Objectives: Mismatch repair (MMR)-deficient (dMMR) colorectal cancer (CRC) have been largely categorized into three subtypes: MLH1-methylated, Lynch syndrome (LS)-associated, and Lynch-like syndrome (LLS)-associated. No studies have examined the prevalence and subtypes of synchronously diagnosed dMMR CRCs in detail. Therefore, this study aimed to examine the frequency and molecular characteristics of the dMMR status among multiple synchronous CRCs to clarify the clinical significance of identifying patients with such tumors. Methods: Immunohistochemistry (IHC) of MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed for surgically and endoscopically resected (in conjunction with surgical resection) lesions from consecutive patients with initially diagnosed multiple synchronous CRCs between July 2014 and June 2020. When necessary, MLH1-methylation analysis and testing of germline and somatic MMR genes were performed. Results: In total, 133 patients (33 females) had 309 lesions. The combinations of synchronous tumor sites were the left-sided colon/rectum only (n=67, 50.4%), both the right-sided colon and left-sided colon/rectum (n=42, 31.6%), and the right-sided colon only (n=24, 18.0%). IHC showed a loss of expression of at least one MMR protein in 10 (7.5%) of 133 patients and 17 (5.5%) of 309 lesions. Molecular analysis revealed that these 10 patients were categorized as having MLH1-methylated (n=5, 3.8% of all patients), LS-associated (n=4, 3.0%), or LLS-associated (n=1, 0.8%) CRC. Conclusions: Our data will be useful for genetic counseling in patients with synchronous CRCs suspected of having LS. Screening for LS using IHC for MMR proteins in individuals with multiple synchronous CRCs is an effective approach.

Peutz–Jeghers syndrome (PJS), a rare genetic disorder characterized by hamartomatous gastrointestinal polyps, poses increased risks of various cancers. Despite the importance of early intervention, the optimal timing for jejunal-ileal polypectomy remains unclear owing to the limited number of comparative studies. Herein, we conducted a nationwide survey in Japan and analyzed data from 184 patients with PJS identified through a two-stage sampling process. The initial screening of 2912 medical institutions yielded 1748 facilities, of which 1077 responded to the survey. Time-dependent Cox proportional hazards models and logistic regression analyses were used to examine the association between the timing of jejunal-ileal polypectomy and the risk of surgery for intussusception. Among 184 patients (47.0

Between January 2020 and November 2024, we retrospectively analyzed the results of mismatch repair protein immunohistochemistry(MMR-IHC)/microsatellite instability(MSI)test, RAS, and BRAF genetic tests in 48 consecutive patients under 50 years of age who underwent primary tumor resection of colorectal cancer. Of these, 35 patients underwent MMR-IHC/ MSI testing, revealing 32 proficient MMR(pMMR)/non-MSI-high and 3 deficient MMR(dMMR)/MSI-high, 2 of whom were diagnosed as having Lynch syndrome. RAS/BRAF testing was performed in 28 patients, identifying 6 with KRAS variants, while no BRAFV600E or KRASG12C were found. The frequencies of dMMR and Lynch syndrome in patients under 50 years old was comparable to our previous report in which testing was conducted as part of research. Our results suggest that in patients under 50 years old(, 1)the utility of BRAF testing as an adjunctive diagnostic tool for Lynch syndrome is limited, and (2)BRAFV600E or KRASG12C was not detected;however, a larger accumulation of cases is necessary.

