Tumor Differentiation as a Prognostic Marker in Clinically Staged T1bN0 Esophageal Adenocarcinoma.

Current guidelines recommend that clinically staged T1N0 esophageal cancers are to be referred to surgery or endoscopic resection. Using the National Cancer Database, we identified 733 individuals with clinically staged T1N0 esophageal carcinoma, who underwent upfront surgery and did not receive any prior treatment. We assessed upstaging, which was defined as ≥ T2 disease or positive lymph nodes. Poorly differentiated adenocarcinomas were associated with upstaging, whereas squamous cell carcinomas were not. Specifically, the percentage of upstaging among individuals with clinically staged T1b and poorly differentiated tumor was 33.8%. Therefore, clinically staged T1bN0 poorly differentiated esophageal adenocarcinomas are at high risk for upstaging following surgery.

The architecture of binding cooperativity between densely bound transcription factors.

The binding of transcription factors (TFs) along genomes is restricted to a subset of sites containing their preferred motifs. TF-binding specificity is often attributed to the co-binding of interacting TFs; however, apart from specific examples, this model remains untested. Here, we define dependencies among budding yeast TFs that localize to overlapping promoters by profiling the genome-wide consequences of co-depleting multiple TFs. We describe unidirectional interactions, revealing Msn2 as a central factor allowing TF binding at its target promoters. By contrast, no case of mutual cooperation was observed. Particularly, Msn2 retained binding at its preferred promoters upon co-depletion of fourteen similarly bound TFs. Overall, the consequences of TF co-depletions were moderate, limited to a subset of promoters, and failed to explain the role of regions outside the DNA-binding domain in directing TF-binding preferences. Our results call for re-evaluating the role of cooperative interactions in directing TF-binding preferences.

Gastric Perforation After Microwave Ablation to Adjacent Hepatocellular Lesion.

Locoregional treatment modalities for hepatocellular carcinoma are generally effective and safe and benefit the subset of patients who are not eligible for surgery or have marginal hepatic function. This case report discusses a 77-year-old patient with cirrhosis who underwent microwave lesion ablation for 3 hepatocellular carcinoma nodules. On the 12th day after ablation, the patient was diagnosed with a perforation of the anterior wall of the stomach near one of the target ablation sites on the left side of the liver. The patient underwent surgical therapy with clinical improvement. This report highlights the potential risks associated with microwave ablation for hepatocellular carcinoma.

A Novel Prediction Tool for Endoscopic Intervention in Patients with Acute Upper Gastro-Intestinal Bleeding.

(1) Background: Predicting which patients with upper gastro-intestinal bleeding (UGIB) will receive intervention during urgent endoscopy can allow for better triaging and resource utilization but remains sub-optimal. Using machine learning modelling we aimed to devise an improved endoscopic intervention predicting tool. (2) Methods: A retrospective cohort study of adult patients diagnosed with UGIB between 2012−2018 who underwent esophagogastroduodenoscopy (EGD) during hospitalization. We assessed the correlation between various parameters with endoscopic intervention and examined the prediction performance of the Glasgow-Blatchford score (GBS) and the pre-endoscopic Rockall score for endoscopic intervention. We also trained and tested a new machine learning-based model for the prediction of endoscopic intervention. (3) Results: A total of 883 patients were included. Risk factors for endoscopic intervention included cirrhosis (9.0% vs. 3.8%, p = 0.01), syncope at presentation (19.3% vs. 5.4%, p < 0.01), early EGD (6.8 h vs. 17.0 h, p < 0.01), pre-endoscopic administration of tranexamic acid (TXA) (43.4% vs. 31.0%, p < 0.01) and erythromycin (17.2% vs. 5.6%, p < 0.01). Higher GBS (11 vs. 9, p < 0.01) and pre-endoscopy Rockall score (4.7 vs. 4.1, p < 0.01) were significantly associated with endoscopic intervention; however, the predictive performance of the scores was low (AUC of 0.54, and 0.56, respectively). A combined machine learning-developed model demonstrated improved predictive ability (AUC 0.68) using parameters not included in standard GBS. (4) Conclusions: The GBS and pre-endoscopic Rockall score performed poorly in endoscopic intervention prediction. An improved predictive tool has been proposed here. Further studies are needed to examine if predicting this important triaging decision can be further optimized.

Artificial Intelligence-Aided Colonoscopy Does Not Increase Adenoma Detection Rate in Routine Clinical Practice.

