Photoactivatable Immunostimulatory Nanomedicine for Immunometabolic Cancer Therapy.

A rationally designed immunostimulant (CC@SiO2-PLG) with a photoactivatable immunotherapeutic function for synergetic tumor therapy is reported. This CC@SiO2-PLG nanoplatform comprises catalase and a photosensitizer (Ce6) co-encapsulated in a silica capsule, to which an immunostimulant is conjugated through a reactive oxygen species-cleavable linker. After accumulating in tumor tissue, CC@SiO2-PLG generates O2 to relieve tumor hypoxia and promotes the production of singlet oxygen (1O2) upon laser irradiation, resulting in not only tumor destruction but also the release of tumor-associated antigens (TAAs). Simultaneously, the linker breakage by the photoproduced 1O2 leads to the remote-controlled release of conjugated indoleamine 2,3-dioxygenase (IDO) inhibitor from CC@SiO2-PLG and consequent immunosuppressive tumor microenvironment reversion. The released TAAs in conjunction with the inhibition of the IDO-mediated tryptophan/kynurenine metabolic pathway induced a boosted antitumor immune response to the CC@SiO2-PLG-mediated phototherapy. Therefore, the growth of primary/distant tumors and lung metastases in a mouse xenograft model was greatly inhibited, which was not achievable by phototherapy alone.

Success and Safety of Needle Knife Papillotomy and Fistulotomy Based on Papillary Anatomy: A Prospective Controlled Trial.

BACKGROUND: Needle knife papillotomy (NKP) and fistulotomy (NKF) are the two most commonly used rescue techniques for patients with difficult biliary cannulation (DBC). Anatomy of the major duodenal papillae (MDP) influences the optimal precut technique for biliary access. However, comparative studies of the success and safety of NKP and NKF based on the anatomy of MDP have been scarce. METHODS: Patients with intact MDPs for therapeutic endoscopic retrograde cholangio-pancreatography (ERCP) in our center were enrolled. Early needle knife precuts were uniformly applied to patients with DBC. Difficult MDPs were classified into one of five types based on their endoscopic anatomy. Each type of MDP was allocated to NKP or NKF treatment. Patients with types 1 and 2 papillae always received NKF, 3 and 4 received NKP, and 5 could receive either. The safety and efficacy were analyzed between NKP and NKF, and among different types of MDPs. RESULTS: A total of 188 out of 1674 patients undergoing ERCP satisfied the criteria for early precutting: 75 patients were assigned to the NKP group and 113 to the NKF group. The total initial success rate of biliary cannulation (ISRBC) of the precut techniques (both NKP and NKF) for patients with DBC was 91.5%. The ISRBC of patients of the NKP group was similar to that of the NKF group (90.7% vs 92.0%, P > 0.05). The ISRBC of the patients in the swollen MDP subgroup (96.1%) was higher than that of patients in the distorted MDP subgroup (81.8%, P = 0.030). The total and specific complications of the patients of the NKP group were similar to those of the NKF group (P > 0.05). CONCLUSIONS: NKP and NKF, as selected on the basis of MDP anatomy, are equally safe and highly efficient for patients with DBC to allow biliary cannulation. Patients with swollen MDPs had a higher ISRBC than patients with distorted MDPs. Selecting a precut method based on MDP anatomy is an effective and safe strategy for patients with DBC.

Clear colonoscopy as a surveillance tool in the prediction and reduction of advanced neoplasms: a randomized controlled trial.