The precise diagnosis and medical management of patients with suspected familial adenomatous polyposis should be based on genetic testing, which may not always be available. Therefore, establishing a new model for predicting the likelihood of a germline pathogenic variant (GPV) of APC based on its clinical manifestations could prove to be useful in clinical practice. The presence of GPVs of APC gene was investigated in 162 patients with adenomatous polyposis (≥ 10 polyps) using a multigene panel or single-gene testing. To generate a predictive model for GPV of the APC gene, a logistic regression analysis was performed using the clinicopathological variables available at the time of the diagnosis of adenomatous polyposis. Ninety (55.6

PURPOSE:This retrospective study was performed to investigate the recent trend of occurrence of cancer of the remnant colorectal segment(RCRS)after ileal-pouch anal anastomosis(IPAA)/ileorectal anastomosis(IRA)and to consider the optimal surveillance methods in patients with familial adenomatous polyposis(FAP)undergoing(procto)colectomy.PATIENTS AND METHODS:The subject was a total of patients with FAP undergoing IPAA or IRA between 2005 and 2022. Clinicopathological data were extracted from medical charts and analyzed. Cumulative incidence of cancer in the RCRS and overall survival after treatment of such tumors were calculated by the Kaplan-Meier method.RESULTS:There were 45 male and 56 female. IPAA was performed in 49 patients(hand-sewn; n=33, stapled; n=16)and IRA was performed in 52 patients. The median age at initial colorectal surgery was 32 years old(range, 13-66 years old). Median postoperative follow-up was 11 years(range, 1-48 years). Eighty-one patients were confirmed to have pathogenic variant of APC by genetic test. The cumulative incidence of cancer of the RCRS did not differ between patients undergoing IPAA and those undergoing IRA(p= 0.73, 4.1% versus 1.9% at 10 years). The cumulative 5-year overall survival rate after additional surgery for the tumor of RCRS was 82%.CONCLUSION:This study has several limitations due to single institutional retrospective study with small cases and non-standardized postoperative endoscopic surveillance. However, our results seem to show satisfactory oncological outcomes of patients with FAP in terms of the control of cancer of the RCRS under postoperative periodic surveillance, regardless of the type of colorectal resection.

Muir-Torre syndrome(MTS)is a disease characterized by the simultaneous occurrence of sebaceous tumors and visceral malignant tumors. This syndrome is now considered to be a phenotypic variant of Lynch syndrome(LS). Our patient was a 58-year-old woman with a history of endometrioid adenocarcinoma of the uterine isthmus at the age of 40 years and left-sided triple negative breast cancer at the age of 44 years. At the age of 52 years, a multigene panel testing revealed a pathogenic variant in MSH2, and the patient was diagnosed with LS. During surveillance for LS in our department, a 2-mm sized intradermal nodule was found on the patient's left shoulder, at the age of 58 years. Histopathological examination of the resected intradermal nodule revealed a sebaceous adenoma. LS can present as MTS, and it is, therefore, important to conduct surveillance not only for visceral malignant tumors but also for skin tumors.

BACKGROUND:Based on molecular characteristics, deficient DNA mismatch repair (dMMR) solid tumors are largely divided into three categories: somatically MLH1-hypermethylated tumors, Lynch syndrome (LS)-associated tumors, and Lynch-like syndrome (LLS)-associated tumors. The incidence of each of these conditions and the corresponding pathogenic genes related to LLS remain elusive. METHODS:We identified dMMR tumors in 3609 tumors from 9 different solid organs, including colorectal cancer, gastric cancer, small-bowel cancer, endometrial cancer, ovarian cancer, upper urinary tract cancer, urinary bladder cancer, prostate cancer, and sebaceous tumor, and comprehensively summarized the characterization of dMMR tumors. Characterization of dMMR tumors were performed as loss of at least one of MMR proteins (MLH1, MSH2, MSH6, and PMS2), by immunohistochemistry, followed by MLH1 promotor methylation analysis and genetic testing for MMR genes where appropriate. Somatic variant analysis of MMR genes and whole exome sequencing (WES) were performed in patients with LLS. RESULTS:In total, the incidence of dMMR tumors was 5.9% (24/3609). The incidence of dMMR tumors and the proportion of the three categorized dMMR tumors varied considerably with different tumor types. One to three likely pathogenic/pathogenic somatic MMR gene variants were detected in 15 out of the 16 available LLS tumors. One patient each from 12 patients who gave consent to WES demonstrated non-MMR germline variants affect function (POLQ or BRCA1). CONCLUSIONS:Our data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.

