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.

Outcomes of Metastatic and Unresectable Small Bowel Adenocarcinoma in Japan According to the Treatment Strategy: A Nationwide Observational Study.

PURPOSE: Limited information is available regarding the characteristics and outcomes of stage IV small bowel adenocarcinoma (SBA) in Japan. This study examined the clinical and pathological characteristics and outcomes according to the treatment strategies in patients with stage IV SBA. METHODS: This retrospective observational study used the data of patients with jejunal or ileal adenocarcinoma collected by the Small Bowel Malignant Tumor Project of the Japanese Society for Cancer of the Colon and Rectum. Descriptive statistics were expressed as the mean (standard deviation) or median (range). Survival analysis was performed using Kaplan-Meier curves and pairwise log-rank tests. RESULTS: Data from 128 patients were analyzed. The treatment strategies were chemotherapy alone (26 of 128, 20.3%), surgery alone (including palliative surgery; 21 of 128, 16.4%), surgery + chemotherapy (74 of 128, 57.8%), and best supportive care (7 of 128, 5.5%). The median (range) overall survival was 16 (0-125) months overall, and 11 (1-38) months, 8 (0-80) months, 18 (0-125) months, and 0 (0-1) months for the chemotherapy, surgery, surgery + chemotherapy, and best supportive care groups, respectively. Three main categories of chemotherapeutic regimen were used: a combination of fluoropyrimidine and oxaliplatin (F + Ox), fluoropyrimidine and irinotecan (F + Iri), and single-agent fluoropyrimidine. Among patients treated with chemotherapy, the median (range) OS was 16 (1-106) months overall, and 17 (1-87) months, 29 (7-39) months, and 16 (1-106) months in patients treated with fluoropyrimidine, F + Iri, and F + Ox, respectively. CONCLUSION: Patients treated with surgery, chemotherapy, or both had a better prognosis than those who received best supportive care. Among patients who received chemotherapy, survival did not differ according to the chemotherapeutic regimen.

Clinicopathological features and prognosis of primary small bowel adenocarcinoma: a large multicenter analysis of the JSCCR database in Japan.

BACKGROUND: The clinicopathological features and prognosis of primary small bowel adenocarcinoma (PSBA), excluding duodenal cancer, remain undetermined due to its rarity in Japan. METHODS: We analyzed 354 patients with 358 PSBAs, between January 2008 and December 2017, at 44 institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum. RESULTS: The median age was 67 years (218 males, 61.6%). The average tumor size was 49.9 (7-100) mm. PSBA sites consisted of jejunum (66.2%) and ileum (30.4%). A total of 219 patients (61.9%) underwent diagnostic small bowel endoscopy, including single-balloon endoscopy, double-balloon endoscopy, and capsule endoscopy before treatment. Nineteen patients (5.4%) had Lynch syndrome, and 272 patients (76.8%) had symptoms at the initial diagnosis. The rates for stages 0, I, II, III, and IV were 5.4%, 2.5%, 27.1%, 26.0%, and 35.6%, respectively. The 5-year overall survival rates at each stage were 92.3%, 60.0%, 75.9%, 61.4%, and 25.5%, respectively, and the 5-year disease-specific survival (DSS) rates were 100%, 75.0%, 84.1%, 59.3%, and 25.6%, respectively. Patients with the PSBA located in the jejunum, with symptoms at the initial diagnosis or advanced clinical stage had a worse prognosis. However, multivariate analysis using Cox-hazard model revealed that clinical stage was the only significant predictor of DSS for patients with PSBA. CONCLUSIONS: Of the patients with PSBA, 76.8% had symptoms at the initial diagnosis, which were often detected at an advanced stage. Detection during the early stages of PSBA is important to ensure a good prognosis.

NTRK2 expression in gastrointestinal stromal tumors with a special emphasis on the clinicopathological and prognostic impacts.

