Background and Aims nsedated colonoscopy is often associated with patient discomfort and may increase procedural difficulty for endoscopists. This study aimed to investigate the influence of perianal lidocaine application on the comfort level of patients and endoscopic operations during unsedated colonoscopy. Methods 122 patients aged 18-40 years were enrolled and randomly allocated to colonoscopy with 2% lidocaine (experiment group, n = 61) or normal saline (control, n = 61) smeared around the anus. The primary outcomes were anal pain score and abdominal pain score during and after colonoscopy, assessed using a visual analogue scale (VAS). Secondary outcomes included cecal intubation time, polyp detection rate, adenoma detection rate, and adverse events. Results There was no statistical difference between groups in terms of abdominal pain scores during unsedated colonoscopy. Abdominal pain scores after colonoscopy were significantly lower in the lidocaine group than in the saline group. (P < 0.001). However, the lidocaine group had significantly lower anal pain scores during and after colonoscopy (P < 0.001) and a shorter cecal intubation time (P < 0.001). Polyp and adenoma detection rates were higher in the lidocaine group (P < 0.05). Junior endoscopists achieved greater improvements in these outcomes compared to senior endoscopists. Conclusion Perianal application of lidocaine may reduce anal pain and may improve procedural efficiency during unsedated colonoscopy, particularly among junior endoscopists.

Corrosive esophageal injury in children may rarely lead to complete atresia. No standardized treatment exists for pediatric corrosive esophageal atresia. This case demonstrates a novel minimally invasive approach. A 12-year-old male developed complete esophageal atresia after accidental ingestion of industrial alkali. He underwent combined antegrade-retrograde endoscopic dilation (CARD) with balloon dilation and covered stent placement. Oral feeding resumed by postoperative day two, and at three-month follow-up, he reported normal eating without complications. To our knowledge, this represents the first reported use of CARD for pediatric corrosive esophageal atresia, demonstrating it as a feasible and effective minimally invasive alternative to surgery in selected cases.

BACKGROUND:Esophageal stricture (ES), a common complication after endoscopic submucosal dissection (ESD), is the consequence of excessive fibrosis and scar formation. The fibroblast-to-myofibroblast differentiation is a key characteristic in the pathogenesis of ES, but the molecular basis remains poorly understood. METHODS:According to the human transcriptome sequencing analysis, which utilized different expression gene analysis and weighted gene co-expression network analysis, the potential gene associated with ES was explored. Furthermore, we utilized the rat model of ES and the temporal progression of ES after drug treatment to elucidate the role of DPP4 in ES. Subsequently, we identified a significant association between DPP4 and the progression of ES. Finally, we validated our conclusions through experiments on Bama pigs. RESULTS:DPP4 expression was consistently elevated in both human ES tissues and the rat ES model. Upon inhibition of DPP4, the proliferative activity of ES primary cells and the expression of fibrosis-related genes were markedly suppressed. In rats, treatment with a DPP4 inhibitor significantly alleviated ES, which was accompanied by a significant reduction in collagen content and downregulation of fibrosis-related targets. These effects were observed in conjunction with changes in the Hippo-YAP pathway, although the data primarily support a parallel association rather than a hierarchical regulatory relationship between DPP4 and this pathway. CONCLUSIONS:Our findings suggest that DPP4 may contribute to the remodeling of the regenerative microenvironment in ES, with its expression and function occurring in parallel with alterations in the Hippo-YAP pathway. Direct mechanistic evidence establishing a linear upstream-downstream relationship between DPP4 and Hippo-YAP signaling remains to be further elucidated.

