Author Correction: Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper. The original Letter has not been corrected.

Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.

Treatments that target immune checkpoints, such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1, have been approved for treating human cancers with durable clinical benefit. However, many patients with cancer fail to respond to compounds that target the PD-1 and PD-L1 interaction, and the underlying mechanism(s) is not well understood. Recent studies revealed that response to PD-1-PD-L1 blockade might correlate with PD-L1 expression levels in tumour cells. Hence, it is important to understand the mechanistic pathways that control PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1-PD-L1 blockade in patients with cancer. Here we show that PD-L1 protein abundance is regulated by cyclin D-CDK4 and the cullin 3-SPOP E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 (hereafter CDK4/6) in vivo increases PD-L1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of speckle-type POZ protein (SPOP) and thereby promoting SPOP degradation by the anaphase-promoting complex activator FZR1. Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumour-infiltrating lymphocytes in mouse tumours and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy enhances tumour regression and markedly improves overall survival rates in mouse tumour models. Our study uncovers a novel molecular mechanism for regulating PD-L1 protein stability by a cell cycle kinase and reveals the potential for using combination treatment with CDK4/6 inhibitors and PD-1-PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.

Risk factors for positive resection margins after endoscopic resection for gastrointestinal neuroendocrine tumors.

BACKGROUND: In recent years, the incidence of gastrointestinal neuroendocrine tumors (GI-NETs) has remarkably increased due to the widespread use of screening gastrointestinal endoscopy. Currently, the most common treatments are surgery and endoscopic resection. Compared to surgery, endoscopic resection possesses a higher risk of resection margin residues for the treatment of GI-NETs. METHODS: A total of 315 patients who underwent surgery or endoscopic resection for GI-NETs were included. We analyzed their resection modality (surgery, ESD, EMR), margin status, Preoperative marking and Prognosis. RESULTS: Among 315 patients included, 175 cases underwent endoscopic resection and 140 cases underwent surgical treatment. A total of 43 (43/175, 24.57%) and 10 (10/140, 7.14%) patients exhibited positive resection margins after endoscopic resection and surgery, respectively. Multivariate regression analysis suggested that no preoperative marking and endoscopic treatment methods were risk factors for resection margin residues. Among the patients with positive margin residues after endoscopic resection, 5 patients underwent the radical surgical resection and 1 patient underwent additional ESD resection. The remaining 37 patients had no recurrence during a median follow-up of 36 months. CONCLUSIONS: Compared with surgery, endoscopic therapy has a higher margin residual rate. During endoscopic resection, preoperative marking may reduce the rate of lateral margin residues, and endoscopic submucosal dissection may be preferred than endoscopic mucosal resection. Periodical follow-up may be an alternative method for patients with positive margin residues after endoscopic resection.

Safety and efficacy of ESD for laterally spreading tumors with hemorrhoids close to the dentate line.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a curative treatment for laterally spreading tumors (LSTs). However, the outcomes of ESD for LSTs with hemorrhoids remain largely unknown. Our study aimed to evaluate the usefulness of ESD in managing LSTs with hemorrhoids. MATERIAL AND METHODS: We retrospectively collected 418 consecutive LST patients treated with ESD between 2011 and 2023. A retrospective comparative analysis was conducted. RESULTS: There were 85 patients included in the hemorrhoids group and 333 patients included in the other group. The en-bloc resection rate, R0 resection rate, and curative resection rate were comparable in these two groups (p > 0.05). The LSTs with hemorrhoids have a significantly higher intraoperative bleeding rate during ESD when compared to the other group (12.9% vs. 5.4%, p = 0.028). Rates of intraoperative perforation and anal pain in the hemorrhoid group were significantly higher than those in the no-hemorrhoid group (2.4% vs. 0%, p = 0.041; 9.4% vs.0.6%, p < 0.001; respectively). Moreover, most of the related manifestations caused by hemorrhoids were relieved to various degrees after ESD. CONCLUSIONS: ESD is a safe and effective treatment strategy for LSTs with hemorrhoids. A multi-center and prospective study should be conducted in the future to validate our results.

