Effects of prior endoscopic resection on recurrence in patients with T1 colorectal cancer who underwent radical surgery.

PURPOSE: Endoscopic resection (ER) is a reliable treatment for early colorectal cancer without lymph node metastasis. We aimed to examine the effects of ER performed prior to T1 colorectal cancer (T1 CRC) surgery by comparing long-term survival after radical surgery with prior ER to that after radical surgery alone. METHODS: This retrospective study included patients who underwent surgical resection of T1 CRC at the National Cancer Center, Korea, between 2003 and 2017. All eligible patients (n = 543) were divided into primary and secondary surgery groups. To ensure similar characteristics between the groups, 1:1 propensity score matching was used. Baseline characteristics, gross and histological features, along with postoperative recurrence-free survival (RFS) between the two groups were compared. Cox proportional hazard model was used to identify the risk factors affecting recurrence after surgery. Cost analysis was performed to examine the cost-effectiveness of ER and radical surgeries. RESULTS: No significant differences were observed in 5-year RFS between the two groups in matched data (96.9% vs. 95.5%, p = 0.596) and in the unadjusted model (97.2% vs. 96.8%, p = 0.930). This difference was also similar in subgroup analyses based on node status and high-risk histologic features. ER before surgery did not increase the medical costs of radical surgery. CONCLUSION: ER prior to radical surgery did not affect the long-term oncologic outcomes of T1 CRC or significantly increased the medical costs. Attempting ER first for suspected T1 CRC would be a good strategy to avoid unnecessary surgery without concerns of worsening cancer-related prognosis.

Subpopulation analysis of survival in high-risk T1 colorectal cancer: surgery versus endoscopic resection only.

BACKGROUND AND AIMS: This study aimed to assess the long-term survival of patients with T1 colorectal cancer (CRC) after local or surgical resection considering the type and number of risk factors for lymph node metastasis. METHODS: This study included patients with high-risk T1 CRC who underwent therapeutic resection at the National Cancer Center, Korea between January 2001 and December 2014. Risk factors included positive resection margin, high-grade histology, deep submucosal invasion, vascular invasion, budding, and no background adenoma (BGA). We statistically divided the population into favorable or unfavorable subpopulations. The favorable subpopulation included the following 5 combinations of risk factors: positive margin only or unconditional for margin status, deep submucosal invasion only, budding only, no BGA only, and budding + no BGA. We analyzed the survival rate according to the resection type (local or surgical) in the total cohort and in each subpopulation. RESULTS: Eighty-one and 466 patients underwent local and surgical resections, respectively. The distant recurrence-free survival (DRFS) and overall survival (OS) rates were significantly high in the surgical group (hazard ratio [HR], .20; 95% confidence interval [CI], .06-.61; P = .0045 and HR, .41; 95% CI, .25-.70; P = .0010, respectively). In the favorable subpopulation, both DRFS and OS rates were not significantly different between the surgical and local groups (HR, .26; 95% CI, .02-4.19; P = .3431 and HR, .58; 95% CI, .27-1.23; P = .1534, respectively). CONCLUSIONS: Intensive surveillance without additional surgery may be another option in selected cases after of high-risk T1 CRC endoscopic resection.

Factors associated with diet failure after colon cancer surgery.

