The first detailed annual record on the National Clinical Database Urology Division in Japan: A report on five surgical procedures.

OBJECTIVES: The National Clinical Database (NCD) Urology Division commenced registration in April 2018 in Japan. This is the first report to focus on five surgeries for which detailed information is registered. METHODS: We herein describe annual trends in and the complication grades of the following five surgeries: partial nephrectomy, radical nephrectomy, radical cystectomy, radical prostatectomy, and pyeloplasty, using the NCD. A total of 149 417 patients treated with the five types of surgeries based on NCD data were enrolled in this report. RESULTS: The number of patients was 55 630 for partial/radical nephrectomy from April 2018 to December 2021, 83 653 for radical prostatectomy from April 2018 to December 2021, and 9342 for radical cystectomy from January 2020 to December 2021. In 2021, partial nephrectomy was performed on 7416 cases, radical nephrectomy on 7739 cases, radical prostatectomy on 22 692 cases, radical cystectomy on 4677 cases, and pyeloplasty on 792 cases. CONCLUSIONS: The results obtained showed that a robot-assisted or laparoscopic procedure has replaced open surgery as the common approach for all five surgeries. An analysis of NCD data may be useful for understanding trends in surgical procedures across the major field of urology.

Outcome research on esophagectomy analyzed using nationwide databases in Japan: evidences generated from real-world data.

Esophagectomy for esophageal cancer is a highly invasive gastrointestinal surgical procedure. The National Clinical Database (NCD) of Japan, initiated in 2011, has compiled real-world data on esophagectomy, one of nine major gastroenterological surgeries. This review examines outcomes after esophagectomy analyzed using the Japanese big databases. Certification systems by the Japanese Society of Gastroenterological Surgery (JSGS) and the Japan Esophageal Society (JES) have shown that institutional certification has a greater impact on short-term surgical outcomes than surgeon certification. Minimally invasive esophagectomy has emerged as a viable alternative to open esophagectomy, although careful patient selection is crucial, especially for elderly patients with advanced tumors. The NCD has significantly contributed to the assessment and enhancement of surgical quality and short-term outcomes, while studies based on Comprehensive Registry of Esophageal Cancer in Japan (CRECJ) have provided data on patient characteristics, treatments, and long-term outcomes. The JES has conducted various questionnaire-based retrospective clinical reviews in collaboration with authorized institutions certified by JES. The Diagnosis Procedure Combination (DPC) database provides administrative claims data including itemized prices for surgical, pharmaceutical, laboratory, and other inpatient services. Analyzing these nationwide databases can offer precise insights into surgical quality for esophageal cancer, potentially leading to improved treatment outcomes.

Genomic Profiling of Small Intestine Cancers From a Real-World Data Set Identifies Subgroups With Actionable Alterations.

PURPOSE: Panel-based comprehensive genomic profiling (CGP) is used in clinical practice worldwide; however, large real-world data (RWD) of patients with advanced small intestine cancer have not been characterized. We investigated differences in the prevalence of clinically relevant alterations across molecularly defined or age-stratified subgroups. PATIENTS AND METHODS: This was a collaborative biomarker study of RWD from CGP testing (Foundation Medicine, Inc). Hybrid capture was conducted on at least 324 cancer-related genes and select introns from up to 31 genes frequently rearranged in cancer. Overall, 1,364 patients with advanced small intestine cancer were available for analyses and were stratified by age (≥40 years/<40 years), microsatellite instability (MSI) status, tumor mutational burden (TMB) status (high ≥10/low <10 Muts/Mb), and select gene alterations. The frequency of alterations was analyzed using a chi-square test with Yate's correction. RESULTS: Genes with frequent alterations included TP53 (59.8%), KRAS (54.8%), APC (27.7%), and CDKN2A (22.4%). Frequent genes with amplifications were MYC (6.7%), MDM2 (5.9%), GATA6 (5.5%), and CCND1 (3.4%). Patients younger than 40 years had significantly lower frequency of APC mutations than those 40 years and older (10.4% v 28.7%; P = .0008). Druggable genomic alterations were detected in 22.3% of patients: BRAF V600E (1.2%), BRCA1 (1.8%), BRCA2 (3.2%), ERBB2 amplification (3.2%), KRAS G12C (3.3%), NTRK1/2/3 fusion (0.07%), MSI-high (7.0%), and TMB-high (12.2%), with no significant differences in the frequency according to age (<40 years v ≥40 years; 22.1% v 22.3%). TMB of 10-20 Mut/Mb was observed in 4.8% of patients, and TMB ≥20 Mut/Mb was seen in 7.3% of the cohort. CONCLUSION: RWD from clinical panel testing revealed the genomic landscape in small intestine cancer by subgroup. These findings provide insights for the future development of treatments in advanced small intestine cancer.

