Differences in the characteristics and functions of brain and spinal cord regulatory T cells.

T cells play an important role in the acquired immune response, with regulatory T cells (Tregs) serving as key players in immune tolerance. Tregs are found in nonlymphoid and damaged tissues and are referred to as "tissue Tregs". They have tissue-specific characteristics and contribute to immunomodulation, homeostasis, and tissue repair through interactions with tissue cells. However, important determinants of Treg tissue specificity, such as antigen specificity, tissue environment, and pathology, remain unclear. In this study, we analyzed Tregs in the central nervous system of mice with ischemic stroke and experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. The gene expression pattern of brain Tregs in the EAE model was more similar to that of ischemic stroke Tregs in the brain than to that of spinal cord Tregs. In addition, most T-cell receptors (TCRs) with high clonality were present in both the brain and spinal cord. Furthermore, Gata3+ and Rorc+ Tregs expressed TCRs recognizing MOG in the spinal cord, suggesting a tissue environment conducive to Rorc expression. Tissue-specific chemokine/chemokine receptor interactions in the spinal cord and brain influenced Treg localization. Finally, spinal cord- or brain-derived Tregs had greater anti-inflammatory capacities in EAE mice, respectively. Taken together, these findings suggest that the tissue environment, rather than pathogenesis or antigen specificity, is the primary determinant of the tissue-specific properties of Tregs. These findings may contribute to the development of novel therapies to suppress inflammation through tissue-specific Treg regulation.

Clinical outcomes of endoscopic submucosal dissection for esophageal squamous cell carcinoma with esophageal varices: Multicenter retrospective study.

OBJECTIVES: Clinical outcomes of endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) with esophageal varices (EVs) are obscure. We aimed to elucidate the clinical outcomes of ESD for ESCC with EVs in a multicenter, retrospective study. METHODS: We established a retrospective cohort of 30 patients with ESCC complicating EVs, who underwent ESD at 11 Japanese institutions. Rates of en bloc resection and R0 resection, procedure time, and adverse events were evaluated as indicators of the feasibility and safety of ESD. Additional treatment, recurrence, and metastasis of the lesions were evaluated as indicators of the long-term efficacy of ESD. RESULTS: Portal hypertension was caused by cirrhosis, of which alcohol was the most common cause. En bloc resection was achieved in 93.3% and R0 resection in 80.0% of the patients. The median procedure time was 92 min. Adverse events included a case of uncontrolled intraoperative bleeding leading to discontinuation of ESD and a case of esophageal stricture due to extensive resection. During the follow-up period of a median for 42 months, a patient with local recurrence and another patient with liver metastasis were observed. One patient died of liver failure after receiving chemoradiotherapy as an additional treatment after ESD. No patient died of ESCC. CONCLUSION: This multicenter, retrospective cohort study demonstrated the safety and efficacy of ESD for ESCC with EVs. Further studies are needed to establish appropriate treatment methods for EVs before ESD and additional treatments for patients with insufficient ESD.

Prognostic significance of Ishii's sarcopenia screening score for patients undergoing curative surgery for obstructive colorectal cancer after intraluminal decompression.

PURPOSE: Sarcopenia influences the short- and long-term outcomes of various medical conditions including malignancy. Ishii's screening test estimates the probability of sarcopenia based on a score calculated by three simple variables: age, grip strength, and calf circumference. We investigated the clinical significance of Ishii's score for patients with non-metastatic obstructive colorectal cancer (OCRC) who underwent curative surgery after intraluminal decompression. METHODS: Ishii's score was calculated in 79 patients with OCRC. Muscle volume loss and decreased muscle quality were evaluated by computed tomography (CT) images as skeletal muscle index (SMI) and intramuscular adipose tissue content (IMAC), respectively. RESULTS: There were 46 men and 33 women, with a median age of 70 years old. The cutoff value for Ishii's score was 155.1 and 15 patients were in the high-score group. The high-score group was significantly associated with worse time to recurrence (TTR) and overall survival (OS), and a high Ishii's score was an independent negative prognostic factor for TTR (hazard ratio = 2.93, P = 0.015). A high Ishii's score was significantly associated with a low SMI value but not with the IMAC value. CONCLUSION: A high Ishii's score was independently associated with poorer TTR in patients with non-metastatic OCRC.