Endoscopic ultrasound-guided bite-on-bite biopsy and endoscopic ultrasound-guided fine-needle aspiration in the diagnosis of gastric tumors with negative malignant endoscopy biopsies: a retrospective cohort study.

BACKGROUND: Specific types of gastric tumors, including gastric linitis plastica and lymphoma, may cause extensive deep-layer infiltration, impeding an accurate diagnosis with endoscopic biopsy. This study aims to evaluate the efficacy of endoscopic ultrasound (EUS)-guided bite-on-bite biopsy and EUS-guided fine-needle aspiration (EUS-FNA) in diagnosing gastric malignancies with negative endoscopic biopsies. METHODS: We retrospectively analyzed suspicious malignant gastric lesion cases in our hospital from October 2017 to August 2023. Clinical manifestations, radiographical examinations, endoscopic examinations, histopathological results, and therapeutic strategies were recorded and analyzed. RESULTS: Forty malignant gastric tumor cases with negative endoscopic biopsies were incorporated into our study. EUS-guided bite-on-bite biopsy was performed in 16 cases exclusively, whereas 17 patients received EUS-FNA exclusively, and seven patients underwent both simultaneously. Among the 23 patients who received the EUS-guided bite-on-bite biopsy, 22 (95.7%) were diagnosed with malignancies. Among the 24 patients who received EUS-FNA, a total of 19 cases with malignancies (79.2%) were confirmed by EUS-FNA (p = 0.11): 13 gastric adenocarcinomas, five metastatic malignancies, and one malignant stromal tumor. No adverse events were observed in any of the cases. CONCLUSIONS: EUS-guided bite-on-bite biopsy and EUS-FNA possess their advantages and disadvantages. EUS-guided bite-on-bite biopsy could serve as a reliable diagnostic method for shallow lesions with negative malignant endoscopic biopsies.

Peroral Endoscopic Myotomy for Achalasia in Older Adults: A Retrospective Analysis of 39 Cases with a Minimum Follow-Up of 5 Years.

Peroral endoscopic myotomy (POEM) has demonstrated favorable short-term safety and efficacy in older adults, while a comprehensive understanding of the long-term outcomes were vague. We aimed to evaluate clinical outcomes in older adults' 5-year postop after undergoing POEM to treatment achalasia. Older adults from a single hospital who received POEM between January 2010 and January 2017 were analyzed. Older persons were reached to evaluate their symptoms at present and encouraged repeat examinations for objective follow-up. The clinical success, POEM-related indicators, POEM-related adverse events, and quality of life were assessed. Thirty-nine older adults with a mean age of 70.82 ± 4.72 who underwent POEM were studied at a mean 84.23 ± 25.06 month follow-up. The preoperative diagnosis was achalasia type I in 7 older adults, achalasia type II in 26 older adults, and achalasia type III in 2 older adults. Sixteen older adults had prior treatment and 21 older adults suffered from comorbidities. The median operative time was 50 (25-120) minutes, and perioperative adverse events were recorded in four older adults. The current Eckardt scores were significantly lower than that before POEM (2.08 ± 2.12 vs. 6.58 ± 1.78, P < 0.001). Besides, long-term clinical success was gained in 66.7% of older adults. Three older adults received postop treatment for symptom recurrence. Ultimately, 80.6% of old adults expressed satisfaction with POEM, while 27.8% of older adults suffered from symptomatic reflux. In conclusion, POEM can provide symptomatic improvement in a large proportion of older adults with achalasia at 5-year postop.

Endoscopic ultrasound guided lauromacrogol sclerotherapy for a large splenic cyst.

Symptomatic splenic cyst is usually managed by surgical resection or ultrasound-guided percutaneous sclerotherapy. In the present case, we demonstrated the safety and feasibility of endoscopic ultrasound-guided sclerotherapy for treatment of splenic cyst. As far as we known. This is the first case report concerning EUS-guided sclerotherapy for splenic cyst.

