Iron deposition in gastric black spots: Clinicopathological insights and NanoSuit-correlative light and electron microscopy analysis.

Objectives: Black spots (BSs) are lentiginous findings observed in the gastric body and fundus during upper gastrointestinal endoscopy and are predominantly seen in patients undergoing Helicobacter pylori eradication treatment. However, the detailed patient background and exact composition are poorly understood. This study aims to clarify the clinicopathological features of BSs, examine patient demographics, and use the NanoSuit-correlative light and electron microscopy (CLEM) method combined with scanning electron microscopy-energy dispersive X-ray spectroscopy for elemental analysis. Methods: Patients who underwent upper gastrointestinal endoscopy between 2017 and 2022 were included. Data on age, medications, blood tests, and H. pylori infection status were retrospectively gathered from medical records. Univariate analysis was conducted to examine BS presence, with results then used in a multivariate model to identify associated risk factors. Additionally, pathological specimens from patients with BSs were analyzed for elemental composition using the NanoSuit-CLEM method combined with scanning electronmicroscopy-energy dispersive X-ray spectroscopy. Results: An analysis of 6778 cases identified risk factors for BSs, including older age and using proton pump inhibitors, statins, corticosteroids, and antithrombotic drugs. Endoscopically, BSs correlated with higher gastric atrophy and lower active H. pylori infection. Iron deposition at BS sites was specifically identified using NanoSuit-CLEM. Conclusions: BSs on gastrointestinal endoscopy may indicate an absence of active H. pylori inflammation. The discovery of iron deposition within BSs using the NanoSuit-CLEM method has offered new insights into the possible causative factors and advances our understanding of the etiology of BSs, bringing us closer to unraveling the underlying mechanisms of their formation.

A family with neuronal intranuclear inclusion disease with focal segmental glomerulosclerosis.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease caused by the expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of NOTCH2NLC. Although increasing evidence suggests that NIID affects various organs, its association with renal involvement remains unclear. We studied the genetic background of a family with NIID, in which four of five members presented with proteinuria as the initial manifestation. The renal pathology of three patients was diagnosed as focal segmental glomerulosclerosis (FSGS) at a previous hospital. These patients also presented with tremors, retinal degeneration, and episodic neurological events. Finally, one patient exhibited reversible bilateral thalamic high-intensity signal changes on diffusion-weighted imaging during episodic neurological events. METHODS: Exome sequencing (ES) and nanopore long-read whole-genome sequencing (LR-WGS) were performed on the index case, followed by nanopore target sequencing using Cas9-mediated PCR-free enrichment and methylation analysis. RESULTS: ES revealed no candidate variants; however, nanopore LR-WGS in the index case revealed expansion of short tandem repeats (STR) in NOTCH2NLC. Subsequent nanopore target sequencing using Cas9-mediated PCR-free enrichment showed STR expansion of NOTCH2NLC in an affected sibling and asymptomatic father. Methylation analysis using nanopore data revealed hypermethylation of the expanded allele in the asymptomatic father and partial hypermethylation in a mildly symptomatic sibling, whereas the expanded allele was hypomethylated in the index case. CONCLUSIONS: This investigation expands the clinical spectrum of NIID, suggesting that STR expansion of NOTCH2NLC is a cause of renal diseases, including FSGS.

Genomic medicine advances for brain tumors.

Cancer genome profiling has revealed important genetic alterations that serve as prognostic indicators and guides for treatment decisions, enabling precision medicine. The shift to molecular diagnosis of brain tumors, as reflected in the 2021 World Health Organization Classification of Tumors of the Central Nervous System, is a crucial role for treatment decision-making. This review discusses the significance and role of cancer genome profiling in precision medicine for malignant brain tumors, particularly gliomas. Furthermore, we explore the progress in cancer genome analysis, focusing on cancer gene panel testing, integration of genomic information in brain tumor classification, and hereditary tumors. Additionally, we discuss the transformative effect of genomic medicine on early detection, risk assessment, and precision medicine strategies. The tumor mutational burden in brain tumors is considered low, but the application of molecular targeted drugs, such as isocitrate dehydrogenase inhibitors, v-raf murine sarcoma viral oncogene homolog B1 inhibitors, fibroblast growth factor receptor inhibitors, neurotrophic tyrosine receptor kinase, mechanistic target of rapamycin inhibitors, and anti-programmed death receptor-1 antibody drugs are promising for glioma treatment. We also discuss the future prospects of molecular targeted drugs.