BACKGROUND: Missed and incompletely resected lesions remain the main cause of the recurrence of advanced neoplasms (ANs) in post-polypectomy patients. This study aims to determine whether the recurrence of ANs can be predicted and reduced by the newly developed clear colonoscopy procedure. METHODS: Between 2006 and 2010, a total of 1350 participants with colorectal neoplasm were equally randomized to clear colonoscopy surveillance (CCS) and routine colonoscopy surveillance (RCS) in our center. Clear colonoscopy was achieved through repeat colonoscopy. On surveillance colonoscopy at 3 (for high-risk patients) and 5 (for low-risk patients) years, the recurrence of ANs and the relationship between the frequency of repeat examinations required for a clear colonoscopy and the recurrence of ANs were analyzed. RESULTS: Surveillance colonoscopy at 3 and 5 years showed that the incidence of ANs in patients belonging to the CCS group was 1.7%, which was lower than 4.7% in patients belonging to the RCS group (P = 0.012) for both high- and low-risk patients. Out of the 1126 patients who achieved clear colonoscopy on first repeat examination, only 5 ( 0.4%) were found to have ANs on surveillance examination, whereas 12 out of the 217 (5.4%) patients on second repeat examination and 5 out of the 29 (17.2%) patients on third repeat examination were found to have ANs (P < 0.001). CONCLUSION: Surveillance based on clear colonoscopy decreased the incidence of ANs in post-polypectomy patients. The number of repeat examinations required for a clear colonoscopy is an important factor in the prediction of the recurrence of ANs.

Polypectomy for complete endoscopic resection of small colorectal polyps.

BACKGROUND AND AIMS: Small colorectal polyps are encountered frequently and may be incompletely removed during colonoscopy. The optimal technique for removal of small colorectal polyps is uncertain. The aim of this study was to compare the incomplete resection rate (IRR) by using EMR or cold snare polypectomy (CSP) for the removal of small adenomatous polyps. METHODS: This was a prospective randomized controlled study from a tertiary-care referral center. A total of 358 patients who satisfied the inclusion criteria (polyp sized 6-9 mm) were randomized to the EMR (n =179) and CSP (n =179) groups, and their polyps were treated with conventional EMR or CSP, respectively. After polypectomy, an additional 5 forceps biopsies were performed at the base and margins of polypectomy sites to assess the presence of residual polyp tissue. The EMR and CSP samples were compared to assess the IRR. RESULTS: Among a total of 525 polyps, 415 (79.0%) were adenomatous polyps, and 41 (16.4%) were advanced adenomas. The overall IRR for adenomatous polyps was significantly higher in the CSP group compared with the EMR group (18/212, 8.5% vs 3/203, 1.5%; P = .001). Logistic regression analysis revealed that the CSP procedure was a stronger risk factor for the IRR (odds ratio [OR] 6.924; 95% confidence interval [CI], 2.098-24.393; P = .003). In addition, piecemeal resection was the most important risk factor for the IRR (OR 28.696; 95% CI, 3.620-227.497; P = .001). The mean procedure time for polypectomy was not significantly different between the EMR and CSP groups (5.5 ± 2.7 vs 4.7 ± 3.4 minutes; P = .410). None of these patients presented with delayed bleeding. There were no severe adverse events related to the biopsies. CONCLUSIONS: EMR was significantly superior to CSP for achieving complete endoscopic resection of small colorectal polyps. Patients with piecemeal resection of polyps had a higher risk for incomplete resection. (Clinical trial registration number: Hongwei-1102-12.).

Needle-knife papillotomy and fistulotomy improved the treatment outcome of patients with difficult biliary cannulation.

BACKGROUND AND AIMS: Needle-knife papillotomy and fistulotomy (NKPF) is a new, modified technique designed for difficult biliary cannulation. The safety and efficacy of performing NKPF based on characteristics of main duodenal papilla (MDP) was evaluated. METHODS: We performed a retrospective review of consecutive patients with intact papilla who were established as candidates for therapeutic ERCP at tertiary referral center. A total of 532 patients were included in conventional endoscopic retrograde cholangiopancreatography (ERCP) group in which repeated cannulation was tried in patients with difficult bile duct cannulation; and 598 patients enrolled in early NKPF group according to predefined parameters. Based on the characteristics of MDP, different types of NKPF were performed. The endoscopic data (mean procedure time, anatomy of the main papilla), rate of cannulation success, and post-ERCP complications were collected. RESULTS: A total of 82 patients underwent NKPF. The mean procedure time of the small papilla group was longer than bulging papilla group (P < 0.05). The success rate of biliary cannulation in the small papilla group (69.3 %) was lower than in the bulging papilla group (100 %, P < 0.01). The overall successful biliary cannulation of patients in the NKPF group was significantly higher than in the conventional group (98.8 vs 90.8 %, P > 0.05). The total complication rate was 6.6 % among conventional group patients and 5.7 % among NKPF group, respectively. The overall complication rate and rates of specific complications (pancreatitis, bleeding, cholangitis, and perforation) in the two groups were similar (P > 0.05). CONCLUSION: Early NKPF based on characteristics of MDP raised the success rate of biliary cannulation when conventional cannulation failed and did not increase the complication rate post-ERCP. Clinic Trials. gov number, Hongwei-1102-12.

