Genotype-phenotype correlation for extracolonic aggressive phenotypes in patients with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) patients develop various life-threatening extracolonic comorbidities that appear individually or within a family. This diversity can be explained by the localization of the adenomatous polyposis coli (APC) variant, but few reports provide definitive findings about genotype-phenotype correlations. Therefore, we investigated FAP patients and the association between the severe phenotypes and APC variants. Of 247 FAP patients, 126 patients from 85 families identified to have APC germline variant sites were extracted. These sites were divided into six groups (Regions A to F), and the frequency of severe comorbidities was compared among the patient phenotypes. Of the 126 patients, the proportions of patients with desmoid tumor stage ≥III, number of FGPs ≥1000, multiple gastric neoplasms, gastric neoplasm with high-grade dysplasia, and Spigelman stage ≥III were 3%, 16%, 21%, 12%, and 41%, respectively, while the corresponding rates were 30%, 50%, 70%, 50%, and 80% in patients with Region E (codons 1398-1580) variants. These latter rates were significantly higher than those for patients with variants in other regions. Moreover, the proportion of patients with all three indicators (desmoid tumor stage ≥III, number of FGPs ≥1000, and Spigelman stage ≥III) was 20% for those with variants in Region E and 0% for those with variants in other regions. Variants in Region E indicate aggressive phenotypes, and more intensive management is required.

Clinical Guidelines for Diagnosis and Management of Peutz-Jeghers Syndrome in Children and Adults.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance. Some patients with PJS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood and sometimes have serious complications that significantly reduce their quality of life. Hamartomatous polyps in the small bowel may cause bleeding, intestinal obstruction, and intussusception. Novel diagnostic and therapeutic endoscopic procedures such as small-bowel capsule endoscopy and balloon-assisted enteroscopy have been developed in recent years. SUMMARY: Under these circumstances, there is growing concern about the management of PJS in Japan, and there are no practice guidelines available. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour and Welfare with specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of PJS together with four clinical questions and corresponding recommendations based on a careful review of the evidence and involved incorporating the concept of the Grading of Recommendations Assessment, Development and Evaluation system. KEY MESSAGES: Herein, we present the English version of the clinical practice guidelines of PJS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with PJS.

Feasibility of underwater endoscopic mucosal resection for endoscopic management of gastric neoplasms in patients with familial adenomatous polyposis.

BACKGROUND: Underwater endoscopic mucosal resection (UEMR) has been developed as an effective endoscopic intervention for colon, rectum, and duodenum neoplasms. However, there are no comprehensive reports regarding the stomach, and its safety and efficacy are unknown. We aimed to examine the feasibility of UEMR for gastric neoplasms in patients with familial adenomatous polyposis (FAP). METHODS: We retrospectively extracted data of patients with FAP who underwent endoscopic resection (ER) for gastric neoplasms at Osaka International Cancer Institute from February 2009 to December 2018. Elevated gastric neoplasms of ≤ 20 mm in diameter were extracted, and conventional endoscopic mucosal resection (CEMR) and UEMR were compared. Furthermore, outcomes after ER until March 2020 were examined. RESULTS: 91 endoscopically resected gastric neoplasms were extracted from 31 patients with 26 pedigrees, and 12 neoplasms underwent CEMR and 25 neoplasms underwent UEMR was compared. The procedure time was shorter for UEMR than for CEMR. There was no significant difference between en bloc resection and R0 resection rates by EMR methods. CEMR and UEMR showed postoperative hemorrhage rates of 8% and 0%, respectively. Residual/local recurrent neoplasms were identified in four lesions (4%), but additional endoscopic intervention (three UEMR and one cauterization) resulted in a local cure. CONCLUSION: UEMR was feasible in gastric neoplasms of FAP patients, especially in elevated lesions and those of ≤ 20 mm in diameter.

