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.

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.

Allogeneic Hematopoietic cell Transplantation Using Alemtuzumab in Asian Patients with Inborn Errors of Immunity.

Alemtuzumab is used with reduced-toxicity conditioning (RTC) in allogeneic hematopoietic cell transplantation (HCT), demonstrating efficacy and feasibility for patients with inborn errors of immunity (IEI) in Western countries; however, the clinical experience in Asian patients with IEI is limited. We retrospectively analyzed patients with IEI who underwent the first allogeneic HCT with alemtuzumab combined with RTC regimens in Japan. A total of 19 patients were included and followed up for a median of 18 months. The donors were haploidentical parents (n = 10), matched siblings (n = 2), and unrelated bone marrow donors (n = 7). Most patients received RTC regimens containing fludarabine and busulfan and were treated with 0.8 mg/kg alemtuzumab with intermediate timing. Eighteen patients survived and achieved stable engraftment, and no grade 3-4 acute graft-versus-host disease was observed. Viral infections were observed in 11 patients (58%) and 6 of them presented symptomatic. The median CD4+ T cell count was low at 6 months (241/µL) but improved at 1 year (577/µL) after HCT. Whole blood cells continued to exhibit > 80% donor type in most cases; however, 3/10 patients exhibited poor donor chimerism only among T cells and also showed undetectable levels of T-cell receptor recombination excision circles (TRECs) at 1 year post-HCT. This study demonstrated the efficacy and safety of alemtuzumab; however, patients frequently developed viral infections and slow reconstitution or low donor chimerism in T cells, emphasizing the importance of monitoring viral status and T-cell-specific chimerism. (238 < 250 words).

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.

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.

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.

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.

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.

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.

Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3.

PURPOSE: Germline loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene result in autosomal dominant hyper IgE syndrome, whereas somatic gain-of-function (GOF) variants in STAT3 are associated with some malignancies. In addition, germline GOF variants in STAT3 are linked to disorders involving autoimmunity and lymphoproliferation. In this study, we describe five Japanese families with germline GOF variants in STAT3, including three novel variants. We also present the clinical and immunological characteristics of these patients. METHODS: Eight patients from five families were enrolled in this study. We performed genetic and immunological analyses, and collected the associated clinical information. RESULTS: We identified five heterozygous variants in STAT3 using whole-exome sequencing and target gene sequencing. Two of these (E286G and T716M) were previously reported and three (K348E, E415G, and G618A) were novel. A STAT3 reporter assay revealed that all of the variants were GOF. However, the immunological and clinical characteristics among the patients were highly variable. CONCLUSION: Patients with STAT3 GOF variants exhibited clinical and immunological heterogeneity with incomplete penetrance.

Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.

PURPOSE: The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). METHODS: We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. RESULTS: The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. CONCLUSIONS: RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.

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.

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.

Histological changes in the human esophagus following triamcinolone injection to prevent esophageal stricture after endoscopic submucosal dissection.

BACKGROUND: Locoregional steroid injection prevents post-endoscopic submucosal dissection (ESD) esophageal stricture, but histological changes that occur following steroid injection in the human esophagus are unclear. This study investigated the histopathological characteristics caused by locoregional triamcinolone acetonide (TA) injection using human esophagectomy specimens. METHODS: From January 2014 to December 2019, among 297 patients (373 lesions) who underwent esophageal ESD, 13 patients who underwent additional esophagectomy after ESD were examined. Seven patients (TA group) with wide excisions were injected with TA after ESD and another six patients (Non-TA group) with smaller tumors were not injected with TA. The clinical background of these patients and histopathological features of ESD ulcer scar obtained from esophagectomy specimens were retrospectively investigated. RESULTS: The circumferential rate of ESD excision was more than three-quarters in all cases in the TA group, whereas it was less than three-quarters in the Non-TA group. No other statistical difference in the clinical background was found between the two groups. The subepithelial fibrous tissue of the ESD ulcer scar in the TA group was significantly thinner than that in the Non-TA group (P < 0.05). There was no significant difference in the thickness of the regenerated epithelium and muscularis propria layer of the ESD ulcer scar. CONCLUSIONS: Histological finding of thinning of the subepithelial fibrous tissue of ESD ulcer scar in the human esophagus after TA injection was obtained. This suggests that TA suppresses the proliferation of the fibrous tissue of the subepithelial layer to help prevent esophageal stricture after widespread ESD in the human esophagus.

Inherited chromosomally integrated human herpesvirus-6 in a patient with XIAP deficiency.