Objectives: Although some studies have evaluated the effectiveness of comprehensive genomic profiling (CGP) in solid tumors, the effectiveness of CGP in metastatic colorectal cancer (mCRC) has not been evaluated using detailed real-world long-outcome data. Methods: This was part of a single institutional non-comparative prospective observational study that observed all patients with solid tumors who underwent CGP at Saitama Medical Center, Saitama Medical University. We enrolled patients with mCRC between June 4, 2020, and March 31, 2023. The primary endpoint was the proportion of patients who received CGP-based therapy. Results: There were 43 patients with mCRC. Of these, six patients (14.0%) received CGP-based therapy. The median overall survival from CGP testing in patients who received CGP-based therapy was 9.7 months. The progression free survival (PFS) ratio of CGP-based therapy and immediate previous therapy ranged from 0.04 to 2.0. The PFS ratio >1.5 was 14.3% (one out of seven treatments). One patient exhibited an exceptional response to pembrolizumab. Before CGP testing, the patient's cancer was classified as non-microsatellite instability-high, although the CGP test revealed a high tumor mutational burden. In Japan, patients with this subtype cannot undergo pembrolizumab without testing for CGP. Conclusions: This prospective observational study's findings provide an overview of CGP testing outcomes in patients with refractory mCRC.

The proband is a 47-year-old woman who underwent a posterior total pelvic exenteration for Stage Ⅲb rectal cancer. Microsatellite instability(MSI)test and immunohistochemistry(IHC)for mismatch repair(MMR)proteins using the resected tumor tissue showed MSI-High and loss of MLH1/PMS2 expression. In addition, although BRAF V600E variant was not identified, MLH1 methylation was detected. Therefore, this patient was diagnosed as having sporadic deficient MMR(MSI-High) rectal cancer. However, the possibility of Lynch syndrome could not be ruled out because of her family history and young age of onset, then we performed a multigene panel testing including MMR genes. Subsequently, a likely pathogenic variant of MSH2(c.2260A>G)was identified. This case suggests that MLH1-methylated rectal cancer can develop in patients with Lynch syndrome and that multigene panel test using next-generation technology would be useful for searching hereditary cancer predisposition syndromes such as Lynch syndrome even in patients with sporadic dMMR colorectal cancer.

More than 90% of Lynch syndrome(LS)associated colorectal cancers show high-frequency microsatellite instability(MSI-H). It is known that ulcerative colitis(UC)is associated with a high incidence of colorectal cancer due to chronic inflammatory changes in the intestinal mucosa. MSI-H is also found in 2.6-40% of ulcerative colitis associated neoplasia(UCAN), and much neoplasia occur at a young age. Our case was a 35-year-old man who had developed ulcerative colitis at the age of 20 and was undergoing treatment. At the age of 35, he complained of right lower abdominal pain and was diagnosed with ascending colon cancer by colonoscopy. As the first stage of a 3-stage operation, laparoscopic total colectomy with ileostomy was performed. The histological type was poorly differentiated adenocarcinoma, and the progression was pT4a pN1bcM0, pStage Ⅲb. Before the start of adjuvant chemotherapy, MSI testing was performed, and the result was MSI-H. Immunohistochemistry revealed loss of expression of MSH2 and MSH6. Although there was no strong family history suggestive of LS, the patient's clinical characteristics, such as early age onset, location in the right-sided colon, and poorly differentiated adenocarcinoma as the primary histological type, were consistent with LS. As he requested genetic testing, Sanger sequencing of MSH2 was performed using peripheral blood, which revealed a likely pathogenic variant in MSH2 (NM_000251.3 c.1045C>T)and led to a diagnosis of LS. MSI-H may be observed in UCAN, and there are many similarities between the clinical and histopathological findings of UCAN and LS. Although the coexistence of UC and LS is rare, it is important to keep this possibility in mind when managing clinical cases.

