Treatment Decision for Locally Resected T1 Colorectal Carcinoma-Verification of the Japanese Guideline Criteria for Additional Surgery Based on Long-Term Clinical Outcomes.

INTRODUCTION: To verify the value of the pathological criteria for additional treatment in locally resected pT1 colorectal carcinoma (CRC) which have been used in the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines since 2009. METHODS: We enrolled 4,719 patients with pT1 CRC treated at 27 institutions between July 2009 and December 2016 (1,259 patients with local resection alone [group A], 1,508 patients with additional surgery after local resection [group B], and 1,952 patients with surgery alone [group C]). All 5 factors of the JSCCR guidelines (submucosal resection margin, tumor histologic grade, submucosal invasion depth, lymphovascular invasion, and tumor budding) for lymph node metastasis (LNM) had been diagnosed prospectively. RESULTS: Any of the risk factors were present in 3,801 patients. The LNM incidence was 10.3% (95% confidence interval 9.3-11.4) in group B/C patients with risk factors, whereas it was 1.8% (95% confidence interval 0.4-5.2) in those without risk factors ( P < 0.01). In group A, the incidence of recurrence was 3.4% in patients with risk factors, but it was only 0.1% in patients without risk factors ( P < 0.01). The disease-free survival rate of group A patients classified as risk positive was significantly worse than those of groups B and C patients. However, the 5-year disease-free survival rate in group A patients with no risk was 99.2%. DISCUSSION: Our large-scale real-world multicenter study demonstrated the validity of the JSCCR criteria for pT1 CRC after local resection, especially regarding favorable outcomes in patients with low risk of LNM.

Assessing the efficacy of target adaptive sampling long-read sequencing through hereditary cancer patient genomes.

Innovations in sequencing technology have led to the discovery of novel mutations that cause inherited diseases. However, many patients with suspected genetic diseases remain undiagnosed. Long-read sequencing technologies are expected to significantly improve the diagnostic rate by overcoming the limitations of short-read sequencing. In addition, Oxford Nanopore Technologies (ONT) offers adaptive sampling and computationally driven target enrichment technology. This enables more affordable intensive analysis of target gene regions compared to standard non-selective long-read sequencing. In this study, we developed an efficient computational workflow for target adaptive sampling long-read sequencing (TAS-LRS) and evaluated it through application to 33 genomes collected from suspected hereditary cancer patients. Our workflow can identify single nucleotide variants with nearly the same accuracy as the short-read platform and elucidate complex forms of structural variations. We also newly identified several SINE-R/VNTR/Alu (SVA) elements affecting the APC gene in two patients with familial adenomatous polyposis, as well as their sites of origin. In addition, we demonstrated that off-target reads from adaptive sampling, which is typically discarded, can be effectively used to accurately genotype common single-nucleotide polymorphisms (SNPs) across the entire genome, enabling the calculation of a polygenic risk score. Furthermore, we identified allele-specific MLH1 promoter hypermethylation in a Lynch syndrome patient. In summary, our workflow with TAS-LRS can simultaneously capture monogenic risk variants including complex structural variations, polygenic background as well as epigenetic alterations, and will be an efficient platform for genetic disease research and diagnosis.

Long-term outcomes after non-curative endoscopic resection for esophageal squamous cell carcinoma followed by additional chemoradiotherapy.