Human herpesvirus-6 (HHV-6) is a common pathogen affecting the human population. Primary HHV-6 infection generally occurs during infancy and causes exanthema subitum. Moreover, HHV-6 may exhibit inherited chromosomally integrated HHV-6 (iciHHV-6) in certain individuals. Although iciHHV-6 is generally known to be nonpathogenic, it may cause reactivation in patients with primary immunodeficiency disease (PID). XIAP deficiency is a rare PID characterized by recurrent hemophagocytic lymphohistiocytosis (HLH). It has been reported that the Epstein-Barr virus primarily causes HLH; however, the other pathogens, including HHV-6, can also cause this complication. We encountered a case of XIAP deficiency accompanied by iciHHV-6. He suffered from recurrent HLH, for which allogeneic bone marrow transplantation (BMT) was performed as a curative therapy. During the course of BMT, the patient experienced HLH three times, but there was no reactivation of endogenous HHV-6 from iciHHV-6. Finally, the patient achieved complete donor chimerism and a decline in HHV-6 DNA copy number in whole blood. This case report demonstrates no evidence of reactivation of iciHHV-6 during BMT in a patient with XIAP deficiency.

The Impact of Hybrid Minimally Invasive Esophagectomy with Neck-Abdominal First Approach on the Short- and Long-Term Outcomes for Esophageal Squamous Cell Carcinoma.

BACKGROUND: Currently, there is no consensus for an optimal minimally invasive esophagectomy (MIE) approach. This study aimed to compare hybrid MIE (hMIE) with neck-abdominal first approach to standard open esophagectomy (OE). METHODS: Data from a cohort of 301 patients were retrospectively analyzed. All participants received either hMIE or OE for the treatment of esophageal squamous cell carcinoma at Tokyo Medical and Dental University between January 2003 and December 2013. Analyses included propensity score matching and the Kaplan-Meier statistical method to determine overall survival (OS) and disease-free survival (DFS) of the cohort. RESULTS: After one-to-one propensity score matching, there were 68 patient pairs. The hMIE group had significantly lower incidence of severe postoperative complications (20.1% vs. 7.4%; p = 0.026) and severe respiratory complications (7.4% vs. 0%; p = 0.058) than the OE group. The 5-year oncological outcomes of the two groups were almost equivalent (OS: OE, 55.0%; hMIE, 69.0%; p = 0.063 and DFS: OE, 54.0%; hMIE, 62.0%; p = 0.28). CONCLUSIONS: This study compared hMIE with neck-abdominal first approach to standard OE. The results showed significantly less severe postoperative complications for hMIE with neck-abdominal first approach in comparison with OE, without a compromise in long-term oncological outcomes.

Identification of autoantibodies using human proteome microarrays in patients with IPEX syndrome.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is one of the inborn errors of immunity, characterized by impaired function of the regulatory T cells. Clinical manifestations of IPEX syndrome are characterized by various autoimmune diseases with autoantibodies. The comprehensive analysis for autoantibodies using human proteome microarrays in the four patients with IPEX syndrome was performed. The numbers of the highly expressed autoantibody showing relative log2 ratios greater than 1 were 1876, 513, 234 and 831 (mean: 864), respectively. Some novel autoantibodies which could explain the phenotypes of patients, adrenal dysfunction, muscular hypotonia, afibrinogenemia, enteropathy and pancytopenia were identified. Various kinds of autoantibodies targeting testis-specific antigens were also identified. Human proteome microarray is a powerful tool to understand the pathophysiology of IPEX syndrome. The larger cohort analysis using this method will provide further understanding of the impaired immune tolerance in humans.

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome.

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome is an autoimmune disorder caused by the dysfunction of FOXP3, which leads to regulatory T-(Treg) cell dysfunction and subsequently autoimmunity including type 1 diabetes mellitus (T1D). Presently, allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for IPEX syndrome, but not for T1D. Generally, after complete loss of pancreatic ß-cells, HSCT cannot improve the prognosis of T1D. Here, we report the case of a 16-year-old adolescent with late-onset of FOXP3 R347H mutation associated IPEX syndrome with T1D, where insulin dependency was ameliorated following HSCT. This patient with insulin-dependent diabetes mellitus required insulin dosage of 1.28 U/kg/day for 1 month before HSCT. Although the results of glucose homeostasis before HSCT revealed impaired insulin secretion and low ΔC-peptide immunoreactivity (CPR, 1.0 ng/mL), the patient withdrew insulin infusion and remained euglycemic at 15 months after HSCT, and had normal ß-cell function with improved ΔCPR (3.4 ng/mL) at 20 months after HSCT. The present case suggests that HSCT for T1D-associated IPEX syndrome improves Treg deficiency and prevents elimination of ß-cells. We speculate that the period from the onset of T1D to HSCT could affect the therapeutic efficacy for T1D with IPEX, and early intervention with HSCT before or immediately after the onset of DM can rescue ß-cells and remit T1D completely. Our study elaborates not only the therapeutic strategy for T1D with IPEX, but also the pathogenic mechanism in general T1D.