Esophagitis Dissecans Superficialis After Thermal Injury.

Esophagitis dissecans superficialis (EDS) is a rare esophageal condition characterized by sloughing of the esophageal mucosal epithelium, typically associated with a desquamating dermatologic disorder or mucosal irritants. We present a case of a 49-year-old man who presented for thermal burns sustained from an outdoor heater explosion. On body trauma imaging, he was incidentally found to have a midcervical esophageal prominence causing asymptomatic posterior tracheal compression. Endoscopy with esophageal biopsy were performed and consistent with EDS. He never exhibited symptoms associated with this diagnosis. To our knowledge, thermal injury has been a purported, albeit without case reference, etiology of EDS.

Safety of cold resection of non-ampullary duodenal polyps: Systematic review and meta-analysis.

Background and study aims Endoscopic resection has traditionally involved electrosurgical cautery (hot snare) to resect premalignant polyps. Recent data have suggested superior safety of cold resection. We aimed to assess the safety of cold compared with traditional (hot) resection for non-ampullary duodenal polyps. Methods We performed a systematic review ending in September 2022. The primary outcome of interest was the adverse event (AE) rate for cold compared with hot polyp resection. We reported odds ratios with 95% confidence intervals (CIs). Secondary outcomes included rates of polyp recurrence and post-polypectomy syndrome. We assessed publication bias with the classic fail-safe test and used forest plots to report pooled effect estimates. We assessed heterogeneity using I 2 index. Results Our systematic review identified 1,215 unique citations. Eight of these met inclusion criteria, seven of which were published manuscripts and one of which was a recent meeting abstract. On random effect modeling, cold resection was associated with significantly lower odds of delayed bleeding compared with hot resection. The difference in the odds of perforation (odds ratio [OR] 0.31 [95% confidence interval [CI] 0.05-2.87], P =0.2, I 2 =0) and polyp recurrence (OR 0.75 [95% CI 0.15-3.73], P =0.72, I 2 =0) between hot and cold resection was not statistically significant. There were no cases of post-polypectomy syndrome reported with either hot or cold techniques. Conclusions Cold resection is associated with lower odds of delayed bleeding compared with hot resection for duodenal tumors. There was a trend toward higher odds of perforation and recurrence following hot resection, but this trend was not statistically significant.

Do the blood anti-Müllerian hormone concentrations in young females correlate with the ovarian follicular population later in life in water buffalo?

In this longitudinal study, the anti-Müllerian hormone (AMH) levels in blood were determined in 32 Murrah buffalo females at 8, 10, 12, 16 and 19 months of age when females were synchronized and the antral follicular population (AFP) was estimated. Correlations of AFP to the AMH level at 19 months of age and retrospectively to younger ages were investigated. Then females were split into high and low AFP, and their AMH levels were compared for all ages and tested as predictors of AFP categories. The highest AMH level (p < .05) was detected at 8 months, reducing but not differing (p > .05) at 10, 12 and 16 months then reducing again (p < .05) at 19 months of age. The mean AFP was 17.6 ± 6.3 follicles, and it was positively correlated with AMH in all ages tested. High AFP females had approximately two times more antral follicles than low AFP (p < .05) and their AMH levels were higher (p < .01) than in low AFP ones in all ages. Only at 8 months, AMH levels can be used to precociously detect high AFP heifers (a cut-off point of 464.7 pg/mL; p < .05), while low AFP heifers could be detected by AMH measurements at 8, 10, 12 and 16 months of age (p < .05). We conclude that AMH of buffalo calves correlates with AFP of heifers later in life and depending on the age, its levels could be used to identify future females with low or high AFP.

Endoscopic submucosal dissection with versus without traction for pathologically staged T1B esophageal cancer: a multicenter retrospective study.