Endoscopic resection (ER) of esophageal squamous cell carcinoma (ESCC) is evaluated pathologically, and additional treatment is recommended for cases resulting in non-curative resection, defined as pMM with lymphovascular invasion (LVI), pSM, or positive vertical margin. This study aimed to assess long-term outcomes and risk factors for recurrence in patients with ESCC treated with non-curative ER followed by additional chemoradiotherapy (CRT). We retrospectively reviewed the clinical courses of patients who underwent non-curative ER followed by additional CRT for ESCCs between August 2007 and December 2017. Recurrence rates and risk factors for recurrence were analyzed. Among 97 patients with non-curative ER, 73 underwent additional CRT. With a median follow-up period of 71 months, recurrences were observed in 10 (14%) of 73 patients, with a median interval of 24.5 (1-59 months). The 3- and 5-year recurrence-free survival were 89 and 85%, respectively, and the 3- and 5-year overall survival rates were 96 and 91%, respectively. Multivariate analysis showed that lymphatic invasion was an independent risk factor for recurrence in patients with non-curative ESCC receiving additional CRT. Among the 10 patients with recurrence, 4, 3, 2, and 1 underwent surgery, chemotherapy, supportive care, and CRT, respectively. Notably, all four patients who underwent surgery survived, regardless of regional and/or distant lymph node metastasis. Lymphatic invasion is an independent risk factor for the recurrence of non-curative ESCCs. Careful follow-up is required for at least 5 years after ER with additional CRT.

Sleeping Beauty transposon mutagenesis in mouse intestinal organoids identifies genes involved in tumor progression and metastasis.

To identify genes important for colorectal cancer (CRC) development and metastasis, we established a new metastatic mouse organoid model using Sleeping Beauty (SB) transposon mutagenesis. Intestinal organoids derived from mice carrying actively mobilizing SB transposons, an activating KrasG12D, and an inactivating ApcΔ716 allele, were transplanted to immunodeficient mice. While 66.7% of mice developed primary tumors, 7.6% also developed metastatic tumors. Analysis of SB insertion sites in tumors identified numerous candidate cancer genes (CCGs) identified previously in intestinal SB screens performed in vivo, in addition to new CCGs, such as Slit2 and Atxn1. Metastatic tumors from the same mouse were clonally related to each other and to primary tumors, as evidenced by the transposon insertion site. To provide functional validation, we knocked out Slit2, Atxn1, and Cdkn2a in mouse tumor organoids and transplanted to mice. Tumor development was promoted when these gene were knocked out, demonstrating that these are potent tumor suppressors. Cdkn2a knockout cells also metastasized to the liver in 100% of the mice, demonstrating that Cdkn2a loss confers metastatic ability. Our organoid model thus provides a new approach that can be used to understand the evolutionary forces driving CRC metastasis and a rich resource to uncover CCGs promoting CRC.

Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation.

OBJECTIVE: The presence of intestinal metaplasia (IM) is a risk factor for gastric cancer. However, it is still controversial whether IM itself is precancerous or paracancerous. Here, we aimed to explore the precancerous nature of IM by analysing epigenetic alterations. DESIGN: Genome-wide DNA methylation analysis was conducted by EPIC BeadArray using IM crypts isolated by Alcian blue staining. Chromatin immunoprecipitation sequencing for H3K27ac and single-cell assay for transposase-accessible chromatin by sequencing were conducted using IM mucosa. NOS2 was induced using Tet-on gene expression system in normal cells. RESULTS: IM crypts had a methylation profile unique from non-IM crypts, showing extensive DNA hypermethylation in promoter CpG islands, including those of tumour-suppressor genes. Also, the IM-specific methylation profile, namely epigenetic footprint, was present in a fraction of gastric cancers with a higher frequency than expected, and suggested to be associated with good overall survival. IM organoids had remarkably high NOS2 expression, and NOS2 induction in normal cells led to accelerated induction of aberrant DNA methylation, namely epigenetic instability, by increasing DNA methyltransferase activity. IM mucosa showed dynamic enhancer reprogramming, including the regions involved in higher NOS2 expression. NOS2 had open chromatin in IM cells but not in gastric cells, and IM cells had frequent closed chromatin of tumour-suppressor genes, indicating their methylation-silencing. NOS2 expression in IM-derived organoids was upregulated by interleukin-17A, a cytokine secreted by extracellular bacterial infection. CONCLUSIONS: IM cells were considered to have a precancerous nature potentially with an increased chance of converting into cancer cells, and an accelerated DNA methylation induction due to abnormal NOS2 expression.

Decoding the basis of histological variation in human cancer.

