[Development of Cancer of the Remnant Colorectal Segment after Ileal-Pouch Anal Anastomosis/Ileorectal Anastomosis in Patients with Familial Adenomatous Polyposis].

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.

[A Case of Transverse Colon Cancer Associated with Lynch Syndrome with Excellent Response to Pembrolizumab].

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.

[Complete Response to Immune Checkpoint Inhibitors in Unresectable Gastric Cancer-A Report of Five Cases].

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.

[A Rare Case of Cronkhite-Canada Syndrome Associated with Gastric Cancer and Gastric Outlet Obstruction].

Cronkhite-Canada syndrome(CCS)is a rare non-inherited disease characterized by gastrointestinal polyposis and ectodermal abnormalities. We report a rare case of CCS associated with gastric cancer and gastric outlet obstruction with a review of the literature. A 75-year-old man was admitted because of frequent vomiting and hypoproteinemia. He was diagnosed with CCS due to typical clinical and laboratory findings including alopecia, nail atrophy, hypoproteinemia, and typical gastrointestinal polyposis. Upper endoscopic examination also pointed out a large gastric cancer mainly located in the antrum and the reversible pyloric obstruction caused by the gastric tumor. Biopsy of the tumor revealed tubular adenocarcinoma. Computed tomography demonstrated the dilated duodenum caused by packing of the gastric tumor. 1.5 months after prednisolone therapy, he underwent total gastrectomy with complete resection of the dilated duodenal bulb. Histological examination revealed gastric cancer(pap>tub1)classified into Stage ⅢC. Postoperative course was uneventful and he moved to another hospital. To our knowledge, including the present case, there were 20 reported cases of CCS associated with gastric cancer from Japan(1979-2022). Also, 7 cases of CCS associated with gastric outlet obstruction was reported.

Endocytoscopic Observation of Esophageal Lesions: Our Own Experience and a Review of the Literature.

This review outlines the process of the development of the endocytoscope (EC) with reference to previously reported studies including our own. The EC is an ultra-high-magnification endoscope capable of imaging at the cellular level. The esophagus is the most suitable site for EC observation because it is amenable to vital staining. The diagnosis of esophageal lesions using EC is based on nuclear density and nuclear abnormality, allowing biopsy histology to be omitted. The observation of nuclear abnormality requires a magnification of ×600 or higher using digital technology. Several staining methods have been proposed, but single staining with toluidine blue or methylene blue is most suitable because the contrast at the border of a cancerous area can be easily identified. A three-tier classification of esophageal lesions visualized by EC is proposed: Type 1 (non-cancerous), Type 2 (endocytoscopic borderline), and Type 3 (cancerous). Since characteristic EC images reflecting pathology can be obtained from non-cancerous esophageal lesions, a modified form of classification with four additional characteristic non-cancerous EC features has also been proposed. Recently, deep-learning AI for analysis of esophageal EC images has revealed that its diagnostic accuracy is comparable to that of expert pathologists.

Preliminary study for developing a navigation system for gastric cancer surgery using artificial intelligence.

PURPOSE: We are attempting to develop a navigation system for safe and effective peripancreatic lymphadenectomy in gastric cancer surgery. As a preliminary study, we examined whether or not the peripancreatic dissection line could be learned by a machine learning model (MLM). METHODS: Among the 41 patients with gastric cancer who underwent radical gastrectomy between April 2019 and January 2020, we selected 6 in whom the pancreatic contour was relatively easy to trace. The pancreatic contour was annotated by a trainer surgeon in 1242 images captured from the video recordings. The MLM was trained using the annotated images from five of the six patients. The pancreatic contour was then segmented by the trained MLM using images from the remaining patient. The same procedure was repeated for all six combinations. RESULTS: The median maximum intersection over union of each image was 0.708, which was higher than the threshold (0.5). However, the pancreatic contour was misidentified in parts where fatty tissue or thin vessels overlaid the pancreas in some cases. CONCLUSION: The contour of the pancreas could be traced relatively well using the trained MLM. Further investigations and training of the system are needed to develop a practical navigation system.

Prognostic Value of Intraoperative Blood Transfusion in Patients with Adenocarcinoma of the Esophagogastric Junction.