BACKGROUND: Since the introduction of Enhanced Recovery After Surgery (ERAS), early diet after surgery has been emphasized and clinical outcomes have improved, though vomiting has been reported frequently. We defined diet failure based on clinical manifestation and images after colon cancer surgery and attempted to analyze underlying risk factors by comparing the early diet group with the conventional diet group. METHODS: All consecutive patients underwent colectomy with curative intent at a single institution between August 2015 and July 2017. The early diet group was started on soft diet on the second day after surgery, while the conventional group started the same after flatulence. The primary outcome was the difference in the incidence of diet failure between the two groups. Secondary outcomes were analyzed to determine risk factors for diet failure and readmission due to ileus. RESULTS: Overall, 293 patients were included in the conventional diet group and 231 in the early diet group. There were no significant differences between the two groups, except for shorter hospital stays in the early diet group (median 8 days, p < 0.001). A total of 46 patients (early diet, n = 20; conventional diet, n = 26, p = 1.000) had diet failure. Multivariate analysis showed that operation time (odds ratio [OR] 1.76, 95% confidence interval [CI] 1.33-2.32) and side-to-side anastomosis compared with the end-to-end method (OR 4.41, 95% CI 2.10-9.24) were independent risk factors for diet failure. Sixteen patients were readmitted due to ileus that occurred within 2 months after surgical operation. Diet resumption time was not a risk factor for both diet failure and ileus. CONCLUSIONS: Early diet resumption does not increase diet failure and can reduce hospital stay. Anastomosis and operation time may be related to diet failure. Our study suggests that evaluation of surgical factors is important for postoperative recovery, and well-designed follow-up studies are needed.

Glycine induces enhancement of bactericidal activity of neutrophils.

Severe bacterial infections are frequently accompanied by depressed neutrophil functions. Thus, agents that increase the microbicidal activity of neutrophils could add to a direct antimicrobial therapy. Lysophosphatidylcholine augments neutrophil bactericidal activity via the glycine (Gly)/glycine receptor (GlyR) α2/TRPM2/p38 mitogen-activated protein kinase (MAPK) pathway. However, the direct effect of glycine on neutrophil bactericidal activity was not reported. In this study, the effect of glycine on neutrophil bactericidal activity was examined. Glycine augmented bactericidal activity of human neutrophils (EC50 = 238 µM) in a strychnine (a GlyR antagonist)-sensitive manner. Glycine augmented bacterial clearance in mice, which was also blocked by strychnine (0.4 mg/kg, s.c.). Glycine enhanced NADPH oxidase-mediated reactive oxygen species (ROS) production and TRPM2-mediated [Ca2+]i increase in neutrophils that had taken up E. coli . Glycine augmented Lucifer yellow uptake (fluid-phase pinocytosis) and azurophil granule-phagosome fusion in neutrophils that had taken up E. coli in an SB203580 (a p38 MAPK inhibitor)-sensitive manner. These findings indicate that glycine augments neutrophil microbicidal activity by enhancing azurophil granule-phagosome fusion via the GlyRα2/ROS/calcium/p38 MAPK pathway. We suggest that glycine could be a useful agent for increasing neutrophil bacterial clearance.

Comparison of endoscopic submucosal dissection and transanal endoscopic microsurgery for T1 rectal neuroendocrine tumors: a propensity score-matched study.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) and transanal endoscopic microsurgery (TEM) are the most effective endoscopic resection methods for T1 rectal neuroendocrine tumors (NETs). We aimed to compare the efficacy and safety of ESD and TEM for rectal NETs ≤20 mm. METHODS: Patients with rectal NETs ≤20 mm who underwent ESD or TEM were enrolled in this retrospective observational study. ESD and TEM groups were matched for pathologic tumor size and EMR history. We evaluated between-group differences in R0 resection rate, adverse event rate, procedure time, and hospital stay. RESULTS: We included 285 patients (ESD = 226, TEM = 59) in the final cohort, with 104 patients in the matched groups (ESD = 52, TEM = 52). The R0 resection rate was significantly higher for TEM (ESD 71.2% vs TEM 92.3%, P = .005). However, the median procedure time (ESD 22 [range, 11-65] vs TEM 35 [17-160] minutes, P < .001) and hospital stay (ESD 2.5 range 1-5] vs TEM 4 [3-8] days, P < .001) were significantly shorter for ESD. In the subgroup analysis of patients divided by tumor size <10 mm (ESD = 218, TEM = 49) and 10 to 20 mm (ESD = 8, TEM = 10)], there was no significant between-group difference in the R0 resection rate (83.5% vs 93.9%, P = .063 and 37.5% vs 80%, P = .145, respectively) or the rate of recurrence. CONCLUSIONS: Although TEM showed a better overall R0 resection rate for rectal NETs ≤20 mm, ESD could be a viable treatment modality concerning adverse events, procedure time, and hospital stay for rectal NETs <10 mm with similar R0 resection rates in comparison with TEM.

