographics and tumor characteristics were identified through provincial cancer registries and chart reviews. For patients with invasive cancer, the six anatomical margins were reported for margin status, width, and pathology type at the margin.

Results

Of the 2494 patients identified, 556 women underwent re-excision, yielding a re-excision rate of 22.29%. Of our 311 patients with invasive cancer who underwent re-excision, 62.7% had residual disease identified on revision. On univariable analysis, the size and grade of the invasive component, nodal stage, and the number of positive margins were associated with residual disease on re-excision (p < 0.05). With the exception of nodal stage, the same variables remained statistically significant on multivariable analysis.

Conclusions

Our results suggest that even in the absence of 'no ink on tumor', the cancer size and grade in lumpectomy specimens are high-risk factors for residual disease, and this subgroup of patients may benefit from re-excision. Long-term follow-up of this cohort is required to determine their risk of recurrence after adjuvant treatment.

https://ift.tt/2kBStbC

The Impact of Metronomic Adjuvant Chemotherapy in Patients with Advanced Oral Cancer

Abstract

Background

This study evaluated the efficacy of tegafur-uracil for advanced oral cancer.

Methods

From January 2008 to December 2013, clinical data from 356 patients with stage III or IV oral squamous cell carcinoma who received curative surgical resection and postoperative concurrent chemoradiotherapy, treated with or without tegafur-uracil, were analyzed from a prospectively designed database. Tegafur-uracil was orally administered to 114 of the 356 patients. Disease-specific survival (DSS), disease-free survival (DFS), and overall survival (OS) rates were studied.

Results

In our study, the 5-year OS (p = 0.0008), DFS (p = 0.0034), and DSS (p = 0.0029) rates were significantly better in the tegafur-uracil group than in the control group. Distant metastasis occurred in 16.28% of patients in the tegafur-uracil group and 45.28% in the control group (odds ratio 4.3). The distant metastasis rate in the tegafur-uracil group was significantly lower than the control group, indicating that administration of tegafur-uracil after curative surgical treatment and concurrent chemoradiotherapy prevented distant metastasis and improved the OS, DFS, and DSS rate.

Conclusions

The result of tegafur-uracil treatment in patients with advanced oral cancer showed significant improvement in the 5-year OS, DFS, and DSS rate, while also showing a decreased distant metastasis rate. Tegafur-uracil treatment is a useful, effective, and well-tolerated anticancer treatment for advanced oral cancer.

https://ift.tt/2swIzeX

Adrenal Incidentalomas During Diagnostic Work-up of Colorectal Cancer Patients: What is the Risk of Metastases?

Abstract

Background

Adrenal incidentalomas (AIs) are regularly discovered on staging computed tomography (CT) of patients with colorectal cancer (CRC). Although CRC is considered unlikely to metastasize to the adrenal gland, it is not known how often an AI appears to be a CRC metastasis. This causes a diagnostic dilemma for many patients with newly diagnosed CRC. This study aimed primarily to describe the incidence of AIs and adrenal metastases in CRC patients.

Methods

A single-center cohort of 475 consecutive patients with newly diagnosed CRC was defined. Retrospectively, all radiology reports and multidisciplinary team meeting reports were assessed for the presence of adrenal abnormalities. All AIs shown on staging CT were reevaluated for the purpose of this study, and the sizes of these adrenal glands were determined. Based on the CT reevaluation, follow-up imaging, and clinical follow-up assessment, conclusions on the presence or absence of adrenal metastases were drawn.

Results

The incidence of AIs in this CRC patient cohort was 10.5% (50/475). In 96% (48/50) of the patients with AIs, adrenal metastases could be ruled out. No solitary adrenal metastases were encountered. In two patients who had widespread systemic disease without curative treatment options, the AIs were considered to be adrenal metastases (cohort incidence, 0.4%).