BACKGROUND AND AIMS: Positive vertical margins (VMs) are common after endoscopic submucosal dissection (ESD) of T1b esophageal cancer (EC) and are associated with an increased risk of recurrence. Traction during ESD provides better exposure of the submucosa and may allow deeper dissection, potentially reducing the risk of positive VMs. We conducted a retrospective multicenter study to compare the proportion of resections with positive VMs in ESD performed with versus without traction in pathologically staged T1b EC. METHODS: Patients who underwent ESD revealing T1b EC (squamous or adenocarcinoma) at 10 academic tertiary referral centers in the United States (n = 9) and Brazil (n = 1) were included. Demographic and clinical data were abstracted. ESD using either traction techniques (tunneling, pocket) or traction devices (clip line, traction wire) were classified as ESD with traction (Tr-ESD) and those without were classified as conventional ESD without traction. The primary outcome was a negative VM. Multivariable logistic regression was used to assess associations with negative VMs. RESULTS: A total of 166 patients with pathologically staged T1b EC underwent Tr-ESD (n = 63; 38%) or conventional ESD without traction (n = 103; 62%). Baseline factors were comparable between both groups. On multivariable analysis, Tr-ESD was found to be independently associated with negative VMs (odds ratio, 2.25; 95% confidence interval, 1.06-4.91; P = .037) and R0 resection (odds ratio, 2.83; 95% confidence interval, 1.33-6.23; P = .008). CONCLUSION: Tr-ESD seems to be associated with higher odds of negative VMs than ESD without traction for pathologically staged T1b EC, and future well-conducted prospective studies are warranted to establish the findings of the current study.

Immunogenicity Threshold in Allogeneic Cells Impacts CTL Response to Nondominant Congenic Antigens.

Transplantation and cancer expose the immune system to neoantigens, including immunogenic (dominant and subdominant) and nonimmunogenic Ags with varying quantities and affinities of immunodominant peptides. Conceptually, immunity is believed to mainly target dominant Ags when subdominant or nondominant Ags are linked within the same cell due to T cell interference. This phenomenon is called immunodominance. However, our previous study in mice showed that linked nonimmunogenic Ags (OVA and GFP) containing immunodominant peptides mount immunity irrespective of the MHC-matched allogeneic cell's immunogenicity. Consequently, we further explored 1) under what circumstances does the congenic marker CD45.1 provoke immunity in CD45.2 mice, and 2) whether linking two dominant or subdominant Ags can instigate an immune response. Our observations showed that CD45.1 (or CD45.2), when connected to low-immunogenic cell types is presented as an immunogen, which contrasts with its outcome when linked to high-immunogenic cell types. Moreover, we found that both dominant and subdominant Ags are presented as immunogens when linked in environments with lower immunogenic thresholds. These findings challenge the existing perception that immunity is predominantly elicited against dominant Ags when linked to subdominant or nondominant Ags. This study takes a fundamental step toward understanding the nuanced relationship between immunogenic and nonimmunogenic Ags, potentially opening new avenues for comprehending cancer immunoediting and enhancing the conversion of cold tumors with low immunogenicity into responsive hot tumors.

Adherence to guideline-directed hepatocellular carcinoma screening: A single-center US experience.

BACKGROUND: The American Association for the Study of Liver Disease recommends screening patients with cirrhosis for hepatocellular carcinoma (HCC) using imaging with or without alpha-fetoprotein every six months. Unfortunately, screening rates remain inadequate. AIM: To assess root causes of screening failure in a subspecialty hepatology clinic. METHODS: The authors identified patients with cirrhosis seen in a subspecialty hepatology clinic and determined whether they underwent appropriate screening, defined as two cross-sectional images between five and seven months apart. The authors characterized the primary driver of screening failure. Finally, other hepatologists were surveyed to determine provider perceptions of screening failure causes. RESULTS: 1034 patients were identified with an average age of 61 years and a mean MELD of 8.1 ± 3.8. Hepatitis C virus was the most common cirrhosis etiology. 489 (47%) underwent appropriate screening. No demographic or clinical differences were detected between those who underwent appropriate screening and those who did not. The most common etiologies of screening failure, in descending order, were: radiology unable to schedule timely imaging, provider did not order imaging, patient canceled follow up appointment, appointments scheduled too far apart, lost to follow up, no-show to radiology appointment, and provider canceled appointment. Hepatologists surveyed believed the most common cause of screening failure was no-show to radiology. CONCLUSION: Rates of screening were poor even in a subspecialty hepatology clinic. Screening failure was mostly due to systemic factors such as radiology availability and time between hepatology appointments rather than individual error.

Importance of carbohydrate antigen (CA 19-9) and carcinoembrionic antigen (CEA) in the prognosis of patients with duodenal adenocarcinoma: a retrospective single-institution cohort study.