Clip closure of defect after endoscopic resection in patients with larger colorectal tumors decreased the adverse events.

BACKGROUND: Clip closure of large colorectal mucosal defects may reduce the rate of adverse events in a cost-effective manner. OBJECTIVE: To assess the adverse events and outcomes of clip closure of defects after endoscopic resection in patients with large colorectal tumors. DESIGN: Prospective, randomized, controlled study. SETTING: Single tertiary referral center. PATIENTS AND INTERVENTIONS: Patients with lesions measuring 1 to 4 cm who were scheduled for endoscopic resection between March 2012 and December 2014 were randomly assigned to a clip-closure group and a no-closure group. In the clip-closure group, the defect of the resection site was completely closed with an endoclip. In the no-closure group, the defect was left open. The following primary outcome measures were assessed: delayed postoperative bleeding, postpolypectomy coagulation syndrome, perforation, and abdominal pain. Secondary outcome measures of length of hospital stay, time required for procedure, and patient's satisfaction were also assessed. RESULTS: Patients and lesions had similar characteristics across both groups. For patients who underwent clip closure (n = 174), the rates of delayed postoperative bleeding (1.1% [2/174]) and postpolypectomy coagulation syndrome (0.6% [1/174]) were lower than those in the no-closure group (6.9% [12/174], P = .01 and 4.6% [8/174], P = .03). Two patients experienced perforation, 1 in each group. In the clip-closure group, 4 patients reported abdominal pain as opposed to 26 in the no-closure group (2.8% vs 16.7%, P < .01). The procedure took longer in the closure group (38.1 minutes vs 30.9 minutes, P = .04). The length of hospitalization was shorter in the closure group (3.1 days vs 4.7 days, P = .03). Total medical expense was similar between the 2 groups. Patients who underwent closure reported greater satisfaction. LIMITATION: This was a single-center analysis. CONCLUSIONS: Clip closure of endoscopic resection defects in patients with large colorectal tumors decreased the rate of procedure-related adverse events and did not increase the cost of hospitalization.

Biomimetic inducer enabled dual ferroptosis of tumor and M2-type macrophages for enhanced tumor immunotherapy.

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment which promotes the formation of the immunosuppressive tumor microenvironment (ITME) through multiple mechanisms, severely counteracting the therapeutic efficacy of immunotherapy. In this study, a novel biomimetic ferroptosis inducer (D@FMN-M) capable of ITME regulation for enhanced cancer ferroptosis immunotherapy is reported. Upon tumor accumulation of D@FMN-M, the intratumoral mild acidity triggers the biodegradation of Fe-enriched nanocarriers and the concurrent co-releases of dihydroartemisinin (DHA) and Fe3+. The released Fe3+ is reduced to Fe2+ by consuming intratumoral glutathione (GSH), which promotes abundant free radical generation via triggering Fenton and Fe2+-DHA reactions, thus inducing ferroptosis of both cancer cells and M2-type TAMs. Resultantly, the anticancer immune response is strongly activated by the massive tumor-associated antigens released by ferroptositic cancer cells. Also importantly, the ferroptosis-sensitive M2-type TAMs will be either damaged or gradually domesticated to ferroptosis-resistant M1 TAMs under the ferroptosis stress, favoring the normalization of ITME and finally amplifying cancer ferroptosis immunotherapeutic efficacy. This work provides a novel strategy for ferroptosis immunotherapy of solid tumors featuring TAMs infiltration and immunosuppression by inducing dual ferroptosis of tumor cells and M2-type TAMs.