G2A Protects Mice against Sepsis by Modulating Kupffer Cell Activation: Cooperativity with Adenosine Receptor 2b.

G2A is a GPCR abundantly expressed in immune cells. G2A-/- mice showed higher lethality, higher plasma cytokines, and an impaired bacterial clearance in response to a murine model of sepsis (cecal ligation and puncture), which were blocked by GdCl3, an inhibitor of Kupffer cells. Anti-IL-10 Ab reversed the impaired bacterial clearance in G2A-/- mice. Indomethacin effectively blocked both the increased i.p. IL-10 levels and the impaired bacterial clearance, indicating that disturbed PG system is the proximal cause of these phenomena. Stimulation with LPS/C5a induced an increase in Escherichia coli phagocytosis and intracellular cAMP levels in G2A+/+ peritoneal macrophages but not G2A-/- cells, which showed more PGE2/nitrite release and intracellular reactive oxygen species levels. Heterologous coexpression of G2A and adenosine receptor type 2b (A2bAR) induced a synergistic increase in cAMP signaling in a ligand-independent manner, with the evidence of physical interaction of G2A with A2bAR. BAY 60-6583, a specific agonist for A2bAR, increased intracellular cAMP levels in Kupffer cells from G2A+/+ but not from G2A-/- mice. Both G2A and A2bAR were required for antiseptic action of lysophosphatidylcholine. These results show inappropriate activation of G2A-/- Kupffer cells to septic insults due to an impaired cAMP signaling possibly by lack of interaction with A2bAR.

Transcriptional regulation of Salmochelin glucosyltransferase by Fur in Salmonella.

Pathogenic bacteria acquire the acquisition of iron from the host to ensure their survival. Salmonella spp. utilizes siderophores, including salmochelin, for high affinity aggressive import of iron. Although the iroBCDEN operon is reportedly responsible for the production and the transport of salmochelin, the molecular mechanisms underlying the regulation of its gene expression have not yet been characterized. Here, we analyzed the expression pattern of iroB using the lacZY transcriptional reporter system and determined the transcription start site in response to iron availability using primer extension analysis. We further examined the regulation of iroB expression by the ferric uptake regulator (Fur), a key regulatory protein involved in the maintenance of iron homeostasis in various bacteria, including Salmonella. Using sequence analysis followed by a gel shift assay, we verified that the Fur box lies within the promoter region of iroBCDE. The Fur box contained the consensus sequence (GATATTGGTAATTATTATC) and overlapped with the -10-element region. The expression of iroB was repressed by Fur in the presence of iron, as determined using an in vitro transcription assay. Therefore, we found that the iron acquisition system is regulated in a Fur-dependent manner in Salmonella.

Comparison of underwater endoscopic mucosal resection and endoscopic submucosal dissection of rectal neuroendocrine tumors (with videos).

BACKGROUND AND AIMS: The first choice of treatment for rectal neuroendocrine tumors (NETs) ≤10 mm in size is endoscopic resection. However, because rectal NETs usually invade the submucosal layer, achieving R0 resection is difficult. Endoscopic submucosal dissection (ESD) has a high R0 resection rate, and underwater endoscopic mucosal resection (UEMR) was recently introduced to ensure a negative resection margin easily and safely. The aim of this study was to evaluate the efficacy and safety of UEMR versus ESD for rectal NETs ≤10 mm in size. METHODS: This retrospective observational study enrolled 115 patients with rectal NETs ≤10 mm in size who underwent ESD or UEMR between January 2015 and July 2019 at the National Cancer Center, Korea. The differences in R0 resection rate, adverse event rate, and procedure time between the ESD and UEMR groups were evaluated. RESULTS: Of the 115 patients, 36 underwent UEMR and 79 underwent ESD. The R0 resection rate was not different between the UEMR and ESD groups (UEMR vs ESD, 86.1% vs 86.1%, P = .996). The procedure time was significantly shorter with UEMR (UEMR vs ESD, 5.8 ± 2.9 vs 26.6 ±13.4 minutes, P < .001). Two patients (2.5%, 2/79) experienced adverse events in the ESD group and but there were no adverse events in the UEMR group; however, this difference was not statistically significant. CONCLUSION: UEMR is a safe and effective technique that should be considered when removing small rectal NETs. Further studies are warranted to define its role compared with ESD.