BACKGROUND: Duodenal adenocarcinoma (DA) is a rare malignancy without validated tumor markers. In practice, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) are often used in the management of DA, though their prognostic value is unknown. MATERIALS AND METHODS: A single-institution retrospective review included patients diagnosed with biopsy-confirmed adenocarcinoma of the duodenum between 2006 and 2021. Peri-ampullary tumors were excluded. Levels of CA 19-9 and CEA were collected as continuous variables and were analyzed as binary variables: normal vs. high, using the maximum normal value as a cut-off (normal Ca 19-9 <35 U/ml; CEA <3 ng/ml). Survival analysis was conducted using Kaplan Meier curves, log-rank test and Cox proportional hazards model. RESULTS: There were 68 patients included in the final analysis. Median age was 67 years old and median follow-up time was 22.2 months. CA 19-9 and CEA were elevated in 36.8% and 48.5% of patients, respectively. A concomitant elevation of both tumor markers was associated with worsened OS (HR 2.140, 95% CI: 1.114-4.112; p = 0.019). After controlling for age and sex on multivariate analysis, elevation in both CA 19-9 ≥35 and CEA ≥3.0 remained significantly associated with increased mortality (HR 2.278, 95% CI: 1.162-4.466; p = 0.016). CONCLUSIONS: In summary, CA 19-9 and, to a lesser extent, CEA, show promise as prognostic markers in DA. Larger studies are needed to validate their use and to evaluate their performance as markers of recurrence.

Safety and feasibility of same-day discharge after endoscopic submucosal dissection: a Western multicenter prospective cohort study.

BACKGROUND AND AIMS: Recent Western studies support the safety and efficacy of endoscopic submucosal dissection (ESD) for lesions throughout the GI tract. Although admission for observation after ESD is standard in Asia, a more selective approach may optimize resource utilization. We aimed to evaluate the safety and feasibility of same-day discharge (SDD) after ESD and factors associated with admission. METHODS: This was a post hoc analysis of a multicenter, prospective cohort of patients undergoing ESD (2016-2021). The primary end points were safety of SDD and factors associated with post-ESD admission. RESULTS: Of 831 patients (median age, 67 years; 57% male) undergoing 831 ESDs (240 performed in the esophagus, 126 in the stomach, and 465 in the colorectum; median lesion size, 44 mm), 588 (71%) were SDD versus 243 (29%) admissions. Delayed bleeding and perforation occurred in 12 (2%) and 4 (.7%) of SDD patients, respectively; only 1 (.2%) required surgery. Of the 243 admissions, 223 (92%) were discharged after ≤24 hours of observation. Interestingly, larger lesion size (>44 mm) was not associated with higher admission rate (odds ratio [OR], .5; 95% confidence interval [CI], .3-.8; P = .001). Lesions in the upper GI tract versus colon (OR, 1.7; 95% CI, 1.1-2.6; P = .01), invasive cancer (OR, 1.9; 95% CI, 1.2-3.1; P = .01), and adverse events (OR, 2.7; 95% CI, 1.5-4.8; P = .001) were independent factors for admission. Admissions were more likely performed by endoscopists with ESD volume <50 cases (OR, 2.1; 95% CI, 1.3-3.3; P = .001) with procedure time >75 minutes (OR, 13.5; 95% CI, 8.5-21.3; P < .0001). CONCLUSIONS: SDD after ESD can be safe and feasible. Patients with invasive cancer, lesions in the upper GI tract, longer procedure times, or procedures performed by low-volume ESD endoscopists are more likely to be admitted postprocedure. Risk stratification of patients for SDD after ESD should help optimize resource utilization and enhance ESD uptake in the West. (Clinical trial registration number: NCT02989818.).

Advanced Hepatocellular Carcinoma in Adults Without Cirrhosis: A Single-Institution Retrospective Review.