[Microglia and macrophages in diseases].

As the brain is a prime immune privileged organ, immune responses in it were not studied as intensively as other peripheral organs in the past. However, the brain is studded with immune cells called microglia, which play important roles particularly in diseased conditions. In addition, from recent descriptive works, we have learned a lot about immune cells in neighboring tissues. Recent progress has rather made it clearer that the immune responses in and around the brain are complicated reactions with both positive and negative effects. And we still have not identified the way(s) we should pursue for clinical applications. Here we introduce microglia and macrophages in the steady state. We also discuss their roles in stroke, a major cause of death and disability in Japan, and Alzheimer's disease, which account for 60 to 70% of dementia.

Low Geriatric Nutritional Risk Index (GNRI) Predicts Poorer Survival in Patients with Obstructive Colorectal Cancer Who Had a Self-Expandable Metallic Stent (SEMS) Inserted as a Bridge to Curative Surgery.

Objectives: The geriatric nutritional risk index (GNRI) is a nutrition-related risk index calculated easily from serum albumin and the ratio of body weight to ideal body weight. We investigated the prognostic values of the GNRI in elderly patients with obstructive colorectal cancer (OCRC) who had a self-expandable metallic stent inserted as a bridge to curative surgery. Methods: We retrospectively evaluated 61 patients aged ≥65 years with pathological stage I to III OCRC. Associations of preoperative GNRI and pre-stenting GNRI (ps-GNRI) with short- and long-term outcomes were examined. Results: Multivariate analyses revealed GNRI of <85.3 and ps-GNRI of <92.9 were independently associated with worse cancer-specific survival (CSS; P = 0.016, and P = 0.041, respectively), and overall survival (OS; P = 0.020, and P = 0.024, respectively). A ps-GNRI of <92.9 was correlated with poorer relapse-free survival (RFS) only in the univariate analysis (P = 0.034). For the OCRC cohort without age restriction (n = 86), GNRI of <85.3 and ps-GNRI of <92.9 were independently associated with worse CSS (P = 0.021), and OS (P = 0.023), respectively. In univariate analysis, ps-GNRI of <92.9 was significantly correlated with poorer RFS (P = 0.006). Moreover, ps-GNRI of <92.9 was significantly associated with Clavien-Dindo grade of ≥III postoperative complications (P = 0.037), anastomotic leak (P = 0.032), infectious complications (P = 0.002), and longer postoperative hospital stay (17 days vs. 15 days; P = 0.048). Conclusions: In OCRC patients, decreased preoperative and pre-stenting GNRI were significantly correlated with poorer survival, and decreased pre-stenting GNRI was significantly associated with worse short- and long-term outcomes.

Increased neutrophils in inflammatory bowel disease accelerate the accumulation of amyloid plaques in the mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is one of the neurodegenerative diseases and characterized by the appearance and accumulation of amyloid-ß (Aß) aggregates and phosphorylated tau with aging. The aggregation of Aß, which is the main component of senile plaques, is closely associated with disease progression. AppNL-G-F mice, a mouse model of AD, have three familial AD mutations in the amyloid-ß precursor gene and exhibit age-dependent AD-like symptoms and pathology. Gut-brain interactions have attracted considerable attention and inflammatory bowel disease (IBD) has been associated with a higher risk of dementia, especially AD, in humans. However, the underlying mechanisms and the effects of intestinal inflammation on the brain in AD remain largely unknown. Therefore, we aimed to investigate the effects of intestinal inflammation on AD pathogenesis. METHODS: Wild-type and AppNL-G-F mice at three months of age were fed with water containing 2% dextran sulfate sodium (DSS) to induce colitis. Immune cells in the brain were analyzed using single-cell RNA sequencing (scRNA-seq) analysis, and the aggregation of Aß protein in the brain was analyzed via immunohistochemistry. RESULTS: An increase in aggregated Aß was observed in the brains of AppNL-G-F mice with acute intestinal inflammation. Detailed scRNA-seq analysis of immune cells in the brain showed that neutrophils in the brain increased after acute enteritis. Eliminating neutrophils by antibodies suppressed the accumulation of Aß, which increased because of intestinal inflammation. CONCLUSION: These results suggest that neutrophils infiltrate the AD brain parenchyma when acute colitis occurs, and this infiltration is significantly related to disease progression. Therefore, we propose that neutrophil-targeted therapies could reduce Aß accumulation observed in early AD and prevent the increased risk of AD due to colitis.

