Diagnosis by combination of endoscopic findings helps differentiate non-Helicobacter pylori Helicobacter-infected gastritis from Helicobacter pylori-infected gastritis.

BACKGROUND: The characteristic endoscopic findings of non-Helicobacter pylori Helicobacter (NHPH) gastritis, including white marbled appearance and crack-like mucosa, have been reported. However, these findings can also manifest in H. pylori (HP)-infected gastritis. This study compared NHPH gastritis and mild atrophic HP gastritis to identify features that may enhance NHPH diagnosis. MATERIALS AND METHODS: A total of 2087 patients underwent upper gastrointestinal endoscopy and were histologically evaluated by multiple gastric mucosal biopsies according to the updated Sydney System (USS) at Shinshu University Hospital between 2005 and 2023. Among them, nine patients were classified into the NHPH group and 134 patients with HP infection and mild atrophy were classified into the HP group for retrospective comparisons of endoscopic findings and clinicopathological characteristics. RESULTS: All nine patients in the NHPH group (eight males [89%], median ± standard deviation [SD] age: 49 ± 13.0 years) were infected with H. suis. The 134 patients in the HP group contained 70 men (52%) and had a median ± SD age of 35 ± 19.9 years. Endoscopic findings were statistically comparable for white marbled appearance (three patients [33%] in the NHPH group and 37 patients [31%] in the HP group) and crack-like mucosa (three patients [33%] and 27 patients [20%], respectively). Diffuse redness was significantly less frequent in the NHPH group (one patient [14%] vs. 97 patients [72%], p < 0.001). White marbled appearance or crack-like mucosa without diffuse redness was significantly more common in the NHPH group (56% vs. 13%, p = 0.004), with a sensitivity and specificity of 56% and 87%, respectively. Mean USS neutrophil infiltration and Helicobacter density scores were significantly higher in the HP group (both p < 0.01), which might have influenced the endoscopic findings of diffuse redness. CONCLUSIONS: When endoscopic findings of white marbled appearance or cracked-like mucosa are present, evaluation for diffuse redness may contribute to a more accurate diagnosis of NHPH gastritis.

Relationship between Helicobacter pylori eradication and Barrett's esophagus elongation.

INTRODUCTION: Helicobacter pylori eradication therapy may worsen gastroesophageal reflux disease that is a significant risk factor for Barrett's esophagus. However, the relationship between eradication therapy and Barrett's esophagus remains controversial. This study evaluated the impact of Helicobacter pylori eradication on the lengthening of Barrett's esophagus. MATERIALS AND METHODS: We conducted a retrospective analysis of consecutive patients who successfully underwent Helicobacter pylori eradication between 2004 and 2017. Endoscopic images obtained before and after eradication therapy were compared for Barrett's esophagus length according to the Prague C&M criteria and the presence of reflux esophagitis based on the Los Angeles classification. RESULTS: A total of 340 patients were analyzed (mean age: 66.9±12.9 years) for a median follow-up of 55 months (interquartile range: 29.8-89.3). At the initial endoscopic assessment, 187 patients (55%) had a hiatal hernia, and all patients had gastric atrophy (C-1: 2%, C-2,3: 47%, O-1,2,3: 51%). Reflux esophagitis was detected in 7 patients (2%) before eradication and in 21 patients (6%) afterward, which was a significant increase (P=0.007). Barrett's esophagus was identified in 69 patients (20%) before eradication, with a median length of C0M1. Elongation after treatment was observed in only 2 patients (0.6%). We observed no significant increase in either the prevalence (P=0.85) or the median length (P=0.5) of Barrett's esophagus. CONCLUSIONS: Only 0.6% of patients exhibited Barrett's esophagus lengthening after Helicobacter pylori eradication therapy, suggesting no significant impact of the treatment on the development or elongation of Barrett's esophagus.

Association between endoscopic evidence of bile reflux and Barrett's esophagus: A large-scale case-control study.