Molecular abnormalities that shape human neoplasms dissociate their phenotypic landscape from that of the healthy counterpart. Through the lens of a microscope, tumour pathology optically captures such aberrations projected onto a tissue slide and has categorized human epithelial neoplasms into distinct histological subtypes based on the diverse morphogenetic and molecular programmes that they manifest. Tumour histology often reflects tumour aggressiveness, patient prognosis and therapeutic vulnerability, and thus has been used as a de facto diagnostic tool and for making clinical decisions. However, it remains elusive how the diverse histological subtypes arise and translate into pleiotropic biological phenotypes. Molecular analysis of clinical tumour tissues and their culture, including patient-derived organoids, and add-back genetic reconstruction of tumorigenic pathways using gene engineering in culture models and rodents further elucidated molecular mechanisms that underlie morphological variations. Such mechanisms include genetic mutations and epigenetic alterations in cellular identity codes that erode hard-wired morphological programmes and histologically digress tumours from the native tissues. Interestingly, tumours acquire the ability to grow independently of the niche-driven stem cell ecosystem along with these morphological alterations, providing a biological rationale for histological diversification during tumorigenesis. This Review comprehensively summarizes our current understanding of such plasticity in the histological and lineage commitment fostered cooperatively by molecular alterations and the tumour environment, and describes basic and clinical implications for future cancer therapy.

Fucoxanthin Inhibits Development of Sigmoid Colorectal Cancer in a PDX Model With Alterations of Growth, Adhesion, and Cell Cycle Signals.

BACKGROUND/AIM: Fucoxanthin (Fx), a dietary marine xanthophyll, exerts potent anticancer effects in various colorectal cancer (CRC) animal models. However, therapeutic effects of Fx in human cancer tissues remain unclear. A patient-derived xenograft (PDX) mouse model transplanted with cancer tissues from patients is widely accepted as the best preclinical model for evaluating the anticancer potential of drug candidates. MATERIALS AND METHODS: Herein, we investigated the anticancer effects of Fx in PDX mice transplanted with cancer tissues derived from a patient with CRC (CRC-PDX) using LC-MS/MS- and western blot-based proteome analysis. RESULTS: The tumor in the patient with CRC was a primary adenocarcinoma (T3N0M0, stage II) showing mutations of certain genes that were tumor protein p53 (TP53), AT-rich interaction domain 1A (ARID1A), neuroblastoma RAS viral oncogene homolog (NRAS), and PMS1 homolog 2 (PMS2). Administration of Fx significantly suppressed the tumor growth (0.6-fold) and tended to induce differentiation in CRC-PDX mice. Fx up-regulated glycanated-decorin (Gc-DCN) expression, and down-regulated Kinetochore-associated protein DSN1 homolog (DSN1), phospho(p) focal adhesion kinase (pFAK)(Tyr397), pPaxillin(Tyr31), and c-MYC involved in growth, adhesion, and/or cell cycle, in the tumors of CRC-PDX mice than in control mice. Alterations in the five proteins were consistent with those in human CRC HT-29 and HCT116 cells treated with fucoxanthinol (FxOH, a major metabolite of Fx). CONCLUSION: Fx suppresses development of human-like CRC tissues, especially through growth, adhesion, and cell cycle signals.

A discrimination model by machine learning to avoid gastrectomy for early gastric cancer.