Analysis of metachronous colorectal neoplasms and survival following segmental or extended resection in patients with hereditary non-polyposis colorectal cancer.

PURPOSE: The high incidence of metachronous colorectal tumours in patients with hereditary non-polyposis colorectal cancer (HNPCC) encourages extended resection (ER); however, the optimal surgical approach remains unclear. We evaluated the incidences of metachronous colorectal neoplasms following curative colorectal cancer segmental resection (SR) vs ER in patients with HNPCC and investigated patients' oncologic outcomes according to surgical modality and mismatch repair status. METHODS: We retrospectively investigated medical records of patients with HNPCC (per the Amsterdam II criteria) treated for primary colon cancer at our institution between 2001 and 2017. All patients underwent intensive endoscopic surveillance. RESULTS: We included 87 patients (36 who underwent SR and 51 who underwent ER). The cumulative incidence of metachronous adenoma was higher in the SR group. One patient in the SR group (2.8%) and 3 in the ER group (5.9%) developed metachronous colon cancer; the difference was not significant (P = 0.693). Four patients in the SR group (11.1%) and 1 in the ER group (2.0%) developed distant recurrences; again, the difference was not significant (P = 0.155). Moreover, no significant differences were observed in the 5-year overall survival rates of patients in the SR and ER groups (88.2% vs 95.5%, P = 0.446); the same was true for 5-year disease-free survival rates (79.5% vs 91.0%, P = 0.147). CONCLUSION: The incidence of metachronous cancer was not significantly different between the ER and SR groups; however, that of cumulative metachronous adenoma was higher in the SR group. Hence, intensive surveillance colonoscopy may be sufficient for patients with HNPCC after non-extensive colon resection.

Autophagy in neutrophils.

Autophagy is a highly conserved intracellular degradation and energy-recycling mechanism that contributes to the maintenance of cellular homeostasis. Extensive researches over the past decades have defined the role of autophagy innate immune cells. In this review, we describe the current state of knowledge regarding the role of autophagy in neutrophil biology and a picture of molecular mechanism underlying autophagy in neutrophils. Neutrophils are professional phagocytes that comprise the first line of defense against pathogen. Autophagy machineries are highly conserved in neutrophils. Autophagy is not only involved in generalized function of neutrophils such as differentiation in bone marrow but also plays crucial role effector functions of neutrophils such as granule formation, degranulation, neutrophil extracellular traps release, cytokine production, bactericidal activity and controlling inflammation. This review outlines the current understanding of autophagy in neutrophils and provides insight towards identification of novel therapeutics targeting autophagy in neutrophils.

Preoperative endoscopic clipping for rectal tumor localization in laparoscopic anterior resection.

Background: Increasing the number of rectal tumors undergoing preoperative chemoradiotherapy or endoscopic resection has increased the importance of accurate tumor localization. This study describes the preoperative endoscopic clipping method for the localization of rectal tumors and evaluated the feasibility of this technique.Material and methods: A total of 109 patients underwent preoperative endoscopic clipping to localize non-palpable rectal adenocarcinomas, which were located within 10 cm from the anal verge. Two endoscopic clips were attached to both lateral sides of the tumor's distal edge. For confirming the distal margin of tumors during surgery, attempts were made to palpate the clips by digital rectal examination.Results: In all 109 cases, endoscopic clips applied to targeted rectal lesions were easily palpable in the operating room. None of the tumors showed involvement at the distal resection margins (median 1.5 cm) in histopathology.Conclusion: Preoperative endoscopic clipping methods can be useful for localizing non-palpable rectal tumors.