BACKGROUND: Although bile reflux plays an important role in the development of Barrett's esophagus, the relationship between endoscopic findings of bile reflux and Barrett's esophagus remains unclear. OBJECTIVE: This study evaluated whether endoscopic evidence of bile reflux was associated with the presence of Barrett's esophagus. METHODS: A retrospective analysis of a prospectively maintained database comprising consecutive patients who underwent screening esophagogastroduodenoscopy was conducted. Endoscopic evidence of bile reflux was defined as the presence of bile-stained fluid in the gastric fundus. We performed multivariate analysis to identify predictive factors that differed significantly between patients with and without Barrett's esophagus. RESULTS: Of 4021 patients, 922 (23%) had Barrett's esophagus, and 1000 (25%) showed endoscopic findings of bile reflux. Multivariate analysis revealed endoscopic evidence of bile reflux as the strongest independent factor associated with the presence of Barrett's esophagus (odds ratio [OR] 5.65, 95% confidence interval [CI] 4.71-6.76) in relation to the presence of hiatal hernia (OR 3.30, 95% CI 2.70-4.04) and male gender (OR 1.54, 95% CI 1.24-1.91). CONCLUSIONS: Endoscopic evidence of bile reflux was independently associated with the presence of Barrett's esophagus. This finding might help identify patients at future risk of Barrett's esophagus who could benefit from increased endoscopy surveillance.

Mucosal damage in pancreaticobiliary maljunction is stronger in the gallbladder than in the bile duct.

BACKGROUND: The frequency of gallbladder carcinoma is high in pancreaticobiliary maljunction (PBM), and the mechanism of carcinogenesis is not well understood. METHODS: The expression of γH2AX, the most sensitive marker for detecting DNA damage, was analyzed using immunohistochemistry in patients with PBM, in which the gallbladder and bile duct were simultaneously resected. Gallbladder and bile ducts were evaluated in non-neoplastic regions in 13 cases of PBM without cancer in the gallbladder and bile ducts. RESULTS: The median frequencies of γH2AX expression in the bile duct and gallbladder within the same case were 5.9% (range 1.7-12.05%) and 9.9% (range 2.8-25%), respectively, and were significantly higher in the gallbladder mucosa (P < 0.0004). γH2AX expression strongly correlated in the bile duct and gallbladder (r = 0.9436, P < 0.0001). PBM caused marked mucosal damage to the gallbladder. CONCLUSIONS: Mucosal damage may be involved in carcinogenesis, which may be useful for predicting malignant transformation.

Artificial intelligence for evaluating the risk of gastric cancer: reliable detection and scoring of intestinal metaplasia with deep learning algorithms.

BACKGROUND AND AIMS: Gastric cancer (GC) is associated with chronic gastritis. To evaluate the risk, the Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) system was constructed and showed a higher GC risk in stage III or IV patients, determined by the degree of intestinal metaplasia (IM). Although the OLGIM system is useful, evaluating the degree of IM requires substantial experience to produce precise scoring. Whole-slide imaging is becoming routine, but most artificial intelligence (AI) systems in pathology are focused on neoplastic lesions. METHODS: Hematoxylin and eosin-stained slides were scanned. Images were divided into each gastric biopsy tissue sample and labeled with an IM score. IM was scored as follows: 0 (no IM), 1 (mild IM), 2 (moderate IM), and 3 (severe IM). Overall, 5753 images were prepared. A deep convolutional neural network (DCNN) model, ResNet50, was used for classification. RESULTS: ResNet50 classified images with and without IM with a sensitivity of 97.7% and specificity of 94.6%. IM scores 2 and 3, involved as criteria of stage III or IV in the OLGIM system, were classified by ResNet50 in 18%. The respective sensitivity and specificity values of classifying IM between scores 0 and 1 and 2 and 3 were 98.5% and 94.9%, respectively. The IM scores classified by pathologists and the AI system were different in only 438 images (7.6%), and we found that ResNet50 tended to miss small foci of IM but successfully identified minimal IM areas that pathologists missed during the review. CONCLUSIONS: Our findings suggested that this AI system would contribute to evaluating the risk of GC accuracy, reliability, and repeatability with worldwide standardization.