Colorectal cancer (CRC) is the most prevalent digestive system malignancy worldwide. The development of targeted therapeutics specifically effective for CRC is currently in dire need. Preclinical studies showed that CDK4/6 inhibitor palbociclib suppressed the growth of CRC, but whether this effect is durable is unclear. In this study, we aimed to evaluate the roles of palbociclib-induced senescence and find a new strategy to maximize its effectiveness in CRC treatment. Animal and cellular experiments revealed that palbociclib-induced senescence and the senescence-associated secretory phenotype (SASP) caused drug resistance, anti-apoptosis, PD-L1 upregulation and inhibition of CD8+ T cells’ function. Using CRISPR/Cas9 screening, we identified MCL1 as a senolytic target to eliminate palbociclib-induced senescent CRC cells in the presence of palbociclib. Mechanically, palbociclib-induced senescent cells upregulated ZHX2 and its transcriptional target MCL1, rendered their resistance to apoptosis and T cell-mediated cytotoxicity, whereases combining palbociclib with MCL1 inhibitor markedly induced apoptosis in senescent cells by activating both extrinsic and intrinsic apoptotic pathways. Lastly, we proposed a seno-therapy consisting of a palbociclib pre-treatment plus a combination treatment of palbociclib and MCL1 inhibitor and found it effectively inhibited tumor growth and improved the survival of CRC xenografted mice. Besides its senolytic effect, seno-therapy also reduced PD-L1-positive cells and enhancing the cytotoxic functions of CD8+ T cells. In conclusion, co-targeting CDK4/6 and MCL1 efficiently eliminates palbociclib-induced senescent CRC cells and offers a promising CDK4/6 inhibitor-based strategy for CRC treatment, ensuring prolonged tumor suppression and reducing the risk of progression or recurrence.

Chemical burns of the rectum are so rare that there are few cases reported about this situation. In fact, chemical burns of the rectum can cause severe serious consequence, such as bleeding, perforation and necrosis, even developing to persistent rectal stricture. Here we present a case report of a 12-year-old child with rectal stenosis who imitates the use of corkage and inserts rust remover into the rectum unsupervised by family members. He underwent endoscopic balloon dilation followed by submucosal injection of bleomycin at the stenosis point.

Duodenal perforation is the most serious complication of endoscopic retrograde cholangiopancreatography (ERCP), with an incidence of 0.09-1.67% but a high mortality rate of 8-23%. The Stapfer classification categorizes ERCP perforations into four types based on location: I) lateral/medial duodenal wall, II) perivaterian, III) distal bile duct related to instrumentation, IV) retroperitoneal air alone. While surgery is recommended for diagnosed perforations due to the mortality risk, there is no established treatment for resulting long-term retroperitoneal infections. We describe our experience managing such cases.

Celiac disease (CeD), triggered by gliadin exposure, necessitates therapeutic strategies that establish an antigen-specific immune tolerance. This study explores the therapeutic efficacy and mechanism of rapamycin-gliadin composite nanoparticles (PLN-GR) for CeD treatment. In vivo analyses demonstrated the efficient uptake of PLN-GR by antigen-presenting cells (APCs), particularly Kupffer cells and splenic dendritic cells (DCs), driving their tolerogenic phenotypic transformation. In a murine CeD model, PLN-GR administration significantly enhanced gluten tolerance and mitigated intestinal inflammation, as indicated by reduced paw edema and improved histopathological parameters. Mechanistically, PLN-GR induced macrophage metabolic reprogramming from glycolysis to oxidative phosphorylation, concomitant with elevated serum itaconate levels. This metabolic shift potentiated interorgan immunoregulatory crosstalk, expanding PD-L1+ tolerogenic splenic DCs while suppressing pathogenic Th1 cell populations. Bone marrow-derived macrophages (BMDMs) from Acod1-/- mice (deficient in itaconate synthesis) failed to induce DC tolerance upon PLN-GR treatment. However, supplementation with the itaconate derivative 4-octyl itaconate (4-OI) restored PD-L1 expression in DC2.4 cells in vitro, revealing that itaconate induces and stabilizes the tolerant DC phenotype. These findings underscore PLN-GR as a novel nanotherapeutic platform for CeD, achieving gliadin-specific tolerance through hepatic-splenic immunometabolic reprogramming and itaconate-dependent PD-L1 regulation, thereby offering a translatable strategy for autoimmune disease management.

Esophageal stenosis after ESD has been recorded high for large-scale esophageal lesion. Risk factors for increasing the occurrence of stenosis includes long type lesions, lesions infiltrating into the muscularis mucosa and muscular layer injury. In this case, postoperative stricture of the patient was highly likely occurred. Smectite is a mucosal protective agent that can resist external stimuli, promote wound healing, and reduce inflammatory factors. Therefore, it can effectively prevent the formation of scars on wounds. This study was carried out in humans for the first time and was successful. In conclusion, endoscopic spraying of smectite may be effective and safe in preventing esophageal stenosis after ESD with large non-circumferential lesions.