Risk of recurrence after endoscopic resection of early colorectal cancer with positive margins.

BACKGROUND AND STUDY AIM: Additional surgery is recommended if an endoscopically resected T1 colorectal cancer (CRC) specimen shows a positive resection margin. We aimed to investigate the significance of a positive resection margin in endoscopically resected T1 CRC. PATIENTS AND METHODS: We enrolled 265 patients with T1 CRC who underwent endoscopic resection between January 2001 and December 2016. The inclusion criteria were: 1) complete resection by endoscopy, and 2) pathology of a positive margin. Among the 265 patients, 213 underwent additional surgery and 52 did not. In the additional surgery group, various clinicopathological factors were evaluated with respect to the presence or absence of residual tumor. The follow-up results were assessed in the group that did not undergo additional surgery. RESULTS: In the 213 patients who underwent additional surgery, residual tumor was detected in 13 patients (6.1 %), and none of the clinicopathological factors was significantly associated with the presence of residual tumor. Among the 52 patients who did not undergo additional surgery, recurrence was detected in 4 (7.7 %), and all 4 underwent salvage surgery. Among these four patients, three had no risk factors for lymph node metastasis and recurrence was at the previous resection site; pathology was high grade dysplasia, rpT3N0M0, and rpT1N0M0, respectively. CONCLUSIONS: A positive resection margin in endoscopically resected T1 CRC is related to a relatively low incidence of residual tumor (6.1 %). Although current guidelines recommend additional surgery for such cases, surveillance and timely salvage surgery could be another option in selected cases.

Risk Factors Associated With Incomplete Colonoscopy Based on the Analysis of Computed Tomographic Colonography Findings.

OBJECTIVE: This study aimed to identify the computed tomographic colonography (CTC) findings of incomplete colonoscopy compared with those of complete colonoscopy. METHODS: The clinical data and CTC imaging data from January 2004 to December 2012 were retrospectively obtained at 2 different institutions and reviewed by the central review system. A total of 71 patients who underwent both videocolonoscopy and CTC were included in this study. The CTC findings and clinical data were evaluated for the completeness of colonoscopy. RESULTS: In the CTC analysis, differences in total colon length, abdominal circumference, and sigmoid colon diameter were statistically significant between both groups (P < 0.05). Body mass index (BMI) and height were identified as significant clinical factors influencing the completeness of colonoscopy. In multiple logistic regression tests, only BMI and sigmoid colon diameter were independent factors (P < 0.05). CONCLUSIONS: High BMI larger diameter of sigmoid colon was associated with incomplete colonoscopy based on CTC.

Autophagy Primes Neutrophils for Neutrophil Extracellular Trap Formation during Sepsis.

RATIONALE: Neutrophils are key effectors in the host's immune response to sepsis. Excessive stimulation or dysregulated neutrophil functions are believed to be responsible for sepsis pathogenesis. However, the mechanisms regulating functional plasticity of neutrophils during sepsis have not been fully determined. OBJECTIVES: We investigated the role of autophagy in neutrophil functions during sepsis in patients with community-acquired pneumonia. METHODS: Neutrophils were isolated from patients with sepsis and stimulated with phorbol 12-myristate 13-acetate (PMA). The levels of reactive oxygen species generation, neutrophil extracellular trap (NET) formation, and granule release, and the autophagic status were evaluated. The effect of neutrophil autophagy augmentation was further evaluated in a mouse model of sepsis. MEASUREMENTS AND MAIN RESULTS: Neutrophils isolated from patients who survived sepsis showed an increase in autophagy induction, and were primed for NET formation in response to subsequent PMA stimulation. In contrast, neutrophils isolated from patients who did not survive sepsis showed dysregulated autophagy and a decreased response to PMA stimulation. The induction of autophagy primed healthy neutrophils for NET formation and vice versa. In a mouse model of sepsis, the augmentation of autophagy improved survival via a NET-dependent mechanism. CONCLUSIONS: These results indicate that neutrophil autophagy primes neutrophils for increased NET formation, which is important for proper neutrophil effector functions during sepsis. Our study provides important insights into the role of autophagy in neutrophils during sepsis.