Transmesenteric approach for laparoscopic endoscopic cooperative surgery for a duodenal adenoma located in the third portion of the duodenum.

We report our experience in a patient with adenoma located in the horizontal part of the duodenum, which was effectively treated with the transmesenteric laparoscopic endoscopic cooperative surgery (LECS) approach. This approach, which entails incising the mesentery of the colon, simplified laparoscopic access to the horizontal part of the duodenum, which was minimally mobilized. Thus, the bulb and descending part of the duodenum were fixed to the retroperitoneum, facilitating stable handling of the endoscope and enabled safe and effective excision of an adenoma located in the horizontal part of the duodenum. This approach enabled safe and effective excision of an adenoma located in the horizontal part of the duodenum. The advantages of this method include a secure field of view, lower probability of damage to large vessels, and minimizing the defect to the intestine caused by the incision.

CD8+ Lymphocyte Infiltration Is a Specific Feature of Colitis Induced by Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICPIs) have revolutionized cancer therapy, although immune-related adverse events (irAEs) remain a serious issue. The clinical characteristics of colitis induced by ICPIs are very similar to inflammatory bowel disease. Recently, cluster of differentiation 8 positive (CD8+) lymphocyte infiltration into organs has been associated with the onset of irAEs. The present study compared the histological infiltration of CD8+ lymphocytes in irAE colitis with that in other colitis. METHODS: Newly diagnosed and untreated patients were retrospectively enrolled. Biopsy specimens were obtained from endoscopic areas of high inflammation for immunohistochemical analysis of the number of cluster of differentiation 4 positive (CD4+) and CD8+ lymphocytes in the high-powered microscopic field with the most inflammation. RESULTS: A total of 102 patients [12 with irAE colitis, 37 with ulcerative colitis (UC), 22 with Crohn's disease (CD), and 31 with ischemic colitis (IC)] were analyzed. In irAE colitis, CD8+ lymphocyte infiltration was significantly greater than that of CD4+ lymphocytes (p < 0.01). The amount of CD8+ lymphocyte infiltration was significantly higher in irAE colitis than in UC (p < 0.05), CD (p < 0.05), and IC (p < 0.01). The CD8+/CD4+ ratio was also significantly higher in irAE colitis (p < 0.01 versus UC, CD, and IC, respectively). The optimal cutoff CD8+/CD4+ ratio for diagnosing irAE colitis was 1.17 (sensitivity 83%, specificity 84%). The optimal cutoff number of CD8+ lymphocytes for diagnosing irAE colitis was 102 cells per high-power field (sensitivity 75%, specificity 81%). CONCLUSIONS: Greater CD8+ lymphocyte infiltration and a higher CD8+/CD4+ ratio may be simple and useful biomarkers to distinguish irAE colitis from other forms of colitis.

Number and distribution of eosinophils and lymphocytes in the Japanese pediatric gastrointestinal tract: in search of a definition for "abnormally increased eosinophils".