Gastrointestinal stromal tumors (GISTs) are typically characterized by activating mutations of the KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type GIST. We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases, and all pan-trk positive cases showed diffuse and strong expression of c-kit. Interestingly, all of these cases showed only trkB but not trkA/trkC expression. Cap analysis of gene expression (CAGE) analysis identified increased number of genes whose promoters were activated in pan-trk/trkB positive GISTs. Imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in any of trkB positive GISTs, despite higher mRNA expression. TrkB expression was found in duodenal GISTs and more than half of small intestinal GISTs, and this subset of cases showed poor prognosis. However, there was not clear difference in clinical outcomes according to the trkB expression status in small intestinal GISTs. These findings may provide a possible hypothesis for trkB overexpression contributing to the tumorigenesis and aggressive clinical outcome in GISTs of duodenal origin.

Characterization of sessile serrated adenomas with dysplasia including intramucosal adenocarcinoma and colorectal carcinoma with a microsatellite instability phenotype.

Recent studies have shown that sessile serrated lesions (SSLs) lead to the development of colorectal cancer (CRC) with a microsatellite instability (MSI) phenotype via a dysplasia-carcinoma sequence. However, the pathological and molecular mechanisms of SSL with dysplasia (SSLD) are unclear. Here, we aimed to examine the clinicopathological and molecular alterations in SSLD and to evaluate the significance of such alterations with regard to lesion progression. Fifty-four SSLDs (20 serrated dysplasia cases and 17 intestinal dysplasia cases, including 30 low-grade dysplasia [LGD] cases, 7 high-grade dysplasia [HGD] cases, and 17 intramucosal adenocarcinomas [IMAs]) were evaluated. Molecular alterations, including immunohistochemical expression of various markers, DNA methylation status, and multiple genetic mutations (using next-generation sequencing), were assessed. Additionally, such alterations were also investigated in 41 CRCs with an MSI phenotype (invasion beyond submucosa). The frequency of mismatch repair (MMR) deficiency in SSLD was 12 of 39 cases (32.4 %), whereas the MMR proficient type was observed in 17 of 39 SSLD cases. SSLD with serrated dysplasia showed a significantly higher frequency of loss of MMR protein expression and methylation status. Moreover, loss of MMR protein expression differed significantly between LGD and IMA. Furthermore, the frequency of TP53 mutation was significantly higher in IMA than in LGD. The current findings demonstrated that SSL with serrated dysplasia may be associated with an increased risk of malignant transformation compared with intestinal dysplasia. Loss of MMR proteins and mutation of TP53 may play important roles in tumor progression from dysplasia to carcinomatous lesions.

Stromal Ki67 Expression Might be a Useful Marker for Distinguishing Fibroadenoma From Benign Phyllodes Tumor of the Breast.

Background. Fibroadenoma (FA) and benign phyllodes tumor (PT) of the breast often have similar appearances on imaging. While an exact diagnosis of biopsy specimens is required to choose adequate treatment, including surgical procedures, it is sometimes difficult to pathologically differentiate these 2 tumors due to histological resemblances. To elucidate markers for distinguishing FA from benign PT, we analyzed clinical samples immunohistochemically. Methods. We retrospectively investigated 80 breast fibroepithelial lesions. As a discovery set, 60 surgical excision samples (30 FA and 30 benign PT) were examined. Twenty biopsy samples (10 FA and 10 benign PT) were examined as a validation set. To determine targets for immunohistochemistry, we first tested some proteins based on previous reports. As a result, Ki67 was chosen for differentiating FA and PT; thus further examinations were conducted with this protein. Results. Among the proteins examined, stromal Ki67 was significantly higher in PT than in FA. Benign PT had significantly higher stromal Ki67 expression both at random and at hotspots (p < .001 and <.001, respectively). The receiver operating characteristic curve analysis identified 3.5% and 8.5% (at random spots and hotspots, respectively) as the optimal cutoff values of stromal Ki67 for distinguishing between these 2 tumors. In the validation cohort employing needle biopsy specimens, we confirmed that these 2 cutoff values properly classified these 2 tumors (p = .043 and .029, respectively). Conclusion.We revealed that stromal Ki67 might be a potential marker for distinguishing FA from benign PT.

Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma.