Helicobacter pylori infection is an independent risk factor for colonic adenomatous neoplasms.

PURPOSE: Helicobacter pylori infection is considered to have a positive association with colorectal neoplasms. In this study, we evaluated the association between H. pylori infection and colorectal adenomas, based on the characteristics of these adenomas in Korea, where the prevalence of H. pylori infection is high and the incidence of colorectal cancer continues to increase. METHODS: The study cohort consisted of 4,466 subjects who underwent colonoscopy and esophagogastroduodenoscopy during screening (1,245 colorectal adenomas vs. 3,221 polyp-free controls). We compared the rate of H. pylori infection between patients with adenoma and polyp-free control cases, using multivariable logistic regression analysis. RESULTS: The overall rate of positive H. pylori infection was higher in adenoma cases than in polyp-free control cases (55.0 vs. 48.5%, p < 0.001). The odds ratio (OR) of positive H. pylori infection in patients with adenoma compared to polyp-free controls was 1.28 (95% CI 1.11-1.47). The positive association of H. pylori infection with colorectal adenomas was more prominent in advanced adenomas (OR 1.84, 95% CI 1.25-2.70) and multiple adenomas (OR 1.72, 95% CI 1.26-2.35). Based on the location of these adenomas, the OR was significant only in patients with colonic adenomas (OR 1.31, 95% CI 1.13-1.52) and not in those with rectal adenoma (OR 0.85, 95% CI 0.58-1.24). CONCLUSION: Helicobacter pylori infection is an independent risk factor for colonic adenomas, especially in cases of advanced or multiple adenomas, but not for rectal adenomas.

Visceral Adipose Tissue Volume and the Occurrence of Colorectal Adenoma in Follow-up Colonoscopy for Screening and Surveillance.

Whether obesity accelerates adenoma recurrence is not yet clear; therefore, we analyzed the risk factors for adenoma occurrence at follow-up colonoscopy, with a focus on visceral adiposity. In total, 1516 subjects underwent index colonoscopy, computed tomography, and questionnaire assessment from February to May 2008; 539 subjects underwent follow-up colonoscopy at the National Cancer Center at least 6 mo after the index colonoscopy. The relationships between the presence of adenoma at follow-up colonoscopy and anthropometric obesity measurements, including body mass index (BMI), waist circumference (WC), visceral adipose tissue (VAT) volume, and subcutaneous adipose tissue (SAT) volume, were analyzed. 188 (34.9%) had adenomatous polyps at follow-up colonoscopy. Multivariate analysis revealed that VAT volume ≥ 1000 cm3 and BMI ≥ 30 kg/m2 were related to the presence of adenoma at follow-up colonoscopy (VAT volume 1000-1500 cm3: odds ratio [OR] = 2.13(95% confidence interval, CI = 1.06-4.26), P = 0.034; VAT volume ≥ 1000 cm3: OR = 2.24(95% CI = 1.03-4.88), P = 0.043; BMI ≥ 30 kg/m2: OR = 4.22(95% CI = 1.12-15.93), P = 0.034). In contrast, BMI 25-29.9 kg/m2, SAT volume, and WC were not associated with the presence of adenoma at follow-up colonoscopy. In conclusion, excess VAT can contribute to the development and growth of new colorectal adenomas, and is a better predictor of colorectal adenoma occurrence at follow-up colonoscopy than BMI, WC, and SAT volume.

Early Outcomes of Endoscopic Submucosal Dissection for Colorectal Neoplasms According to Clinical Indications.