Progression of duodenal neoplasia to advanced adenoma in patients with familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) have a lifetime risk of developing duodenal adenomas approaching 100%, and the relative risk for duodenal cancer compared with the general population is high. We conducted a retrospective study to investigate the progression of non-ampullary duodenal adenomas (NADAs) and risk factors for advanced lesions in patients with FAP. METHODS: Of 248 patients with 139 pedigrees at 2 institutes, we assessed 151 patients with 100 pedigrees with a pathogenic germline variant in the adenomatous polyposis coli gene, excluding mosaic variants. We evaluated the prevalence of NADAs in patients with FAP, the progression of these adenomas to advanced adenoma during the observation period, and the risk factors for the lifetime development of high-grade dysplasia (HGD), large (≥ 10 mm) duodenal adenomas, and Spiegelman stage IV. RESULTS: During the median observation period of 7 years, the incidences of patients with NADAs, with more than 20 polyps, with polyps ≥ 10 mm, with HGD, and with stage IV at the last esophagogastroduodenoscopy were increased 1.6-fold, 1.7-fold, 5-fold, 22-fold, and 9-fold, respectively. Intramucosal cancer occurred in three patients (2%), but no patients developed invasive cancer during the observation period because we performed endoscopic intervention for advanced adenomas. Stage progression was observed in 71% of 113 patients. Stage IV was more common in women, patients with a history of colectomy, and those with a 3' side mutation in their adenomatous polyposis coli gene. CONCLUSIONS: NADAs in patients with FAP frequently become exacerbated. Our findings suggest that patients with FAP who develop duodenal adenomas should be surveyed to prevent the development of duodenal cancer.

Gastric neoplasms in patients with familial adenomatous polyposis: endoscopic and clinicopathologic features.

BACKGROUND AND AIMS: Gastric neoplasms in patients with familial adenomatous polyposis (FAP) occur at a high rate and can cause death. The endoscopic findings of gastric neoplasms in these patients are characteristic but not well recognized. To identify the relevant characteristics to enable early detection, we retrospectively investigated endoscopic findings of gastric neoplasms in patients with FAP and then compared the clinical, histopathologic, and genetic features among subgroups. METHODS: Of 234 patients with 171 pedigrees at 2 institutes, 56 cases (24%, 133 gastric neoplasms) with 44 pedigrees were examined. Immunostaining was performed for histopathologic evaluation by 1 blinded pathologist. According to the endoscopic findings, gastric neoplasms were divided into 4 types based on location (L: antrum and pylorus, UM: the rest of the stomach) and color (W: white, T: translucent, R: reddish) and their clinicopathologic features examined. RESULTS: Of the cases, 93% could be classified into a single type. Among histologic phenotypes, high-grade dysplasia was present in 26% (type L), 41% (type UM-W), 0% (type UM-T), and 22% (type UM-R). The immunologic phenotype comprised the gastric type in 69% (93% in Type UM) and the intestinal phenotype, including the mixed type, in 31% (61% in type L). Moreover, 96% of patients had concurrent duodenal neoplasms. Adenomatous polyposis coli gene status was identified in 93% of patients; the pathogenic variant was detected in 98% but did not influence any endoscopic features. CONCLUSIONS: Gastric neoplasms in patients with FAP were stratified into 4 types according to their endoscopic findings. The endoscopic phenotype was related to the histopathologic phenotype but not to germline variants.

Clinical Features of Venous Thromboembolism in Patients With Coronavirus Disease 2019 (COVID-19) in Japan　- A Case Series Study.

BACKGROUND: Suspicion that the coronavirus disease 2019 (COVID-19) caused venous thromboembolism (VTE).Methods and Results:We conducted a case series study of 5 VTE patients with COVID-19 in Japan. The median body mass index was 27.7 kg/m2, and all patients required mechanical ventilation during hospitalization. Patients were diagnosed as VTE in the intensive care unit (ICU), general ward, and outpatient ward. CONCLUSIONS: The current case series study revealed some clinical features of VTE patients with COVID-19 in Japan, including obese patients and those requiring mechanical ventilation during hospitalization, who should be followed closely for VTE, even after leaving the ICU.