Background: Although up to one in five cases of hepatocellular carcinoma (HCC) occurs in patients without cirrhosis, there is scarce literature characterizing non-cirrhotic HCC (NCHCC). Existing NCHCC research is primarily limited to surgical case series and there is a lack of data on unresectable NCHCC. Aim: The purpose of this retrospective review was to compare the characteristics of unresectable NCHCC and cirrhotic hepatocellular carcinoma (CHCC). Methods: A retrospective chart review of adult patients with unresectable HCC treated from 2007 to 2017 was performed at the University of Florida Shands Hospital. The data set was stratified into two cohorts: NCHCC and CHCC. Continuous variables were compared using Wilcoxon-Mann-Whitney tests and Kruskal-Wallis rank-sum tests. Categorical variables were compared using Pearson's Chi-squared tests and Fisher's exact tests. Overall survival was explored utilizing the Kaplan-Meier and log-rank method. Results: There were 1494 adult patients included in the final analysis, including 264 patients (17.7%) with NCHCC and 1230 patients (82.3%) with CHCC. Median age was 61.0 years old and median follow-up time was 30.2 months. NCHCC patients were older than CHCC patients (66.3 years vs 61.9 years; p < 0.0001). NHCC tumors were larger than CHCC tumors (7.92 ± 4.85 vs 4.38 ± 3.12 cm; p < 0.0001) and more likely to be associated with distant metastases (23.35% vs 15.91%; p = 0.0055). There was no difference in overall survival, with a median of 23.5 months in NCHCC and 22.4 months in CHCC (p = 0.9196). Conclusion: Our findings suggest that unresectable NCHCC and CHCC have unique characteristics but similar overall survival. To the best of our knowledge, this is the largest comparison of CHCC and NCHCC.

Cytomegaloviral colitis in primary CMV viraemia in a young immunocompetent adult.

A man in his 20s presented with a 2-week history of fever, fatigue and diarrhoea. On arrival to the emergency department, he had clinical findings of sepsis. The care team initially suspected sepsis secondary to bacterial colitis and administered antibiotics. Further workup including a stool PCR assay for gastrointestinal pathogens failed to establish a diagnosis, and he had no evidence of immune compromise. Colonoscopy revealed mucosal ulceration presumed to be ulcerative colitis. Histopathology obtained after discharge revealed severe colitis with cytomegalovirus (CMV) inclusions. Serological studies indicated a primary CMV infection. To our knowledge, this is the first report of a primary CMV infection presenting as severe colitis and systemic disease in a young immunocompetent patient without underlying disease.

Natural Antibodies Alert the Adaptive Immune System of the Presence of Transformed Cells in Early Tumorigenesis.

Recent studies have revealed a critical role for natural Abs (NAbs) in antitumor immune responses. However, the role of NAbs in cancer immunosurveillance remains unexplored, mainly because of the lack of in vivo models that mimic the early recognition and elimination of transforming cells. In this article, we propose a role for NAbs in alerting the immune system against precancerous neoantigen-expressing cells immediately after they escape intrinsic tumor suppression mechanisms. We identify four distinct reproducible, trackable, MHC-matched neoantigen-expressing cell models that do not form tumors as the end point. This amplified readout in the critical window prior to tumor formation allows investigation of new mediators of cancer immunosurveillance. We found that neoantigen-expressing cells adoptively transferred in NAb-deficient mice persisted, whereas they were eliminated in wild-type mice, indicating that the circulating NAb repertoire alerts the immune system to the presence of transformed cells. Moreover, immunity is mounted against immunogenic and nonimmunogenic neoantigens contained in the NAb-tagged cells, regardless of whether the NAb directly recognizes the neoantigens. Beyond these neoantigen-expressing model systems, we observed a significantly greater tumor burden in chemically and virally induced tumor models in NAb-deficient mice compared with wild-type mice. Restoration of the NAb repertoire in NAb-deficient mice elicited the recognition and elimination of neoantigen-expressing cells and cancer. These data show that NAbs are required and sufficient for elimination of transformed cells early in tumorigenesis. These models can now be used to investigate how NAbs stimulate immunity via recognition receptors to eliminate precancerous cells.

Systematic review of the cost-effectiveness of screening for lung cancer with low dose computed tomography.

OBJECTIVES: Lung cancer (LC) remains a burden for patients and healthcare systems, with most cases only diagnosed once disease is late stage. Screening for LC with low-dose computed tomography (LDCT) has shown a stage shift and led to a lung cancer-specific mortality reduction. Economic evaluations have been conducted which explore the benefits and costs of screening, however, previous systematic reviews concluded results were heterogeneous. LC screening has evolved and there have been further cost-effectiveness analyses conducted. The aim of this study was to provide an up-to-date systematic review of the cost-effectiveness of LC screening with LDCT. METHODS AND MATERIALS: Databases were searched for full papers published in English 01/1994-02/2022. Inclusion criteria was full economic evaluation of LC screening using LDCT compared to either no screening or chest X-ray. RESULTS: Forty-five evaluations were identified, three conducted alongside trials and 42 modelling studies. Thirty-nine evaluations (86.7%) found LC screening with LDCT to be cost-effective. Several findings were broadly consistent across studies: cost-effectiveness was optimal in those age 55-75 years and smoking history of at least 20 pack-years. Biennial screening was often more cost-effective than annual screening and would likely result in less additional findings and radiation exposure. A smoking cessation intervention alongside screening improved cost-effectiveness, but which intervention was optimal was unclear. Risk predictions models using more parameters to target participants for screening did not have more benefits than those using age and smoking alone, and cost-effectiveness was equivalent. Cost-effectiveness was sensitive to cost and specificity of LDCT, and disutility associated with screening. CONCLUSION: Overall, LC screening with LDCT is cost-effective in a high-risk population. Questions remain regarding risk prediction models, smoking cessation interventions and appropriateness of utility values in the screened population. Once these uncertainties are addressed, further economic evaluation may be required to inform policymakers prior to implementation.

