Loss-of-phosphorylation of IKZF1 results in gain-of-function associated with immune dysregulation.

BACKGROUND: Immune dysregulation often presents as autoimmunity, inflammation, and/or lymphoproliferation. Several germline genetic defects have been associated with immune dysregulation; they include heterozygous gain-of-function (GOF) mutations in IKZF1, an essential transcription factor for hematopoiesis containing zinc finger domains (ZFs). However, in a large percentage of patients, the genetic origin of their immunedysregulation remains undetermined. OBJECTIVE: A family with 2 members presenting immune dysregulation signs was studied to identify the genetic cause of their disease. METHODS: Whole exome sequencing, analysis of immunologic parameters, and functional assays (including Western blotting, electrophoretic mobility shift assay during the cell cycle, and TH cell differentiation) were performed. RESULTS: The 2 patients carried a novel heterozygous mutation in IKZF1 (IKZF1T398M). IKZF1 heterozygous mutations have previously been shown to be responsible for several distinct human immunologic diseases by directly affecting the ability of ZFs to bind to DNA or to dimerize. Herein, we showed that the IKZF1T398M, which is outside the ZFs, caused impaired phosphorylation of IKZF1, resulting in enhanced DNA-binding ability at the S phase of the cell cycle, reduction of the G1-S phase transition, and decreased proliferation. Confirming these data, similar functional alterations were observed with IKZF1T398A, but not with IKZF1T398D, mimicking dephosphorylation and phosphorylation, respectively. In T lymphocytes, expression of IKZF1T398M led to TH cell differentiation skewed toward TH2 cells. Thus, our data indicate that IKZF1T398M behaves as a GOF variant underlying immune dysregulation. CONCLUSION: Disturbed IKZF1 phosphorylation represents a novel GOF mechanism (GOF by loss of phosphorylation (termed as GOF-LOP) associated with immune dysregulation, highlighting the regulatory role of IKZF1 during cell cycle progression through phosphorylation.

Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency.

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.

Long-term outcomes of robot-assisted versus minimally invasive esophagectomy in patients with thoracic esophageal cancer: a propensity score-matched study.

BACKGROUND: Recently, robot-assisted minimally invasive esophagectomy (RAMIE) has gained popularity worldwide. Some studies have compared the long-term results of RAMIE and minimally invasive esophagectomy (MIE). However, there are no reports on the long-term outcomes of RAMIE in Japan. This study compared the long-term outcomes of RAMIE and MIE. METHODS: This retrospective study included 86 patients with thoracic esophageal cancer who underwent RAMIE or MIE at our hospital from June 2010 to December 2016. Propensity score matching (PSM) was employed, incorporating co-variables such as confounders or risk factors derived from the literature and clinical practice. These variables included age, sex, body mass index, alcohol consumption, smoking history, American Society of Anesthesiologists stage, comorbidities, tumor location, histology, clinical TNM stage, and preoperative therapy. The primary endpoint was 5-year overall survival (OS), and the secondary endpoints were 5-year disease-free survival (DFS) and recurrence rates. RESULTS: Before PSM, the RAMIE group had a longer operation time (min) than the MIE group (P = 0.019). RAMIE also exhibited significantly lower blood loss volume (mL) (P < 0.001) and fewer three-field lymph node dissections (P = 0.028). Postoperative complications (Clavien-Dindo: CD ≥ 2) were significantly lower in the RAMIE group (P = 0.04), and postoperative hospital stay was significantly shorter than the MIE group (P < 0.001). After PSM, the RAMIE and MIE groups consisted of 26 patients each. Blood loss volume was significantly smaller (P = 0.012), postoperative complications (Clavien-Dindo ≥ 2) were significantly lower (P = 0.021), and postoperative hospital stay was significantly shorter (P < 0.001) in the RAMIE group than those in the MIE group. The median observation period was 63 months. The 5-year OS rates were 73.1% and 80.8% in the RAMIE and MIE groups, respectively (P = 0.360); the 5-year DFS rates were 76.9% and 76.9% in the RAMIE and MIE groups, respectively (P = 0.749). Six of 26 patients (23.1%) in each group experienced recurrence, with a median recurrence period of 41.5 months in the RAMIE group and 22.5 months in the MIE group. CONCLUSIONS: Compared with MIE, RAMIE led to no differences in long-term results, suggesting that RAMIE is a comparable technique.

Establishment of "Ring-Size-Divergent" Synthetic Strategy: Divergent Synthesis, Stereochemical Assignments, and Biological Activity Studies of Nerolidol-Type Sesquiterpenoids and Feroniellins.