A decreased preoperative platelet-to-lymphocyte ratio, systemic immune-inflammation index, and pan-immune-inflammation value are associated with the poorer survival of patients with a stent inserted as a bridge to curative surgery for obstructive colorectal cancer.

PURPOSE: Inflammation is one of the hallmarks of cancer, and inflammation-based markers that are calculated easily from laboratory results have shown predictive abilities. We investigated the prognostic values of the preoperative platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and pan-immune-inflammation value (PIV) in patients with non-metastatic obstructive colorectal cancer (OCRC) and a self-expandable metallic stent inserted as a bridge to curative surgery. METHODS: The subjects of this retrospective study were 86 patients with pathological stage I to III OCRC. We examined the associations of these biomarkers with short- and long-term outcomes. RESULTS: Multivariate analyses revealed that a preoperative PLR < 149, SII < 597, and PIV < 209 were independently associated with poorer relapse-free survival (RFS) (P = 0.007, P < 0.001, and P = 0.002, respectively) and that a PIV < 209 was independently associated with poorer cancer-specific survival (P = 0.030). A platelet count < 240 was significantly associated with worse RFS, whereas the lymphocyte count was not. Pre-stenting PLR < 221 was an independent poor prognostic factor for RFS (P = 0.045). CONCLUSION: This study showed that decreased preoperative PLR, SII, PIV, and pre-stenting PLR were associated with poorer RFS, contrary to the findings of most previous studies. Our results suggest that platelets and obstruction contributed primarily to the opposite relationships, which might provide new insight into the possible pathophysiology of platelet-tumor interactions generated in the OCRC environment.

In Vitro Generation of Brain Regulatory T Cells by Co-culturing With Astrocytes.

Regulatory T cells (Tregs) are normally born in the thymus and activated in secondary lymphoid tissues to suppress immune responses in the lymph node and at sites of inflammation. Tregs are also resident in various tissues or accumulate in damaged tissues, which are now called tissue Tregs, and contribute to homeostasis and tissue repair by interacting with non-immune cells. We have shown that Tregs accumulate in the brain during the chronic phase in a mouse cerebral infarction model, and these Tregs acquire the characteristic properties of brain Tregs and contribute to the recovery of neurological damage by interacting with astrocytes. However, the mechanism of tissue Treg development is not fully understood. We developed a culture method that confers brain Treg characteristics in vitro. Naive Tregs from the spleen were activated and efficiently amplified by T-cell receptor (TCR) stimulation in the presence of primary astrocytes. Furthermore, adding IL-33 and serotonin could confer part of the properties of brain Tregs, such as ST2, peroxisome proliferator-activated receptor γ (PPARγ), and serotonin receptor 7 (Htr7) expression. Transcriptome analysis revealed that in vitro generated brain Treg-like Tregs (induced brain Tregs; iB-Tregs) showed similar gene expression patterns as those in in vivo brain Tregs, although they were not identical. Furthermore, in Parkinson's disease models, in which T cells have been shown to be involved in disease progression, iB-Tregs infiltrated into the brain more readily and ameliorated pathological symptoms more effectively than splenic Tregs. These data indicate that iB-Tregs contribute to our understanding of brain Treg development and could also be therapeutic for inflammatory brain diseases.

Prognostic significance of the mean corpuscular volume (MCV) and red cell distribution width (RDW) in obstructive colorectal cancer patients with a stent inserted as a bridge to curative surgery.

