'Long-term outcomes after endoscopic submucosal dissection for relative indication early gastric cancer in non-surgical candidates'.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is effective in treating early gastric cancer (EGC). It's role in the comorbid with more advanced disease is unknown. We sought to evaluate this in a large Western cohort. METHODS: Consecutive patients who underwent ESD for EGC in a single tertiary Western endoscopy centre over 10 years were prospectively analyzed. The primary outcomes were long term overall survival (OS) and disease-free survival (DFS) up to 5 years. Secondary outcomes were efficacy and serious adverse events (SAE). RESULTS: ESD for 157 EGC in 149 patients were performed in an elderly and comorbid cohort with mean age 73.7 years and age-adjusted Charleson Comorbidity Index 4.2. Over a median follow-up period of 51.6 months, there was no significant difference in 5-year OS (88.9% vs 77.9%, P = 0.290) and DFS (83.2% vs 75.1%, P = 0.593) between absolute indication (AI) EGC and relative indication (RI) EGC. AI EGC cohort achieved higher en bloc (96.3% vs 87.5%, P = 0.069) and R0 resection rate (93.6% vs 62.5%, P <0.001) when compared to RI EGC. There were no significant differences in SAE (7.3% vs 12.5%, P = 0.363). No mortality or surgical resection ensued from ESD complications. CONCLUSION: ESD safely confers DFS in poor surgical candidates with RI EGC in a large Western cohort. Patients who are elderly and comorbid or decline surgical resection may benefit from ESD and avoid the risks of surgery and its long-term sequelae.

Development of AI-based hybrid soft computing models for prediction of critical river water quality indicators.

Prediction of river water quality indicators (RWQIs) using artificial intelligence (AI)-based hybrid soft computing modeling techniques could provide essential predictions required for efficient river health planning and management. The study described the development of a novel AI-based relative weighted ensemble (AIRWE) hybrid model for predicting critical RWQIs, i.e., biochemical oxygen demand (BOD) and total coliform (TC). The study involved comprehensive water quality (WQ) monitoring from 30 locations along the Damodar River to establish the baseline data and delineate the WQ. The representative input features showing a strong association with BOD and TC were identified using Spearman's rank-coupled orthogonal linear transformation (SOT). The relative weighted ensemble (RWE) method was applied to determine the relative weights for base learners in the AIRWE model. The statistical analysis of the developed model revealed that it was most efficient and accurate for predicting BOD (R2, 0.97; RMSE, 0.06; MAE, 0.04) and TC (R2, 0.98; RMSE, 0.06; MAE, 0.05) over the traditional techniques. The tstat (BOD 0.02 and TC 0.47) was lesser than tcrit (1.672), confirming its unbiased predictions. The SOT technique removed the data noise and multicollinearity, whereas RWE curtailed the individual model's limitations and predicted more reliable results. The model resulted 97% accuracy with high precision (96%) in classifying the river water quality for various end uses. The study describes a novel approach for researchers, scientists, and decision-makers for modeling and predicting various environmental attributes.

A simplified algorithm to evaluate the risk of submucosal invasive cancer in large (>/=20mm) non-pedunculated colonic polyps.

BACKGROUND AND AIMS: Recognition of submucosal invasive cancer (SMIC) in large (20mm) non-pedunculated colonic polyps (LNPCPs) informs selection of the optimal resection strategy. LNPCP location, morphology and size influence the risk of SMIC, however currently no meaningful application of this information has simplified the process to make it accessible and broadly applicable. We developed a decision-making algorithm to simplify the identification of LNPCP subtypes with increased risk of potential SMIC. METHODS: Patients referred for LNPCP resection from September 2008-November 2022 were enrolled. LNPCPs with SMIC were identified from endoscopic resection specimens, lesion biopsies, or surgical outcomes. Decision tree analysis of lesion characteristics identified in multivariable analysis was used to create a hierarchical classification of SMIC prevalence. RESULTS: 2451 LNPCPs were analysed. 1289 (52.6%) were flat, 1043 (42.6%) nodular and 118 (4.8%) depressed. SMIC was confirmed in 273 (11.1%) of LNPCPs and associated with depressed and nodular versus flat morphology (OR 35.7 CI 22.6-56.5 and 3.5 CI 2.6-4.9, p<0.001 respectively); left versus right colon location (OR 3.2, CI 2.5-4.1, p<0.001); non-granular (NG) versus granular (G) (OR 2.4 CI 1.9-3.1, p<0.001) and size (OR 1.12 per 10mm increase CI 1.05-1.19, p<0.001). Decision tree analysis targeting SMIC identified 8 terminal nodes: SMIC prevalence was 62% in depressed LNPCPs, 19% in nodular left colon LNPCPs and 20% in nodular right colon NG LNPCPs. CONCLUSIONS: This decision-making algorithm simplifies identification of LNPCPs with an increased risk of potential SMIC. When combined with surface optical evaluation, it facilitates accurate lesion characterisation and resection choices.