Annual record on the number of general urological surgeries registered in the National Clinical Database system between April 2018 and December 2021 in Japan.

BACKGROUND: The Japanese National Clinical Database (NCD) is a large-scale, nationwide, web-based data entry system that covers the majority of surgical cases performed in Japan. An NCD specializing in urological surgery was launched based on the NCD system in 2018. METHODS: All urological surgeries performed at more than 1000 institutions were registered from 2018. We herein report the number of surgeries conducted as stipulated in the "Certified Urology Surgeon Training Curriculum" between April 2018 and December 2021. RESULTS: A total of 1 377 677 cases were registered from 1185 facilities nationwide under the initiative of the Japanese Urological Association. We examined the number of procedures performed every year for each of the 10 categories. CONCLUSIONS: The NCD system sustainably provides important information relating to the preoperative status, operational outcome, and best practice for urological surgery in Japan.

Virion-surface display of a chimeric immunoglobulin Fc domain facilitating uptake by antigen-presenting cells.

Antigen-presenting cells (APCs) play an important role in virus infection control by bridging innate and adaptive immune responses. Macrophages and dendritic cells (DCs) possess various surface receptors to recognize/internalize antigens, and antibody binding can enhance pathogen-opsonizing uptake by these APCs via interaction of antibody fragment crystallizable (Fc) domains with Fc receptors, evoking profound pathogen control in certain settings. Here, we examined phagocytosis-enhancing potential of Fc domains directly oriented on a retroviral virion/virus-like particle (VLP) surface. We generated an expression vector coding a murine Fc fragment fused to the transmembrane region (TM) of a retroviral envelope protein, deriving expression of the Fc-TM fusion protein on the transfected cell surface and production of virions incorporating the chimeric Fc upon co-transfection. Incubation of Fc-displaying simian immunodeficiency virus (SIV) with murine J774 macrophages and bone marrow-derived DCs derived Fc receptor-dependent enhanced uptake, being visualized by imaging cytometry. Alternative preparation of a murine leukemia virus (MLV) backbone-based Fc-displaying VLP loading an influenza virus hemagglutinin (HA) antigen resulted in enhanced HA internalization by macrophages, stating antigen compatibility of the design. Results show that the Fc-TM fusion molecule can be displayed on certain viruses/VLPs and may be utilized as a molecular adjuvant to facilitate APC antigen uptake.

Hypertrophic cardiomyopathy-related left ventricular pseudoaneurysm: A case report.