Research progress in cuproptosis in liver cancer. / é“œæ­»äº¡åœ¨è‚ç™Œä¸­çš„ç ”ç©¶è¿›å±•.

Copper, like iron, is an essential trace metal element for human cells. The role of iron overload and ferroptosis has been gradually clarified in tumors, but the role of copper overload and cuproptosis is still being explored. Cuproptosis is a novel mode of cell death, secondary to impaired mitochondrial function induced by copper overload, and characterized by copper-dependent and programmed. The excessive copper leads to protein toxicity stress by binding to sulfhydryl proteins in the tricarboxylic acid (TCA) cycle of mitochondria, disrupting cellular homeostasis and triggering cuproptosis. Copper accumulation has carcinogenic effects on normal cells, dual effects on tumor cells. Liver cancer is one of the most common malignant tumors in China and even globally, with hepatocellular carcinoma (HCC) being the most common histological subtype. Copper exhibits dualism in HCC, as it both contributes to the growth and invasion of HCC cells, and exerts anticancer effects by inducing cuproptosis. Also, cuproptosis-related genes can be the evaluation of immunotherapy effect and the construction of prognostic models. Clarifying the role of copper death in liver cancer can help explore new methods for liver cancer screening, treatment, and prognosis evaluation.

Safety and efficacy of surgical and endoscopic resection in the treatment of duodenal subepithelial lesions.

BACKGROUND: Duodenal subepithelial lesions (D-SELs) are rare and their resection is challenging. Unfortunately, data on surgical and endoscopic resection of D-SELs are scarce. This study aimed to assess the safety and efficacy of surgical resection and endoscopic resection (ER) for D-SELs. METHODS: We retrospectively analyzed clinical data of patients with non-ampullary D-SELs who underwent ER or surgery and compared the outcomes between ER and surgery with no/low-risk SELs over 15 mm from March 2010 to August 2020. Clinicopathologic findings, procedure-related parameters, and follow-up data were analyzed. RESULTS: A total of 107 patients (108 lesions) were enrolled; 52 patients (53 lesions) received ER and 55 patients (55 lesions) received surgery. In ER group, en bloc resection rate and R0 resection rate were 94 and 89%, respectively. Major adverse events rate was 6%. One (2%) patient experienced local recurrence. In surgery group, R0 resection was achieved in all cases. Major adverse events rate was 20%. Recurrence rate and distant metastases rate were 4 and 8%, respectively. One (2%) patient died from septicemia during follow-up. Thirty-three patients in each group were enrolled in the comparison. There were no significant differences in age, sex, lesion size and location (P > 0.05). More histologically GISTs and muscularis propria-originated lesions were treated by surgery (P < 0.05). ER was significantly associated with a shorter operation time, shorter hospital stay, lower cost, less estimated blood loss, and lower major adverse events rate compared to the surgery group (P < 0.05). However, R0 resection rate, mortality, recurrence rate, and metastases rate were not significant different (P > 0.05). CONCLUSIONS: ER is an effective and safe treatment modality for selected patients with non-ampullary D-SELs by expert endoscopists. Surgery is a radical method for D-SELs that should be reserved for D-SELs not amenable to ER.

Successful endoscopic removal of a giant duodenal bulb mass.

A 53-year-old man presented to our hospital for resection of a duodenal mass because of the increasing diameter. Esophagogastroduodenoscopy revealed a giant oval mass in the back wall of duodenal bulb, which was protruded to the second part of duodenum(Figure 1). Endoscopic ultrasonography (EUS) revealed a submucosal mass with heterogeneous echogenicity and regular shape(Figure 2). Eventually, the patient received endoscopic submucosal dissection (ESD) after signing informed consent. The mass was resected completely and measured 6.0×4.2×3.0 cm [Figure 3]. Histopathological examination revealed a brunner's gland adenoma. There was no complication besides minor intraoperative bleeding. Both surgery and endoscopic resection (ER) are alternative treatments for duodenal adenoma, but the best way remains controversial. Due to the thin wall, narrow cavity and plentiful vascular network of the duodenal bulb, ER is challenging because of the technical difficulty and probability of perforation and bleeding [1]. Our previous study found that ER is an effective and safe way for treating duodenal adenoma on experienced hands, and ER possesses several advantages over surgical resection for selected patients [2，3]. In the present case, we removed the giant BGA by ESD, as far as we know, this is the largest yet removed by ER.