Conclusion

This is the first study to report on adrenal incidentalomas in CRC patients. In newly diagnosed CRC patients without disseminated disease, AIs can be considered benign, and no additional imaging is indicated to rule out adrenal metastases in this group.

https://ift.tt/2JbndOz

Implementing a Program of Talimogene laherparepvec

Abstract

Background

Oncolytic viruses are genetically engineered or naturally occurring viruses that selectively replicate in cancer cells without harming normal cells. Talimogene laherparepvec (Imlygic^®), the first oncolytic viral therapy approved for treatment of cancer, was approved for treatment of locally advanced melanoma in October 2015.

Purpose

As a biologic product, use of T. laherparepvec in the clinical setting requires pretreatment planning and a unique systematic approach to deliver the therapy. The processes we describe herein could be adopted by other centers that choose to prescribe T. laherparepvec.

Methods

We studied our clinical trial experience with T. laherparepvec before we embarked on using commercially available T. laherparepvec. We created a standard operating procedure (SOP) with multidisciplinary buy-in and oversight from leadership in Infection Control at our institution. We reflected on clinical cases and the actual procedures of administering T. laherparepvec to create the SOP.

Results

The preimplementation planning, patient selection, identification of lesions to treat, the actual procedure, and ongoing assessment of patients are described. Tumoral-related factors that lead to unique challenges are described.

Conclusions

A process to ensure safe and responsible implementation of a program to administer T. laherparepvec for treatment of melanoma may improve the quality of treatment for patients who suffer from advanced melanoma.

https://ift.tt/2IUtbUB

Stage- and Histologic Subtype-Dependent Frequency of Lymph Node Metastases in Patients with Epithelial Ovarian Cancer Undergoing Systematic Pelvic and Paraaortic Lymphadenectomy

Abstract

Purpose

Tumor stage and distinct histological subtypes in epithelial ovarian cancer (EOC) show different prognostic outcome. The aim of this study is to evaluate whether the frequency of lymph node (LN) metastases in patients with different tumor stages and histological subtypes undergoing systematic pelvic and paraaortic lymphadenectomy is coincidentally divergent.

Methods

Patients with EOC treated with upfront staging or debulking surgery between January 2000 and December 2016 were included. Systematic lymphadenectomy was performed in all consecutive patients with optimal debulking and without medical contraindications.

Results

Seven hundred sixty-two patients including 27.2% with early-stage EOC were included. The median number of removed LNs was 69, and metastases to LNs were found in 54.7%. No LN metastases were found in patients with low-grade endometrioid carcinoma, independently of tumor stage. LN metastases in early-stage low-grade serous (N = 5), mucinous (N = 31), and clear cell (N = 28) EOC were found in one (20%), zero, and one (3.6%) patient, respectively. LN metastases were detected in more than 10% of patients with all other histological subtypes. On multivariate analyses, overall survival was significantly impaired in patients with LN metastases, as compared with patients without LN metastases (p = 0.001).

Conclusions

The risk of LN metastases in patients with EOC is dependent on stage and histological subtype. Patients with incidental finding of early mucinous or low-grade endometrioid EOC are at very low risk of retroperitoneal lymph node metastases. Reoperation for lymph node staging only should be discussed individually with caution.

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Together We Make a Difference

https://ift.tt/2kCd2og

Adjuvant Therapy in the Treatment of Melanoma

https://ift.tt/2spWRxD

A Novel Physiobiological Parameter-Based Grading System for Resectable Pancreatic Cancer

Abstract

Background

Preoperative methods to estimate disease-specific survival (DSS) for resectable pancreatic cancer are limited.

Objective

The aim of this study was to develop and validate a pretreatment physiobiological prognostic model in patients with radiologically resectable pancreatic cancer.

Methods

A retrospective review of a prospectively maintained institutional database was undertaken to identify patients who underwent potentially curative resection for radiologically resectable pancreatic cancer. Demographics, treatments, and relationships between the potential prognostic factors and survival rate were analyzed, and prognostic nomograms were established.