Are People With Type 1 Diabetes Mellitus Appropriately Following Insulin Injection Technique Practices: A Review of Literature.

People with type 1 diabetes mellitus (T1DM) need to take multiple doses of insulin injections daily throughout their lives. However, a notable portion of people with diabetes mellitus (DM) show suboptimal insulin injection technique practices. They are supposed to follow the recommended insulin injection technique guidelines. Our explorative literature search, including studies from the past 30 years, is expected to identify the deficiencies of self-injection insulin techniques and the associated complications in people with T1DM, where we have summarised the overall incidence of complications that have occurred due to nonadherence of the prescribed guidelines, along with their associated risk factors. We have attempted to include multiple systematic reviews, meta-analyses, literature reviews, case reports, and original articles from the search engines and databases like PubMed, Scopus, ScienceDirect, Cochrane Library, Google Scholar, and BioMed Central, and studies with only human participants were included in this search. The knowledge sharing from this research may be utilised for enhancing the structured education diabetes programme and implementing the population-based corrective measures, including the thrust areas in future multi-centre longitudinal research studies and recommendations, which can prevent unnecessary complications and enhance their quality of life. Correct insulin administration technique, abstaining from administration of injection at the areas with lipohypertrophy, rotation of injection sites, and ultrasound scanning can be used as a complimentary method to detect the lipohypertrophy at an early stage. Liposuction is beneficial in reducing the extensive lipohypertrophic tissues but helps achieve only cosmetically satisfactory outcome; thus, empowering people to follow insulin injection technique guidelines is one of the best strategies to reduce the high prevalence of lipohypertrophy. To conclude, education among the people with DM, especially T1DM who have to take insulin regularly, needs to be carried out consistently in the clinical settings, to prevent the severe complications caused due to inappropriate insulin injection techniques.

When less is more: lower esophageal sphincter-preserving peroral endoscopic myotomy is effective for non-achalasia esophageal motility disorders.

BACKGROUND: Non-achalasia esophageal motility disorders (NAEMDs), encompassing distal esophageal spasm (DES) and hypercontractile esophagus (HCE), are rare conditions. Peroral endoscopic myotomy (POEM) is a promising treatment option. In NAEMDs, unlike with achalasia, the lower esophageal sphincter (LES) functions normally, suggesting the potential of LES preservation during POEM. METHODS: This retrospective two-center observational study focused on patients undergoing LES-preserving POEM (LES-POEM) for NAEMD. Eckardt scores were assessed pre-POEM and at 6, 12, and 24 months post-POEM, with follow-up endoscopy at 6 months to evaluate for reflux esophagitis. Clinical success, defined as an Eckardt score ≤3, served as the primary outcome. RESULTS: 227 patients were recruited over 84 months until May 2021. Of these, 16 underwent LES-POEM for an NAEMD (9 with HCE and 7 with DES). The median pre-POEM Eckardt score was 6.0 (interquartile range [IQR] 5.0-7.0), which decreased to 1.0 (IQR 0.0-1.8; P<0.001) 6 months post-POEM. This was sustained at 24 months, with an Eckardt score of 1.0 (IQR 0.0-1.8; P<0.001). Two patients (12.5%) developed Los Angeles grade A or B esophagitis. CONCLUSIONS: LES-POEM for NAEMD demonstrates favorable clinical outcomes, with infrequent esophagitis and reintervention for LES dysfunction rarely required.