Anemia induced by hemangioma at the duodenal papilla, resected by endoscopic mucosal resection.

A 7-year-old ever healthy girl presented to our hospital with anemia for half-a-year, and her lowest hemoglobin level was 75g/L. She denied any hematemesis or melena, however her fecal occult blood test was positive. Computed tomography revealed an oval lesion in the descending duodenum.

M1 Macrophage exosomes MiR-21a-5p aggravates inflammatory bowel disease through decreasing E-cadherin and subsequent ILC2 activation.

Abnormal immune regulation is a key feature of the complex pathogenic mechanism of ulcerative colitis (UC). In particular, macrophages and group 2 innate lymphoid cells (ILC2s) are important components of natural immunity that have been shown to play important roles in the pathogenesis of UC, as well as decreased E-cadherin expression on the colonic mucosa. However, it remains unclear how these components interact with each other. In this study, we investigated the molecular mechanisms of UC mediated by macrophage-derived exosomes. We showed for the first time that miR-21a-5p expression is increased in the peritoneal exosomes of mice with dextran sulphate sodium induced enteritis and that miR-21a-5p expression correlates negatively with E-cadherin expression in enterocytes. Moreover, we confirmed that miR-21a-5p was mainly derived from M1 macrophages and demonstrated that KLRG1, a surface inhibitory receptor on ILC2s, participated in excessive ILC2 activation in UC by promoting GATA-3. In conclusion, our results suggest molecular targets and provide a theoretical basis for elucidating the pathogenesis of UC and improving its treatment.

Thalidomide Attenuates Colitis and Is Associated with the Suppression of M1 Macrophage Polarization by Targeting the Transcription Factor IRF5.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease. The TNF-α inhibitor thalidomide is reported to be effective for inducing remission in pediatric Crohn's disease (CD) and adults with refractory CD. The mechanisms underlying the immunomodulatory and anti-inflammatory properties of thalidomide are unclear. METHODS: Histological assessments were firstly performed in thalidomide treated UC patients. Then the effect of thalidomide in vivo was detected in DSS-induced murine colitis. The mechanism involving IRF5, and M1 macrophage polarization was investigated by using plasmid transfection, western blotting, and real-time PCR. Finally, AOM/DSS model was used to detect the role of thalidomide in colitis associated cancer. RESULTS: We first found that treatment with thalidomide could ameliorate colon inflammation for 8 weeks and promote mucosal healing in human UC. Moreover, treatment with thalidomide protected mice from dextran sodium sulfate (DSS)-induced acute colitis, with treated mice presenting with a higher body weight, lower histological score, and lower DAI. Concomitantly, in comparison with control mice, mice treated with thalidomide showed accelerated recovery following colitis after 10 days of thalidomide treatment. Mechanistically, we observed that thalidomide could increase epithelial cell self-renewal capacity and modulate M1/M2 polarization by decreasing M1 markers CD86 and CCR7 and increasing M2 protein signatures CD206 and Arg-1. Thalidomide controls M1 macrophage polarization by targeting the transcription factor IRF5. Finally, by using the classical AOM/DSS model, we found that thalidomide-treated mice presented with a lower incidence and growth of colitis-associated carcinoma (CAC) than negative control mice. CONCLUSIONS: In summary, thalidomide suppresses M1 polarization in the inflammatory microenvironment, which not only attenuates colonic inflammation to facilitate mucosal healing after DSS-induced injury but also represses the progression of CAC.

Patients with upper gastrointestinal foreign bodies are more likely to consult later and with a higher rate of hospitalization during the COVID-19 pandemic.