Biomimetic epoxide-opening cascade cyclizations of polyepoxides enable the efficient and rapid construction of polyether skeletons. In this study, we discovered a method for switching the cyclization mode from tetrahydrofuran to tetrahydropyran (THP) formation in epoxide-opening cascades of polyepoxides. The THP formation proceeded via an epoxonium-ion intermediate by simple heating in neutral water. Next, by expanding the switching reaction, we successfully established a "ring-size-divergent" synthetic strategy that enabled the synthesis of the five-, six-, and seven-membered ether rings from identical diepoxide cyclization precursors under simple acidic or neutral conditions. The "ring-size-divergent" synthetic strategy was applied to the short divergent synthesis of nerolidol-type sesquiterpenoids and feroniellins, resulting in the revision of the proposed stereochemistry of certain natural products and the determination of all of the absolute configurations. Additionally, the anti-inflammatory activities of the synthetic samples were evaluated.

Bone Marrow Failure and Immunodeficiency Associated with Human RAD50 Variants.

PURPOSE: The MRE11-RAD50-NBN (MRN) complex plays a key role in recognizing and signaling DNA double-strand breaks. Pathogenic variants in NBN and MRE11 give rise to the autosomal-recessive diseases, Nijmegen breakage syndrome (NBS) and ataxia telangiectasia-like disorder, respectively. The clinical consequences of pathogenic variants in RAD50 are incompletely understood. We aimed to characterize a newly identified RAD50 deficiency/NBS-like disorder (NBSLD) patient with bone marrow failure and immunodeficiency. METHODS: We report on a girl with microcephaly, mental retardation, bird-like face, short stature, bone marrow failure and B-cell immunodeficiency. We searched for candidate gene by whole-exome sequencing and analyzed the cellular phenotype of patient-derived fibroblasts using immunoblotting, radiation sensitivity assays and lentiviral complementation experiments. RESULTS: Compound heterozygosity for two variants in the RAD50 gene (p.Arg83His and p.Glu485Ter) was identified in this patient. The expression of RAD50 protein and MRN complex formation was maintained in the cells derived from this patient. DNA damage-induced activation of the ATM kinase was markedly decreased, which was restored by the expression of wild-type (WT) RAD50. Radiosensitivity appeared inconspicuous in the patient-derived cell line as assessed by colony formation assay. The RAD50R83H missense substitution did not rescue the mitotic defect in complementation experiments using RAD50-deficient fibroblasts, whereas RAD50WT did. The RAD50E485X nonsense variant was associated with in-frame skipping of exon 10 (p.Glu485_545del). CONCLUSION: These findings indicate important roles of RAD50 in human bone marrow and immune cells. RAD50 deficiency/NBSLD can manifest as a distinct inborn error of immunity characterized by bone marrow failure and B-cell immunodeficiency.

Inherited TNFSF9 deficiency causes broad Epstein-Barr virus infection with EBV+ smooth muscle tumors.

Epstein-Barr virus (EBV) can infect smooth muscle cells causing smooth muscle tumors (SMTs) or leiomyoma. Here, we report a patient with a heterozygous 22q11.2 deletion/DiGeorge syndrome who developed a unique, broad, and lethal susceptibility to EBV characterized by EBV-infected T and B cells and disseminated EBV+SMT. The patient also harbored a homozygous missense mutation (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection. We show that wild-type CD137L was up-regulated on activated monocytes and dendritic cells, EBV-infected B cells, and SMT. The CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells. Therefore, these results highlight the critical role of the CD137-CD137L pathway in anti-EBV immunity, in particular in the control of EBV+SMT.

Preliminary study for developing a navigation system for gastric cancer surgery using artificial intelligence.

PURPOSE: We are attempting to develop a navigation system for safe and effective peripancreatic lymphadenectomy in gastric cancer surgery. As a preliminary study, we examined whether or not the peripancreatic dissection line could be learned by a machine learning model (MLM). METHODS: Among the 41 patients with gastric cancer who underwent radical gastrectomy between April 2019 and January 2020, we selected 6 in whom the pancreatic contour was relatively easy to trace. The pancreatic contour was annotated by a trainer surgeon in 1242 images captured from the video recordings. The MLM was trained using the annotated images from five of the six patients. The pancreatic contour was then segmented by the trained MLM using images from the remaining patient. The same procedure was repeated for all six combinations. RESULTS: The median maximum intersection over union of each image was 0.708, which was higher than the threshold (0.5). However, the pancreatic contour was misidentified in parts where fatty tissue or thin vessels overlaid the pancreas in some cases. CONCLUSION: The contour of the pancreas could be traced relatively well using the trained MLM. Further investigations and training of the system are needed to develop a practical navigation system.