BACKGROUND: Primary eosinophilic gastrointestinal disorders (EGIDs) constitute chronic allergic inflammation. The number of eosinophils is one of the diagnostic criteria; more than 20 eosinophils per high-power field (HPF) in the gastrointestinal (GI) tract are considered abnormal in Japan. However, the quantity of eosinophils considered normal varies according to anatomical location and geographical region; such values have not been reported in Japanese pediatric patients, nor have the numbers of lymphocytes in the normal pediatric stomach. To establish a reference for defining diagnostic criteria for EGIDs, we evaluated the number of eosinophils in the normal Japanese pediatric GI tract. METHODS: We examined 131 biopsy cases without significant clinical history, endoscopic abnormality, or histological abnormality. Immunohistochemical analysis of CD3 and CD20 was performed. RESULTS: The mean eosinophil density was highest in the cecum (49.5 ± 22.4 per HPF). Counts of more than 20 eosinophils per HPF were observed in the duodenum [bulb (20.0 ± 9.6) and second portion (30.0 ± 15.8)], terminal ileum (38.3 ± 22.7), cecum (49.5 ± 22.4), ascending colon (42.3 ± 25.3), transverse colon (29.4 ± 17.0), and descending colon (32.2 ± 17.9). Counts of fewer than 10 eosinophils per HPF were observed in the stomach and rectum; a count of fewer than one eosinophil per HPF was observed in the esophagus. More than 100 CD3-positive T cells per HPF were observed in the stomach. CONCLUSIONS: The mean numbers of eosinophils in the bowel were greater than 20 per HPF. For Japanese pediatrics, the current threshold eosinophil count should be revised.

Gastric Cancer After Helicobacter pylori Eradication for Nodular Gastritis in an Adolescent.

A 16-year-old girl underwent esophagogastroduodenoscopy (EGD) after the detection of Helicobacter pylori (H. pylori) antibodies in her urine during a school health screening, which revealed nodular gastritis (NG). She was diagnosed as having H. pylori infection histologically and by biopsy culture specimens and soon commenced eradication therapy. Eight weeks later, eradication was confirmed by a urea breath test. At the age of 19, however, she was referred to our hospital with epigastralgia and lower back pain. EGD revealed ulcerative lesions with enlarged folds at the greater curvature of the gastric body. Biopsy specimens of the lesions revealed poorly differentiated adenocarcinoma and signet ring cell carcinoma. The cancer was classified as stage IV with pancreatic invasion. Although NG with pangastritis is considered a high-risk factor for diffuse-type gastric carcinoma, the course of NG after eradication remains unknown. Careful histological assessment before eradication by endoscopic biopsy and close follow-up after eradication are therefore recommended, even in young patients.

Histopathologically defined intestinal metaplasia in lesser curvature of corpus prior to Helicobacter pylori eradication is a risk factor for gastric cancer development.

BACKGROUND AND AIM: Helicobacter pylori eradication has been shown to reduce the risk of gastric cancer (GC), with the number of eradication therapy cases on the rise. However, GC can still occur after successful treatment, and the histological differences prior to eradication in patients with and without GC are unclear. This study investigated the pre-treatment histological risk factors for GC development following eradication therapy. METHODS: We retrospectively enrolled consecutive adult patients diagnosed as having H. pylori infection between April 2004 and December 2018. Atrophy and intestinal metaplasia (IM) were histologically assessed according to the updated Sydney System. The operative link on gastritis assessment and the operative link on gastric intestinal metaplasia (OLGIM) were evaluated as well. RESULTS: Of the 247 patients analyzed in this study, 11 (4.5%) experienced GC after eradication therapy. Histological IM scores in the GC group were significantly higher at all gastric biopsy sites (p < .05), and the proportion of OLGIM III/IV stage was significantly greater in GC patients (81.8% vs. 31.8%, p < .01). For GC prediction, the area under the receiver operating characteristic curve for IM score at the lesser curvature of the corpus was the highest among all biopsy sites and not inferior to OLGIM results. CONCLUSIONS: Patients with histological IM prior to H. pylori eradication, especially at the lesser curvature of the corpus, may be at elevated risk for GC development after eradication therapy and require close surveillance.

Association between endoscopic pressure study integrated system (EPSIS) and high-resolution manometry.