Effect of endoscopic submucosal dissection on histologic diagnosis in Barrett's esophagus visible neoplasia.

BACKGROUND AND AIMS: Data are limited on the role of endoscopic submucosal dissection (ESD) as a potential diagnostic and staging tool in Barrett's esophagus (BE) neoplasia. We aimed to evaluate the frequency and factors associated with change of histologic diagnosis by ESD compared with pre-ESD histology. METHODS: This was a multicenter, prospective cohort study of patients who underwent ESD for BE visible neoplasia. A change in histologic diagnosis was defined as "upstaged" or "downstaged" if the ESD specimen had a higher or lower degree, respectively, of dysplasia or neoplasia when compared with pre-ESD specimens. RESULTS: Two hundred five patients (median age, 69 years; 81% men) with BE visible neoplasia underwent ESD from 2016 to 2021. Baseline histology was obtained using forceps (n = 182) or EMR (n = 23). ESD changed the histologic diagnosis in 55.1% of cases (113/205), of which 68.1% were upstaged and 31.9% downstaged. The frequency of change in diagnosis after ESD was similar whether baseline histology was obtained using forceps (55.5%) or EMR (52.2%) (P = .83). In aggregate, 23.9% of cases (49/205) were upstaged to invasive cancer on ESD histopathology. On multivariate analysis, lesions in the distal esophagus and gastroesophageal junction (odds ratio, 2.1; 95 confidence interval, 1.1-3.9; P = .02) and prior radiofrequency ablation (odds ratio, 2.5; 95% confidence interval, 1.2-5.5; P = .02) were predictors of change in histologic diagnosis. CONCLUSIONS: ESD led to a change of diagnosis in more than half of patients with BE visible neoplasia. Selective ESD can serve as a potential diagnostic and staging tool, particularly in those with suspected invasive disease. (Clinical trial registration number: NCT02989818.).

Margin marking before colorectal endoscopic mucosal resection and its impact on neoplasia recurrence (with video).

BACKGROUND AND AIMS: Ablation of resection margins after EMR of large nonpedunculated colorectal polyps decreases recurrence. Margin marking before EMR (EMR-MM) may represent an alternative method to achieve a healthy resection margin. We aimed to determine the efficacy of EMR-MM in reducing neoplasia recurrence. METHODS: We conducted a single-center historical control study of EMR cases (EMR-MM vs conventional EMR) for nonpedunculated polyps ≥20 mm between 2016 and 2021. For EMR-MM, cautery marks were placed along the lateral margins of the polyp with the snare tip. EMR was then performed to include resection of the healthy mucosa containing the marks. We compared recurrence at surveillance colonoscopy after EMR-MM versus historical control subjects. Multivariable logistic regression was performed to identify factors associated with recurrence. RESULTS: Two hundred ten patients with 210 polyps (median size, 30 mm; interquartile range: 25-40) underwent EMR-MM (n = 74) or conventional EMR (n = 136). Patient and lesion characteristics were similar between the groups. At a median follow-up of 6 months, the recurrence rate was lower with EMR-MM (6/74; 8%) compared with historical control subjects (39/136; 29%) (P < .001). EMR-MM was not associated with an increased rate of adverse events. On multivariable analysis, EMR-MM remained the strongest predictor of recurrence (odds ratio, .20; 95% confidence interval, .13-.64; P = .003) aside from polyp size (odds ratio, 2.81; 95% confidence interval, 1.35-6.01; P = .008). CONCLUSIONS: In this single-center historical control study, EMR-MM of large nonpedunculated colorectal polyps reduced the recurrence risk by 80% when compared with conventional EMR. This simple technique may provide an alternative to margin ablation.