A limited number of patients with lung squamous cell carcinoma (SCC) benefit clinically from molecular targeted drugs because of a lack of targetable driver alterations. We aimed to understand the prevalence and clinical significance of lysine-specific demethylase 5D (KDM5D) copy number loss in SCC and explore its potential as a predictive biomarker for ataxia-telangiectasia and Rad3-related (ATR) inhibitor treatment. We evaluated KDM5D copy number loss in 173 surgically resected SCCs from male patients using fluorescence in situ hybridization. KDM5D copy number loss was detected in 75 of the 173 patients (43%). Genome-wide expression profiles of the transcription start sites (TSSs) were obtained from 17 SCCs, for which the cap analysis of gene expression assay was performed, revealing that upregulated genes in tumors with the KDM5D copy number loss are associated with 'cell cycle', whereas downregulated genes in tumors with KDM5D copy number loss were associated with 'immune response'. Clinicopathologically, SCCs with KDM5D copy number loss were associated with late pathological stage (p = 0.0085) and high stromal content (p = 0.0254). Multiplexed fluorescent immunohistochemistry showed that the number of tumor-infiltrating CD8+ /T-bet+ T cells was lower in SCCs with KDM5D copy number loss than in wild-type tumors. In conclusion, approximately 40% of the male patients with SCC exhibited KDM5D copy number loss. Tumors in patients who show this distinct phenotype can be 'cold tumors', which are characterized by the paucity of tumor T-cell infiltration and usually do not respond to immunotherapy. Thus, they may be candidates for trials with ATR inhibitors.

Mixed Mesonephric-like Adenocarcinoma, Clear Cell Carcinoma, and Endometrioid Carcinoma Arising from an Endometriotic Cyst.

Mesonephric-like adenocarcinoma is a rare neoplasm of the uterine corpus and ovary. Unlike prototypical mesonephric adenocarcinoma of the uterine cervix, which is considered of Wolffian origin, recent evidence suggests that mesonephric-like adenocarcinoma is a Mullerian tumor associated with endometriosis. We report here on a 48-year-old woman with a mixed carcinoma of the ovary that consisted of mesonephric-like adenocarcinoma, clear cell carcinoma, and endometrioid carcinoma, arising from an endometriotic cyst. The mesonephric-like adenocarcinoma consisted of cuboidal cells with vesicular nuclei presenting with a tubular, ductal, papillary, and solid architecture forming nodules. Each component showed distinct immunophenotypes that were consistent with their morphology. The mesonephric-like adenocarcinoma showed diffuse positive staining for paired box 8 and GATA binding protein 3, and negative staining for estrogen and progesterone receptors. A p53 stain exhibited wild-type immunoreactivity. A complete loss of AT-rich interactive domain-containing protein 1A (ARID1A) expression was suggestive of an ARID1A mutation. Manual macrodissection and Sanger sequencing revealed identical KRAS and PIK3CA mutations in all three components. To the best of our knowledge, this is the first report of mesonephric-like adenocarcinoma combined with a clear cell carcinoma and endometrioid carcinoma, which supports the hypothesis that mesonephric-like adenocarcinoma is an endometriosis-associated neoplasm. The report also highlights a potential pitfall in diagnosing mesonephric-like adenocarcinoma combined with clear cell carcinoma.

Endoscopic Diagnosis Strategy of Raspberry-Shaped Gastric Lesion in Helicobacter Pylori-Uninfected Patient.

OBJECTIVES: We aimed to clarify the endoscopic and clinicopathological features of raspberry-shaped gastric lesions (RSGLs) and to establish an endoscopic diagnostic algorithm for RSGLs. METHODS: We collected RSGLs from an endoscopic database at our hospital between May 2009 and August 2021. All RSGLs were histopathologically classified and compared based on their endoscopic and clinicopathological characteristics. RESULTS: Sixty-five RSGLs in 54 patients were classified into five histopathological types: gastric adenocarcinoma of foveolar type (GA-FV, n = 43), gastric adenocarcinoma of fundic-gland type (GA-FG, n = 2), gastric adenocarcinoma of fundic-gland mucosa type (GA-FGM, n = 4), hyperplastic polyp (HP, n = 12), and proton pump inhibitor-related lesion (PPI-L, n = 4). All RSGLs exhibited polygonal or curved marginal crypt epithelium (MCE). GA-FV lesions had homogenously reddish (95%) and an irregular microvascular (MV) pattern (91%). GA-FG lesions were heterogeneously reddish with a submucosal tumor shape (100%) and had a regular MV pattern (50%). GA-FGM lesions were homogen+ously reddish (75%) and occasionally had a submucosal tumor shape (50%) with an irregular MV pattern (75%). HPs and PPI-Ls were homogeneously reddish (93%), with linear or dotted MCE (81%) and a regular MV pattern (100%). CONCLUSION: Our diagnostic algorithm for RSGLs constructed using endoscopic features might be useful for the endoscopic differential diagnosis of RSGLs.