The performance of artificial intelligence-aided colonoscopy (AIAC) in a real-world setting has not been described. We compared adenoma and polyp detection rates (ADR/PDR) in a 6-month period before (pre-AIAC) and after introduction of AIAC (GI Genius, Medtronic) in all endoscopy suites in our large-volume center. The ADR and PDR in the AIAC group was lower compared with those in the pre-AIAC group (30.3% vs 35.2%, P < 0.001; 36.5% vs 40.9%, P = 0.004, respectively); procedure time was significantly shorter in the AIAC group. In summary, introduction of AIAC did not result in performance improvement in our large-center cohort, raising important questions on AI-human interactions in medicine.

Serum Syndecan-1: A Novel Biomarker for Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Syndecan-1 (SDC1) has multiple functions in tumorigenesis in general and specifically in pancreatic cancer. We aimed to evaluate SDC1 as a diagnostic and prognostic biomarker in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: In this case-control study, patients newly diagnosed with a biopsy-proven PDAC were enrolled alongside healthy individuals in a derivation-validation cohort design. Serum SDC1 was measured by enzyme-linked immunoassay. The diagnostic accuracy of SDC1 levels for diagnosing PDAC was computed. A unified cohort enriched with additional early-stage patients with PDAC was used to evaluate the association of SDC1 with survival outcomes and patient characteristics. RESULTS: In the derivation cohort, serum SDC1 levels were significantly higher in patients with PDAC (n = 39) compared with healthy controls (n = 20) (40.1 ng/mL, interquartile range 29.8-95.3 vs 25.6 ng/mL, interquartile range 17.1-29.8, respectively; P < 0.001). The receiver operating characteristic analysis area under the curve was 0.847 (95% confidence interval 0.747-0.947, P < 0.001). These results were replicated in a separate age-matched validation cohort (n = 38 PDAC, n = 38 controls; area under the curve 0.844, 95% confidence interval 0.757-0.932, P < 0.001). In the combined-enriched PDAC cohort (n = 110), using a cutoff of 35 ng/mL, the median overall 5-year survival between patients below and above this cutoff was not significantly different, although a trend for better survival after 1 year was found in the lower level group (P = 0.06). There were 12 of the 110 patients with PDAC (11%) who had normal CA 19-9 in the presence of elevated SDC1. DISCUSSION: These findings suggest serum SDC1 as a promising novel biomarker for early blood-based diagnosis of pancreatic cancer.

Prognostic Implications of Tumor Differentiation in Clinical T1N0 Gastric Adenocarcinoma.

BACKGROUND: Current guidelines recommend neoadjuvant chemotherapy in patients with locoregional gastric adenocarcinoma. Patients diagnosed with early stage gastric adenocarcinoma are usually managed with upfront surgical intervention. However, pathologic staging in a subset of these clinically staged patients identifies more advanced locoregional disease requiring adjuvant treatment. Therefore, identifying these patients prior to surgical intervention is critical to ensure employment of the appropriate treatment paradigm. The aim of the current study was to define patient characteristics associated with clinical understaging in early gastric cancer. METHODS: Using the National Cancer Database (2004-2014) we identified 3,892 individuals with clinical T1N0 gastric adenocarcinoma who underwent upfront definitive surgery, had negative surgical margins, and did not receive preoperative chemotherapy or radiotherapy. Patient characteristics were compared between those with pathologic stage T1N0 disease and those who were upstaged upon surgery. RESULTS: Twenty-seven percent of clinical T1N0 gastric adenocarcinomas had a change in stage because of pathologically defined ≥T2 disease or positive lymph nodes. Individuals who were upstaged had a higher tumor grade compared with those with pathologic stage T1N0 disease. Specifically, 41.9% (530/1,264) of individuals with a poorly differentiated tumor were upstaged, compared with only 10.7% (70/656) with a well-differentiated tumor. Approximately 75% of cases involved upstaging because of T misclassification. The highest percentage of upstaging was shown for tumors located at the fundus and body of the stomach. CONCLUSION: Upstaging of clinical T1N0 gastric adenocarcinoma is characterized by higher tumor grade and is mostly a result of a change in T stage. These findings mandate thorough workup in order to identify patients with clinically staged T1N0 disease requiring preoperative chemotherapy. IMPLICATIONS FOR PRACTICE: Upstaging of clinical T1N0 gastric adenocarcinoma is characterized by higher tumor grade and is mostly a result of a change in T stage. These findings mandate thorough workup in order to identify patients with clinically staged T1N0 disease requiring preoperative chemotherapy.