PURPOSE: The prognostic significance of the mean corpuscular volume (MCV) and red cell distribution width (RDW) in patients with malignancy have not been intensely investigated and are largely overlooked. We, therefore, investigated the clinical significance of MCV and RDW in non-metastatic obstructive colorectal cancer (OCRC) patients with a self-expandable metallic stent inserted as a bridge to curative surgery. METHODS: Eighty-five pathological stage II and III OCRC patients were retrospectively evaluated. The associations of the preoperative MCV and RDW values with short- and long-term outcomes were examined. RESULTS: There were 50 males and 35 females, and the median age was 71 years old. The median interval between stenting and surgery was 17 days, and the median postoperative hospital stay was 16 days. Fifty-six patients were in the MCV ≥ 87 group, and 47 were in the RDW ≥ 13.8 group. Multivariate analyses revealed the MCV ≥ 87 status to be independently associated with a poor relapse-free survival (hazard ratio [HR] = 4.70, 95% confidence interval [CI] 1.52-14.58, P = 0.007). The RDW ≥ 13.8% was an independent predictor of postoperative infectious complications (HR = 7.28, 95% CI 1.24-42.70, P = 0.028). CONCLUSION: The MCV and RDW are simple but strong predictors of postoperative outcomes in OCRC patients.

[Endoscopic mucosal resection of localized plasmablastic lymphoma with early rectal cancer:a rare case report and literature review].

A 79-year-old male with a positive fecal occult blood test result underwent total colonoscopy, which revealed a 15-mm-semipedunculated polyp in the rectum. The polyp appeared to be an adenoma using narrow-band imaging observation in magnifying endoscopy, although a 3mm reddish segment with a different surface structure was identified adjacent to the base of the polyp. En-bloc endoscopic mucosal resection (EMR) was performed. From the pathological evaluation using the specimen, the polyp was mainly a tubular adenoma with an adenocarcinoma component within the lesion. Additionally, a tiny plasmablastic lymphoma (PBL) component, which was positive for CD45, CD79a, CD30, CD38, MUM1, and lambda light chain;negative for CD3, CD5, CD20, CD56, CD138, cyclin D1, PAX5, IgG, IgA, IgM, IgE, HHV8, and kappa light chain, coexisted near the stalk. The proliferation index using Ki-67 immunohistochemistry was approximately 80%. Furthermore, Epstein-Barr virus-encoded RNAs were identified in in-situ hybridization, although the human immunodeficiency virus was not detected. The patient received contrast-enhanced computed tomography (CT) and positron emission tomography-CT (PET-CT) follow-ups after treatment without recurrence for two years. This is the first report of gastrointestinal PBL that could be treated using EMR.

A longer interval after stenting compromises the short- and long-term outcomes after curative surgery for obstructive colorectal cancer.

PURPOSE: Intestinal decompression using self-expandable metallic colonic stents (SEMSs) as a bridge to surgery is now considered an attractive alternative to emergency surgery. However, data regarding the optimal timing of surgery after stenting are limited. METHODS: We investigated the impact of the interval between stenting and surgery on short- and long-term outcomes in 92 obstructive colorectal cancer (OCRC) patients who had a SEMS inserted and subsequently received curative surgery. RESULTS: The median age of the patients was 70.5 years, and the median interval between SEMS insertion and the surgery was 17 (range 5-47) days. There were 35 postoperative complications, including seven major postoperative complications. An interval of more than 16 days was an independent predictor of a poor relapse-free survival (hazard ratio [HR] = 3.12, 95% confidence interval [CI] 1.24-7.81, p = 0.015). An interval of more than 35 days was independently associated with major postoperative complications (HR = 16.6, 95% CI 2.21-125, p = 0.006). CONCLUSION: A longer interval between stenting and surgery significantly compromised the short- and long-term outcomes. Surgery within 16 days after stenting might help maximize the benefit of SEMS without interfering with short- and long-term outcomes.

Endoscopic Ultrasonography-guided Fine-needle Aspiration Cytology Combined with a Cell-block Method for Gastrointestinal Subepithelial Lesions.