The impact of lymphadenectomy on lymph node recurrence after performing various treatments for esophageal squamous cell carcinoma.

BACKGROUND: Treatment for regional lymph node recurrence after initial treatment for esophageal squamous cell carcinoma (ESCC) differs among institutions. Though some retrospective cohort studies have shown that lymphadenectomy for cervical lymph node recurrence is safe and leads to long-term survival, the efficacy remains unclear. In this study, we investigated the long-term outcomes of patients who underwent lymphadenectomy for regional recurrence after treatment for ESCC. PATIENTS AND METHODS: We retrieved 20 cases in which lymphadenectomy was performed for lymph node recurrence after initial treatment for ESCC in our hospital from January 2003 to December 2016. Initial treatments included esophagectomy, endoscopic resection (ER) and chemoradiotherapy/chemotherapy (CRT/CT). Overall survival (OS) and recurrence-free survival (RFS) after lymphadenectomy were calculated by the Kaplan-Meier method. We also used a univariate analysis with a Cox proportional hazards model to determine factors influencing the long-term outcomes. RESULTS: The five-year OS and RFS of patients who underwent secondary lymphadenectomy for recurrence after initial treatment were 50.0% and 26.7%, respectively. The five-year overall survival rates of patients who received esophagectomy, ER and CRT/CT as initial treatments, were 40.0%, 75.0% and 50.0%, respectively. The five-year OS rates of patients with Stage I and Stage II-IVB at initial treatments were 83.3% and 33.3%, respectively. CONCLUSIONS: Lymphadenectomy for regional recurrence after initial treatment for ESCC is effective to some degree. Patients with regional recurrence after initial treatment for Stage I ESCC have a good prognosis; thus, lymphadenectomy should be considered for these cases.

Prognostic Value of Intraoperative Blood Transfusion in Patients with Adenocarcinoma of the Esophagogastric Junction.

Background and objectives: Adenocarcinoma of the esophagogastric junction (AEG) has a complicated surgical anatomy, due to which it sometimes induces excessive intraoperative blood loss that necessitates intraoperative blood transfusion (BTF). However, few reports have focused on the impact of BTF on the survival outcomes of patients with AEG. We aimed to evaluate the impact of BTF on AEG prognosis. Materials andMethods: We included 63 patients who underwent surgical resection for AEG at our hospital between January 2010 and September 2020. Clinicopathological characteristics and survival outcomes were compared between patients with (n = 12) and without (n = 51) BTF. Multivariate analysis was performed to identify the independent prognostic factors for overall survival. Results: None of the patients who underwent minimally invasive surgery received BTF. Patients who received BTF had a significantly worse 5-year survival rate than those who did not (67.8% vs. 28.3%, p = 0.001). BTF was an independent risk factor for overall survival (hazard ratio: 3.90, 95% confidence interval 1.30-11.7), even after patients who underwent minimally invasive surgery were excluded. Conclusions: BTF adversely affected the survival outcomes of patients with AEG who underwent curative surgery. To avoid BTF, surgeons should strive to minimize intraoperative bleeding.

Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation.

IKZF1/IKAROS is a key transcription factor of lymphocyte development expressed throughout hematopoiesis. Heterozygous germline IKZF1 haploinsufficient (IKZF1HI) and dominant-negative (IKZF1DN) variants in humans cause B cell immune deficiency and combined immunodeficiency. Here, we identified previously unidentified heterozygous IKZF1 variants (R183C/H) located in the DNA binding domain in eight individuals with inflammatory, autoimmune, allergic symptoms, and abnormal plasma cell (PC) proliferation. Leukocytes of patients exhibited specific defects including impaired IL-2 production by T cells, T helper (TH) skewing toward TH2, low numbers of regulatory T cells (Treg), eosinophilia, and abnormal PC proliferation. In contrast to IKZF1HI and IKZF1DN, IKZF1R183H/C proteins showed increased DNA binding associated with increased gene expression of TH2 and PC differentiation, thus demonstrating that IKZF1R183H/C behave as gain-of-function (GOF) alleles. In vitro treatment with lenalidomide, known to degrade IKZF1, corrected TH2 and PC abnormalities caused by IKZF1R183H/C. These data extend the spectrum of pathological mechanisms associated with IKZF1 deficiencies and highlight the role of IKZF1 in late lymphoid differentiation stages.

Mucosal Congestion on the First Day Following Endoscopy Predicts Anastomotic Stricture After Esophagectomy.