The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus.

Diabetes mellitus is a metabolic disorder approaching epidemic proportions. Non-alcoholic fatty liver disease (NAFLD) regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. Recently, we demonstrated that the voltage-dependent anion channel 1 (VDAC1) is involved in NAFLD. VDAC1 is an outer mitochondria membrane protein that serves as a mitochondrial gatekeeper, controlling metabolic and energy homeostasis, as well as crosstalk between the mitochondria and the rest of the cell. It is also involved in mitochondria-mediated apoptosis. Here, we demonstrate that the VDAC1-based peptide, R-Tf-D-LP4, affects several parameters of a NAFLD mouse model in which administration of streptozotocin (STZ) and high-fat diet 32 (STZ/HFD-32) led to both type 2 diabetes (T2D) and NAFLD phenotypes. We focused on diabetes, showing that R-Tf-D-LP4 peptide treatment of STZ/HFD-32 fed mice restored the elevated blood glucose back to close to normal levels, and increased the number and average size of islets and their insulin content as compared to untreated controls. Similar results were obtained when staining the islets for glucose transporter type 2. In addition, the R-Tf-D-LP4 peptide decreased the elevated glucose levels in a mouse displaying obese, diabetic, and metabolic symptoms due to a mutation in the obese (ob) gene. To explore the cause of the peptide-induced improvement in the endocrine pancreas phenotype, we analyzed the expression levels of the proliferation marker, Ki-67, and found it to be increased in the islets of STZ/HFD-32 fed mice treated with the R-Tf-D-LP4 peptide. Moreover, peptide treatment of STZ/HFD-32 fed mice caused an increase in the expression of ß-cell maturation and differentiation PDX1 transcription factor that enhances the expression of the insulin-encoding gene, and is essential for islet development, function, proliferation, and maintenance of glucose homeostasis in the pancreas. This increase occurred mainly in the ß-cells, suggesting that the source of their increased number after R-Tf-D-LP4 peptide treatment was most likely due to ß-cell proliferation. These results suggest that the VDAC1-based R-Tf-D-LP4 peptide has potential as a treatment for diabetes.

Graphene-graphite hybrid epoxy composites with controllable workability for thermal management.

The substantial heat generation in highly dense electronic devices requires the use of materials tailored to facilitate efficient thermal management. The design of such materials may be based on the loading of thermally conductive fillers into the polymer matrix applied - as a thermal interface material - on the interface between two surfaces to reduce contact resistance. On the one hand, these additives enhance the thermal conductivity of the composite, but on the other hand, they increase the viscosity of the composite and hence impair its workability. This in turn could negatively affect the device-matrix interface. To address this problem, we suggest a tunable composite material comprising a combination of two different carbon-based fillers, graphene nanoplatelets (GNPs) and graphite. By adjusting the GNP:graphite concentration ratio and the total concentration of the fillers, we were able to fine tune the thermal conductivity and the workability of the hybrid polymer composite. To facilitate the optimal design of materials for thermal management, we constructed a 'concentration-thermal conductivity-viscosity phase diagram'. This hybrid approach thus offers solutions for thermal management applications, providing both finely tuned composite thermal properties and workability. We demonstrate the utility of this approach by fabricating a thermal interface material with tunable workability and testing it in a model electronic device.

Breaking through the Solid/Liquid Processability Barrier: Thermal Conductivity and Rheology in Hybrid Graphene-Graphite Polymer Composites.

Thermal conductivity (TC) enhancement of an insulating polymer matrix at low filler concentration is possible through the loading of a high aspect ratio, thermally conductive single filler. Unfortunately, the dispersion of high-aspect-ratio particles greatly influences the rheological behavior of the polymer host at relatively low volume fractions, which makes further polymer processing or mixing difficult. A possible remedy is using two (hybrid) fillers, differing in their aspect ratios: (1) a plate-like filler, which sharply increases both viscosity and TC, and (2) an isotropic filler, which gradually increases these properties. We examine this hypothesis in a thermosetting silicone rubber by loading it with different ratios, (1)/(2), of graphene nanoplatelets (GNPs) (1) and graphite powder (2). We constructed a "phase diagram" delineating two composite processability regions: solid-like (moldable) or fluid-like (pourable). This diagram may be employed to tailor the mixture's viscosity to a desired TC value by varying the fillers' volume fraction. The phase diagram highlights the low volume fraction value, above which the composite is solid-like (low processability) for a single high-aspect-ratio nanofiller. By using hybrid filling, one can overcome this limit and prepare a fluid-like composite at a desired TC, not accessible by the single nanofiller. Thus, it provides an indicative tool for polymer processing, especially in applications such as the encapsulation of electronic devices. This approach was demonstrated for a heat source (resistor) potted by silicon rubber graphene-graphite composites, for which a desired TC was obtained in both solid- and liquid-like regions.