Background: Myocardial infarction-related left ventricular pseudoaneurysm (LVP), covered by the adjacent pericardial or scar tissue, is a fatal sequela of left ventricular rupture. Whereas hypertrophic cardiomyopathy (HCM) may cause left ventricular true aneurysm. Differentiating LVP from left ventricular true aneurysm is crucial because their natural histories and treatment strategies are distinct. However, the incidence and management of HCM-related LVP remain unknown. Case presentation: An 88-year-old man was admitted to our hospital with sudden-onset chest pain. Upon initial examination, vital signs were stable, and a grade 4/6 systolic murmur was noted. An electrocardiogram revealed atrial fibrillation and poor R-wave progression without ST-T changes or negative T-waves. An echocardiography showed mild left ventricular hypertrophy, mid-ventricular obstruction with a significant intraventricular pressure gradient, left ventricular outflow tract obstruction, and a small left ventricular apical outpouching. Cardiac computed tomography angiography (CCTA) assisted in the diagnosis of LVP, and an accompanying pericardial effusion suggested impending cardiac rupture. Because the patient initially refused our proposed urgent surgery, medication was initiated with continuous hemodynamic monitoring in the intensive care unit; however, the patient's condition did not improve. During a semi-urgent surgical repair of the aneurysmal wall, LVP was observed and confirmed by pathology. Myocardial tissue adjacent to the pseudoaneurysm was consistent with that of HCM. Subsequently, a final diagnosis of HCM-related LVP was made. The postoperative course was notable for transient profound hypotension. Thereafter, the patient died of non-occlusive mesenteric ischemia on day 6. Conclusions: To our knowledge, this is the first reported case of HCM-related LVP mimicking impending cardiac rupture. Our case highlights the importance of considering HCM-related LVP in patients with left ventricular outpouching and CCTA in the LVP diagnosis. In further research, data on the appropriate management of HCM-related LVP should be accumulated.

Prognostic factors for patients 85 years or older undergoing endoscopic submucosal dissection for early gastric cancer.

BACKGROUND: Little is known about prognostic factors for patients 85 years or older undergoing endoscopic submucosal dissection for early gastric cancer. Therefore, this study aimed to identify such prognostic factors. METHODS: We retrospectively evaluated the long-term outcomes and prognostic factors of 143 patients 85 years or older undergoing endoscopic submucosal dissection for early gastric cancer at a single-center between October 2005 and September 2020. Using the Kaplan-Meier method and a Cox proportional hazards regression model, we examined the relationships of patient characteristics and endoscopic curability (additional gastrectomy recommended [eCuraC-2] or not recommended) with overall survival. RESULTS: The median age of the patients was 86 years, and most patients were men (65%). The eCuraC-2 rate was 14.7%. During the follow-up period, 55 patients died; however, only two patients died due to gastric cancer. The 3-year and 5-year overall survival rates were 91.5% and 74.7%, respectively. Male sex (hazard ratio, 2.23; 95% confidence interval, 1.16-4.30), American Society of Anesthesiologists Physical Status of 3 (hazard ratio, 2.57; 95% confidence interval, 1.32-4.99), body mass index < 18.9 kg/m2 (hazard ratio, 2.21; 95% confidence interval, 1.11-4.40), and eCuraC-2 (hazard ratio, 3.04; 95% confidence interval, 1.37-6.75) were identified as independent prognostic factors. Moreover, patients with eCuraC-2 had significantly more poor prognostic factors than those who did not. CONCLUSIONS: The decision to perform endoscopic submucosal dissection for patients with the aforementioned prognostic factors should be carefully considered because follow-up without endoscopic submucosal dissection is possible.

Effects of the COVID-19 pandemic on short-term postoperative outcomes for colorectal perforation: A nationwide study in Japan based on the National Clinical Database.

Aim: Possible negative effects of the COVID-19 pandemic on short-term postoperative outcomes for colorectal perforation in Japan were examined in this study. Methods: The National Clinical Database (NCD) is a large-scale database including more than 95% of surgical cases in Japan. We analyzed 13 107 cases of colorectal perforation from 2019 to 2021. National data were analyzed, and subgroup analyses were conducted for subjects in prefectures with high infection levels (HILs) and metropolitan areas (Tokyo Met. and Osaka Pref.). Postoperative 30-day mortality, surgical mortality, and postoperative complications (Clavien-Dindo grade ≥3) were examined. Months were considered to have significantly high or low mortality or complication rates, if the 95% confidence interval (CI) of the standardized mortality (morbidity) ratio (SMR) does not contain 1. Results: In the NCD, postoperative 30-day mortality occurred in 1371 subjects (10.5%), surgical mortality in 1805 (13.8%), and postoperative complications in 3950 (30.1%). Significantly higher SMRs were found for 30-day mortality in November 2020 (14.6%, 1.39 [95% CI: 1.04-1.83]) and February 2021 (14.6%, 1.48 [95% CI: 1.10-1.96]), and for postoperative complications in June 2020 (37.3%, 1.28 [95% CI: 1.08-1.52]) and November 2020 (36.4%, 1.21 [95% CI: 1.01-1.44]). The SMRs for surgical mortality were not significantly high in any month. In prefectures with HILs and large metropolitan areas, there were few months with significantly higher SMRs. Conclusions: The COVID-19 pandemic had limited negative effects on postoperative outcomes in patients with colorectal perforation. These findings suggest that the emergency system for colorectal perforation in Japan was generally maintained during the pandemic.