Objective The diagnostic accuracy of an endoscopic ultrasound-guided fine-needle aspiration cytology/biopsy combined with a cell-block method (FNA-CB) for gastrointestinal subepithelial lesions (GI-SELs) has not been fully studied. Methods A total of 109 patients (with 110 GI-SELs) were evaluated to clarify the rate of obtaining evaluable histology specimens using FNA-CB. In addition, we investigated the following: 1) the accuracy for determining the histology, 2) effects of the number of cell clusters obtained via FNA-CB, 3) correlation of the Ki67 labelling index (Ki67LI) of the gastrointestinal stromal tumor (GIST) lesions between FNA-CB and resected specimens, and 4) clinical courses for patients followed up after FNA-CB. Results Of the 110 GI-SELs for which FNA-CB was performed, 95 (86%) were able to be histologically evaluated using the first FNA-CB. For the 70 resected GI-SELs, the accuracy of FNA-CB to determine histology was 96%, remaining at 90% even when only a few cell clusters were obtained. The concordance rate of the risk-grouping of GIST (high-risk, Ki67LI ≥8; low-risk, <8) between FNA-CB and resected specimens was 84%. Of the 29 patients followed up after the first FNA-CB, 12 with benign GI-SELs determined using the first FNA-CB showed no obvious increases in their GI-SEL sizes. Conclusion Since FNA-CB can be used to determine the histology and reproductive activity of GI-SELs accurately, not only preoperative histological confirmation but also reliable information to determine clinical plans, such as follow-up without surgery or neoadjuvant chemotherapy, can be obtained.

Safety and Recipient Satisfaction of Propofol Sedation in Outpatient Endoscopy: A 24-Hour Prospective Investigation Using a Questionnaire Survey.

BACKGROUND/AIMS: The aim of this study was to evaluate the safety of sedation with propofol as an alternative to benzodiazepine drugs in outpatient endoscopy. METHODS: In this prospective study, examinees who underwent outpatient endoscopy under propofol sedation and submitted a nextday questionnaire with providing informed consent were evaluated. Periprocedural acute responses, late adverse events within 24 hours, and examinee satisfaction were evaluated. RESULTS: Among the 4,122 patients who received propofol in the 17,978 outpatient-based endoscopic examinations performed between November 2016 and March 2018, 2,305 eligible examinees (esophagogastroduodenoscopy for 1,340, endoscopic ultrasonography for 945, and total colonoscopy for 20) were enrolled, and their responses to a questionnaire were analyzed. The mean propofol dose was 69.6±24.4 mg (range, 20-200 mg). Diazepam, midazolam, and/or pentazocine in combination with propofol was administered to 146 examinees. Mild oxygen desaturation was observed in 59 examinees (2.6%); and mild bradycardia, in 2 (0.09%). Other severe reactions or late events did not occur. After eliminating 181 invalid responses, 97.7% (2,065/2,124) of the patients desired propofol sedation in future examinations. CONCLUSION: Propofol sedation was found to be safe-without severe adverse events or accidents-for outpatient endoscopy on the basis of the patients' next-day self-evaluation. Given the high satisfaction level, propofol sedation might be an ideal tool for painless endoscopic screening.

Predictive Factors for Short-Term Survival after Non-Curative Endoscopic Submucosal Dissection for Early Gastric Cancer.

BACKGROUND/AIMS: For early gastric cancer (EGC) treated using endoscopic submucosal dissection (ESD) with poor curability defined by the Japanese Guidelines (non-curative EGC, N-EGC), additional gastrectomy has been recommended. However, N-EGC patients without additional gastrectomy often die of other diseases within a relatively short interval after ESD. It has been unclear whether additional gastrectomy is beneficial or not for such patients. The aim of this study was to clarify predictors for short-term survival of N-EGC patients without additional gastrectomy after ESD. METHODS: One hundred six N-EGC patients without additional gastrectomy were included in this study. Factors related to short-term survival, defined as death within 3 years after ESD, were evaluated using uni- and multivariate analyses by comparing patients with and without short-term survival (Groups S and C, respectively). RESULTS: During the mean follow-up period of 89 months, 39 patients died (14 patients died within 3 years, being Group S). The cause of death was gastric cancer for only 1 patient in the Group C. The 3- and 5-year overall survival rates were 86.8 and 81.8%, respectively, and the 3- and 5-years disease-specific survival rates were 100 and 98.9%, respectively. Univariate analyses showed that short-term survival was statistically associated with elevated morphology, high-risk status for lymph node metastases as defined by the eCura system, severe comorbidity (Charlson Comorbidity Index [CCI] ≥3), low level of activity in daily living (being unable to go out by oneself), habitation (a nursing home), and several poor nutritional prognostic indices (neutrophil to lymphocyte ratio ≥2.5, geriatric nutritional risk index <92, C-reactive protein ≥1.0). In the multivariate analysis, a high CCI (≥3) was the independent predictor for short-term survival after ESD (odds ratio, 8.1; 95% confidence interval, 1.53-43.0; p = 0.014). CONCLUSIONS: Severe comorbidity indicated by a high CCI score (≥3) was the independent predictor for short-term survival for EGC patients without additional gastrectomy after non-curative ESD. Since the cause of death for most patients was not gastric cancer, observational follow-ups without additional gastrectomy might be a reasonable option for patients with a poor general status indicated by a CCI ≥3.