Metformin (Met) is a pharmaceutical agent for the treatment of type 2 diabetes mellitus. Intriguingly, it may also play a role in the gastrointestinal tract, the gut microbial communities, and the tissue-resident immune cells. The present study aimed to investigate whether the administration of Met achieved protective effects on high-fat diet (HFD)-fed mice with colorectal adenomas (CRA) and elucidated its mechanism via the gut microbiota. AOM/DSS was administered in an HFD-induced diet to induce CRA in mice. 16 S rRNA sequencing was conducted to analyze the gut microbiota profile of mice. Met reduced the inflammatory response in the intestine and alleviated HFD-induced intestinal flora disturbances, and Roseburia intestinalis (R. intestinalis) colonization enhanced the efficacy of Met. Met suppressed CRA cell proliferation, which was further reduced by R. intestinalis. Met blocked NF-κB signaling by activating GILZ through increased R. intestinalis abundance. GILZ deletion in macrophages weakened the inhibition of CRA growth by Met and R. intestinalis, leading to increased macrophage M1 polarization. Inhibition of the NF-κB signaling reversed the activation of macrophage M1 polarization by knockdown of GILZ and reduced the proliferation of CRA cells. Our results shed light on the impact of Met on gut microbiome alteration in treating CRA.

Letter to: Endoscopic screening of the upper gastrointestinal tract for second primary tumors in patients with head and neck cancer in a Western countryEndoscopy 2023; 55(11): 981-990DOI: 10.1055/a-2111-5935

The limited treatment options for colorectal cancer (CRC) and its adverse effects of chemotherapy underscore the urgent need for innovative therapeutic strategies. Focusing on early cellular glycosylation, particularly through the targeting of O-GlcNAcylation with small-molecule inhibitors, emerges as a promising direction. In this study, we developed artificial cell-like nanovesicles with a bilayer membrane structure to encapsulate OSMI-1, a specific inhibitor of O-GlcNAc transferase, aimed at inhibiting CRC progression. To enhance the effectiveness and specificity of the treatment, these self-targeted nanovesicles (T–Se–Lip–OSMI) were reinforced using internal diselenide bridges enabling redox-responsive release within the tumor microenvironment. In vitro assays revealed that T–Se–Lip–OSMI substantially diminished CRC cell proliferation, migration, and invasion. This was further validated using patient-derived organoid models, which highlighted the superior therapeutic efficacy of T–Se–Lip–OSMI over nanovesicles without the diselenide bridge. Subsequent in vivo studies confirmed its targeted delivery and pronounced suppression of tumor growth. Further mechanistic analysis illustrated that the therapeutic effect was mediated through the inhibition of O-GlcNAcylation of the Yes-associated protein (YAP), ultimately preventing the nuclear translocation of YAP and the activation of oncogenic downstream targets. This study leverages the unique properties of the diselenide bridge to enhance stability and functionality of the nanovesicles, offering a novel avenue for targeted CRC treatment.

Palbociclib is an excellent CDK4/6 inhibitor, but its clinical application is mainly limited to the treatment of advanced ER+/HR+ and HER2- breast cancer. Its efficacy in colorectal cancer (CRC) is evaluated in multiple trials and so far remains undetermined. We found that the PIK3CA-mutant CRC cells were insensitive to palbociclib treatment compared with the PIK3CA wild-type counterparts, and they were in an OIS (oncogene-induced senescence) state which was predisposed to a strong senescence-associated secretory phenotype (SASP) upon treatment. These senescent cells excessively secreted various SASP factors LCN2, and ultimately caused palbociclib-resistance via upregulation of EGFR in the non-senescent CRC cells. Importantly, a drug combination screen identified that erlotinib could synergize with palbociclib to overcome the SASP-induced resistance. Overall, we found that PIK3CA mutation-induced senescence compromised the efficacy of palbociclib treatment in CRC but co-targeting EGFR could minimize the OIS-associated side effects while preserving the beneficial effects. ### Competing Interest Statement The authors have declared no competing interest.