Background and objectives: Adenocarcinoma of the esophagogastric junction (AEG) has a complicated surgical anatomy, due to which it sometimes induces excessive intraoperative blood loss that necessitates intraoperative blood transfusion (BTF). However, few reports have focused on the impact of BTF on the survival outcomes of patients with AEG. We aimed to evaluate the impact of BTF on AEG prognosis. Materials andMethods: We included 63 patients who underwent surgical resection for AEG at our hospital between January 2010 and September 2020. Clinicopathological characteristics and survival outcomes were compared between patients with (n = 12) and without (n = 51) BTF. Multivariate analysis was performed to identify the independent prognostic factors for overall survival. Results: None of the patients who underwent minimally invasive surgery received BTF. Patients who received BTF had a significantly worse 5-year survival rate than those who did not (67.8% vs. 28.3%, p = 0.001). BTF was an independent risk factor for overall survival (hazard ratio: 3.90, 95% confidence interval 1.30-11.7), even after patients who underwent minimally invasive surgery were excluded. Conclusions: BTF adversely affected the survival outcomes of patients with AEG who underwent curative surgery. To avoid BTF, surgeons should strive to minimize intraoperative bleeding.

AI analysis and modified type classification for endocytoscopic observation of esophageal lesions.

Endocytoscopy (EC) facilitates real-time histological diagnosis of esophageal lesions in vivo. We developed a deep-learning artificial intelligence (AI) system for analysis of EC images and compared its diagnostic ability with that of an expert pathologist and nonexpert endoscopists. Our new AI was based on a vision transformer model (DeiT) and trained using 7983 EC images of the esophagus (2368 malignant and 5615 nonmalignant). The AI evaluated 114 randomly arranged EC pictures (33 ESCC and 81 nonmalignant lesions) from 38 consecutive cases. An expert pathologist and two nonexpert endoscopists also analyzed the same image set according to the modified type classification (adding four EC features of nonmalignant lesions to our previous classification). The area under the curve calculated from the receiver-operating characteristic curve for the AI analysis was 0.92. In per-image analysis, the overall accuracy of the AI, pathologist, and two endoscopists was 91.2%, 91.2%, 85.9%, and 83.3%, respectively. The kappa value between the pathologist and the AI, and between the two endoscopists and the AI showed moderate concordance; that between the pathologist and the two endoscopists showed poor concordance. In per-patient analysis, the overall accuracy of the AI, pathologist, and two endoscopists was 94.7%, 92.1%, 86.8%, and 89.5%, respectively. The modified type classification aided high overall diagnostic accuracy by the pathologist and nonexpert endoscopists. The diagnostic ability of the AI was equal or superior to that of the experienced pathologist. AI is expected to support endoscopists in diagnosing esophageal lesions based on EC images.

Mucosal Congestion on the First Day Following Endoscopy Predicts Anastomotic Stricture After Esophagectomy.

BACKGROUND: Anastomotic stricture is a relatively common postoperative complication after esophagectomy. Previous studies have indicated that impaired perioperative blood perfusion at the anastomosis is associated with the occurrence of stricture. Therefore, we analyzed the association between endoscopically assessed blood perfusion during the early postoperative period and anastomotic stricture. METHODS: This retrospective study evaluated patients who underwent esophagectomy at Tokyo Medical and Dental University between 2010 and 2015. The patients had undergone nasal endoscopy on the 1st and 8th postoperative days. The findings were used to evaluate blood perfusion at the anastomosis and gastric tube, which was classified based on mucosal color as ischemia (white) or congestion (blue or black). Univariate and multivariable logistic regression analyses were performed to identify risk factors for anastomotic stricture. RESULTS: The study included 197 patients and anastomotic stricture was observed in 60 patients (30.4%). The multivariable analysis revealed that postoperative gastric tube congestion was a risk factor for stricture (odds ratio [OR]: 6.440, 95% confidence interval [CI]: 2.660-15.600; p < 0.001). Lower risks of anastomotic stricture were associated with pathological stage III-IV disease (OR: 0.325, 95% CI: 0.161-0.656; p = 0.002). CONCLUSION: This study revealed that endoscopically detected congestion at the anastomosis on the first postoperative day was a risk factor for anastomotic stricture.

[A Case of Curative Resection of a Retroperitoneal Liposarcoma].

A 55-year-old woman had been admitted to a hospital with abdominal bloating. Retroperitoneal liposarcoma was suspected and diagnosed as not resectable. She was then referred to our hospital with dyspnea and difficulties with movement due to the huge mass. An abdominal CT revealed a large mass originating in the left retroperitoneum. The tumor occupied most of the abdominal cavity, resulting in the displacement of her organs. However, there was no evidence of infiltration of the tumor into the aorta and inferior vena cava. Under a provisional diagnosis of retroperitoneal liposarcoma, a surgical resection was undertaken. The resected specimen had a maximum diameter of 48 cm and weighed 14 kg. Histopathological examination revealed a differentiated liposarcoma. The patient remains alive 6 months after the operation, without recurrence.