Ustekinumab effectiveness in Crohn's disease with lesions in the intestines.

Ustekinumab is prescribed for the treatment of patients with steroid-resistant moderate to severe Crohn's disease. We investigated its clinical outcome in patients with small and large intestinal lesions. Patients who were newly administered ustekinumab between March 2014 and December 2020 at Hamamatsu University Hospital were included in the study. The primary endpoint was Crohn's disease activity index score at baseline and weeks 8, 24, and 48 after the initiation of treatment, and secondary endpoints were albumin, hemoglobin, and C-reactive protein at these time points. Ustekinumab treatment retention was examined in both groups; the 2 groups were compared using the Friedman test, Mann-Whitney U test, or Fisher exact test. Overall, Crohn's disease activity index scores improved between baseline and 48 weeks, but the difference was not significant. However, there was a significant improvement between baseline and 48 weeks in patients with lesions in the small intestine only. Overall, patients showed significant improvement in albumin levels between baseline and 48 weeks but not in C-reactive protein or hemoglobin levels. When limited to patients with lesions in the small intestine, albumin and hemoglobin levels showed significant improvement. Both types showed high rates of treatment retention, although there was no significant difference. Ustekinumab appears to be a safe and effective treatment option that may be particularly effective in patients with lesions in the small intestine only.

Multicenter study of invasive gastric cancer detected after 10 years of Helicobacter pylori eradication in Japan: Clinical, endoscopic, and histopathologic characteristics.

Objectives: Gastric cancer can be diagnosed even in patients long after Helicobacter pylori eradication. Most cases involve intramucosal lesions; however, some are invasive and require surgery. To clarify appropriate long-term surveillance methods, this study compared invasive gastric cancer diagnosed ≥10 and <10 years after eradication. Methods: This retrospective multicenter study included 14 institutions. We included 377 patients with gastric cancer with submucosal or deep invasion after surgical or endoscopic resection. Ordered logistic regression analysis was used to explore the factors contributing to the pathological stage and histological type. Results: Invasive gastric cancer was detected in 84 patients (Group L) and 293 patients (Group S) ≥10 and <10 years after H. pylori eradication, respectively. Endoscopic mucosal atrophy at the time of cancer detection was similar in both groups; 50% of the patients had severe atrophy. Annual endoscopy correlated with early pathological stage (odds ratio [OR] 0.28, 95% confidence interval [CI] 0.14-0.54, p < 0.001). Group L exhibited an independent correlation with the advanced pathological stage (OR 2.27, 95% CI 1.06-4.88, p = 0.035) and the undifferentiated type (OR 2.12, 95% CI 1.16-3.90, p = 0.015). The pure differentiated type and early pathological stage significantly (p = 0.001) correlated with severe mucosal atrophy in Group S but not in Group L. Conclusions: Invasive cancers diagnosed ≥10 years after H. pylori eradication were likely to be more malignant in histological type and pathological stage. Gastric cancer surveillance should continue regardless of endoscopic atrophy, particularly ≥10 years after eradication.

Long-term prognosis after stapled and hand-sewn ileal pouch-anal anastomoses for familial adenomatous polyposis: a multicenter retrospective study.

PURPOSE: The long-term prognosis of stapled and hand-sewn ileal pouch-anal anastomoses in familial adenomatous polyposis patients in Japan remains unknown. This study aimed to compare the overall survival in familial adenomatous polyposis patients who underwent stapled or hand-sewn ileal pouch-anal anastomosis. METHODS: This multicenter retrospective study was conducted at 12 institutions in Shizuoka Prefecture, Japan. The clinical outcomes of 53 eligible familial adenomatous polyposis patients who underwent stapled (n = 24) and hand-sewn (n = 29) ileal pouch-anal anastomosis were compared. RESULTS: The median follow-up duration was 171.5 months. The incidence of adenoma in the remnant rectum or anal transitional zone and metachronous rectal cancer was significantly more common in stapled ileal pouch-anal anastomosis (adenoma: stapled, 45.8%, vs. hand-sewn, 10.3%, p = 0.005; metachronous rectal cancer: 29.2%, vs. none, p = 0.002). The number of deaths was remarkably higher in stapled ileal pouch-anal anastomosis (p = 0.002). Metachronous rectal cancer was the most common cause of death. Overall survival was worse in stapled ileal pouch-anal anastomosis than in hand-sewn ileal pouch-anal anastomosis (120 months, 90.7% vs. 96.6%; 240 months, 63.7% vs. 96.6%; p = 0.044). Cox regression analysis revealed the independent effects of preoperative advanced colorectal cancer and stapled ileal pouch-anal anastomosis on overall survival. CONCLUSION: Stapled ileal pouch-anal anastomosis negatively affected the overall survival of familial adenomatous polyposis patients. Therefore, hand-sewn ileal pouch-anal anastomosis is recommended for better prognosis in these patients.