Incidence and Clinical Features of Venous Thromboembolism in Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) in Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19) reportedly causes venous thromboembolism (VTE), but the status of this complication in Japan was unclear.Methods and Results:The VTE and COVID-19 in Japan Study is a retrospective, multicenter cohort study enrolling hospitalized patients with COVID-19 who were evaluated with contrast-enhanced computed tomography (CT) examination at 22 centers in Japan between March 2020 and October 2020. Among 1,236 patients with COVID-19, 45 (3.6%) were evaluated with contrast-enhanced CT examination. VTE events occurred in 10 patients (22.2%), and the incidence of VTE in mild, moderate, and severe COVID-19 was 0%, 11.8%, and 40.0%, respectively. COVID-19 patients with VTE showed a higher body weight (81.6 vs. 64.0 kg, P=0.005) and body mass index (26.9 vs. 23.2 kg/m2, P=0.04), and a higher proportion had a severe status for COVID-19 compared with those without. There was no significant difference in the proportion of patients alive at discharge between patients with and without VTE (80.0% vs. 88.6%, P=0.48). Among 8 pulmonary embolism (PE) patients, all were low-risk PE. CONCLUSIONS: Among a relatively small number of patients undergoing contrast-enhanced CT examination in Japanese real-world clinical practice, there were no VTE patients among those with mild COVID-19, but the incidence of VTE seemed to be relatively high among severe COVID-19 patients, although all PE events were low-risk without significant effect on mortality risk.

Long-term outcomes after endoscopic submucosal dissection for differentiated-type early gastric cancer that fulfilled expanded indication criteria: A prospective cohort study.

BACKGROUND AND AIM: Endoscopic resection for early gastric cancer (EGC) is widely performed. However, there is still a paucity of strong evidence regarding long-term outcomes after endoscopic submucosal dissection (ESD) for the expanded indication criteria of the Japanese guidelines (ver. 2010). METHODS: Endoscopic submucosal dissection was performed in patients with EGC that met the expanded indication criteria: (i) cT1a, differentiated-type EGC of 2 to 5 cm, ulcer negative or (ii) cT1a, differentiated-type EGC of ≤3 cm, ulcer positive. Patients whose pathological examination fulfilled the curative resection criteria were then enrolled in this cohort study: negative vertical margin, negative lymphovascular invasion, and (i) pT1a, differentiated-type, and ulcer negative; (ii) pT1a, differentiated-type, ≤3 cm, and ulcer positive; or (iii) pT1b1 (<500-µm submucosal invasion), differentiated-type, and ≤3 cm. Patients with only a positive horizontal margin as a noncurative factor were included for follow-up. RESULTS: From September 2003 to February 2012, a total of 356 patients underwent ESD, and 214 were enrolled in the survival analysis. One hundred twenty patients (56%) had >2 cm in diameter and ulcer-negative lesions, and 94 (44%) had ≤3 cm and ulcer-positive lesions. The vital status at 5 years after ESD was confirmed in all (100%) patients. No local or metastatic recurrence was detected; however, 26 metachronous gastric cancers developed, and 1 patient died of metachronous gastric cancer. The 5-year disease-specific and overall survival rates were 99.5% (95% confidence interval [CI], 97.2%-100%) and 93.9% (95% CI, 89.8%-96.4%), respectively. CONCLUSION: ESD for EGC that fulfills the expanded criteria is feasible and shows favorable long-term outcomes.

Influence of Type 2 Endoleaks on Long-Term Outcomes after Endovascular Repair for Abdominal Aortic Aneurysms: A National Hospital Organization Network Study for Abdominal Aortic Aneurysms in Japan.

BACKGROUND: Although endovascular repair (EVAR) is the first-line treatment for abdominal aortic aneurysm, type 2 endoleak (EL), which is associated with late sac enlargement or rupture, remains a concern. The present study aimed to assess the influence of type 2 EL on long-term outcomes after EVAR. METHODS: Among 550 patients who underwent EVAR between 2007 and 2013 at 14 Japanese national hospitals, 135 patients had type 2 EL diagnosed on follow-up computed tomography (CT) within 12 months after EVAR (EL2[+] group) and 415 patients did not have EL within 12 months (EL2[-] group). The cumulative incidences of sac enlargement, late intervention, and aneurysm-related death after EVAR were estimated using the cumulative incidence function method, and prognostic factors were investigated using the Fine-Gray hazard model. RESULTS: The median follow-up period was 5 years, and the 5-year cumulative incidence rates of sac enlargement, late intervention, and aneurysm-related death were 30.7% ± 4.4%, 25.3% ± 4.1%, and 2.6% ± 1.4%, respectively, in the EL2(+) group, and 8.7% ± 1.6%, 7.6% ± 1.4%, and 0.3% ± 0.3%, respectively, in the EL2(-) group. The cumulative incidence rates of sac enlargement (P = 0.002), late intervention (P < 0.001), and aneurysm-related death (P = 0.015) were significantly different between the 2 groups. As the first-line treatment for sac enlargement with type 2 EL, transcatheter coil embolization was performed in 30 patients. Information about sac behavior on CT after coil embolization was available in 20 of the 30 patients. Among these patients, no patients experienced sac shrinkage, and the aneurysmal sac dilated after coil embolization in 18 patients. CONCLUSIONS: Type 2 EL affects the long-term outcomes after EVAR. It is not recommended to observe large aneurysmal sacs conservatively as they tend to dilate in the presence of type 2 EL.