Presurgical mild anemia is a risk factor for severe postoperative complications of rectal cancer surgery: A Japanese nationwide retrospective cohort study.

Background: Anemia has negative effects on long-term outcomes of rectal cancer patients; however, its status as a risk factor for severe complications is disputed. Perioperative risks may differ based on the severity of pre-surgical anemia; nonetheless, no previous study has investigated these differences. This study identified risks of severe postoperative complications in rectal cancer patients based on severity of their pre-surgical anemia. Materials and Methods: This study enrolled patients who underwent low anterior resection for rectal cancer and were registered in the Japanese National Clinical Database (NCD) between 2017 and 2019. Anemia severity was categorized into three levels: mild, moderate, and severe. A logistic regression model was applied to calculate the risk-adjusted odds ratio (OR) of severe complications after surgery. Results: This study analyzed a cohort of 51 765 rectal cancer patients who underwent low anterior resection. Results showed that severe complications occurred in 10.9% of patients and were significantly more frequent in patients with anemia (13.6%) than those with normal hemoglobin levels (9.2%). Risk-adjusted ORs of severe complications in the severe, moderate, and mild anemia groups versus the normal group for males were 1.19 (95% confidence interval [CI]: 0.89-1.58), 1.47 (1.34-1.62), and 1.21 (1.12-1.31), respectively. Those for females were 1.39 (0.90-2.15), 1.64 (1.37-1.97), and 1.36 (1.16-1.58), respectively. Conclusions: According to this large cohort study, pre-surgical anemia significantly increases the risk of severe postoperative complications in rectal cancer patients. Even mild anemia presents a significant risk.

Investigation of the impact of COVID-19 on postoperative outcomes using a nationwide Japanese database of patients undergoing laparoscopic distal gastrectomy and low anterior resection for gastric cancer and rectal cancer.

Background: The COVID-19 outbreak made conventional medical care impossible, forcing changes in both healthcare providers and patients. In Japan, COVID-19 infection began spreading in earnest in 2020 and exploded in 2021. There was concern that the medical impact of COVID-19 in 2021 would differ from that in 2020. We aimed to clarify the impact of COVID-19 on mortality and anastomotic leakage in laparoscopic surgery for gastric cancer and rectal cancer in Japan using the National Clinical Database (NCD). Methods: We collected data from patients who underwent laparoscopic distal gastrectomy (LDG) and laparoscopic low anterior resection (LLAR) from January 2018 to December 2021 from the NCD, a web-based surgical registration system in Japan. The number of surgical cases, monthly incidence of mortality and morbidity (anastomotic leakage), standardized mortality ratio (SMR), and standardized morbidity-leakage ratio (SMLR [ratio of observed patients to expected patients calculated using the risk calculator established in the NCD]) were evaluated. Results: The numbers of LDG and LLAR cases continued to decline in the first year of the pandemic in 2020 and were as low in 2021 as in 2020. Although the numbers of robot-assisted LDG and LLAR cases increased, the growth rate was lower than the rate of increase prior to the pandemic. Mortality and anastomotic leakage, two of the most important complications, as assessed by SMR and SMLR, did not worsen during the pandemic in comparison to the pre-pandemic period. Conclusions: Laparoscopic surgeries were performed safely in Japan and were not affected by the COVID-19 pandemic.

Prophylactic vaccination inducing anti-Env antibodies can result in protection against HTLV-1 challenge in macaques.