Complications of diagnostic colonoscopy, upper endoscopy, and enteroscopy.

Endoscopy is an inherent and an invaluable tool in every gastroenterologist's armamentarium. The prerequisite for quality and safety remains foremost. Adverse events should be minimized and proactive steps should taken before, during and after the endoscopic procedure. Upper endoscopy and colonoscopy are part of basic endoscopy and their major complications will be reviewed here, together with those of enteroscopy. The most common of all endoscopy related complications are cardiopulmonary and thus they will be addressed in detail first. Colonoscopy's major complications are bleeding and perforation. Their epidemiology, mechanisms/risk factors, diagnosis, treatment and prevention will be addressed. The incidence of both of these complications increases significantly with polypectomy. Thus clinical judgment and experience in both polypectomy techniques and the ways to treat these complications, especially with the advanced endoscopic options advanced in the last decade, are of paramount importance. Post-polypectomy syndrome, infection and gas explosion are less frequent and will be reviewed briefly. Bleeding and perforation are upper endoscopy's major complications as well. Advances in endoscopic techniques in recent years offer endoscopic treatment instead of directly resorting to surgery, as was used to be the case and still is if the first fails. Enteroscopy is generally a more advanced procedure and overall complication rate is often quoted as 1%, most of them have been attributed to the passage of the overtube. Perforation and bleeding are the major complications, and a unique upper enteroscopy-associated complication is pancreatitis.

Optimizing Anti-TNF-α Therapy: Serum Levels of Infliximab and Adalimumab Are Associated With Mucosal Healing in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: It is not clear what serum levels of anti-tumor necrosis factor are associated with reduced intestinal inflammation in patients with inflammatory bowel disease (IBD). We aimed to identify serum levels of infliximab and adalimumab associated with mucosal healing in patients with IBD and to evaluate the putative gain in control of inflammation by incremental increases in drug levels. METHODS: We performed a retrospective cross-sectional study of 145 patients with IBD treated with infliximab (n = 78) or adalimumab (n = 67) at a medical center in Israel from 2009 through 2014. We collected data from colonoscopy examinations; mucosal healing was defined as simple endoscopic score of <3 or a Mayo score ≤1. These data were compared with serum levels of anti-tumor necrosis factor agents, clinical scores, and levels of C-reactive protein. RESULTS: Median serum levels of infliximab and adalimumab were significantly higher in patients with mucosal healing than patients with active disease (based on endoscopy) (for infliximab, 4.3 vs 1.7 µg/mL, P = .0002; for adalimumab, 6.2 vs 3.1 µg/mL, P = .01). Levels of infliximab above 5 µg/mL (area under the curve = 0.75; P < .0001) and levels of adalimumab above 7.1 µg/mL (area under the curve = 0.7; P = .004) identified patients with mucosal healing with 85% specificity. Increasing levels of infliximab beyond 8 µg/mL produced only minimal increases in the rate of mucosal healing, whereas the association between higher level of adalimumab and increased rate of mucosal healing reached a plateau at 12 µg/mL. In patients with measurable levels of infliximab >3 µg/mL, the presence of antibodies to infliximab was associated with a lower rate of mucosal healing compared with patients with similar drug level without antibodies (16% vs 50%, respectively; P = .003). CONCLUSIONS: In a retrospective study, we found significant association between serum levels of anti-tumor necrosis factor agents and level of mucosal healing. We propose that serum levels of 6-10 µg/mL for infliximab and 8-12 µg/mL for adalimumab are required to achieve mucosal healing in 80%-90% of patients with IBD, and that this could be considered as a "therapeutic window." Exceeding these levels produces only a negligible gain in proportion of patients with mucosal healing.