A three-tier classification system based on the depth of submucosal invasion and budding/sprouting can improve the treatment strategy for T1 colorectal cancer: a retrospective multicenter study.

More than 85% of patients with T1 colorectal cancer have no lymph node metastasis and can be cured by endoscopic resection. To avoid unnecessary surgery after complete endoscopic resection, accurate histologic methods for evaluating resected specimens are needed to discriminate those at high risk for lymph node metastasis. A retrospective multi-institutional, cross-sectional study of 806 T1 colorectal cancer patients was conducted. A budding/sprouting score was incorporated for predicting lymph node metastasis in addition to other parameters, including the depth of submucosal invasion, histologic grade, and lymphovascular invasion. Lymph node metastasis was detected in 97 patients. Independent predictors of lymph node metastasis by multivariate analysis were depth of submucosal invasion ≥1000 µm (odds ratio (95% confidence interval)=5.56 (2.14-19.10)) and high-grade budding/sprouting (3.14 (1.91-5.21)). Among lesions with a depth of submucosal invasion ≥1000 µm, lymph node metastasis was detected in 59 (29%) of 207 patients with high-grade budding/sprouting, and in 34 (9%) of 396 with low-grade budding/sprouting. Lymph node metastasis was detected in only 4 (2%) of 203 lesions with a depth of submucosal invasion <1000 µm. Of these four tumors, three invaded lymphatic and/or venous vessels. Thus, the risk for lymph node metastasis can be classified into three groups: high risk with a depth of submucosal invasion ≥1000 µm and high-grade budding/sprouting, intermediate-risk with a depth of submucosal invasion ≥1000 µm and low-grade budding/sprouting, and low-risk with a depth of submucosal invasion <1000 µm. These findings revealed that a depth of submucosal invasion ≥1000 µm and high-grade budding/sprouting are powerful predictive parameters for lymph node metastasis in T1 colorectal cancer. This three-tier risk classification system will facilitate the decision for additional major surgery for T1 colorectal cancer patients after successful endoscopic treatment.

Endoscopic optical diagnosis provides high diagnostic accuracy of esophageal squamous cell carcinoma.

BACKGROUND: Recent technological advances have stimulated the development of endoscopic optical biopsy technologies. This study compared the accuracy of endoscopic diagnosis using magnifying narrow-band imaging (NBI) and histologic diagnosis of esophageal squamous lesions. METHODS: Patients at high risk for esophageal squamous cell carcinoma were examined with endoscopy and subsequent biopsy. The lesions diagnosed as cancer on NBI and the lesions diagnosed as cancer on biopsy were resected endoscopically or surgically. Histological diagnoses of resected specimens, the reference standards in this study, were made by a pathologist who was blind to both the endoscopic and biopsy diagnoses. The primary outcome was the accuracy of endoscopic and biopsy diagnosis. A noninferiority trial design with a noninferiority margin of -10% was chosen to investigate the accuracy of endoscopic diagnosis using magnifying NBI. RESULTS: Between November 2010 and October 2012, a total of 111 lesions in 85 patients were included in the analysis. The accuracy of endoscopic diagnosis and biopsy diagnosis for all lesions was 91.0% (101/111) and 85.6% (95/111), respectively. The difference in diagnostic accuracy was 5.4% (95% confidence interval: -2.9%-13.7%). The accuracy of endoscopic diagnosis and biopsy diagnosis of invasive cancers was 94.9% (74/78) and 84.6% (66/78), respectively. The difference was 10.3% (95% confidence interval: 1.6%-19.0%) for invasive cancers. The lower bound of the 95% confidence interval was above the prestated -10% in both cases. CONCLUSION: Noninferiority of endoscopic diagnosis by magnifying NBI to histologic diagnosis by biopsy was established in this study (p = 0.0001). TRIAL REGISTRATION: The study was registered on 9th November 2010 in the University Hospital Medical Network Clinical Trials Registry as number: UMIN000004529.