BACKGROUND: Although endoscopic submucosal dissection has been shown to be safe and effective for colorectal tumors, its clinical outcomes vary. OBJECTIVE: The aim of this study is to assess the outcomes of endoscopic submucosal dissection according to clinical indications. DESIGN: This is a prospective, multicenter, single-arm study. SETTING: The study was conducted at special hospitals for colorectal diseases and cancers. PATIENTS: The study population included consecutive patients aged 20 to 80 years who underwent colorectal endoscopic submucosal dissection for 1) early colorectal cancer, 2) laterally spreading tumors ≥2 cm in diameter, and 3) submucosal tumors. INTERVENTIONS: Procedures were performed by experienced colonoscopists. MAIN OUTCOME MEASURES: The primary end points were en bloc and curative resection rates. En bloc resection was defined as endoscopic one-piece resection without tumor fragmentation. Curative resection was defined as en bloc resection and no pathologic requirement for additional surgery. Secondary end points included procedure time, complications, and hospital stay. RESULTS: Of 321 patients, 317 (98.8%) underwent en bloc resection and 231 (72.0%) underwent curative resection. The mean procedure time was 46.2 minutes. Mean hospital stay after the procedure was 3.1 days. Perforation occurred in 2 patients (0.6%), and bleeding occurred in 10 (3.1%) patients. All patients with complications were treated by endoscopic clipping or nonoperative management. Fifteen patients (4.7%) underwent additional radical surgery owing to the risks of lymph node metastasis. Although tumor size was smaller and procedure time shorter in the submucosal tumor group than in the laterally spreading tumor or early colorectal cancer group, there were no differences in clinical outcomes including en bloc and curative resection rates. Submucosal fibrosis was the only factor affecting endoscopic submucosal dissection procedure-related complications. LIMITATIONS: Early outcomes in a limited population and the potential for selection bias were limitations of this study. CONCLUSIONS: Outcomes of colorectal endoscopic submucosal dissection were acceptable in selected patients, with no difference in outcomes according to clinical indications. Because submucosal fibrosis can increase complications, it should be minimized before endoscopic submucosal dissection.

IL-4/10 prevents stress vulnerability following imipramine discontinuation.

BACKGROUND: Identifying stress vulnerability after antidepressant discontinuation may be useful in treating relapses in depression. Previous studies have suggested significant effects of the immune system as well as the central nervous system (CNS) on progression and induction of major depression. In the present study, we hypothesized that the factors that are not rescued by a tricyclic antidepressant imipramine may be associated with stress vulnerability and relapses in depression. METHODS: To address this issue, mice were exposed to 2 h of restraint stress for 21 consecutive days (chronic restraint stress (CRS)) with or without co-treatment of imipramine. These groups were exposed to an electronic foot shock (FS) as additional stress after imipramine washout. Main targets of stress and antidepressants were analyzed in the hippocampus, lymph node, and serum after a series of depression-like behavior analysis. RESULTS: In this study, we found for the first time that mice exposed to CRS with a tricyclic antidepressant imipramine co-treatment, which did not show depressive-like behaviors, were vulnerable to subsequent stressful stimuli compared to the non-stressed mice after imipramine washout. CRS mice with imipramine co-treatment did not show any difference in BDNF, serotonin receptors, pro-inflammatory cytokines, or kynurenine pathway in the hippocampus compared to the controls. However, peripheral IL-4, IL-10, and alternatively activated microglial phenotypes in the hippocampus were not restored with sustained reduction in CRS mice despite chronic imipramine administration. Supplementing recombinant IL-4 and IL-10 in co-Imi+CRS mice prevented the stress vulnerability on additional stress and restored factors related to alternatively activated microglia (M2) in the hippocampus. CONCLUSION: Thus, our results suggest that the reduced IL-4 and IL-10 levels in serum with hippocampal M2 markers may be involved in the stress vulnerability after imipramine discontinuation, and the restoration and modulation of these factors may be useful to some forms of depression-associated conditions.