BACKGROUND: Anastomotic stricture is a relatively common postoperative complication after esophagectomy. Previous studies have indicated that impaired perioperative blood perfusion at the anastomosis is associated with the occurrence of stricture. Therefore, we analyzed the association between endoscopically assessed blood perfusion during the early postoperative period and anastomotic stricture. METHODS: This retrospective study evaluated patients who underwent esophagectomy at Tokyo Medical and Dental University between 2010 and 2015. The patients had undergone nasal endoscopy on the 1st and 8th postoperative days. The findings were used to evaluate blood perfusion at the anastomosis and gastric tube, which was classified based on mucosal color as ischemia (white) or congestion (blue or black). Univariate and multivariable logistic regression analyses were performed to identify risk factors for anastomotic stricture. RESULTS: The study included 197 patients and anastomotic stricture was observed in 60 patients (30.4%). The multivariable analysis revealed that postoperative gastric tube congestion was a risk factor for stricture (odds ratio [OR]: 6.440, 95% confidence interval [CI]: 2.660-15.600; p < 0.001). Lower risks of anastomotic stricture were associated with pathological stage III-IV disease (OR: 0.325, 95% CI: 0.161-0.656; p = 0.002). CONCLUSION: This study revealed that endoscopically detected congestion at the anastomosis on the first postoperative day was a risk factor for anastomotic stricture.

Identification of Germline Non-coding Deletions in XIAP Gene Causing XIAP Deficiency Reveals a Key Promoter Sequence.

PURPOSE: X-linked inhibitor of apoptosis protein (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome of type 2 (XLP-2), is a rare immunodeficiency characterized by recurrent hemophagocytic lymphohistiocytosis, splenomegaly, and inflammatory bowel disease. Variants in XIAP including missense, non-sense, frameshift, and deletions of coding exons have been reported to cause XIAP deficiency. We studied three young boys with immunodeficiency displaying XLP-2-like clinical features. No genetic variation in the coding exons of XIAP was identified by whole-exome sequencing (WES), although the patients exhibited a complete loss of XIAP expression. METHODS: Targeted next-generation sequencing (NGS) of the entire locus of XIAP was performed on DNA samples from the three patients. Molecular investigations were assessed by gene reporter expression assays in HEK cells and CRISPR-Cas9 genome editing in primary T cells. RESULTS: NGS of XIAP identified three distinct non-coding deletions in the patients that were predicted to be driven by repetitive DNA sequences. These deletions share a common region of 839 bp that encompassed the first non-coding exon of XIAP and contained regulatory elements and marks specific of an active promoter. Moreover, we showed that among the 839 bp, the exon was transcriptionally active. Finally, deletion of the exon by CRISPR-Cas9 in primary cells reduced XIAP protein expression. CONCLUSIONS: These results identify a key promoter sequence contained in the first non-coding exon of XIAP. Importantly, this study highlights that sequencing of the non-coding exons that are not currently captured by WES should be considered in the genetic diagnosis when no variation is found in coding exons.

A case of autoimmune enteropathy with CTLA4 haploinsufficiency.

Autoimmune enteropathy (AIE) is a rare disease, characterized by intractable diarrhea, villous atrophy of the small intestine, and the presence of circulating anti-enterocyte autoantibodies. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and mutations in FOXP3, which is a master gene of regulatory T cells (Tregs), are major causes of AIE. Recent studies have demonstrated that mutations in other Treg-associated genes, such as CD25 and CTLA4, show an IPEX-like phenotype. We present the case of a 13-year-old girl with CTLA4 haploinsufficiency, suffering from recurrent immune thrombocytopenic purpura and intractable diarrhea. We detected an autoantibody to the AIE-related 75 kDa antigen (AIE-75), a hallmark of the IPEX syndrome, in her serum. She responded well to a medium dose of prednisolone and a controlled dose of 6-mercaptopurine (6-MP), even after the cessation of prednisolone administration. Serum levels of the soluble interleukin-2 receptor and immunoglobulin G (IgG) were useful in monitoring disease activity during 6-MP therapy. In conclusion, autoimmune-mediated mechanisms, similar to the IPEX syndrome, may be involved in the development of enteropathy in CTLA4 haploinsufficiency. Treatment with 6-MP and monitoring of disease activity using serum levels of soluble interleukin-2 receptor and IgG is suggested for such cases.

Effect of adding magnifying BLI, magnifying NBI, and iodine staining to white light imaging in diagnosis of early esophageal cancer.