Human T cell leukemia/T-lymphotropic virus type 1 (HTLV-1) infection occurs by cell-to-cell transmission and can induce fatal adult T cell leukemia. Vaccine development is critical for the control of HTLV-1 transmission. However, determining whether vaccine-induced anti-Env antibodies can prevent cell-to-cell HTLV-1 transmission is challenging. Here, we examined the protective efficacy of a vaccine inducing anti-Env antibodies against HTLV-1 challenge in cynomolgus macaques. Eight of 10 vaccinated macaques produced anti-HTLV-1 neutralizing antibodies (NAbs) and were protected from an intravenous challenge with 108 HTLV-1-producing cells. In contrast, the 2 vaccinated macaques without NAb induction and 10 unvaccinated controls showed HTLV-1 infection with detectable proviral load after challenge. Five of the eight protected macaques were administered with an anti-CD8 monoclonal antibody, but proviruses remained undetectable and no increase in anti-HTLV-1 antibodies was observed even after CD8+ cell depletion in three of them. Analysis of Env-specific T cell responses did not suggest involvement of vaccine-induced Env-specific T cell responses in the protection. These results indicate that anti-Env antibody induction by vaccination can result in functionally sterile HTLV-1 protection, implying the rationale for strategies aimed at anti-Env antibody induction in prophylactic HTLV-1 vaccine development.

The Molecular Landscape of Gastric Cancers for Novel Targeted Therapies from Real-World Genomic Profiling.

BACKGROUND: Panel-based comprehensive genomic profiling is used in clinical practice worldwide; however, large real-world datasets of patients with advanced gastric cancer are not well known. OBJECTIVE: We investigated what differences exist in clinically relevant alterations for molecularly defined or age-stratified subgroups. METHODS: This was a collaborative biomarker study of a real-world dataset from comprehensive genomic profiling testing (Foundation Medicine, Inc.). Hybrid capture was carried out on at least 324 cancer-related genes and select introns from 31 genes frequently rearranged in cancer. Overall, 4634 patients were available for analyses and were stratified by age (≥ 40/< 40 years), microsatellite instability status, tumor mutational burden status (high 10 ≥ /low < 10 Muts/Mb), Epstein-Barr virus status, and select gene alterations. We analyzed the frequency of alterations with a chi-square test with Yate's correction. RESULTS: Genes with frequent alterations included TP53 (60.1%), ARID1A (19.6%), CDKN2A (18.2%), KRAS (16.6%), and CDH1 (15.8%). Differences in comprehensive genomic profiling were observed according to molecularly defined or age-stratified subgroups. Druggable genomic alterations were detected in 31.4% of patients; ATM (4.4%), BRAF V600E (0.4%), BRCA1 (1.5%), BRCA2 (2.9%), ERBB2 amplification (9.2%), IDH1 (0.2%), KRAS G12C (0.7%), microsatellite instability-high (4.8%), NTRK1/2/3 fusion (0.13%), PIK3CA mutation (11.4%), and tumor mutational burden-high (9.4%). CDH1 alterations and MET amplification were significantly more frequent in patients aged < 40 years (27.7 and 6.2%) than in those aged ≥ 40 years (14.7 and 4.0%). CONCLUSIONS: Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer.

Short-term outcomes after liver resection with vascular reconstruction: Results from a study with the National Clinical Database of Japan.

BACKGROUND: Although curative resection with vascular reconstruction improves the prognosis of blood-invading locally advanced hepatobiliary tumors, the mortality and morbidity of the procedure remains unclear. This study aimed to clarify the risk factors associated with mortality and morbidity in patients undergoing liver resection with vascular reconstruction. METHODS: This retrospective observational study included 1215 patients undergoing hepatectomy of more than one section with vascular reconstruction, except for left lateral sectionectomy registered in the National Clinical Database (NCD) between 2015 and 2019. The rates of surgical mortality and relevant clinical factors were evaluated. RESULTS: Among the four types of vascular reconstruction, portal venous reconstruction was frequently performed in 724 patients (59.6% of the enrolled patients). Surgical mortality was 8.1%. Patients with hepatic artery reconstruction had the highest surgical mortality rate of 15.8%. In other types of reconstruction, surgical mortality was 9.1% in the portal vein, 5.2% in inferior vena cava, and 4.9% in hepatic vein. Factors significantly associated with surgical mortality include age, sex (male), preoperative comorbidity (American Society of Anesthesiologists grade >3, respiratory distress, diabetes, preoperative pneumonia, weight loss, and obstructive jaundice), poorer liver functional reserve (indocyanine green retention rate at 15 min and prothrombin time/international normalized ratio >1.1) and accompanying biliary reconstruction. CONCLUSIONS: The NCD revealed the detailed status of liver resection combined with vascular reconstruction in Japan. Based on the results of this analysis, understanding the factors that influence the outcome and postoperative course of each procedure will provide patients with accurate information and opportunities to improve future outcomes.