Results

We identified 240 patients who fulfilled our eligible criteria. The 1-, 3-, and 5-year DSS rates after surgery were 77.8, 40.9, and 31.3%, respectively. On multivariate analysis, increased neutrophil/lymphocyte ratio [hazard ratio (HR) 1.60, 95% confidence interval (CI) 1.17–2.17; p < 0.01], reduced Prognostic Nutritional Index (HR 2.08, 95% CI 1.68–3.20; p < 0.01), and elevated preoperative serum carbohydrate antigen 19-9 level (HR 2.12, 95% CI 1.55–2.88; p < 0.01) were associated with worse DSS. Although curative resection was the operative aim for all patients, 131 (54.6%) patients had recurrence within 12 months after curative resection of resectable pancreatic cancer. There was a significant correlation between recurrence pattern and physiobiological characteristics.

Conclusion

We developed a new grading system for radiologically resectable pancreatic cancer. This system is simple and reliably predicts differences in survival after pancreatic resection.

https://ift.tt/2kysguq

Salvage Abdominoperineal Resection for Squamous Cell Anal Cancer: A 30-Year Single-Institution Experience

ABSTRACT

Background

Failure of chemoradiotherapy (CRT) for anal squamous cell carcinoma (SCC) results in persistent or recurrent anal SCC. Treatment with salvage abdominoperineal resection (APR) can potentially achieve cure. The aims of this study are to analyze oncological and surgical outcomes of our 30-year experience with salvage APR for anal SCC after failed CRT and identify prognostic factors for overall survival (OS).

Methods

All consecutive patients who underwent salvage APR between 1990 and 2016 for histologically confirmed persistent or recurrent anal SCC after failed CRT were retrospectively analyzed.

Results

Forty-seven patients underwent salvage APR for either persistent (n = 24) or recurrent SCC (n = 23). Median OS was 47 months [95% confidence interval (CI) 10.0–84.0 months] and 5-year survival was 41.6%, which did not differ significantly between persistent or recurrent disease (p = 0.551). Increased pathological tumor size (p < 0.001) and lymph node involvement (p = 0.014) were associated with impaired hazard for OS on multivariable analysis, and irradical resection only (p = 0.001) on univariable analysis. Twenty-one patients developed local recurrence after salvage APR, of whom 8 underwent repeat salvage surgery and 13 received palliative treatment. Median OS was 9 months (95% CI 7.2–10.8 months) after repeat salvage surgery and 4 months (95% CI 2.8–5.1 months) following palliative treatment (p = 0.055).

Conclusions

Salvage APR for anal SCC after failed CRT resulted in adequate survival, with 5-year survival of 41.6%. Negative prognostic factors for survival were increased tumor size, lymph node involvement, and irradical resection. Patients with recurrent anal SCC after salvage APR had poor prognosis, irrespective of performance of repeat salvage surgery, which never resulted in cure.

https://ift.tt/2ss6xaU

Clinicopathological Features and Prognosis of Primary GISTs with Tumor Rupture in the Real World

Abstract

Background

Patients with ruptured gastrointestinal stromal tumor (GIST) are recommended for imatinib adjuvant therapy; however, their clinicopathological features and prognosis in the era of imatinib are unknown.

Patients and Methods

The study cohort included 665 patients with histologically proven primary GISTs who underwent R0 or R1 surgery between 2003 and 2007; the validation cohort included 182 patients between 2000 and 2014. The definitions of tumor rupture in the study included perforation at tumor site, tumor fracture, piecemeal resection including open biopsy, and macroscopic injuries to the pseudocapsule.

Results

Tumor rupture occurred in 21 (3.2%) of 665 and 5 (2.9%) of 182 patients in the study and validation cohort, respectively. Ruptured GISTs were more symptomatic, were larger in size, and had higher mitotic count than nonruptured GISTs but were not associated with tumor location or laparoscopic surgery. GISTs with intraoperative rupture had clinicopathological features and prognostic outcomes similar to those with preoperative rupture. Recurrence rates were higher and median recurrence-free survival (RFS) and overall survival (OS) were shorter with ruptured than nonruptured GIST. Tumor rupture was one of the independent prognostic factors for RFS, but not OS, according to multivariate analysis.