Safety and efficacy of physician-administered balanced-sedation for the endoscopic mucosal resection of large non-pedunculated colorectal polyps.

Background and study aims Because of concerns about peri-procedural adverse events (AEs), guidelines recommend anesthetist-managed sedation (AMS) for long and complex endoscopic procedures. The safety and efficacy of physician-administered balanced sedation (PA-BS) for endoscopic mucosal resection (EMR) of large non-pedunculated colorectal polyps (LNPCPs) ≥20 mm is unknown. Patients and methods We compared PA-BS with AMS in a retrospective study of prospectively collected data from consecutive patients referred for management of LNPCPs (NCT01368289; NCT02000141). A per-patient propensity analysis was performed following a 1:2 nearest-neighbor (Greedy-type) match, based on age, gender, Charlson comorbidity index, and lesion size. The primary outcome was any peri-procedural AE, which included hypotension, hypertension, tachycardia, bradycardia, hypoxia, and new arrhythmia. Secondary outcomes were unplanned admissions, 28-day re-presentation, technical success, and recurrence. Results Between January 2016 and June 2020, 700 patients underwent EMR for LNPCPs, of whom 638 received PA-BS. Among them, the median age was 70 years (interquartile range [IQR] 62-76 years), size 35 mm (IQR 25-45 mm), and duration 35 minutes (IQR 25-60 minutes). Peri-procedural AEs occurred in 149 (23.4%), most commonly bradycardia (116; 18.2%). Only five (0.8%) required an unplanned sedation-related admission due to AEs (2 hypotension, 1 arrhythmia, 1 bradycardia, 1 hypoxia), with a median inpatient stay of 1 day (IQR 1-3 days). After propensity-score matching, there were no differences between PA-BS and AMS in peri-procedural AEs, unplanned admissions, 28-day re-presentation rates, technical success or recurrence. Conclusions Physician-administered balanced sedation for the EMR of LNPCPs is safe. Peri-procedural AEs are infrequent, transient, rarely require admission (<1%), and are experienced in similar frequencies to those receiving anesthetist-managed sedation.

Acalabrutinib as a novel hope for the treatment of breast and lung cancer: an in-silico proof of concept.

Drug repurposing is proved to be a groundbreaking concept in the field of cancer research, accelerating the pace of de novo drug discovery by investigating the anti-cancer activity of the already approved drugs. On the other hand, it got highly benefitted from the advancement in the in-silico tools and techniques, which are used to build up the initial "proof of concept" based on the drug-target interaction. Acalabrutinib (ACL) is a well-known drug for the treatment of hematological malignancies. But, the therapeutic ability of ACL against solid tumors is still unexplored. Thereby, the activity of ACL on breast cancer and lung cancer was evaluated utilizing different computational methods. A series of proteins such as VEGFR1, ALK, BCL2, CXCR-4, mTOR, AKT, PI3K, HER-2, and Estrogen receptors were selected based on their involvement in the progression of the breast as well as lung cancer. A multi-level computational study starting from protein-ligand docking to molecular dynamic (MD) simulations were performed to detect the binding potential of ACL towards the selected proteins. Results of the study led to the identification of ACL as a ligand that showed a high docking score and binding energy with HER-2, mTOR, and VEGFR-1 successively. Whereas, the MD simulations study has also shown good docked complex stability of ACL with HER2 and VEGFR1. Our findings suggest that interaction with those receptors can lead to preventive action on both breast and lung cancer, thus it can be concluded that ACL could be a potential molecule for the same purpose.Communicated by Ramaswamy H. Sarma.

Direct diverticular peroral endoscopic myotomy for the treatment of thoracic esophageal diverticula: technique and outcomes.