[A Case of Malignant Peripheral Nerve Sheath Tumor of the Anus Resected by Robot Assisted-APR].

An 81-year-old female visited a local hospital with complaints of anal pain. A tumor was found on the right side of her anus, and the histopathological diagnosis was a non-epithelial malignant tumor. Therefore, the patient was referred to our hospital. Result of imaging inspection revealed that the tumor had invaded the lower rectum, but had not distantly metastasized. Based on the findings of another biopsy, the patient was diagnosed with a malignant peripheral nerve sheath tumor (MPNST). Robot-assisted abdominoperineal resection(D1)was performed, and the lesion was resected without any pathological remnants. During the postoperative period, the patient developed perineal wound infection. Subsequently, the patient was discharged from the hospital on postoperative day 10. At the 6-month postoperative follow-up, no recurrence was noted. Most MPNSTs occur in the limbs, trunk, and neck. MPNST in the primary gastrointestinal tract or in the vicinity of the gastrointestinal tract is relatively rare, and in principle, combined resection of the intestinal tract is required for surgical treatment. Here, we report a case of MPNST that occurred near the anus and infiltrated to the lower rectum and was completely resected by robot-assisted abdominoperineal resection.

[A Case Report of Perianal Paget's Disease Treated with Robot-Assisted Surgery for Positive Margins after Local Excision].

The patient is a 73-year-old man who was diagnosed with perianal Paget's disease by skin biopsy. Biopsy from the dentate line did not show any tumor cells. The patient was considered to undergo sphincter-preserving local resection and subsequently underwent the procedure. Histopathological examination of the resected specimen revealed perianal Paget's disease with a positive anorectal margin. The patient was referred to our department due to postoperative anal stenosis. On the 32nd postoperative day, a double barreled sigmoid colostomy was performed. However, considering the inability to adequately check for detect due to anorectal stenosis and the expected unfavorable anorectal function caused by sphincter- preserving re-operation, a robot-assisted abdominoperineal resection(D1)was performed 7 months after the initial surgery. Histopathological examination of the resected specimen revealed no residual tumor cells in the resected specimen. After local excision for perianal Paget's disease, the skin of the buttock becomes scarred due to skin valve formation and skin grafting, making closure of the perineal wound difficult when performing abdominoperineal resection. In robot-assisted surgery, it is relatively easy to remove the anorectal muscles from the abdominal cavity and reach the sciatico-rectal fossa, thus reducing the size of the perineal wound.

EpiPanGI Dx: A Cell-free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers.

PURPOSE: DNA methylation alterations have emerged as front-runners in cell-free DNA (cfDNA) biomarker development. However, much effort to date has focused on single cancers. In this context, gastrointestinal (GI) cancers constitute the second leading cause of cancer-related deaths worldwide; yet there is no blood-based assay for the early detection and population screening of GI cancers. EXPERIMENTAL DESIGN: Herein, we performed a genome-wide DNA methylation analysis of multiple GI cancers to develop a pan-GI diagnostic assay. By analyzing DNA methylation data from 1,781 tumor and adjacent normal tissues, we first identified differentially methylated regions (DMR) between individual GI cancers and adjacent normal, as well as across GI cancers. We next prioritized a list of 67,832 tissue DMRs by incorporating all significant DMRs across various GI cancers to design a custom, targeted bisulfite sequencing platform. We subsequently validated these tissue-specific DMRs in 300 cfDNA specimens and applied machine learning algorithms to develop three distinct categories of DMR panels RESULTS: We identified three distinct DMR panels: (i) cancer-specific biomarker panels with AUC values of 0.98 (colorectal cancer), 0.98 (hepatocellular carcinoma), 0.94 (esophageal squamous cell carcinoma), 0.90 (gastric cancer), 0.90 (esophageal adenocarcinoma), and 0.85 (pancreatic ductal adenocarcinoma); (ii) a pan-GI panel that detected all GI cancers with an AUC of 0.88; and (iii) a multi-cancer (tissue of origin) prediction panel, EpiPanGI Dx, with a prediction accuracy of 0.85-0.95 for most GI cancers. CONCLUSIONS: Using a novel biomarker discovery approach, we provide the first evidence for a cfDNA methylation assay that offers robust diagnostic accuracy for GI cancers.