Background and study aims The endoscopic pressure study integrated system (EPSIS), a novel diagnostic tool for gastroesophageal reflux disease (GERD), allows evaluation of the anti-reflux barrier using endoscopy by monitoring the intragastric pressure (IGP) during insufflation. In this study, we evaluated the association between EPSIS results and lower esophageal sphincter (LES) function measured by high-resolution manometry (HRM) to elucidate whether EPSIS can evaluate the LES function. Patients and methods A retrospective, single-center study of patients with GERD symptoms who underwent endoscopy, pH-impedance monitoring, EPSIS, and HRM was conducted. The primary outcome was basal LES pressure and the secondary outcomes were end-respiratory LES pressure and integrated relaxation pressure (IRP). As EPSIS parameters, the following were measured: 1) pressure difference (mmHg), the difference between maximum and basal IGP; and 2) pressure gradient (mmHg/s), calculated by dividing pressure difference by the insufflating time. Pressure difference < 4.7 mmHg or pressure gradient < 0.07 mmHg/s was defined as an EPSIS GERD pattern. Results Forty-seven patients (median age: 53 years, 37 female) were analyzed. Pressure difference and pressure gradient significantly correlated with basal LES pressure (ρ = 0.29; P =  0.04 and ρ = 0.29; P =  0.04). Patients with EPSIS GERD pattern showed significantly lower basal LES pressure [13.2 (4.8-26.6) vs 25.3 (10.4-66.7) mmHg, P =  0.002], lower end-respiratory LES pressure [8.5 (1.1-15.9) vs 15.5 (1.9-43.9) mmHg, P =  0.019] and lower IRP [5.9 (1.0-12.0) vs 9.8 (1.3-17.8) mmHg, P =  0.020]. Conclusions This study showed a close association between EPSIS results and LES pressures measured by HRM. This indicates that EPSIS can evaluate the LES function during endoscopy and endorse the role of EPSIS as a diagnostic tool for GERD.

Gastric adenocarcinoma arising from hamartomatous inverted polyp during 8-year follow-up.

Gastric hamartomatous inverted polyp (GHIP) is rare, with few reports of carcinogenesis from GHIP during long-term follow-up. A 51-year-old woman was diagnosed as having a submucosal tumor (SMT) during esophagogastroduodenoscopy (EGD) in 2008. In 2016, although the size and height of the lesion had not changed, she was referred to our hospital for further investigation of the lesion. EGD depicted a gastric SMT of 20 mm in diameter in the greater curvature of the upper gastric body, and a biopsy specimen showed a well to poorly differentiated adenocarcinoma. Following successful laparoscopic total gastrectomy, histopathological examination revealed an intramucosal adenocarcinoma arising in GHIP.

Comparison of scope holding sign on endoscopy and lower esophageal sphincter contraction on high-resolution manometry: A pilot study.

Objectives: Lower esophageal sphincter (LES) plays a key role in gastroesophageal reflux disease (GERD) pathogenesis. In retroflexion and under sufficient insufflation, it can be seen how the lower esophagus grasps the endoscope, which we named scope holding sign (SHS). This study aimed to compare the SHS and LES pressure on high-resolution manometry (HRM), to elucidate whether the sphincter can be visualized endoscopically. Methods: This was a single-center, prospective pilot study. Patients with symptoms of GERD, who underwent endoscopy and HRM between February 2021 and April 2021, were included. A manometry catheter and an ultra-slim endoscope were inserted, and the resting LES pressure was measured. The lower esophagus holding (SHS-positive) and releasing (SHS-negative) the endoscope and catheter were observed. The LES pressures during SHS-positive and SHS-negative were compared. Results: Eleven patients (median age: 57 years; eight men) with normal esophageal motility were analyzed. The median LES pressure in SHS-positive was significantly higher than the resting LES pressure (40.4 [22.9-74.0] vs. 25.9 [2.0-66.7] mm Hg; p = 0.001) and the LES pressure in SHS-negative (4.6 [1.5-9.3]; p = 0.001). Furthermore, the LES pressure in SHS-negative was significantly lower than the resting LES pressure (4.6 [1.5-9.3] vs. 25.9 [2.0-66.7] mm Hg; p = 0.005). Conclusions: This study demonstrated that the SHS parallels LES pressure, indicating that the sphincter can be observed endoscopically. This may enable us to evaluate LES function during endoscopy in patients with GERD, thus, deserving further evaluation in future studies.