BACKGROUND: Diverticular peroral endoscopic myotomy (POEM) is an alternative to surgery for the management of symptomatic thoracic esophageal diverticula. Conventionally, this requires proximal tunnel formation but a direct approach may simplify the technique. Herein, we report the outcomes of direct diverticular-POEM (DD-POEM). METHODS: We conducted a single-center prospective observational study evaluating DD-POEM. This involved a direct approach to the diverticulum. Success was defined as an Eckardt score of ≤ 3 without the need for reintervention. RESULTS: 10 patients underwent DD-POEM (median age 72 years; interquartile range [IQR] 14.3; male 60 % [n = 6]). Median diverticulum size was 40 mm (IQR 7.5) and median location was 35 cm from the incisors (IQR 8.3). Five patients (50 %) had an underlying dysmotility disorder. The median procedure duration was 60 minutes (IQR 28.8). There were no adverse events. The median hospital stay was 1 day (IQR 0.75). The pre-procedure median Eckardt score of 6 (IQR 4) significantly improved to 0 (IQR 0.75; P < 0.001) at a median follow-up of 14.5 months (IQR 13.8). Success was achieved in all patients. CONCLUSIONS: DD-POEM was a safe technique for the management of thoracic esophageal diverticula. Owing to its simplicity and excellent performance it should be further evaluated for the treatment of this disorder.

Hybrid resection versus conventional resection for laterally spreading lesions of the papilla.

BACKGROUND AND AIMS: Although conventional hot snare resection (CR) of laterally spreading lesions of the major papilla (LSL-Ps) is effective, it can be associated with delayed bleeding in upward of 25% of cases. Given the excellent safety profile of cold snare polypectomy in the colorectum, we investigated the efficacy and safety of a novel hybrid resection (HR) technique for LSL-P management, consisting of hot snare papillectomy plus cold snare resection of the laterally spreading component. METHODS: A prospective cohort of patients underwent HR in a tertiary referral center over 60 months until December 2022. This cohort was compared with a historical cohort of patients who underwent CR at the same institution over 120 months until August 2017. The primary outcomes were recurrence and bleeding. RESULTS: Twenty patients underwent HR (14 female; mean age 65.2 ± 12.2 years). Median lesion size was 30 mm (interquartile range, 25.0-47.5 mm). Recurrent or residual adenoma (RRA) was greater with HR (58.8% [n = 10] vs 29.8% [n = 14]; P = .034). The odds ratio for recurrence was 3.6 times (95% CI, 1.2-11.0) higher with HR (P = .027). RRA was multifocal in 4 (40%) and had a composite RRA volume >10 mm in 7 (70%). The median number of procedures required to treat RRA was higher with HR (4 vs 1, P = .002). There was no difference between CR and HR for intraprocedural bleeding (41.1% [n = 23] vs 25% [n = 5]; P = .587) or delayed bleeding (25.0% vs 10.0%, P = .211). There were no perforations. CONCLUSIONS: The novel HR technique for LSL-P management is associated with a high rate of RRA that is recalcitrant to treatment, without mitigating the risk of intraprocedural or delayed bleeding. Therefore, CR should remain the mainstay management option for treating patients with an LSL-P. (Clinical trial registration number: NCT02306603.).

Geometry of cold snare polypectomy and risk of incomplete resection.

BACKGROUND: Cold snare polypectomy (CSP) is safer than and equally efficacious as hot snare polypectomy (HSP) for the removal of small (<10mm) colorectal polyps. The maximum polyp size that can be effectively managed by piecemeal CSP (p-CSP) without an excessive burden of recurrence is unknown. METHODS: Resection error risks (RERs), defined as the estimated likelihood of incomplete removal of adenomatous tissue for a single snare resection pass, for CSP and HSP were calculated, based on an incomplete resection rate. Polyp area, snare size, estimated number of resections, and optimal resection defect area were modeled. Overall risk of incomplete resection (RIR) was defined as RIR=1 - (1 - p)n, where p is the RER and n the number of resections. RESULTS: A 40-mm polyp has a four times greater area than a 20-mm polyp (314.16mm2 vs. 1256.64mm2), and requires three times more resections (11 vs. 33, respectively, assuming 8-mm piecemeal resection pieces for p-CSP). RIRs for a 40-mm polyp by HSP and p-CSP were 15.1%-23% and 40.74%-60.60% respectively. CONCLUSION: RER is more important with p-CSP than with HSP. The number of resections, n, and consequently RIR increases with increasing polyp size. Given the overwhelming safety of CSP, specific techniques to minimize the RER should be studied and developed.