HLA Class I Expression Is Associated with DNA Damage and Immune Cell Infiltration into Dysplastic and Neoplastic Lesions in Ulcerative Colitis.

Human leukocyte antigen class I (HLA-I) is considered a genetic pathogen for ulcerative colitis (UC). This study aimed to investigate the significance of DNA damage and HLA-I expression in infiltrating immune cells and immune checkpoint protein PD-L1 expression in dysplasia/colitic cancer (CC) and sporadic colorectal cancer (SCRC). We performed immunohistochemical staining for HLA-I, PD-L1, γH2AX (DNA damage marker), and immune cell markers such as CD8, FOXP3, CD68, and CD163 (in surgically resected specimens from 17 SCRC patients with 12 adjacent normal mucosa (NM) and 9 UC patients with 18 dysplasia/CC tumors. The ratio of membrane HLA-I-positive epithelial cells in UC and dysplasia/CC tissues was significantly higher than that in NM and SCRC. High HLA-I expression in dysplasia/CC was associated with high positivity of γH2AX and PD-L1 expression compared to SCRC. The infiltration of CD8-positive T cells and CD68-positive macrophages in HLA-I-high dysplasia/CC was significantly higher than in UC and SCRC. Dysplasia/CC specimens with DNA damage exhibited high levels of HLA-I-positive epithelial cells with high CD8- and CD68-positive immune cell infiltration compared to UC and SCRC specimens. Targeting DNA damage in UC may regulate immune cell infiltration, immune checkpoint proteins, and carcinogenesis by modulating DNA damage-induced HLA-I antigen presentation.

Frequent nuclear ß-catenin expression in pulmonary enteric-type adenocarcinoma according to the current World Health Organization criteria.

Based on the current World Health Organization classification criteria, five of 3895 consecutive cases of surgically resected primary lung carcinomas (0.13%) categorized as enteric-type were analyzed. Three cases completely comprised tumor cells that resemble colorectal adenocarcinoma, while the other two cases exhibited features of conventional adenocarcinomas admixed with enteric components. Immunohistochemically, all patients expressed at least three of the five intestinal markers: CDX2, CK20, HNF4α, MUC2, and SATB2. None of the patients expressed TTF-1 and NKX3.1. Three cases showed nuclear accumulation of ß-catenin, indicating activation of the Wnt/ß-catenin signaling pathway; APC mutations were detected in one of these cases. TP53 mutations were detected in three cases. Mutated EGFR or ALK fusions were not detected. Our study demonstrates that pulmonary enteric-type adenocarcinomas share immunohistochemical features and genetic alterations with colorectal adenocarcinomas, which are characterized by frequent activation of the Wnt/ß-catenin signaling pathway and a lack of actionable mutations.