PHLDA1 expression in ulcerative colitis: A potential role in the management of dysplasia.

Pleckstrin homology-like domain, family A, member 1 (PHLDA1) is a protein involved in cell proliferation, adhesion and migration in colon cancer. In normal large intestinal mucosa, this protein is expressed only in the crypts. By contrast, its expression in adenomas and cancers of the large intestine is spread throughout the glandular ducts, and it has been reported that PHLDA1 may be involved in the process of carcinogenesis. PHLDA1 may also be involved in the pathogenesis of ulcerative colitis (UC). The expression levels of PHLDA1 in tissues from patients with UC were analyzed using immunohistochemistry, and its relationship with the development of UC-associated colorectal cancer (UC-CRC) was examined. Overall, tissue samples from 143 lesions (90 colitis lesions, 39 dysplastic lesions and 14 UC-CRC lesions) were prepared from excised specimens of 49 patients with UC who underwent surgery in Tokyo Medical and Dental University Hospital between January 2004 and December 2017. Subsequently, immunostaining for PHLDA1 was performed. PHLDA1 expression was evaluated in UC-CRC and dysplastic tissues within the entire lesion area on the slide and in colitis over the area of the accompanying duct. The cytoplasmic staining intensity was classified into four levels, and the expression score (0-2 points) was calculated. The median PHLDA1 expression score was 0.295 for colitis, 0.607 for dysplasia and 0.865 for UC-CRC. The dysplasia expression score was significantly higher than the colitis score (P<0.001), while the UC-CRC expression score was significantly higher than the dysplasia score (P=0.003). The expression levels of PHLDA1 in UC cases were higher in colitis, followed by dysplasia and UC-CRC, which suggested that this protein may be involved in the carcinogenesis of UC-CRC. In addition, PHLDA1 immunostaining may help in the diagnosis of dysplasia, which is a type of precancerous lesion.

Preoperative lymphocyte-to-monocyte ratio is the most predictive inflammatory response marker of survival in gastric cancer.

PURPOSE: Systemic inflammatory responses play a key role in cancer progression, and detecting the predictive inflammatory response markers is needed. The present study explored inflammatory response markers capable of predicting survival in patients with gastric cancer. METHODS: We enrolled 264 patients, who underwent curative gastrectomy for clinical stage (cStage) I-III gastric cancer between 2012 and 2015. The cut-off point of eight preoperative inflammatory response markers was determined by receiver operating characteristic (ROC) curve analysis. The marker with the highest Harrell's concordance index (C-index) was adopted for subsequent univariate and multivariate analyses using the Cox proportional-hazards model. RESULTS: Among eight representative inflammatory response markers, lymphocyte-to-monocyte ratio (LMR; cut-off point, 4.60) achieved the highest C-index (0.633). The 5-year survival rate was significantly worse in patients with LMR < 4.60 than in those with LMR ≥ 4.60 (67.5% versus 89.0%, P < 0.001). In multivariate analysis, LMR < 4.60 was identified as an independent prognostic factor (hazard ratio: 2.372; 95% confidence interval: 1.266-4.442; P = 0.007). CONCLUSION: In this study, LMR had the strongest ability to predict the survival of patients with gastric cancer among other inflammatory response markers, with lower LMRs being associated with poor survival following curative gastrectomy.

Impact of Preoperative Time Interval on Survival in Patients With Gastric Cancer.

BACKGROUND: A time interval between diagnosis and surgery for gastric cancer is necessary, although its impact on survival remains controversial. We evaluated the impact of preoperative time interval on survival in gastric cancer patients. METHODS: We enrolled 332 patients who underwent curative gastrectomy for clinical stage (cStage) I-III gastric cancer between 2012 and 2015. We separately analyzed early- (cStage I) and advanced-stage (cStages II and III) patients. Early-stage patients were divided according to preoperative time interval: short (≤ 42 days) and long (> 42 days) groups. Advanced-stage patients were also divided into short (≤ 21 days) and long (> 21 days) groups. We compared the survival between the short and long groups in early- and advanced-stage patients. RESULTS: The median preoperative time interval was 29 days, and no significant differences were found in patient characteristics between the short and long groups in early- and advanced-stage patients. In early-stage patients, the 5-year survival rates of the short and long groups were 86.5% and 88.4%, respectively (P = 0.917). In advanced-stage patients, the 5-year survival rates were 72.1% and 70.0%, respectively (P = 0.552). In multivariate analysis, a longer time interval was not selected as an independent prognostic factor in early- and advanced-stage patients. CONCLUSIONS: In this study, survival difference was not found based upon preoperative time interval. The results do not affirm the delay of treatment without reason, however, imperative extension of preoperative time interval may be justified from the standpoint of long-term survival.