Impact of mixed-infection rate of clarithromycin-susceptible and clarithromycin-resistant Helicobacter pylori strains on the success rate of clarithromycin-based eradication treatment.

BACKGROUND: Clarithromycin (CAM) resistance is a major contributor to the failure to eradicate Helicobacter pylori (H. pylori). The mixed-infection ratio of CAM-susceptible and CAM-resistant H. pylori strains differs among individuals. Pyrosequencing analysis can be used to quantify gene mutations at position each 2142 and 2143 of the H. pylori 23S rRNA gene in intragastric fluid samples. Herein, we aimed to clarify the impact of the rate of mixed infection with CAM-susceptible and CAM-resistant H. pylori strains on the success rate of CAM-containing eradication therapy. MATERIALS AND METHODS: Sixty-four H. pylori-positive participants who received CAM-based eradication therapy, also comprising vonoprazan and amoxicillin, were enrolled in this prospective cohort study. Biopsy and intragastric fluid samples were collected during esophagogastroduodenoscopy. H. pylori culture and CAM-susceptibility tests were performed on the biopsy samples, and real-time PCR and pyrosequencing analyses were performed on the intragastric fluid samples. The mutation rates and eradication success rates were compared. RESULTS: The overall CAM-based eradication success rate was 84% (54/64): 62% (13/21) for CAM-resistant strains, and 95% (39/41) for CAM-sensitive strains. When the mutation rate of the 23S rRNA gene was 20% or lower for both positions (2142 and 2143), the eradication success rate was 90% or more. However, when the mutation rate was 20% or higher, the eradication success rate was lower (60%). CONCLUSIONS: The mutation rate of the CAM-resistance gene was related to the success of eradication therapy, as determined via pyrosequencing analysis.

An approach for improvement of the accuracy of cancer gene panel testing.

BACKGROUND: Tissue-based comprehensive genomic profiling (CGP) is increasingly being employed for genotype-directed therapies in patients with advanced cancer. However, tissue availability may limit their potential applications. In Japan, the cost of cancer gene panel tests is covered by public insurance for patients diagnosed with advanced solid tumors once in their lifetime. Therefore, it is essential to improve the success rate (reportability) and accuracy of CGP tests. The purpose of this study was to identify the factors associated with efficient and accurate CGP testing using relevant information obtained from real-world data. METHODS: This study included 159 samples analyzed using tumor-only panel FoundationOne® CDx cancer genome profiling (F1CDx) and 85 samples analyzed using matched-pair panel OncoGuide™ NCC Oncopanel system (NCCOP) at St. Marianna University Hospital. Sample characteristics (fixation conditions, storage period, histology, tumor cell ratio, and genomic tumor cell content), CGP performance, and quality control status were evaluated across all 244 tested samples. RESULTS: In 237/244 samples (97.1%), CGP testing results were successfully obtained [F1CDx, 99.4% (158/159) and NCCOP, 92.9% (79/85)]. An increased number of fibroblasts, inflammatory cells, and necrotic tumor cells, long-term storage, and/or prolonged fixation of tissue sections were involved in the unreported results and/or qualified CGP results. In addition, a negative correlation between median insert size values and ΔΔCq was observed in the NCCOP system. CONCLUSION: We identified various factors associated with efficient and accurate CGP testing using relevant information obtained from real-world data, suggesting that thorough selection and preparation of tissue sections could optimize CGP and maximize useful information.