Albumin change predicts failure in ulcerative colitis treated with adalimumab.

Anti-tumor necrosis factor (TNF) -α antibodies, including infliximab (IFX), adalimumab (ADA), and golimumab, which were the first biologic therapeutic agents, have a crucial position in advanced therapy for ulcerative colitis (UC). We aimed to investigate serum albumin (Alb) change as a prognostic factor for the therapeutic effect of ADA in UC. Thirty-four patients with UC treated with ADA were enrolled in this study and were divided into failure and non-failure groups. Biological data, such as Alb were compared between the two groups. Thirteen patients showed failure within six months. Examination of the biological data showed a significant difference between the two groups only in the week 2/week 0 Alb ratio. In receiver-operating characteristic (ROC) curve analysis to predict failure, the cut-off value of week 2/week 0 Alb ratio was 1.00, and the area under the curve was 0.868 (95% confidence interval: 0.738-0.999). In addition, in the sub-group analysis of only clinically active patients, the week 2/week 0 Alb ratio of the non-failure group was significantly higher than that of the failure group, and the cut-off-value in ROC analysis was 1.00. Week 2/week 0 Alb ratio ≤ 1 predicts failure within six months of ADA for UC.

Comparison of fecal calprotectin levels and endoscopic scores for predicting relapse in patients with ulcerative colitis in remission.

BACKGROUND: Although the usefulness of endoscopic scores, such as the Mayo Endoscopic Subscore (MES), Ulcerative Colitis Endoscopic Index of Severity (UCEIS), and Ulcerative Colitis Colonoscopic Index of Severity (UCCIS), and biomarkers such as fecal calprotectin (FC) for predicting relapse in ulcerative colitis (UC) has been reported, few studies have included endoscopic scores for evaluating the entire colon. AIM: To compare the usefulness of FC value and MES, UCEIS, and UCCIS for predicting relapse in patients with UC in clinical remission. METHODS: In total, 75 patients with UC in clinical and endoscopic remission who visited our institution between February 2019 and March 2022 were enrolled. The diagnosis of UC was confirmed based on the clinical presentation, endoscopic findings, and histology, according to the current established criteria for UC. Fecal samples were collected the day before or after the colonoscopy for measurement of FC. Endoscopic evaluations were performed using MES, UCEIS, and UCCIS. The primary outcome measure of this study was the assessment of the association between relapse within 12 mo and MES, UCEIS, UCCIS, and FC. The secondary outcome was the comparison between endoscopic scores and biomarkers in enrolled patients with UC with mucosal healing. RESULTS: FC and UCCIS showed a significant correlation with UCEIS (r = 0.537, P < 0.001 and r = 0.957, P < 0.001, respectively). Receiver-operating characteristic analysis for predicting MES 0 showed that the area under the curve of UCCIS was significantly higher than that of FC (P < 0.01). During the 1-year observation period, 18 (24%) patients experienced a relapse, and both the FC and UCCIS of the relapse group were significantly higher than that of the remission group. The cut-off values for predicting relapse were set at FC = 323 mg/kg and UCCIS = 10.2. The area under the curve of the receiver-operating characteristic analysis for predicting relapse did not show a significant difference between FC and UCCIS. The accuracy of the endoscopic scores and biomarkers in predicting relapse was 86.7% for UCCIS, 85.3% for UCEIS, 76.0% for FC, and 73.3% for MES. CONCLUSION: The three endoscopic scores and FC may predict UC relapse during clinical remission. Among these scores, UCEIS may be the most useful in terms of ease of evaluation and accuracy.