The effectiveness of plasma miR-33a-5p as a predictive biomarker for the efficacy of colorectal cancer chemotherapy.

Several chemotherapeutic options are available for patients with metastatic colorectal cancer (mCRC), making it important to individualize treatment regimens. Individualization requires the clinical application of biomarkers for regimen selection, which is presently insufficient. miRNAs serve an important role in the control of biological processes in several types of cancer, acting as plasma biomarkers. The current study aimed to evaluate novel plasma microRNAs for predicting chemo-resistance in chemotherapy for patients with colorectal cancer (CRC) by employing a Toray 3D-Gene microRNA array-based approach, which compared plasma content before and during treatment. Specific miRNAs that acted as biomarkers of the fluoropyrimidine (FP) + oxaliplatin (OX) + bevacizumab (BEV) regime, a common first-line treatment for mCRC, were searched. The plasma samples of 110 patients with mCRC who had received the FP+OX+BEV regimen were subjected to microarray analyses using the 3D-Gene miRNA microarray platform, after which miRNAs levels were quantified via reverse transcription- quantitative PCR. Patients exhibiting complete response, partial response (PR) and reduced stable disease (SD) were defined as responders. Patients with extended SD and progression disease (PD) were defined as non-responders. Following microarray analysis, miR-33a-5p was selected as the candidate miRNA as it was upregulated in non-responder plasma samples. The expression of miR-33a-5p was upregulated in the non-responders (n=15) compared with the responders (n=95) (P=0.032). The high expression group demonstrated significantly poor progression-free survival (P<0.01). To evaluate whether miR-33a-5p can serve as a marker of chemo-resistance, miR-33a-5p expression levels were assessed at the following three time-points: Pre-point (before chemotherapy); PR-point (3-months after chemotherapy began); and PD-point (the time at which recurrence or progression was recorded). The results revealed that expression levels were significantly increased at the PD-point when compared with that at the pre-point (P=0.024). The current study determined that the miR-33a-5p expression level in the plasma may serve as a predictive marker of efficacy and as a biomarker of chemo-resistance.

Minimally Invasive Surgery for Colorectal Cancer.

In recent years, minimally invasive surgery for colorectal cancer has seen remarkable improvement. For the laparoscopic surgery for colon cancer, earlier postoperative recovery and reduced hospital stays can be expected compared to those for open surgery. Also, no increase in perioperative morbidity and mortality has been shown. Furthermore, long-term oncological outcomes comparable to open surgery have been obtained. Although laparoscopic surgery for rectal cancer has shown good short-term postoperative outcomes, recent randomized controlled trials could not demonstrate non-inferiority to open surgery with respect to oncological safety. Further studies are required to confirm the impact of robotic surgery on colon and rectal cancer and the appropriate indications for transanal total mesorectal excision for rectal cancer.

Substantial Epstein-Barr virus reactivation in a case of severe refractory ulcerative colitis: a possible role in exacerbation.

Ulcerative colitis (UC) is an inflammatory bowel disease that causes chronic inflammation in the colon. 5-aminosalicylic acid and immunosuppressive medications such as corticosteroids, immunomodulators, and biologic agents are used to treat these patients. However, patients with UC who receive immunosuppressive medications may be at risk for certain opportunistic infections. Epstein-Barr virus (EBV) is one of those opportunistic infections, and its pathogenic role has been implicated in refractory UC, but its pathogenicity should be further investigated. Here, we report a surgical case of refractory UC that demonstrated a serologically post-infected pattern of EBV at admission but that later had a high load of EBV in both the peripheral blood and colonic mucosa. These findings suggest that EBV may have been reactivated in the colon, after which it damaged the colonic mucosa and aggravated inflammation in this patient with UC. Thus, EBV might lead to severity and a refractory response against corticosteroids and anti-TNFα agents, necessitating emergency surgery. Viral surveillance for EBV in patients with refractory UC may facilitate understanding of the patient's pathophysiology and predicting response to medications, and the development of antiviral intervention for those patients may improve their prognosis.