Endoscopic resection of large anastomotic polyps is safe and effective.

BACKGROUND: Large (≥20mm) adenomatous anastomotic polyps (LAAPs) are uncommon. Data pertaining to their prevalence, characteristics, and the efficacy of endoscopic resection (ER) are absent. A safe and effective strategy for ER would reduce morbidity and healthcare costs. METHODS: Large nonpedunculated colorectal polyps of ≥20mm (LNPCPs) referred for ER were prospectively studied. Multiple data points were recorded including anastomotic location, polyp morphology, resection modality, complications, and technical success. RESULTS: Over 7 years until November 2022, 2629 lesions were referred. Of these, 10 (0.4%) were LAAPs (median size 35 mm [interquartile range (IQR) 30-40mm]). All LAAPs were removed by piecemeal endoscopic mucosal resection (EMR), most (n=9; 90%) in combination with cold-forceps avulsion with adjuvant snare-tip soft coagulation (CAST). On comparison of the LAAP group with the conventional LNPCP group, CAST was more commonly used (90% vs. 9%; P<0.001) and deep mural injury (DMI) type II was more frequent (40% vs. 11%, P=0.003); however, significant DMI (III-V) did not occur. At 6 month (IQR 5.25-6 months) surveillance, there was no recurrence in any of the 10 cases. There were no serious adverse events. CONCLUSIONS: LAAPs present unique challenges owing to their location overlying an anastomosis. Despite these challenges they can be safely and effectively managed endoscopically without recurrence at endoscopic follow-up.

Design, synthesis, and biological evaluation of HDAC6 inhibitors targeting L1 loop and serine 531 residue.

Histone deacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones, leading to the silencing of genes. Targeting specific isoforms of HDACs has emerged as a promising approach for cancer therapy, as it can overcome drawbacks associated with pan-HDAC inhibitors. HDAC6 is a unique HDAC isoform that deacetylates non-histone proteins and is primarily located in the cytoplasm. It also has two catalytic domains and a zinc-finger ubiquitin binding domain (Zf-UBD) unlike other HDACs. HDAC6 plays a critical role in various cellular processes, including cell motility, protein degradation, cell proliferation, and transcription. Hence, the deregulation of HDAC6 is associated with various malignancies. In this study, we report the design and synthesis of a series of HDAC6 inhibitors. We evaluated the synthesized compounds by HDAC enzyme assay and identified that compound 8g exhibited an IC50 value of 21 nM and 40-fold selective activity towards HDAC6. We also assessed the effect of compound 8g on various cell lines and determined its ability to increase protein acetylation levels by Western blotting. Furthermore, the increased acetylation of α-tubulin resulted in microtubule polymerization and changes in cell morphology. Our molecular docking study supported these findings by demonstrating that compound 8g binds well to the catalytic pocket via L1 loop of HDAC6 enzyme. Altogether, compound 8g represents a preferential HDAC6 inhibitor that could serve as a lead for the development of more potent and specific inhibitors.

Correction: Duodenal neuroendocrine tumors: Short-term outcomes of endoscopic submucosal dissection performed in the Western setting.

[This corrects the article DOI: 10.1055/a-2181-0320.].

Duodenal neuroendocrine tumors: Short-term outcomes of endoscopic submucosal dissection performed in the Western setting.