Microsatellite instability: A 2024 update.

Deficient mismatch repair (dMMR) results in microsatellite instability (MSI), a pronounced mutator phenotype. High-frequency MSI (MSI-H)/dMMR is gaining increasing interest as a biomarker for advanced cancer patients to determine their eligibility for immune checkpoint inhibitors (ICIs). Various methods based on next-generation sequencing (NGS) have been developed to assess the MSI status. Comprehensive genomic profiling (CGP) testing can precisely ascertain the MSI status as well as genomic alterations in a single NGS test. The MSI status can be also ascertained through the liquid biopsy-based CGP assays. MSI-H has thus been identified in various classes of tumors, resulting in a greater adoption of immunotherapy, which is hypothesized to be effective against malignancies that possess a substantial number of mutations and/or neoantigens. NGS-based studies have also characterized MSI-driven carcinogenesis, including significant rates of fusion kinases in colorectal cancers (CRCs) with MSI-H that are targets for therapeutic kinase inhibitors, particularly in MLH1-methylated CRCs with wild-type KRAS/BRAF. NTRK fusion is linked to the colorectal serrated neoplasia pathway. Recent advances in investigations of MSI-H malignancies have resulted in the development of novel diagnostic or therapeutic techniques, such as a synthetic lethal therapy that targets the Werner gene. DNA sensing in cancer cells is required for antitumor immunity induced by dMMR, opening up novel avenues and biomarkers for immunotherapy. Therefore, clinical relevance exists for analyses of MSI and MSI-H-associated genomic alterations in malignancy. In this article, we provide an update on MSI-driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies.

Descriptive analysis of long-term survival after aortic valve replacement for dialysis patients: importance of renal pathologies and age.

OBJECTIVES: This study analyzed the long-term survival of dialysis patients undergoing AVR using the Japanese National Clinical Database with additional survival data. METHODS: De-novo AVR for dialysis-dependent patients between 2010 and 2012 who were registered in the Japan Cardiovascular Surgery Database were included. Concomitant aortic surgery and transcatheter aortic valve replacement were excluded. An additional questionnaire was sent to each hospital regarding the underlying kidney disease, the duration of dialysis initiation to the surgery, and clinical outcomes. The Kaplan-Meier survival curve was descriptively shown for all cohorts and each renal pathology. Furthermore, we compared the incidence of bioprosthetic valve failure in patients who were < 65 years old (group Y) and ≧65 years old (group O). RESULTS: Of these 1529 patients, diabetic nephropathy was 517, chronic glomerulonephritis was 437, and renal sclerosis was 210, regarding renal pathology. 1, 3, and 5-year survival in each pathology was 78.4%, 58.6%, 45.9% in diabetic nephritis, 78.8%, 68.4%, 58.2% in chronic glomerulonephritis, 79.0%, 67.8%, 52.1% in renal sclerosis, and 74.4%, 62.6%, 49.2% in others. Active infectious endocarditis was more prevalent in group Y (O 2.7% vs. Y 9.6%). The incidence of bioprosthetic valve failure requiring re-hospitalization was too small to analyze. 1, 3, and 5-year survival was 76.0%, 63.4%, 49.2% in group O and 74.3%, 64.2%, and 47.7% in group Y. CONCLUSIONS: Long-term survival of AVR for dialysis-dependent was higher in patients with chronic glomerulonephritis and lower in patients with diabetic nephritis than in other pathologies.

Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency.

Inflammatory bowel disease (IBD) occurring following allogeneic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis needs to be better defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stem cell donors. This is despite the fact that more than 100 inborn errors of immunity may cause or contribute to IBD. We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient's blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in the patient's serum, and in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic CD25 expression and production of inflammatory cytokines were preserved. TIM-3 expression was barely detectable in the immune cells of the patient's intestinal mucosa, while being detected unambiguously in the inflamed and non-inflamed colon from unrelated individuals. In conclusion, we report the first case of acquired, "transplanted" insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.