Predictors of recurrence of dysplasia or cancer in patients with dysplastic Barrett's esophagus following complete eradication of dysplasia: a single-center retrospective cohort study.

BACKGROUND AND AIMS: Endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) for Barrett's esophagus (BE)-related high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EAC) are considered effective treatments for eradication of BE. Little is known about the impact of achieving complete eradication of intestinal metaplasia (CE-IM) following the complete eradication of neoplasia (CE-N), specifically if CE-IM reduces the risk of recurrent dysplasia. METHODS: Retrospective cohort study of consecutive patients with BE and HGD or intramucosal cancer (IMC)-treated endoscopically at a tertiary referral center between 2001 and 2019. Association between CE-IM and recurrent dysplasia after CE-N was evaluated. RESULTS: A total of 433 patients treated with EMR and/or RFA were included. Of these, 381 (88%) achieved CE-N, of which 345 (80%) had adequate follow-up for inclusion in the analysis. A total of 266 (77%) patients achieved CE-IM; with a median follow-up since initial treatment for HGD/IMC of 45.9 months (IQR 25.9, 93.1); 20 patients (5.8%) had recurrent dysplasia after achieving CE-N. Kaplan Meier survival curves revealed that time free of recurrence in those who achieved CE-IM was significantly higher (p = 0.002). In the multivariable analysis, CE-IM was associated with a significant lower hazard of recurrence (HR 0.2, 95% CI 0.1, 0.6), whereas the number of endoscopic treatments to achieve CE-N was associated with a significant higher hazard of recurrence (HR 1.1, 95% CI 1.0, 1.2). CONCLUSION: Achieving CE-IM following CE-N reduces the risk of recurrent dysplasia and should be considered a treatment target among patients with BE undergoing endoscopic therapies for HGD or EAC.

A Case of Multiple Perineuriomas in the Colon With Underlying Neurofibromatosis Type I.

A 45-year-old woman was referred to us after a positive fecal occult blood test. Colonoscopy revealed a 20-mm polyp in the transverse colon and a 10-mm polyp in the sigmoid colon. Endoscopic mucosal resection was performed as a diagnostic treatment. Both resected polyps were histologically diagnosed as perineuriomas. She was later found to exhibit multiple café-au-lait spots on the skin and subsequently diagnosed as having neurofibromatosis type I (NF-1). Perineuriomas are rare benign peripheral nerve sheath tumors, with no reports of multiple colonic lesions in a patient with NF-1 to date. NF-1 might be associated with the onset of multiple perineuriomas.

Clinicopathological features of nodular gastritis in three classes of age.

BACKGROUND: Nodular gastritis is most often one of the manifestations of Helicobacter pylori (H. pylori) infection, which is a risk factor for gastric cancer. This study aimed to determine if the histological characteristics of nodular gastritis differed across classes of age. METHODS: We conducted a retrospective analysis of consecutive patients who had undergone esophagogastroduodenoscopy with multiple mucosal biopsies of the stomach between 2003 and 2019 for evaluation of updated Sydney System scores. We analyzed and compared the histological characteristics of pediatric (≤15 years old), young (16-29 years old), and older (≥30 years old) patients. RESULTS: Of the 1321 patients enrolled, 1027 patients (78%) had H. pylori infection, with 214 patients (21%) of them displaying nodular gastritis. Among nodular gastritis patients, mononuclear cell infiltration Sydney System scores in the gastric body were significantly higher in the older group than in the pediatric (p < .001) and young (p < .001) groups. Similar results were seen for neutrophil infiltration scores in the gastric body. To clarify the characteristics of older nodular gastritis, we investigated 1056 older patients (66 with nodular gastritis, 754 with atrophic gastritis, and 236 H. pylori-negative). The scores for mononuclear and neutrophil cell infiltration in the gastric body were significantly higher in nodular gastritis patients than in atrophic gastritis patients (both p < .001) and patients negative for H. pylori (both p < .001). CONCLUSIONS: The inflammatory changes in the gastric body in older nodular gastritis patients were more severe as compared with those in pediatric and young nodular gastritis patients in addition to older atrophic gastritis patients.