Aim: Gastrectomy is recommended for patients with early gastric cancer (EGC) because the possibility of lymph node metastasis (LNM) cannot be completely denied. The aim of this study was to develop a discrimination model to select patients who do not require surgery using machine learning. Methods: Data from 382 patients who received gastrectomy for gastric cancer and who were diagnosed with pT1b were extracted for developing a discrimination model. For the validation of this discrimination model, data from 140 consecutive patients who underwent endoscopic resection followed by gastrectomy, with a diagnosis of pT1b EGC, were extracted. We applied XGBoost to develop a discrimination model for clinical and pathological variables. The performance of the discrimination model was evaluated based on the number of cases classified as true negatives for LNM, with no false negatives for LNM allowed. Results: Lymph node metastasis was observed in 95 patients (25%) in the development cohort and 11 patients (8%) in the validation cohort. The discrimination model was developed to identify 27 (7%) patients with no indications for additional surgery due to the prediction of an LNM-negative status with no false negatives. In the validation cohort, 13 (9%) patients were identified as having no indications for additional surgery and no patients with LNM were classified into this group. Conclusion: The discrimination model using XGBoost algorithms could select patients with no risk of LNM from patients with pT1b EGC. This discrimination model was considered promising for clinical decision-making in relation to patients with EGC.

Phase II Trial of Nivolumab in Metastatic Rare Cancer with dMMR or MSI-H and Relation with Immune Phenotypic Analysis (the ROCK Trial).

PURPOSE: Mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) are positive predictive markers for immune checkpoint inhibitors. However, data on the activity of nivolumab in advanced dMMR/MSI-H rare cancers and more accurate biomarkers are worth exploring. PATIENTS AND METHODS: We conducted a multicenter phase II, open-label, single-arm clinical trial to explore the effectiveness and safety of nivolumab monotherapy in patients with advanced rare cancers with dMMR/MSI-H, in parallel with immune phenotype analysis, to explore new biomarkers. A Bayesian adaptive design was applied. Characterization of peripheral blood mononuclear cells (PBMC) was characterized by multicolor flow cytometric analysis and CyTOF using samples collected before and after the intervention. The dMMR was identified by the complete loss of MLH1/MSH2/MSH6/PMS2. RESULTS: From May 2018 to March 2021, 242 patients were screened, and 11 patients were enrolled, of whom 10 were included in the full analysis. Median follow-up was 24.7 months (interquartile range, 12.4-31.5). Objective response rate was 60% [95% confidence interval (CI), 26.2-87.8] by central assessment and 70% (95% CI, 34.8-93.3) by local investigators. Median progression-free survival was 10.1 months (95% CI, 0.9-11.1). No treatment-related adverse events of grade 3 or higher were observed. Patients with a tumor mutation burden of ≥10/Mb showed a 100% response rate (95% CI, 47.8-100). Responders had increased T-bet+ PD-1+ CD4+ T cells in PBMC compared with nonresponders (P < 0.05). CONCLUSIONS: The trial met its primary endpoint with nivolumab, demonstrating clinical benefit in advanced dMMR/MSI-H rare solid cancers. Besides, the proportion of T-bet+ PD-1+ CD4+ T-cells may serve as a novel predictive biomarker.

A comprehensive appraisal of HER2 heterogeneity in HER2-amplified and HER2-low colorectal cancer.

BACKGROUND: This study aimed to elucidate the clinicopathological and molecular features of HER2-amplified and HER2-low colorectal cancers (CRCs). We also characterised HER2 expression statuses in CRCs focusing on their intratumoral heterogeneity and alterations in metastatic lesions to establish practical HER2 status assessment. METHODS: We evaluated 1009 CRCs for HER2 expression and HER2 amplification by immunohistochemistry and FISH, respectively, and correlated the results to clinicopathological and molecular data. For HER2-positive tumours, HER2 expression in metastatic lesions was also assessed. RESULTS: Twenty-five HER2-amplified (2.5%) and 46 HER2-low tumours (4.6%) were identified. HER2-amplified tumours consistently lacked a mucinous component and HER2-low tumours tended to be in the right colon, but no other clinicopathological features were noted. KRAS, NRAS or BRAF mutations were detected in only two HER2-amplified tumours (8%), whereas 23 HER2-low tumours (50%) had one of these mutations. Most HER2-amplified and HER2-low tumours showed a homogeneous or mosaic HER2 expression pattern and a clustered heterogeneous expression pattern was rather rare. HER2 expression was maintained in most metastatic lesions in both HER2-amplified (93%) and HER2-low tumours (81%). CONCLUSIONS: These results suggest that biopsy-based assessment of primary lesions is appropriate for the identification of CRC patients eligible for systemic HER2-targeted therapy.