Bacterial Metabolism-Initiated Nanocatalytic Tumor Immunotherapy.

The low immunogenicity of tumors remains one of the major limitations of cancer immunotherapy. Herein, we report a bacterial metabolism-initiated and photothermal-enhanced nanocatalytic therapy strategy to completely eradicate primary tumor by triggering highly effective antitumor immune responses. Briefly, a microbiotic nanomedicine, designated as Cu2O@ΔSt, has been constructed by conjugating PEGylated Cu2O nanoparticles on the surface of an engineered Salmonella typhimurium strain (ΔSt). Owing to the natural hypoxia tropism of ΔSt, Cu2O@ΔSt could selectively colonize hypoxic solid tumors, thus minimizing the adverse effects of the bacteria on normal tissues. Upon bacterial metabolism within the tumor, Cu2O@ΔSt generates H2S gas and other acidic substances in the tumor microenvironment (TME), which will in situ trigger the sulfidation of Cu2O to form CuS facilitating tumor-specific photothermal therapy (PTT) under local NIR laser irradiation on the one hand. Meanwhile, the dissolved Cu+ ions from Cu2O into the acidified TME enables the nanocatalytic tumor therapy by catalyzing the Fenton-like reaction of decomposing endogenous H2O2 into cytotoxic hydroxyl radicals (·OH) on the other hand. Such a bacterial metabolism-triggered PTT-enhanced nanocatalytic treatment could effectively destroy tumor cells and induce a massive release of tumor antigens and damage-associated molecular patterns, thereby sensitizing tumors to checkpoint blockade (ICB) therapy. The combined nanocatalytic and ICB therapy results in the much-inhibited growth of distant and metastatic tumors, and more importantly, induces a powerful immunological memory effect after the primary tumor ablation.

Clip-assisted endoloop ligation of the mucosal defect after resection of colorectal polyps decreased postprocedural delayed bleeding.

Background: Postprocedural delayed bleeding (PDB) remains the most common major complication of colorectal polypectomy. Incomplete clip closure of mucosal defect and unclosed injured blood vessels in gaps between clips may be the risk factors for PDB. Objectives: To observe whether completely no-gap closure of mucosal defect after polypectomy can reduce PDB occurrence. Design: Single-center, retrospective case-control study. Methods: In this study based on historical comparisons of patients in 2 time periods, only the patients with polyps sized between 6 and 15 mm were included. A new clip-assisted endoloop ligation (CAEL, treatment group) method was used between January 2019 and December 2020, and a traditional simple clip closure (SCC, control) was used Between January 2017 and December 2018 to prevent PDB after polypectomy. The rate of PDB of two groups and risk factors for PDB were evaluated. Results: Totally 4560 patients were included in the study; 2418 patients belong to CAEL group, and 2142 patients belong to SCC group. The overall rate of PDB was significantly lower in CAEL group compared to SCC group (0.6% versus 1.5%, p < 0.00). On multivariate logistic analysis, CAEL was a significant independent preventive factor for PDB (odds ratio (OR), 0.092; 95% confidence interval (CI), 0.029-0.3335; p = 0.000). Polyps located at rectum (colon versus rectum) represented a significant independent risk factor for PDB (OR, 11.888; 95% CI, 3.343-42.269; p = 0.001). Conclusion: Completely no-gap closure of mucosal defect after polypectomy further reduced the rate of PDB for polyps sized between 6 and 15 mm. CAEL may be a significant independent preventive factor for PDB. Polyps located at the rectum may be a significant independent risk factor for PDB.

Paneth cell ablation increases the small intestinal injury during acute necrotizing pancreatitis in rats.