Conclusions

Ruptured GISTs were symptomatic larger tumors with high mitotic activity, frequent relapse, and shorter RFS. Tumor rupture was an independent prognostic factor for RFS, but not for OS, in the era of imatinib.

https://ift.tt/2IUFQGU

Rates of TP53 Mutation are Significantly Elevated in African American Patients with Gastric Cancer

Abstract

Background

Gastric adenocarcinoma is a heterogenous disease that results from complex interactions between environmental and genetic factors, which may contribute to the disparate outcomes observed between different patient populations. This study aimed to determine whether genomic differences exist in a diverse population of patients by evaluating tumor mutational profiles stratified by race.

Methods

All patients with gastric adenocarcinoma between 2012 and 2016 who underwent targeted next-generation sequencing of cancer genes by the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform were identified. Patient race was categorized as Asian, African American, Hispanic, or Caucasian. Fisher's exact test was used to examine differences in mutation rates between racial designations for the most common mutations identified. The p values in this study were adjusted using the false discovery rate method.

Results

The study investigated 595 mutations in 119 patients. The DNA alterations identified included missense mutations (66%), frame-shift deletions (13%), and nonsense mutations (9%). Silent mutations were excluded. The most frequently mutated genes were ARID1A, CDH1, ERBB3, KRAS, PIK3CA, and TP53. Of these, TP53 was the most frequently mutated gene, affecting 50% of patients. The proportion of patients with TP53 mutations differed significantly between races (p = 0.012). The findings showed TP53 mutations for 89% (16/18) of the African American patients, 56% (10/18) of the Asian patients, 43% (9/21) of the Hispanic patients, and 40% (25/62) of the Caucasian patients.

Conclusions

Significantly higher rates of TP53 mutations were identified among the African American patients with gastric adenocarcinoma. This is the first study to evaluate tumor genomic differences in a diverse population of patients with gastric adenocarcinoma.

https://ift.tt/2H2S1Mi

Efficacy of Endoscopic Ultrasonography for Determining Clinical T Category for Esophageal Squamous Cell Carcinoma: Data From 1434 Surgical Cases

Abstract

Background

The efficacy of endoscopic ultrasonography (EUS) for determining T category is variable for esophageal squamous cell carcinoma (ESCC). We aimed to assess the efficacy of EUS in accurately identifying T category for ESCC based on the 8th AJCC Cancer Staging Manual.

Methods

A retrospective analysis was conducted using a prospectively collected ESCC database from January 2003 to December 2015, in which all patients underwent EUS examination followed by esophagectomy. The efficacy of EUS was evaluated by sensitivity, specificity, and accuracy compared with pathological T category as gold standard. Overall survival of different EUS-T (uT) categories was assessed.

Results

In total, 1434 patients were included, of whom 58.2% were correctly classified by EUS, with 17.9% being overstaged and 23.9% being understaged. The sensitivity and accuracy of EUS for Tis, T1a, T1b, T2, T3, and T4a categories were 15.8 and 98.8%, 16.3 and 95.7%, 33.1 and 89.3%, 56.8 and 65.0%, 65.8 and 70.0%, and 27.3 and 97.5%, respectively. The survival difference between uT1a and uT1b was not statistically significant (p = 0.90), nor was that between uT4a and uT4b (p = 0.34). However, when uT category was integrated as uTis, uT1, uT2, uT3, and uT4, overall survival was clearly distinguished between the categories (p < 0.01).

Conclusions

EUS is in general feasible for classifying clinical T category for ESCC. However, EUS should be used with caution for discriminating between Tis, T1a, and T1b disease, as well as T4 disease.

https://ift.tt/2IZJnUk

Postoperative Adjuvant Trans-Arterial Chemoembolization for Patients with Hepatocellular Carcinoma and Portal Vein Tumor Thrombus

Abstract

Background

It remains uncertain whether patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) benefit from postoperative adjuvant trans-arterial chemoembolization (PA-TACE).

Methods

We retrospectively identified 540 patients to form the crude cohort and adopted propensity score matching analysis to assemble another cohort of 464 patients with similar baseline characteristics. Univariate and multivariate Cox analyses were performed in exploratory subgroups to identify the independent effect of PA-TACE on overall survival (OS).