Missed diagnosis of lymphoma presenting with humoral hypercalcemia of malignancy due to cessation of oncological workup after negative computed tomography scans.

Malignancy is the most common cause of hypercalcemia among hospitalised patients and is frequently caused by elevations in parathyroid hormone-related peptide (PTHrP). The most common PTHrP-producing cancers are carcinomas of the head, neck and lung. Hypercalcemia can be the presenting sign of cancer and, in these cases, solid tumours are usually discovered on CT scan. In rare cases, lymphoma may also present with hypercalcemia. CT scan is less sensitive for lymphoma than for most solid tumours and the diagnosis may be missed. We present the case of a 69-year-old woman who presented with hypercalcemia in the setting of severe weight loss and elevated PTHrP. Oncological workup was stopped after unrevealing CT scans and an underlying lymphoma was missed. Our case emphasises the need for a comprehensive oncological workup for patients with unexplained hypercalcemia and elevated PTHrP, even when CT scans are unrevealing.

Plasma Hydrogen Sulfide Is Positively Associated With Post-operative Survival in Patients Undergoing Surgical Revascularization.

Objective: Hydrogen sulfide (H2S) is a gaseous signaling molecule and redox factor important for cardiovascular function. Deficiencies in its production or bioavailability are implicated in atherosclerotic disease. However, it is unknown if circulating H2S levels differ between vasculopaths and healthy individuals, and if so, whether H2S measurements can be used to predict surgical outcomes. Here, we examined: (1) Plasma H2S levels in patients undergoing vascular surgery and compared these to healthy controls, and (2) the association between H2S levels and mortality in a cohort of patients undergoing surgical revascularization. Methods: One hundred and fifteen patients undergoing carotid endarterectomy, open lower extremity revascularization or lower leg amputation were enrolled at a single institution. Peripheral blood was also collected from a matched control cohort of 20 patients without peripheral or coronary artery disease. Plasma H2S production capacity and sulfide concentration were measured using the lead acetate and monobromobimane methods, respectively. Results: Plasma H2S production capacity and plasma sulfide concentrations were reduced in patients with PAD (p < 0.001, p = 0.013, respectively). Patients that underwent surgical revascularization were divided into high vs. low H2S production capacity groups by median split. Patients in the low H2S production group had increased probability of mortality (p = 0.003). This association was robust to correction for potentially confounding variables using Cox proportional hazard models. Conclusion: Circulating H2S levels were lower in patients with atherosclerotic disease. Patients undergoing surgical revascularization with lower H2S production capacity, but not sulfide concentrations, had increased probability of mortality within 36 months post-surgery. This work provides insight on the role H2S plays as a diagnostic and potential therapeutic for cardiovascular disease.

Endoscopic resection outcomes and predictors of failed en bloc endoscopic mucosal resection of colorectal polyps ≤ 20 mm among advanced endoscopy trainees.

Background and study aims En bloc endoscopic mucosal resection (EMR) is preferred over piecemeal resection for polyps ≤ 20 mm. Data on colorectal EMR training are limited. We aimed to evaluate the en bloc EMR rate of polyps ≤ 20 mm among advanced endoscopy trainees and to identify predictors of failed en bloc EMR. Methods This was a multicenter prospective study evaluating trainee performance in EMR during advanced endoscopy fellowship. A logistic regression model was used to identify the number of procedures and lesion cut-off size associated with an en bloc EMR rate of ≥ 80 %. Multivariate analysis was performed to identify predictors of failed en bloc EMR. Results Six trainees from six centers performed 189 colorectal EMRs, of which 104 (55 %) were for polyps ≤ 20 mm. Of these, 57.7 % (60/104) were resected en bloc. Trainees with ≥ 30 EMRs (OR 6.80; 95 % CI: 2.80-16.50; P  = 0.00001) and lesions ≤ 17 mm (OR 4.56;95 CI:1.23-16.88; P  = 0.02) were more likely to be associated with an en bloc EMR rate of ≥ 80 %. Independent predictors of failed en bloc EMR on multivariate analysis included: larger polyp size (OR:6.83;95 % CI:2.55-18.4; P  = 0.0001), right colon location (OR:7.15; 95 % CI:1.31-38.9; P  = 0.02), increased procedural difficulty (OR 2.99; 95 % CI:1.13-7.91; P  = 0.03), and having performed < 30 EMRs (OR: 4.87; 95 %CI: 1.05-22.61; P  = 0.04). Conclusions In this pilot study, we demonstrated that a relatively low proportion of trainees achieved en bloc EMR for polyps ≤ 20 mm and identified procedure volume and lesion size thresholds for successful en bloc EMR and independent predictors for failed en bloc resection. These preliminary results support the need for future efforts to define EMR procedure competence thresholds during training.