BACKGROUND AND AIM:Peutz-Jeghers syndrome (PJS) and juvenile polyposis syndrome (JPS) are autosomal dominant diseases associated with high cancer risk. In Japan, knowledge about the prevalence and incidence of PJS and JPS is lacking despite being crucial for providing appropriate medical support. We aimed to determine the prevalence and incidence of these diseases. METHODS:In 2022, a nationwide questionnaire survey was conducted to determine the number of patients with PJS or JPS by sex and the number of newly confirmed cases from 2019 to 2021. The target facilities included gastroenterology, pediatrics, and pediatric surgery departments, which were stratified into seven classes on the basis of the total number of beds. We randomly selected target facilities using different extraction rates in each class, resulting in 1748/2912 facilities (extraction rate: 60%) as the final sample. We calculated the estimated number of patients using the response and extraction rates. RESULTS:A total of 1077 facilities responded to the survey. The estimated numbers of patients with PJS and JPS were 701 (95% confidence interval [CI]: 581-820) and 188 (95% CI: 147-230), respectively. The 3-year period prevalences of PJS and JPS were 0.6/100000 and 0.15/100000, whereas the incidences in 2021 were 0.07/100000 and 0.02/100000, respectively. Male patients constituted 53.5% and 59.6% in the PJS and JPS groups, respectively. CONCLUSIONS:We determined the prevalence and incidence of PJS and JPS in Japan for the first time. Further research is needed to obtain more detailed information, including the clinical differences and outcomes in Japan.

A 47-year-old woman diagnosed with transverse colon cancer with liver, peritoneal, and lymph node metastases was admitted. Modified FOLFOX6(mFOLFOX6)regimen was given as a first line chemotherapy and was followed by pembrolizumab after 1 cycle of the mFOLFOX6, because microsatellite instability(MSI)test of the tumor showed high-frequency MSI. Because of the transverse colon obstruction after 2 cycles of pembrolizumab, she underwent right hemicolectomy. Histological examination of the resected specimen revealed no residual tumor cells in the primary tumor and reginal lymph nodes. Immunohistochemistry for mismatch repair proteins(IHC-MMR)showed loss of MSH2 and MSH6 expression. Genetic test identified a MSH2 pathogenic variant leading to the diagnosis of Lynch syndrome. The present case shows the importance of MSI test or IHC-MMR before the treatment of metastatic colorectal cancer.

Immune checkpoint inhibitors(ICIs)are widely used for the treatment of unresectable gastric cancer. We treated approximately 70 patients with ICIs. ICI treatment with pembrolizumab was administered for MSI-high cases and nivolumab for MSS cases in the second- or third-line chemotherapy. We observed 5 cases of complete response. Among these, 2 patients presented with liver metastases, 2 with peritoneal disseminations, and 1 with pulmonary metastasis. In 1 patient, the primary tumor invaded the diaphragm and descending aorta; whereas, in another patient the primary tumor invaded the pancreas and liver. All patients had progressive disease after first-line chemotherapy.