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).

Clinical Guidelines for Diagnosis and Management of Juvenile Polyposis Syndrome in Children and Adults-Secondary Publication.

Juvenile polyposis syndrome (JPS) is a rare disease characterized by multiple hamartomatous polyps within the gastrointestinal tract. SMAD4 or BMPR1A is known as a causative gene of JPS. Approximately 75% of newly diagnosed cases have an autosomal-dominantly inherited condition, whereas 25% are sporadic without previous history of polyposis in the family pedigree. Some patients with JPS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood. JPS is classified into three categories according to phenotypic features of polyp distributions, including generalized juvenile polyposis, juvenile polyposis coli, and juvenile polyposis of the stomach. Juvenile polyposis of the stomach is caused by germline pathogenic variants of SMAD4 with a high risk leading to gastric cancer. Pathogenic variants of SMAD4 are also associated with hereditary hemorrhagic telangiectasia-JPS complex, inducing regular cardiovascular survey. Despite growing concerns regarding the managing JPS in Japan, there are no practical guidelines. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labor and Welfare involving specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of JPS with three clinical questions and corresponding recommendations based on a careful review of the evidence and involve incorporating the concept of the Grading of Recommendations, Assessment, Development, and Evaluation system. Herein, we present the clinical practice guidelines of JPS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with JPS.

Clinical Guidelines for Diagnosis and Management of Juvenile Polyposis Syndrome in Children and Adults­Secondary Publication

Juvenile polyposis syndrome (JPS) is a rare disease characterized by multiple hamartomatous polyps within the gastrointestinal tract. SMAD4 or BMPR1A is known as a causative gene of JPS. Approximately 75% of newly diagnosed cases have an autosomal-dominantly inherited condition, whereas 25% are sporadic without previous history of polyposis in the family pedigree. Some patients with JPS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood. JPS is classified into three categories according to phenotypic features of polyp distributions, including generalized juvenile polyposis, juvenile polyposis coli, and juvenile polyposis of the stomach. Juvenile polyposis of the stomach is caused by germline pathogenic variants of SMAD4 with a high risk leading to gastric cancer. Pathogenic variants of SMAD4 are also associated with hereditary hemorrhagic telangiectasia-JPS complex, inducing regular cardiovascular survey. Despite growing concerns regarding the managing JPS in Japan, there are no practical guidelines. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labor and Welfare involving specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of JPS with three clinical questions and corresponding recommendations based on a careful review of the evidence and involve incorporating the concept of the Grading of Recommendations, Assessment, Development, and Evaluation system. Herein, we present the clinical practice guidelines of JPS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with JPS.

Comparison of clinicopathological and genomic profiles in anal squamous cell carcinoma between Japanese and Caucasian cohorts.

Anal squamous cell carcinoma (ASCC) is a rare tumor of the gastrointestinal tract. We aimed to compare the genetic backgrounds and their effect on clinical outcomes between Japanese and Caucasian patients with ASCC. Forty-one patients diagnosed with ASCC at the National Cancer Center Hospital were enrolled and evaluated for clinicopathological features, human papillomavirus (HPV) infection, HPV genotypes, p16 expression, PD-L1, and association of p16 status with the efficacy of concurrent chemoradiotherapy (CCRT). Target sequencing for hotspot mutations in 50 cancer-related genes was performed using genomic DNA from 30 available samples. Of 41 patients, 34 were HPV-positive (among them, HPV 16 was predominant; 73.2%); 38 patients were p16-positive (92.7%); and 39 patients received CCRT, of whom 36 were p16-positive and three p16-negative. p16-positive patients showed better complete response than p16-negative patients. Among 28 samples, 15 showed mutations in PIK3CA, FBXW7, ABL1, TP53, and PTEN; no difference in mutation profiles between the Japanese and Caucasian cohorts was observed. Actionable mutations were detected in both Japanese and Caucasian patients with ASCC. Genetic backgrounds, such as the HPV 16 genotype and PIK3CA mutations, were common regardless of ethnicity. p16 status may be a prognostic biomarker for CCRT in Japanese patients with ASCC.