Background and study aims We investigated the effect of adding magnifying blue laser imaging (BLI), magnifying narrow-band imaging (NBI), and iodine staining to white light imaging in diagnosis of early esophageal squamous cell carcinoma (EESCC) in high-risk patients. Patients and methods Between May 2013 and March 2016, two parallel prospective cohorts of patients received either primary WLI followed by NBI-magnifying endoscopy (ME) or primary WLI followed by BLI-ME, were studied. At the end of screening, both groups underwent iodine staining. The percentage of patients with newly detected esophageal malignant lesions in each group and the diagnostic ability of image-enhanced endoscopy (IEE)-ME were evaluated. Results There are 258 patients assigned to the NBI-ME group and 254 patients assigned to the BLI-ME group. The percentage of patients with one or more malignant lesions detected in the WLI + NBI-ME examination was similar in the WLI + BLI-ME examination (15 of 258 patients or 5.81 % vs. 14 of 254 patients or 5.51 %). However, four of 19 lesions in the NBI-ME group and six of 21 lesions in the BLI-ME group were overlooked and were detected by iodine staining. NBI-ME and BLI-ME showed similar accuracy in differentiation of cancerous lesions from non-cancerous lesions in diagnosis of EESCC (NBI/BLI: sensitivity, 87.5/89.5; specificity, 78.9/76.6; accuracy, 80.8/79.5; positive predictive value, 53.8/53.1; negative predictive value, 95.7/96.1). Conclusions Both NBI and BLI were useful for detection of EESCC. However, because some lesions were overlooked by even NBI and BLI, high-risk patients may benefit from use of iodine staining during endoscopic screening of EESCC (UMIN000023596).

Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency.

BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment. OBJECTIVE: To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT. METHODS: A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed. RESULTS: Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT. CONCLUSIONS: This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.

Preoperative lymphocyte-to-monocyte ratio is the most predictive inflammatory response marker of survival in gastric cancer.

PURPOSE: Systemic inflammatory responses play a key role in cancer progression, and detecting the predictive inflammatory response markers is needed. The present study explored inflammatory response markers capable of predicting survival in patients with gastric cancer. METHODS: We enrolled 264 patients, who underwent curative gastrectomy for clinical stage (cStage) I-III gastric cancer between 2012 and 2015. The cut-off point of eight preoperative inflammatory response markers was determined by receiver operating characteristic (ROC) curve analysis. The marker with the highest Harrell's concordance index (C-index) was adopted for subsequent univariate and multivariate analyses using the Cox proportional-hazards model. RESULTS: Among eight representative inflammatory response markers, lymphocyte-to-monocyte ratio (LMR; cut-off point, 4.60) achieved the highest C-index (0.633). The 5-year survival rate was significantly worse in patients with LMR < 4.60 than in those with LMR ≥ 4.60 (67.5% versus 89.0%, P < 0.001). In multivariate analysis, LMR < 4.60 was identified as an independent prognostic factor (hazard ratio: 2.372; 95% confidence interval: 1.266-4.442; P = 0.007). CONCLUSION: In this study, LMR had the strongest ability to predict the survival of patients with gastric cancer among other inflammatory response markers, with lower LMRs being associated with poor survival following curative gastrectomy.

Impact of Preoperative Time Interval on Survival in Patients With Gastric Cancer.

BACKGROUND: A time interval between diagnosis and surgery for gastric cancer is necessary, although its impact on survival remains controversial. We evaluated the impact of preoperative time interval on survival in gastric cancer patients. METHODS: We enrolled 332 patients who underwent curative gastrectomy for clinical stage (cStage) I-III gastric cancer between 2012 and 2015. We separately analyzed early- (cStage I) and advanced-stage (cStages II and III) patients. Early-stage patients were divided according to preoperative time interval: short (≤ 42 days) and long (> 42 days) groups. Advanced-stage patients were also divided into short (≤ 21 days) and long (> 21 days) groups. We compared the survival between the short and long groups in early- and advanced-stage patients. RESULTS: The median preoperative time interval was 29 days, and no significant differences were found in patient characteristics between the short and long groups in early- and advanced-stage patients. In early-stage patients, the 5-year survival rates of the short and long groups were 86.5% and 88.4%, respectively (P = 0.917). In advanced-stage patients, the 5-year survival rates were 72.1% and 70.0%, respectively (P = 0.552). In multivariate analysis, a longer time interval was not selected as an independent prognostic factor in early- and advanced-stage patients. CONCLUSIONS: In this study, survival difference was not found based upon preoperative time interval. The results do not affirm the delay of treatment without reason, however, imperative extension of preoperative time interval may be justified from the standpoint of long-term survival.