Clinicopathological Impacts of Expression of Neuronal Markers in Lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a tuberous sclerosis complex (TSC)-associated tumor, characterized by the expression of neural crest lineages including neuronal markers. Neural crest cells can differentiate into multiple cell types that contribute to tissues associated with TSC-related tumors, and TSC-related tumors could be specifically associated with distinct neural crest subtypes. This study aimed to clarify the clinicopathological effects of expression of neuronal markers in LAM. Lung tissues from 40 patients with LAM (of whom 13, 1, and 26 had undergone lung transplantation, lobectomy, and partial lung resection, respectively) were immunohistochemically analyzed. All patients were women, and their median age was 36 years (range: 24-62 y). All patients who underwent lung transplantation or lobectomy were classified as LAM histologic score (LHS)-3, whereas those who underwent partial lung resection were classified as LHS-1. LAM cells expressed peripherin (65%), and neuron-specific ßIII-tubulin (43%). A comparison of the early (LHS-1) and advanced (LHS-3) stages of LAM revealed that neuron-specific ßIII-tubulin was significantly expressed in the early stage of LAM ( P = 0.0009). Neuron-specific ßIII-tubulin-positive LAM was associated with younger age ( P < 0.0001), the coexistence of renal angiomyolipoma ( P = 0.027), and the absence of retroperitoneal LAM ( P = 0.045). Furthermore, based on the expression levels of immunohistochemical markers in LAM, 2 distinct clusters with different expression levels of neuronal markers were observed. Approximately 40% to 60% of patients with LAM expressed neuron-specific ßIII-tubulin and peripherin. Neuronal expression may be associated with disease severity.

E-learning system to improve the endoscopic diagnosis of early gastric cancer.

We developed three e-learning systems for endoscopists to acquire the necessary skills to improve the diagnosis of early gastric cancer (EGC) and demonstrated their usefulness using randomized controlled trials. The subjects of the three e-learning systems were "detection," "characterization," and "preoperative assessment." The contents of each e-learning system included "technique," "knowledge," and "obtaining experience." All e-learning systems proved useful for endoscopists to learn how to diagnose EGC. Lecture videos describing "the technique" and "the knowledge" can be beneficial. In addition, repeating 100 self-study cases allows learners to gain "experience" and improve their diagnostic skills further. Web-based e-learning systems have more advantages than other teaching methods because the number of participants is unlimited. Histopathological diagnosis is the gold standard for the diagnosis of gastric cancer. Therefore, we developed a comprehensive diagnostic algorithm to standardize the histopathological diagnosis of gastric cancer. Once we have successfully shown that this algorithm is helpful for the accurate histopathological diagnosis of cancer, we will complete a series of e-learning systems designed to assess EGC accurately.

Clinicopathological characteristics of gastric adenocarcinoma with enteroblastic differentiation and gastric adenocarcinoma with enteroblastic marker expression.

Gastric adenocarcinoma (GA) with enteroblastic differentiation (GAED) is an aggressive carcinoma histologically characterized by a glycogen-rich clear cytoplasm and fetal gut-like structures. GAED shows the expression of at least one of the following enteroblastic markers (EMs): glypican-3 (GPC3), spalt-like transcription factor 4 (SALL4), and α-fetoprotein (AFP). Despite the absence of clear cytoplasm, we often encounter GA with EMs expression (GA with EM); however, the clinicopathological characteristics of GA with EM remain unclear. Immunohistochemical (IHC) expression of three EMs (AFP, GPC3, and SALL4) was examined on tissue microarray. According to the status of the clear cytoplasm of tumor cells, GAs showing IHC expression of EMs were classified as either GAED or GA with EM, and this analysis categorized 688 GAs into 94 GAEDs (13.7%), 58 GAs with EM (8.4%), and 536 conventional GAs (CGAs). Both GAED and GA with EM showed frequent lymphovascular invasion, lymph node metastasis, and liver metastasis compared to CGA. However, a higher frequency of venous invasion, but not of lymphatic invasion, was noted for GAED in comparison to CGA. GAED and GA with EM showed similar overall survival. GAED had significantly poorer prognosis than CGA; however, not for GA with EM. Furthermore, GA showing EM expression had a worse prognosis than CGA. Interestingly, GA showing EM-positive group was more aggressive than CGA group as they had frequent venous invasion and liver metastasis despite its smaller tumor size. GAED and GA with EM can be clinically classified as aggressive tumors but pathologically they seem to be slightly different.

Assessment of Elastic Laminal Invasion Contributes to an Objective pT3 Subclassification in Colon Cancer.