Multiancestry genomic and transcriptomic analysis of gastric cancer.

Gastric cancer is among the most common malignancies worldwide, characterized by geographical, epidemiological and histological heterogeneity. Here, we report an extensive, multiancestral landscape of driver events in gastric cancer, involving 1,335 cases. Seventy-seven significantly mutated genes (SMGs) were identified, including ARHGAP5 and TRIM49C. We also identified subtype-specific drivers, including PIGR and SOX9, which were enriched in the diffuse subtype of the disease. SMGs also varied according to Epstein-Barr virus infection status and ancestry. Non-protein-truncating CDH1 mutations, which are characterized by in-frame splicing alterations, targeted localized extracellular domains and uniquely occurred in sporadic diffuse-type cases. In patients with gastric cancer with East Asian ancestry, our data suggested a link between alcohol consumption or metabolism and the development of RHOA mutations. Moreover, mutations with potential roles in immune evasion were identified. Overall, these data provide comprehensive insights into the molecular landscape of gastric cancer across various subtypes and ancestries.

Nomogram as a novel predictive tool for lymph node metastasis in T1 colorectal cancer treated with endoscopic resection: a nationwide, multicenter study.

BACKGROUND AND AIMS: Since 2009, the Japanese Society for Cancer of the Colon and Rectum guidelines have recommended that tumor budding and submucosal invasion depth, in addition to lymphovascular invasion and tumor grade, be included as risk factors for lymph node metastasis (LNM) in patients with T1 colorectal cancer (CRC). In this study, a novel nomogram was developed and validated by usirge-scale, real-world data, including the Japanese Society for Cancer of the Colon and Rectum risk factors, to accurately evaluate the risk of LNM in T1 CRC. METHODS: Data from 4673 patients with T1 CRC treated at 27 high-volume institutions between 2009 and 2016 were analyzed for LNM risk. To prepare a nonrandom split sample, the total cohort was divided into development and validation cohorts. Pathologic findings were extracted from the medical records of each participating institution. The discrimination ability was measured by using the concordance index, and the variability in each prediction was evaluated by using calibration curves. RESULTS: Six independent risk factors for LNM, including submucosal invasion depth and tumor budding, were identified in the development cohort and entered into a nomogram. The concordance index was .784 for the clinical calculator in the development cohort and .790 in the validation cohort. The calibration curve approached the 45-degree diagonal in the validation cohort. CONCLUSIONS: This is the first nomogram to include submucosal invasion depth and tumor budding for use in routine pathologic diagnosis based on data from a nationwide multi-institutional study. This nomogram, developed with real-world data, should improve decision-making for an appropriate treatment strategy for T1 CRC.

Unexpected adhesive bowel obstruction after endoscopic submucosal dissection of early sigmoid colon cancer.

Various complications of colorectal endoscopic submucosal dissection (ESD) have been reported, including bleeding, penetration, perforation, and coagulation syndrome. However, the occurrence of bowel obstruction after ESD is rare. We report a case of adhesive bowel obstruction after ESD for a laterally spreading tumor in the sigmoid colon. The 35-mm tumor was successfully removed by ESD without intraoperative complications. The patient had a fever, lower abdominal pain, and a small amount of bloody stool the day after ESD. Endoscopy revealed minor bleeding from the ESD scar, which was treated by hemostatic clips. Pathological analysis showed adenocarcinoma was exposed to the vertical margin; therefore, the resection was non-curative. At 39 days after ESD and 36 days after discharge, the patient had abdominal pain and nausea. She was readmitted with a diagnosis of adhesive bowel obstruction. Conservative treatment was ineffective; therefore, she underwent sigmoidectomy combined with partial resection of the small intestine because of small intestinal stenosis caused by inflammation. The pathological examination showed localized peritonitis around the sigmoid colon where ESD was performed. There was more fibrosis along the serous surface of the small intestine than on the sigmoid colon. We concluded that there was a micro-perforation that could not be detected by endoscopy or physical examination. This case indicates that adhesive bowel obstruction may occur as a complication of ESD.