Diagnosis of congenital esophageal stenosis in adults and treatment with peroral endoscopic myotomy.

BACKGROUND: Congenital esophageal stenosis (CES) in adults is a rare disorder that can present as achalasia, particularly in the distal esophagus. We describe the salient features of CES in adults and identify the feasibility and short-term outcomes of peroral endoscopic myotomy (POEM) for CES. METHODS: In this retrospective, single-center case series, we included 6 patients with a "misdiagnosis" of achalasia established elsewhere, ultimately diagnosed with CES and referred to our institution for POEM. Symptom improvement (clinical success rate), defined as an Eckardt Symptom Score (ESS) of <3 at 2-month follow up was assessed. RESULTS: Six patients (median age: 40 [range: 18-58] years; 4 males) were included. A long-standing history of dysphagia, ring-shaped stenosis on endoscopic examination, "lopsided hourglass" sign on barium esophagogram, and high-resolution manometry findings indicated by a compartmentalized intrabolus pressure pattern with distinction between the stenotic area and the lower esophageal sphincter were the salient features identified. POEM could not be completed in the first 2 cases due to technical challenges. All subsequent 4 patients who underwent successful POEM, exhibited improved ESS of ≤3 (clinical success rate 100%) at 2 months post-POEM. CONCLUSIONS: Along with identification of salient features on several diagnostic modalities, a differential diagnosis of CES in adults must be considered in patients presenting with long-standing history of dysphagia arising from childhood and persisting into adulthood. Although favorable short-term outcomes of POEM were achieved, further evaluation is still warranted, and an inexperienced operator should not attempt POEM on CES patients due to its technical difficulties.

Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy.

AIMS: Claudin 18 (CLDN18) is a member of the claudin family of cell surface proteins, which are widely expressed in epithelial cells and play a role in cell-cell adhesion. CLDN18 isoform 2 (CLDN18.2) is specifically expressed in gastric epithelial cells, and is frequently expressed at high levels in gastric adenocarcinoma. On the basis of this, zolbetuximab, a targeted monoclonal antibody, has been developed for patients with CLDN18.2-positive gastro-oesophageal adenocarcinoma. Colitis-associated colorectal adenocarcinomas (CACs) tend to lose intestinal markers and show aberrant gastric mucin expression. Furthermore, clinical trials of human epidermal growth factor receptor 2 (HER2) inhibitor therapy for colorectal carcinoma are ongoing. However, the expression profile of CLDN18.2 and HER2 has not been described in a series of human CACs. METHODS AND RESULTS: We performed immunohistochemistry for CLDN18 and HER2 on 56 consecutive CACs from 55 inflammatory bowel disease patients, and compared the expression profile with that of a control group of 56 sporadic colorectal adenocarcinomas (CRCs). CLDN18.1 expression and CLDN18.2 expression were validated by reverse transcription polymerase chain reaction (PCR) in paraffin-embedded CRC tissues. CLDN18 was positive in 27% (15/56) of CACs and in 5% (3/56) of sporadic CRCs (P = 0.004), and CLDN18-positive CACs were more likely to have lymph node metastasis than CLDN18-negative CACs (67% versus 36%; P = 0.017). CLDN18 expression was significantly associated with MUC5AC expression (P < 0.001) and loss of special AT-rich sequence-binding protein 2 expression (P = 0.005) in CACs. CLDN18.2 was expressed in CRCs that were immunoreactive for CLDN18. Only 4% of CACs were immunoreactive for HER2, and no differences were identified in sporadic CRCs. CONCLUSIONS: These findings suggest that certain CAC cases may be candidates for targeted zolbetuximab therapy.