The Controlling Nutritional Status (CONUT) Score as a prognostic factor for obstructive colorectal cancer patients received stenting as a bridge to curative surgery.

PURPOSE: The Controlling Nutritional Status (CONUT) Score, originally developed as a nutritional screening tool, is a cumulative score calculated from the serum albumin level, total cholesterol level, and total lymphocyte count. Previous studies have demonstrated that the score has significant prognostic value in various malignancies. We investigated the relationship between the CONUT score and long-term survival in obstructive colorectal cancer (OCRC) patients who underwent self-expandable metallic colonic stent placement and subsequently received curative surgery. METHODS: We retrospectively analyzed 57 pathological stage II and III OCRC patients between 2013 and 2019. The associations between the preoperative CONUT score and clinicopathological factors and patient survival were evaluated. RESULTS: A receiver operating characteristic curve analysis revealed that the optimal cut-off value for the CONUT score was 7. A CONUT score of ≥ 7 was significantly associated with elevated CA19-9 level (p = 0.03). Multivariate analyses revealed that a CONUT score of ≥ 7 was independently associated with cancer-specific survival (hazard ratio [HR] = 10.2, 95% confidence interval [CI] 1.2-85.9, p = 0.03) and disease-free survival (HR = 7.1, 95% CI 2.3-21.7, p = 0.0006). CONCLUSION: The results demonstrated that the CONUT score was a potent prognostic indicator. Evaluating the CONUT score might result in more precise patient assessment and tailored treatment.

[Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue (MALT) lymphoma with MALT translocation gene 1 diagnosed using an endoscopic submucosal dissection specimen].

A 15-mm whitish, depressed lesion was observed in the stomach of a 39-year-old using screening esophagogastroduodenoscopy. The lesion had grown to a size of 40mm and had a cobblestone-like appearance at an 11-year endoscopic follow-up. Using endoscopic submucosal dissection (ESD) as a diagnostic therapy, gastric mucosa-associated lymphoid tissue (MALT) lymphoma with MALT translocation gene 1 without Helicobacter pylori infection was detected. Although the patient did not undergo additional treatments, he remained alive without for recurrence 5 years after ESD.

The prognostic value of the prognostic nutritional index and inflammation-based markers in obstructive colorectal cancer.

PURPOSE: Inflammation-based markers predict long-term outcomes of various malignancies. We investigated the relationship between these markers and the long-term survival in obstructive colorectal cancer (OCRC) patients with self-expandable metallic colonic stents (SEMSs) who subsequently received curative surgery. METHODS: We retrospectively analyzed 72 consecutive pathological stage II and III OCRC patients between 2013 and 2019. The prognostic significance of the prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), and platelet-lymphocyte ratio (PLR) was evaluated. RESULTS: The overall survival (OS), cancer-specific survival, and disease-free survival (DFS) were significantly shorter in the PNI < 35 group than in the PNI ≥ 35 group (p = 0.006, p < 0.001, and p = 0.003, respectively), and multivariate analyses revealed the PNI to be the only inflammation-based marker independently associated with the survival. A PNI < 35 was significantly associated with an elevated CA 19-9 level (p = 0.04) and longer postoperative hospital stay (p = 0.03). Adjuvant chemotherapy was also significantly associated with the OS (p = 0.040) and DFS (p = 0.011) in multivariate analyses. CONCLUSION: The results showed that the PNI was a potent prognostic indicator. For OCRC patients, both systemic inflammation and the nutrition status seem to be important for predicting the prognosis, and administering adjuvant chemotherapy was very important.