Results

In the overall study population, univariate analysis showed PA-TACE was associated with longer OS [odds ratio (OR) = 0.55, p = 0.001], and stratified analyses indicated an interaction between PVTT types and PA-TACE on OS (p = 0.057 for interaction). After matching, all of the characteristics were well balanced between the PA-TACE and control groups (all p > 0.05). Multivariate Cox analysis validated that the protective role of PA-TACE was significant greater with the expansion of PVTT (type I, OR 0.66; type II, OR 0.33; and type III, OR 0.33, respectively, p = 0.011 for interaction). There also was evidence of treatment effect modification by PVTT type in the crude cohort (type I, OR 0.60; type II, OR 0.32; and type III, OR 0.32, respectively, p = 0.011 for interaction).

Conclusions

In patients with HCC and PVTT, PA-TACE was associated with a lower risk of death, particularly, among those with PVTT involving right/left or main portal vein, after excluding patients who were unsuitable for this procedure at 1 month after surgery.

https://ift.tt/2H2r5w8

Clinical applications of diffusion weighted imaging in neuroradiology

Abstract

Diffusion-weighted imaging (DWI) has revolutionised stroke imaging since its introduction in the mid-1980s, and it has also become a pillar of current neuroimaging. Diffusion abnormalities represent alterations in the random movement of water molecules in tissues, revealing their microarchitecture, and occur in many neurological conditions. DWI provides useful information, increasing the sensitivity of MRI as a diagnostic tool, narrowing the differential diagnosis, providing prognostic information, aiding in treatment planning and evaluating response to treatment. Recently, there have been several technical improvements in DWI, leading to reduced acquisition time and artefacts and enabling the development of diffusion tensor imaging (DTI) as a tool for assessing white matter. We aim to review the main clinical uses of DWI, focusing on the physiological mechanisms that lead to diffusion abnormalities. Common pitfalls will also be addressed.

Teaching Points

• DWI includes EPI, TSE, RESOLVE or EPI combined with reduced volume excitation.

• DWI is the most sensitive sequence in stroke diagnosis and provides information about prognosis.

• DWI helps in the detection of intramural haematomas (arterial dissection).

• In diffusion imaging, ADC is inversely proportional to tumour cellularity.

• DWI and DTI derived parameters can be used as biomarkers in different pathologies.

https://ift.tt/2H4DkIh

Evidence for the temporal regulation of insect segmentation by a conserved sequence of transcription factors [RESEARCH ARTICLE]

Erik Clark and Andrew D. Peel

Long-germ insects, such as the fruit fly Drosophila melanogaster, pattern their segments simultaneously, whereas short-germ insects, such as the beetle Tribolium castaneum, pattern their segments sequentially, from anterior to posterior. Although the two modes of segmentation at first appear quite distinct, much of this difference might simply reflect developmental heterochrony. We now show here that, in both Drosophila and Tribolium, segment patterning occurs within a common framework of sequential Caudal, Dichaete and Odd-paired expression. In Drosophila, these transcription factors are expressed like simple timers within the blastoderm, whereas in Tribolium they form wavefronts that sweep from anterior to posterior across the germband. In Drosophila, all three are known to regulate pair-rule gene expression and influence the temporal progression of segmentation. We propose that these regulatory roles are conserved in short-germ embryos, and that therefore the changing expression profiles of these genes across insects provide a mechanistic explanation for observed differences in the timing of segmentation. In support of this hypothesis, we demonstrate that Odd-paired is essential for segmentation in Tribolium, contrary to previous reports.

https://ift.tt/2H0o1k5

CLERK is a novel receptor kinase required for sensing of root-active CLE peptides in Arabidopsis [RESEARCH ARTICLE]

Pauline Anne, Amelia Amiguet-Vercher, Benjamin Brandt, Lothar Kalmbach, Niko Geldner, Michael Hothorn, and Christian S. Hardtke