The extent of tumor spread influences on the clinical outcome, and which determine T stage of colorectal cancer. However, pathologic discrimination between pT3 and pT4a in the eighth edition of the American Joint Committee on Cancer (AJCC)-TNM stage is subjective, and more objective discrimination method for deeply invasive advanced colon cancer is mandatory for standardized patient management. Peritoneal elastic laminal invasion (ELI) detected using elastic staining may increase the objective discrimination of deeply invasive advanced colon cancer. In this study, we constructed ELI study group to investigate feasibility, objectivity, and prognostic utility of ELI. Furthermore, pT classification using ELI was investigated based on these data. At first, concordance study investigated objectivity using 60 pT3 and pT4a colon cancers. Simultaneously, a multi-institutional retrospective study was performed to assess ELI's prognostic utility in 1202 colon cancer cases from 6 institutions. In the concordance study, objectivity, represented by κ, was higher in the ELI assessment than in pT classification. In the multi-institutional retrospective study, elastic staining revealed that ELI was a strong prognostic factor. The clinical outcome of pT3 cases with ELI was significantly and consistently worse than that of those without ELI. pT classification into pT3 without ELI, pT3 with ELI, and pT4a was an independent prognostic factor. In this study, we revealed that ELI is an objective method for discriminating deeply invasive advanced colon cancer. Based on its feasibility, objectivity, and prognostic utility, ELI can subdivide pT3 lesions into pT3a (without ELI) and pT3b (with ELI).

Tyrosine kinase alterations in colorectal cancer with emphasis on the distinct clinicopathological characteristics.

AIMS: Tyrosine kinase (TK) alterations, such as anaplastic lymphoma kinase (ALK) fusion, neurotrophic tyrosine receptor kinase (NTRK) fusion, c-ros oncogene 1 (ROS1) fusion and mesenchymal-epithelial transition factor (MET) exon 14 skipping, have been reported in colorectal cancers (CRC). We have previously reported CRCs with NTRK fusion among our cohort. However, their clinicopathological features have not been fully elucidated. METHODS AND RESULTS: Tissue microarray (TMA)-based immunohistochemistry (IHC) was performed on 951 CRC lesions from 944 patients. IHC was evaluated as positive or negative for ALK and ROS1 and 0 to 3+ for c-MET. For ALK and ROS1 IHC-positive cases, RNA-based imbalanced gene expression assays, Archer FusionPlex assays and reverse transcription-polymerase chain reaction (RT-PCR) followed by Sanger sequencing were performed. For c-MET IHC 3+ cases, RT-PCR followed by Sanger sequencing were performed. ALK IHC was positive in three cases (0.2%) and all showed imbalanced ALK gene expression. The following ALK fusions were confirmed: EML4 (exon 21)::ALK (exon 20), EML4 (exon 6)::ALK (exon 19) and HMBOX1 (exon 6)::ALK (exon 20). Two showed microsatellite instability-high/mismatch repair (MMR)-deficient, and all were located in the right colon. ROS1 IHC was positive in one case; however, imbalanced expression and ROS1 fusion was negative. Forty-two cases (4.4%) showed c-MET IHC3+. MET exon 14 skipping was confirmed in nine cases. All cases were microsatellite stable/MMR-proficient, and eight were located in the left colon and rectum. CONCLUSIONS: CRCs with these TK alterations had distinct clinicopathological features. Together with our previous study, 15 cases (1.6%) harboured targetable TK alterations (three NTRK fusion, three ALK fusion, nine MET exon 14 skipping).

A missense variant at the RAC1-PAK1 binding site of RAC1 inactivates downstream signaling in VACTERL association.

RAC1 at 7p22.1 encodes a RAC family small GTPase that regulates actin cytoskeleton organization and intracellular signaling pathways. Pathogenic RAC1 variants result in developmental delay and multiple anomalies. Here, exome sequencing identified a rare de novo RAC1 variant [NM_018890.4:c.118T > C p.(Tyr40His)] in a male patient. Fetal ultrasonography indicated the patient to have multiple anomalies, including persistent left superior vena cava, total anomalous pulmonary venous return, esophageal atresia, scoliosis, and right-hand polydactyly. After birth, craniofacial dysmorphism and esophagobronchial fistula were confirmed and VACTERL association was suspected. One day after birth, the patient died of respiratory failure caused by tracheal aplasia type III. The molecular mechanisms of pathogenic RAC1 variants remain largely unclear; therefore, we biochemically examined the pathophysiological significance of RAC1-p.Tyr40His by focusing on the best characterized downstream effector of RAC1, PAK1, which activates Hedgehog signaling. RAC1-p.Tyr40His interacted minimally with PAK1, and did not enable PAK1 activation. Variants in the RAC1 Switch II region consistently activate downstream signals, whereas the p.Tyr40His variant at the RAC1-PAK1 binding site and adjacent to the Switch I region may deactivate the signals. It is important to accumulate data from individuals with different RAC1 variants to gain a full understanding of their varied clinical presentations.