The COVID-19 has great impact on the health behavior of all people around the world, however its influence on patients with upper gastrointestinal foreign bodies remains unknown. In the present study, we found for the first time that during COVID-19 pandemic, patients with upper gastrointestinal foreign bodies were more likely to consult later and with a higher rate of hospitalization.

Efficacy and safety of submucosal tunneling endoscopic resection for gastric submucosal tumors: a systematic review and meta-analysis.

INTRODUCTION: submucosal tunneling endoscopic resection (STER) can be an effective treatment for submucosal tumors (SMTs) in the esophagus and cardia. However, STER may be more difficult to perform in the stomach than in the esophagus due to special anatomical and physiological features. The feasibility of STER to remove gastric STMs has not been systematically investigated. Therefore, this meta-analysis aimed to evaluate the safety and efficacy of STER for gastric SMTs. MATERIAL AND METHODS: a comprehensive literature search of the Medline, Embase, PubMed, and Cochrane Library databases was conducted. Complete resection and en-bloc resection rates were considered as the primary outcome measures. The secondary outcome measure was the pooled estimate of complications. RESULTS: nine studies including 301 patients with 305 lesions were finally included. The pooled estimate of en-bloc resections was 95.1 % (95 % CI: 88.9-97.9 %), Cochran's Q-test, p = 0.151, and the weighted pooled rate (WPR) for complete resection was 97.9 % (95 % CI: 93.6-99.3 %), Cochran's Q-test, p = 0.778. In addition, the pooled estimate of gas-related complications was 8.7 % (95 % CI: 4.6-15.9 %), Cochran's Q-test, p = 0.057. The pooled estimate for mucosal laceration was 4.2 % (95 % CI: 2.2-7.9 %), Cochran's Q-test, p = 0.572. The pooled estimate for delayed bleeding was 2.1 % (95 % CI: 0.9-4.8 %), Cochran's Q-test, p = 0.985. The pooled estimate of inflammation-related complications was 8.6 % (95 % CI: 5.2-13.9 %), Cochran's Q-test, p = 0.308. CONCLUSION: STER is an effective and safe technique for removing gastric SMTs with low complications, and complications, when encountered, can be treated conservatively.

A novel large deletion in the APC gene associated with Gardner syndrome in a Chinese family.

INTRODUCTION: Gardner syndrome is a hereditary disease characterized by familial adenomatous polyposis (FAP), accompanied by soft tissue tumors. MATERIAL AND METHODS: a Chinese FAP family was enrolled and followed-up for three years. RESULTS: a novel large germline fragment deletion (EX10_16DEL) of the adenomatous polyposis coli (APC) gene was identified by multiplex ligation-dependent probe amplification (MLPA). An unexpected abdominal tumor grew two years after a subtotal colectomy of the proband. The immunohistochemistry study of the abdominal tumor showed SMA(focal+), calponin(+), ß-catenin(nucleus+) and CD34(focal+), CD117(-), which was consistent with a desmoid tumor. CONCLUSION: when a FAP related desmoid tumor appears, the possibility of Gardner syndrome should be considered. This is the first largest deletion of the APC gene in the Chinese population associated with Gardner syndrome.

Factors that predict the technical difficulty during endoscopic full-thickness resection of a gastric submucosal tumor.