Microsatellite instability (MSI) testing, an established technique that has gained prominence in recent years for its predictive potential regarding the efficacy of immune checkpoint inhibitors, is used to evaluate DNA mismatch repair (MMR) deficiency (dMMR). As with other methods, the immunohistochemistry (IHC) of MMR proteins is also widely adopted. Although both techniques have been validated, their concordance rate remains unknown, particularly regarding non-colorectal cancer. Therefore, the aim of the present study was to explore and elucidate their concordance in the context of gastric cancer (GC). A total of 489 surgically resected primary GC tissues were analyzed to compare the results yielded by the MSI test and those from IHC. Of 488 GC cases, 56 (11.5%) exhibited a loss of MMR proteins, whereas 52 (10.7%) were classified as high-frequency MSI (MSI-H). The concordance rate between these two categories was 99.2%. The microsatellite markers BAT26 and MONO27 demonstrated 100% sensitivity and 99.5% specificity in detecting dMMR GC. In addition, histopathological analysis revealed that MSI-H was more prevalent in GCs exhibiting coexisting Tub2 and Por1 subtypes. However, four discordant cases were observed. All four cases were microsatellite-stable cases but exhibited loss of MLH1 protein expression with hypermethylation of the MLH1 promoter. The results of the present study highlight that while there is a strong concordance between MSI and IHC testing results for determining dMMR status, IHC testing may offer superior efficacy in detecting dMMR.

The microsatellite instability (MSI)/mismatch repair (MMR) status is one of the critical genomic biomarkers for predicting patient response to immune checkpoint inhibitors (ICIs). In this study, we aimed to investigate the concordance among the MSIsensor score obtained from whole-exome sequencing (WES), which could be a futuristic clinical cancer sequencing method, using only tumor tissues, MSI-PCR results, and immunohistochemistry (IHC) results to analyze various solid cancer types. We first endeavored to set the cut-off value of MSIsensor to determine functional deficient mismatch repair (f-dMMR) status. The MSI status of 1054 patients analyzed using WES was evaluated using MSIsensor. In addition, 87 of these patients were further analyzed using MSI-PCR and MMR IHC to calculate the sensitivity and specificity of the MSIsensor cut-off score. Our results showed that score 12.5 was an adequate cut-off score equivalent to PCR-confirmed MSS/MSI-low and MSI-high statuses, with sensitivity, specificity, and area under the curve values of 95.2%, 100%, and 0.998, respectively. Moreover, we identified false-positive cases of tumors with high mutational burden with an MSIsensor score <12.5, and optional IHC examination could rescue these cases. In conclusion, the MSIsensor score obtained using WES with tumor tissue showed a high clinical validity, with a cut-off value of 12.5 for f-dMMR detection, in combination with optional IHC analysis for MMR. Our novel algorithm will provide insights into the development of ICIs for cancer treatment, particularly when WES becomes a more common cancer genomic test in the near future.

Li-Fraumeni syndrome(LFS)is a hereditary cancer disorder caused by germline variant in TP53 and characterized by various malignancies. Multidisciplinary treatment is needed for tumors of LFS, however, radiation therapy is a relative contraindication because of frequent development of secondary malignancy such as sarcoma in the irradiated field. Case 1: A 22- year-old woman who was diagnosed with LFS by genetic test when she developed upper rectal cancer. Her rectal tumor with marked bilateral lateral lymph node dissection was successfully removed by low anterior resection with extensive lateral lymph node dissection. She underwent resection for ovarian metastasis followed by chemotherapy and radiotherapy but subsequently died by the disease 32 months postoperatively. Case 2(elder sister of Case 1): A brain tumor was identified in the left high frontal lobe to the parietal lobe because of consciousness disorder, after the genetic diagnosis of LFS. The brain tumor was successfully resected. Histological examination revealed diffuse astrocytoma(WHO grade Ⅱ). Local recurrence was observed 46 months later, and radiation therapy was performed. Six months have passed since radiation therapy, no exacerbation of local recurrence has been observed.