Randomised clinical trial: 3-year interim analysis results of the VISION trial to evaluate the long-term safety of vonoprazan as maintenance treatment in patients with erosive oesophagitis.

BACKGROUND: VISION is a randomised, phase 4, open-label, parallel-group, multicentre study conducted in 33 centres in Japan. The aim of this study was to assess the long-term safety of vonoprazan for maintenance treatment of healed erosive oesophagitis versus lansoprazole. METHODS: Patients with endoscopically diagnosed erosive oesophagitis were randomised 2:1 to once-daily vonoprazan 20 mg or lansoprazole 30 mg, for a 4- to 8-week healing phase. Patients with endoscopically confirmed healing entered a 260-week maintenance phase with a once-daily starting dose of vonoprazan 10 mg or lansoprazole 15 mg. Primary endpoint was change in gastric mucosal histopathology. RESULTS: Of 208 patients (vonoprazan, n = 139; lansoprazole, n = 69) entering the healing phase, 202 entered the maintenance phase (vonoprazan, n = 135; lansoprazole, n = 67). At 3 years, 109 vonoprazan-treated and 58 lansoprazole-treated patients remained on treatment. Histopathological evaluation of gastric mucosa showed that hyperplasia of parietal, foveolar and G cells was more common with vonoprazan than lansoprazole at week 156 of the maintenance phase. There was no marked increase in the occurrence of parietal, foveolar and G cell hyperplasia among patients in the vonoprazan group from week 48 to week 156. Histopathological evaluation of the gastric mucosa also showed no neoplastic changes in either group. No new safety issues were identified. CONCLUSIONS: In this interim analysis of VISION, no new safety concerns were identified in Japanese patients with healed erosive oesophagitis receiving vonoprazan or lansoprazole as maintenance treatment for 3 years. (CT.gov identifier: NCT02679508; JapicCTI-163153; Japan Registry of Clinical Trials: jRCTs031180040).

Gastric Juvenile Polyposis with Intramucosal Cancer Diagnosed by Magnifying Endoscopy with Narrow-band Imaging.

Although gastric juvenile polyposis (GJP) often coexists with gastric cancer, a preoperative accurate diagnosis is still difficult to obtain. A 70-year-old woman was referred for epigastralgia and anemia. Esophagogastroduodenoscopy with a conventional endoscope showed numerous gastric polyps with no cancerous findings. Magnifying endoscopy with narrow-band imaging (M-NBI) showed cancerous findings, and a target biopsy revealed adenocarcinoma. Histopathological findings after endoscopic resection confirmed a diagnosis of juvenile polyposis with intramucosal adenocarcinoma. Genetic analyses revealed a germline pathogenic variant of SMAD4. A target biopsy using M-NBI and endoscopic resection proved useful for confirming the preoperative diagnosis of coexisting cancerous lesions in GJP.

Successful Treatment of Steroid-resistant Eosinophilic Gastrointestinal Disease with Mepolizumab.

We experienced a case of treatment-resistant eosinophilic gastrointestinal disease (EGID). The patient, a 46-year-old man, presented with a fever, persistent abdominal pain, and an elevated peripheral eosinophil count. Eosinophil infiltration of the intestinal mucosa was also observed, and EGID was diagnosed. Corticosteroid therapy was initiated, but no improvement was seen. However, after mepolizumab (anti-interleukin 5 antibody) was administered, the patient's disease was controlled. Currently, the indications for mepolizumab are limited to bronchial asthma and paraneoplastic eosinophilic polyangiitis, but the experience herein reported suggests its usefulness in the treatment of EGID.