Safety and short-term efficacy of preoperative FOLFOX therapy in patients with resectable esophageal squamous cell carcinoma who are ineligible for cisplatin.

BACKGROUND: The standard preoperative treatment for resectable locally advanced esophageal squamous cell carcinoma (LAESCC) in Japan is docetaxel, cisplatin (CDDP), and 5-fluorouracil. However, patients with renal or cardiac dysfunction and elderly patients are ineligible for a CDDP-containing regimen because of toxicities. Oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) therapy has less renal toxicity than CDDP-containing regimens and does not require hydration. However, there are limited data on preoperative FOLFOX therapy in these patients. METHODS: This retrospective study analyzed patients with resectable LAESCC who were aged ≥ 75 years or had renal or cardiac dysfunction and received preoperative FOLFOX between 2019 and 2021. FOLFOX was administered every 2 weeks for 3 or 4 cycles and was followed by surgery. Adverse events associated with chemotherapy, the complete resection (R0) rate, relative dose intensity (RDI), and histopathological response were evaluated. RESULTS: Thirty-five patients were eligible. Median age was 77 (range 65-89) years; 68.6% were aged ≥ 75 years, 74.3% had renal dysfunction, and 17.1% had cardiac dysfunction. The RDI was 70.2% and 87.1% for bolus and continuous intravenous 5-fluorouracil, respectively and 85.2% for oxaliplatin. The most common grade ≥ 3 adverse events were neutropenia (60.0%) and leucopenia (28.6%). Two patients (5.7%) had febrile neutropenia and grade 3 pneumonia. Thirty-one patients underwent surgery. The R0 resection rate was 87.1%, and there was no histopathological evidence of residual tumor in 16.1%. There were no treatment-related deaths. CONCLUSIONS: Preoperative FOLFOX had a manageable safety profile and showed favorable short-term efficacy in patients with resectable LAESCC who were ineligible for CDDP-containing treatment.

Sporadic and Familial Adenomatous Polyposis-associated Foveolar-type Adenoma of the Stomach.

Gastric foveolar-type adenoma (FA) is a rare benign neoplasm occurring either sporadically or in patients with familial adenomatous polyposis (FAP). However, the molecular features of FA and the relationship between sporadic and syndromic lesions remain unclear. In this study, we performed clinicopathological, immunohistochemical, and genetic analyses of 18 sporadic and 30 FAP-associated FAs. Most sporadic and FAP-associated FAs were located in the upper or middle third of the stomach, on a background of fundic gland mucosa. Most lesions were low-grade, but 3 lesions had a high-grade component. Sporadic FAs included 2 morphologically distinct subtypes, that is, flat and raspberry-like FAs, which we distinguished based on the endoscopic features. Seven lesions were regarded as flat FAs, appearing as large, slightly elevated lesions and measuring 11 to 87 mm in size. Conversely, 10 raspberry-like FAs were small bright-red polyps, measuring 2 to 8 mm in size. FAP-associated FAs, particularly larger lesions, exhibited morphologic features resembling flat FAs but varied significantly in size (2 to 103 mm). Mutation analysis identified APC and KRAS mutations in all flat FAs but never in raspberry-like FAs. Remarkably, somatic APC and KRAS mutations were also detected in 19 (63%) and 27 (90%) of FAP-associated FAs, respectively. This indicates that they are genetically equivalent to sporadic, flat FAs. This study showed that sporadic FA includes at least 2 morphologically and genetically distinct subtypes: flat and raspberry-like FA. Furthermore, flat FA represents a sporadic counterpart of FAP-associated FA.