This study aimed to assess current trends in morbidity and mortality among patients with familial adenomatous polyposis (FAP). These data can be used for optimal surveillance and management of such patients. Data (November 2001 and April 2020) of genetically confirmed patients with FAP (n = 87) and their first-degree relatives with FAP phenotype (n = 20) were extracted from the Saitama Medical Center database. Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) were estimated using indirect method. Overall, 46 men and 61 women were included; the median age at FAP diagnosis was 28.0 years for both. The SMR for all causes of death was 47.7 (95% confidence interval [CI] 19.1–98.2) in women and 26.5 (95% CI 9.73–57.8) in men. The SIR for colorectal cancer (CRC) was 860 (95% CI 518–1340) in women and 357 (95% CI 178–639) in men. The SMR for CRC was 455 (95% CI 93.7–1330) in women and 301 (95% CI 62.0–879) in men. Thirteen patients died during the observation period, and CRC was the leading cause of death (46%). Other causes of death included desmoid tumor (n = 2), small intestinal cancer (n = 2), ovarian cancer (n = 1), duodenal cancer (n = 1), and sepsis (n = 1). The mortality ratio, estimated using SMR, remained high. CRC was the leading cause of death, whereas almost half of the causes of deaths were extra-colonic tumors. Life-long management of extra-colonic diseases may improve the prognosis in these patients.

Background: Laparoscopic proximal gastrectomy (LPG) is an attractive option for the treatment of early gastric cancer in the upper third of the stomach. No optimal method of reconstruction after LPG has been established because of problems associated with postoperative reflux. Gastric tube reconstruction, a type of esophagogastrostomy, is a simple procedure, but it is associated with a high frequency of reflux esophagitis (RE). We investigated the relationship between RE and gastric emptying, along with nutritional parameters. Subjects and Methods: We compared gastric emptying in patients who had undergone curative LPG with gastric tube reconstruction for gastric cancer with that of patients after total gastrectomy (TG), distal gastrectomy (DG) and of healthy volunteers and patients after DG. The LPG group was divided into an RE LPG-RE (+) group and a non-reflux esophagitis (non-RE) an LPG-RE (−) group, and we compared gastric emptying and indices of nutrition, such as body weight and laboratory findings, between those among LPG-RE (+), LPG-RE (−), and TG groups. Results: The time lag between ingestion and peak 13CO2 expiration (T lag) in the healthy volunteer group was significantly shorter in the LPG group longer than those in the healthy volunteer LPG group and TG group. The T lag was significantly shorter in the RE LPG-RE (+) group than in the non-RE LPG-RE (−) group. The percentage change in body weight percentage in the non-RE LPG-RE (−) group was significantly larger than that in the RE LPG-RE (+) group at 12 months after surgery. Both the serum albumin and hemoglobin levels in the non-RE LPG-RE (−) tended to be preserved compared with those in the RE LPG-RE (+) group and TG group. Conclusions: Gastric emptying was accelerated after LPG, and was associated with RE. Our data suggest that RE could be associated with body weight loss after LPG.

BACKGROUND The attention on mismatch repair-deficient (dMMR) gastric cancer has increased in this era of anti-PD-1 blockade therapy; however, the prevalence and molecular genetics of patients with dMMR gastric cancer have not been completely investigated. METHODS Immunohistochemistry of MMR proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary gastric cancers of 513 consecutive patients. Genetic and/or epigenetic alterations of the MMR genes were also investigated. RESULTS Loss of expression of one or more MMR proteins was observed in 58 patients (11.3%); 54 patients showed loss of MLH1/PMS2, 3 patients showed loss of MLH1/PMS2/MSH6 and 1 patient showed loss of PMS2 alone. Among these 58 patients, 55 showed hypermethylation of the promoter region of MLH1. Genetic testing revealed that the remaining three patients had Lynch syndrome (n = 1) or Lynch-like syndrome (n = 2). A total of 15 patients (25.9% of all patients with dMMR gastric cancer and 2.9% of all patients with gastric cancer), including 11 patients with stage I-III dMMR gastric cancer who had recurrence and 4 patients with stage IV dMMR gastric cancer, are potential candidates for the use of anti-PD-1 blockades. CONCLUSIONS This is the first study to investigate the frequency and molecular genetic mechanisms of dMMR gastric cancer comprehensively, focusing on the benefit of using PD-1 blockades. Our observations will be beneficial in the clinical practice of metastatic gastric cancer.