BACKGROUND AND AIM: endoscopic full-thickness resection (EFTR) is widely accepted for the treatment of gastric submucosal tumors (SMTs). However, technical difficulties sometimes occur. The aim of the present study was to assess the safety and efficacy of EFTR for gastric SMTs and to explore risk factors for technical difficulty. METHODS: the clinical data of patients who received EFTR for gastric SMTs was retrospectively collected from April 2011 to September 2019. Efficacy was defined as an en bloc resection. Difficult EFTR was defined as a procedure time ≥ 120 minutes and/or the occurrence of major adverse events, such as major bleeding, abdominal pain or peritonitis. Finally, risk factors for technical difficulty of EFTR such as gender, age, tumor location, size, symptomatic, regular, outgrowth, operator experience and pathology were analyzed in a univariate and multivariate analysis. RESULTS: one hundred SMTs were removed by EFTR. The average surgery time was 75.73 ± 45.9 (range: 20-250) minutes and the average tumor size was 16.23 ± 7.73 (range: 6-40) mm. With regard to efficacy, en bloc resection was achieved in 98 cases (98 %). A total of ten patients (9.9 %) had complications, namely two intra-operative bleeding, one delayed bleeding and seven patients had abdominal pain (overt peritonitis). EFTR was ceased in one patient due to massive intra-operative bleeding and conversion to laparoscopic surgery was necessary. One patient required laparoscopic surgery due to delayed bleeding, and other complications were resolved with a conservative treatment. A total of 18 cases (17.8 %) encountered a difficult EFTR: tumor size ≥ 3 cm (p = 0.008) and location at the gastric corpus (p = 0.007) were risk factors for a difficult EFTR according to the logistic analysis. CONCLUSION: EFTR is safe and effective for the treatment of gastric SMTs. Tumor size of ≥ 3 cm and location at the gastric corpus are risk factors for a difficult EFTR.

Simultaneous peroral endoscopic myotomy and submucosal tunneling endoscopic resection for coexisting achalasia and a submucosal tumor.

Co-existence of achalasia and SMT is rare. Herein, we presented a case with coexisted achalasia and submucosal tumor, who treated with simultaneous peroral endoscopic myotomy and submucosal endoscopic tunneling resection in the same tunnel.

Gastric per-oral endoscopic myotomy (G-POEM) is a promising treatment for refractory gastroparesis: a systematic review and meta-analysis.

AIM: to evaluate the efficacy and safety of gastric per-oral endoscopic myotomy (G-POEM) for the treatment of refractory gastroparesis. METHODS: PubMed, Embase and Cochrane databases were searched and used for study inclusion. Clinical studies since January 2013 to October 2019 were identified as suitable for inclusion. Conference papers, review articles, case reports, animal studies, letters, studies with repetitive data, studies that did not mention the Gastroparesis Cardinal Symptom Index (GCSI) score/gastric emptying scintigraphy (GES) hours or were not indicated in the standard form were excluded. GCSI score, GCSI reduction, gastric emptying scintigraphy at four hours (GES-4h) and GES time (GET) reduction were considered as major indexes and the meta-analysis was achieved using Review Manager 5.3. Research bias was measured according to Cochrane handbook. RESULTS: nine studies were included with a total of 235 patients that underwent G-POEM, and the technical success rate was 100%. After G-POEM, patients reported changes in GCSI score (6/9 studies, mean difference 1.41 [CI: 0.93, 1.88], p < 0.0001), GCSI reduction (8/9 studies, odds ratio 3.00 [CI: 2.24, 4.03], p < 0.0001), GES-4h (8/9 studies, mean difference 23.78 [CI: 19.88, 27.68], p < 0.00001) and GET reduction (6/9 studies, odds ratio 3.50 [CI: 2.12, 5.78], p < 0.00001). The intra-procedure complication rate was 5.1% (12/235), including capnoperitoneum (seven cases) and accidental mucotomy (five cases). The post-procedure complication rate was 6.8% (16/235), including abdominal pain (three cases), bleeding (three cases), ulcer (one case), difficulty swallowing (one case) and others (eight cases). Both per- and post-procedure complications were easily managed by conservative or endoscopic treatments. CONCLUSION: the results show that gastroparesis patients can benefit from G-POEM, the success rate was impressive and the complication rate was relatively low. However, caution is necessary when interpreting the results, primarily due to the limitations of uncontrolled studies. Randomized control studies are still needed for further evaluations.

Single tunnel-assisted endoscopic submucosal dissection for a 13-cm giant colorectal laterally spreading tumor.

We report the case of a 60-year-old male with a giant colorectal laterally spreading tumor at the recto-sigmoid junction. A single tunnel-assisted endoscopic submucosal dissection was performed that constructed a submucosal tunnel along the longitude axis of the tumor. An en bloc resection was achieved with no perforation or post-operative bleeding and a comparatively low procedure time.