CLAVATA3/EMBRYO SURROUNDING REGION (CLE) peptides are secreted endogenous plant ligands that are sensed by receptor kinases (RKs) to convey environmental and developmental inputs. Typically, this involves an RK with narrow ligand specificity that signals together with a more promiscuous co-receptor. For most CLEs, biologically relevant (co-)receptors are unknown. The dimer of the receptor-like protein CLAVATA 2 (CLV2) and the pseudokinase CORYNE (CRN) conditions perception of so-called root-active CLE peptides, the exogenous application of which suppresses root growth by preventing protophloem formation in the meristem. clv2 as well as crn null mutants are resistant to root-active CLE peptides, possibly because CLV2-CRN promotes expression of their cognate receptors. Here, we have identified the CLE-RESISTANT RECEPTOR KINASE (CLERK) gene, which is required for full sensing of root-active CLE peptides in early developing protophloem. CLERK protein can be replaced by its close homologs, SENESCENCE-ASSOCIATED RECEPTOR-LIKE KINASE (SARK) and NSP-INTERACTING KINASE 1 (NIK1). Yet neither CLERK nor NIK1 ectodomains interact biochemically with described CLE receptor ectodomains. Consistently, CLERK also acts genetically independently of CLV2-CRN. We, thus, have discovered a novel hub for redundant CLE sensing in the root.

https://ift.tt/2IY3ySQ

Modulation of F-actin dynamics by maternal Mid1ip1L controls germ plasm aggregation and furrow recruitment in the zebrafish embryo [RESEARCH ARTICLE]

Celeste Eno and Francisco Pelegri

During the early embryonic cell cycles, zebrafish germ plasm ribonucleoparticles (RNPs) gradually multimerize and become recruited to the forming furrows. RNPs multimerization occurs prior to and during furrow initiation, as forming aggregates move outward through their association with the tips of growing interphase astral microtubules. Germ plasm RNPs are also associated with short cortical F-actin. We show that, in embryos mutant for the cytoskeletal regulator mid1ip1l, germ plasm RNPs fail to become recruited to the furrow, accumulating instead at the periphery of the blastodisc. RNP aggregates are associated with zones of mid1ip1l-dependent cyclical local cortical F-actin network enrichments, as well as contractions at both the cortex and the contractile ring. F-actin inhibition in wild-type embryos mimics the RNP peripheral accumulation defect of mid1ip1l mutants. Our studies suggest that a common mechanism underlies distinct steps of germ plasm RNP segregation. At the cortex, this process attenuates microtubule-dependent outward RNP movement to retain RNPs in the blastodisc cortex and allow their recruitment to the furrows. F-actin network contraction likely also facilitates higher-order germ plasm RNP multimerization.

https://ift.tt/2spKamJ

Slow calcium waves mediate furrow microtubule reorganization and germ plasm compaction in the early zebrafish embryo [RESEARCH ARTICLE]

Celeste Eno, Timothy Gomez, Diane C. Slusarski, and Francisco Pelegri

Zebrafish germ plasm ribonucleoparticles (RNPs) become recruited to furrows of early zebrafish embryos through their association with astral microtubules ends. During the initiation of cytokinesis, microtubules are remodeled into a furrow microtubule array (FMA), which is thought to be analogous to the mammalian midbody involved in membrane abscission. During furrow maturation, RNPs and FMA tubules transition from their original distribution along the furrow to enrichments at the furrow distal ends, which facilitates germ plasm mass compaction. We show that nebel mutants exhibit reduced furrow-associated slow calcium waves (SCWs), caused at least in part by defective enrichment of calcium stores. RNP and FMA distal enrichment mirrors the medial-to-distal polarity of SCWs, and inhibition of calcium release or downstream mediators such as Calmodulin affects RNP and FMA distal enrichment. Blastomeres with reduced or lacking SCWs, such as early blastomeres in nebel mutants and wild-type blastomeres at later stages, exhibit medially bundling microtubules similar to midbodies in other cell types. Our data indicate that SCWs provide medial-to-distal directionality along the furrow to facilitate germ plasm RNP enrichment at the furrow ends.

https://ift.tt/2IWpMoc