Breast cancer growth and proliferation is suppressed by the mitochondrial targeted furazano[3,4-b]pyrazine BAM15.

BACKGROUND: Enhanced metabolic plasticity and diversification of energy production is a hallmark of highly proliferative breast cancers. This contributes to poor pharmacotherapy efficacy, recurrence, and metastases. We have previously identified a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 that selectively reduces bioenergetic coupling efficiency and is orally available. Here, we evaluated the antineoplastic properties of uncoupling oxidative phosphorylation from ATP production in breast cancer using BAM15. METHODS: The anticancer effects of BAM15 were evaluated in human triple-negative MDA-MB-231 and murine luminal B, ERα-negative EO771 cells as well as in an orthotopic allograft model of highly proliferative mammary cancer in mice fed a standard or high fat diet (HFD). Untargeted transcriptomic profiling of MDA-MB-231 cells was conducted after 16-h exposure to BAM15. Additionally, oxidative phosphorylation and electron transfer capacity was determined in permeabilized cells and excised tumor homogenates after treatment with BAM15. RESULTS: BAM15 increased proton leak and over time, diminished cell proliferation, migration, and ATP production in both MDA-MB-231 and EO771 cells. Additionally, BAM15 decreased mitochondrial membrane potential, while inducing apoptosis and reactive oxygen species accumulation in MDA-MB-231 and EO771 cells. Untargeted transcriptomic profiling of MDA-MB-231 cells further revealed inhibition of signatures associated with cell survival and energy production by BAM15. In lean mice, BAM15 lowered body weight independent of food intake and slowed tumor progression compared to vehicle-treated controls. In HFD mice, BAM15 reduced tumor growth relative to vehicle and calorie-restricted weight-matched controls mediated in part by impaired cell proliferation, mitochondrial respiratory function, and ATP production. LC-MS/MS profiling of plasma and tissues from BAM15-treated animals revealed distribution of BAM15 in adipose, liver, and tumor tissue with low abundance in skeletal muscle. CONCLUSIONS: Collectively, these data indicate that mitochondrial uncoupling may be an effective strategy to limit proliferation of aggressive forms of breast cancer. More broadly, these findings highlight the metabolic vulnerabilities of highly proliferative breast cancers which may be leveraged in overcoming poor responsiveness to existing therapies.

Dynamin-related protein 1 regulates substrate oxidation in skeletal muscle by stabilizing cellular and mitochondrial calcium dynamics.

Mitochondria undergo continuous cycles of fission and fusion to promote inheritance, regulate quality control, and mitigate organelle stress. More recently, this process of mitochondrial dynamics has been demonstrated to be highly sensitive to nutrient supply, ultimately conferring bioenergetic plasticity to the organelle. However, whether regulators of mitochondrial dynamics play a causative role in nutrient regulation remains unclear. In this study, we generated a cellular loss-of-function model for dynamin-related protein 1 (DRP1), the primary regulator of outer membrane mitochondrial fission. Loss of DRP1 (shDRP1) resulted in extensive ultrastructural and functional remodeling of mitochondria, characterized by pleomorphic enlargement, increased electron density of the matrix, and defective NADH and succinate oxidation. Despite increased mitochondrial size and volume, shDRP1 cells exhibited reduced cellular glucose uptake and mitochondrial fatty acid oxidation. Untargeted transcriptomic profiling revealed severe downregulation of genes required for cellular and mitochondrial calcium homeostasis, which was coupled to loss of ATP-stimulated calcium flux and impaired substrate oxidation stimulated by exogenous calcium. The insights obtained herein suggest that DRP1 regulates substrate oxidation by altering whole-cell and mitochondrial calcium dynamics. These findings are relevant to the targetability of mitochondrial fission and have clinical relevance in the identification of treatments for fission-related pathologies such as hereditary neuropathies, inborn errors in metabolism, cancer, and chronic diseases.