Background and study aims Endoscopic resection (ER) is recommended for the management of duodenal neuroendocrine tumors (D-NETs) confined to the submucosal layer, without lymph node or distant metastasis. While this is accepted practice for lesions < 10 mm, consensus for larger lesions remains unclear. Although endoscopic submucosal dissection (ESD) has been proposed as the preferred ER technique for DNETs ≥10 mm, there are limited data on efficacy and safety, particularly in the Western setting. Patients and methods We performed a retrospective analysis of patients with D-NETs who underwent ESD between 2012 and 2022 in three tertiary referral centers in Australia, France, and Belgium. Results Fourteen patients with 15 D-NETs were evaluated. Median patient age was 64 years (interquartile range [IQR] 58-70 years). All D-NETs were confined to the duodenal bulb. Median D-NET size was 10 mm (IQR 7-12 mm) and specimen size was 15 mm (IQR 15-20 mm). Median procedure time was 60 minutes (IQR 25-90 minutes). The rate of en bloc resection was 100%. Intra-procedural perforation occurred in four patients (26.7%), with all closed endoscopically without long-term sequelae. There were no episodes of clinically significant bleeding. No local recurrence, lymph node or distant metastasis was observed at a median follow-up of 19.9 months (IQR 10.3-49.3 months). Conclusions In experienced hands, ESD for D-NETs can achieve a 100% en bloc resection rate. There were no cases of local recurrence or distant metastatic spread, indicating that ESD may be a viable option for patients with D-NETs 10 to 15 mm that are not surgical candidates.

Western outcomes of circumferential endoscopic submucosal dissection for early esophageal squamous cell carcinoma.

BACKGROUND AND AIMS: Circumferential endoscopic submucosal dissection (cESD) in the esophagus has been reported to be feasible in small Eastern case series. We assessed the outcomes of cESD in the treatment of early esophageal squamous cell carcinoma (ESCC) in Western countries. METHODS: We conducted an international study at 25 referral centers in Europe and Australia using prospective databases. We included all patients with ESCC treated with cESD before November 2022. Our main outcomes were curative resection according to European guidelines and adverse events. RESULTS: A total of 171 cESDs were performed on 165 patients. En bloc and R0 resections rates were 98.2% (95% confidence interval [CI], 95.0-99.4) and 69.6% (95% CI, 62.3-76.0), respectively. Curative resection was achieved in 49.1% (95% CI, 41.7-56.6) of the lesions. The most common reason for noncurative resection was deep submucosal invasion (21.6%). The risk of stricture requiring 6 or more dilations or additional techniques (incisional therapy/stent) was high (71%), despite the use of prophylactic measures in 93% of the procedures. The rates of intraprocedural perforation, delayed bleeding, and adverse cardiorespiratory events were 4.1%, 0.6%, and 4.7%, respectively. Two patients died (1.2%) of a cESD-related adverse event. Overall and disease-free survival rates at 2 years were 91% and 79%. CONCLUSIONS: In Western referral centers, cESD for ESCC is curative in approximately half of the lesions. It can be considered a feasible treatment in selected patients. Our results suggest the need to improve patient selection and to develop more effective therapies to prevent esophageal strictures.

The ultrastructural features of the infundibulum of the green iguana, Iguana iguana.

The purpose of this study is to describe, in detail, the ultrastructure of the infundibulum of the sexually mature and active female green iguana, Iguana iguana. The infundibulum of five iguanas was remarkably distinct from the uterus, and was also clearly demarcated into cranial (expanded v-shaped) and caudal (tubular) divisions. Tissue samples obtained from five portions (three from the cranial division and two from the caudal division) of the infundibulum were processed conventionally for light and electron microscopy. The epithelial lining of the most anterior, middle, and posterior, parts of the cranial division displayed nonciliated cells predominantly, and occasionally ciliated cells. The numerous secretory granules in nonciliated type 1 cell found in the fimbrial aspect of the infundibulum were homogenous and deeply electron-dense, but those in the other two regions were variants of this cell type because they contained variably electron-dense secretory granules. Two main types of nonciliated cells (type 2 and its variant, type 3, as well as type 4) occurred in the epithelial lining of the caudal division of the infundibulum, but they, clearly, showed no dense secretory granules. Whereas the nonciliated type 2 cell and its variant (type 3 cell) contained large glycogen deposits, the type 4 cell lacked these deposits but its apical part contained large lipid-like droplets and, remarkably, blebbed into the duct lumen. The nonciliated cells lining the mucosal tubular glands contained highly electron-dense secretory granules, which were similar to those found in the nonciliated type 1 cell in the epithelial lining of the fimbrial part of the cranial division of the infundibulum.