The present work aimed to investigate the role of Paneth cells in small intestinal injury during acute necrotizing pancreatitis (ANP) using rat models established by injection of dithizone, a metal chelator of zinc with the ability to selectively ablate Paneth cells. Sprague­Dawley rats were randomly divided into four groups: Sham­operated group, ANP group (3.5% sodium taurocholate solution, 1 ml/kg body weight), dithizone group (100 mg/kg of body weight) and ANP + dithizone group (sodium taurocholate solution was administered 6 h after dithizone injection). Each group was further divided into five subgroups (6, 12, 24, 36 and 48 h) based on the time period between induction of the model and sample collection. The present results suggested the number of Paneth cells was gradually decreased in the ANP group in a time­dependent manner. Most of the Paneth cells were ablated in the ANP + dithizone group at 6 h, but a subset of Paneth cells recovered after 24­48 h. Compared with the ANP group, combination of dithizone and ANP significantly induced more severe histopathological injuries in the pancreas and distal ileum, with higher Schmidt and Chiu's scores, respectively. Additionally, increased expression levels of tumor necrosis factor­α (TNF­α), interleukin (IL)­1ß and IL­17A were detected in the ileum, causing an increase in intestinal permeability, as assessed by a decrease in the expression level of the intestinal tight junction protein occludin and high plasma levels of diamine oxidase and D­lactate. The increase in intestinal permeability led to the translocation of bacteria to the bloodstream, triggering systemic inflammation, as assessed by the increased plasma levels of TNF­α, IL­1ß and IL­17A, reducing the survival rates of rats, which was 66.7% and 83.3% in the ANP + dithizone and the ANP group, respectively. The increase in intestinal endoplasmic reticulum stress, as assessed by high expression levels of binding­immunoglobulin protein and activating transcription factor 6, may be one mechanism associated with Paneth cells loss and intestinal barrier impairment during ANP. Collectively, the present study suggested that the absence of Paneth cells may be an important factor involved in intestinal injury, promoting the progression of ANP.

Antimicrobial prophylaxis in patients with colorectal lesions undergoing endoscopic resection.

AIM: To investigate the effect of prophylaxis with antibiotics on clinical adverse events in patients who underwent endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR) for colorectal lesions. METHODS: From June 2011 to December 2013, a total of 428 patients were enrolled into the study, of which 214 patients admitted to hospital underwent EMR or ESD procedures. These patients were randomized to an antibiotic group, in which patients were given cefuroxime 1.5 g iv half an hour before and 6 h after surgery respectively, and a control group, in which patients were not given any antibiotic. A further 214 outpatients with small polyps treated by polypectomy were compared with controls that were matched by age and gender, and operations were performed as outpatient surgery. Recorded patient parameters were demographics, characteristics of lesions and treatment modality, and the size of the wound area. The primary outcome measures were clinical adverse events, including abdominal pain, diarrhea, hemotachezia, and fever. Secondary outcome measures were white blood cell count, C-reactive protein and blood culture. Additionlly, the relationship between the size of the wound area and clinical adverse events was analyzed. RESULTS: A total of 409 patients were enrolled in this study, with 107 patients in the control group, 107 patients in the antibiotic group, and another 195 cases in the follow-up outpatient group. The patients' demographic characteristics, including age, gender, characteristics of lesions, treatment modality, and the size of the wound area were similar between the 2 groups. The rates of adverse events in the antibiotic group were significantly lower than in the control group: abdominal pain (2.8% vs 14.9%, P < 0.01), diarrhea (2.0% vs 9.3%, P < 0.05), and fever (0.9% vs 8.4%, P < 0.05) respectively. The levels of inflammatory markers also decreased significantly in the antibiotic group compared with the control group: leukocytosis (2.0% vs 11.2%, P < 0.01), and C-reactive protein (2.0% vs 10.7%, P < 0.05). Additionally, clinical adverse events were related to the size of the surgical wound area. When the surgical wound area was larger than 10 mm × 10 mm, there were more clinical adverse events. CONCLUSION: Clinical adverse events are not uncommon after EMR or ESD procedures. Prophylactic antibiotics can reduce the incidence of clinical adverse events. This should be further explored.