Evaluation of mycophenolic acid exposure in a patient with immune-related hepatotoxicity caused by nivolumab and ipilimumab therapy for malignant melanoma: a case report.

BACKGROUND: Guidelines such as the National Comprehensive Cancer Network recommend mycophenolate mofetil (MMF) for the treatment of severe steroid-refractory immune-related hepatotoxicity. Mycophenolic acid (MPA) is an active form of MMF that suppresses T- and B-lymphocyte proliferation and immune-related adverse events caused by immune checkpoint inhibitors. MPA has a narrow therapeutic range (37-70 µg·h/mL) and overexposure increases the risk of leukopenia in transplantation. However, the optimal use of MMF in oncology has not yet been established; thus, monitoring plasma MPA concentrations is necessary to avoid excessive immunosuppression in oncology practice. CASE PRESENTATION: We evaluated plasma MPA concentration in a 75-year-old man with immune-related hepatotoxicity following nivolumab and ipilimumab combination therapy for malignant melanoma. The patient developed severe hepatotoxicity after immunotherapy, and immunosuppressant therapy with corticosteroids was initiated. The patient then developed steroid-refractory immune-related hepatotoxicity; therefore, MMF (1,000 mg twice daily) was co-administered. Seven days after the administration of MMF, the plasma MPA concentration was measured using an enzyme multiplied immunoassay technique. The area under the plasma concentration-time curve for MPA from 0 to 12 h was 41.0 µg·h/mL, and the same dose of MMF was continued. Grade 2 lymphocytopenia, which could be attributed to MMF, was observed during the administration period. Unfortunately, the patient was infected with SARS-CoV-2 and died from respiratory failure. CONCLUSION: Our patient did not exceed the upper limit of MPA levels as an index of the onset of side effects of kidney transplantation and achieved rapid improvement in liver function. Prompt initiation of MMF after assessment of the steroid effect leads to adequate MPA exposure. Therapeutic drug monitoring should be considered when MMF is administered, to avoid overexposure.

A case of endoscopic submucosal dissection of esophageal acantholytic Paget's disease with discontinuously spreading and unclear neoplastic extension.

BACKGROUND: Paget's disease (PD) is a carcinoma, in which irregular atypical cells with abundant cytoplasm proliferate mainly within the epithelium and is classified into PD occurring in the breast and extramammary Paget's disease (EMPD) occurring outside the breast. Essentially, extramammary PD is reported as a tumor for which it is difficult for surgeons to properly determine the line of resection. CASE PRESENTATION: An 83-year-old male was admitted to our hospital because of roughness of the esophageal epithelium during the follow-up examination for a gastric ulcer. A preoperative biopsy revealed squamous cell carcinoma; therefore, endoscopic submucosal dissection (ESD) was performed. CONCLUSIONS: The characteristic feature in this patient was the distribution of tumor cells and, accordingly, the difficulty in identifying the neoplastic distribution. In this patient, the odd distribution and growth pattern of the tumor cells made it difficult for the operator to identify the distribution of the lesion preoperatively.

Intraoperative diagnosis using sentinel node biopsy with indocyanine green dye in gastric cancer surgery: an institutional trial by experienced surgeons.

BACKGROUND: Reliable indicators that can intraoperatively determine the absence of nodal metastasis are in great demand to avoid unnecessary lymphadenectomy. However, little has been reported about the intraoperative diagnostic performance of sentinel node (SN) biopsy. METHODS: Sentinel node biopsy by subserosal or submucosal injection of indocyanine green (ICG) was performed in 241 patients with American Joint Committee on Cancer tumor, node, metastasis staging system, 7th edition, clinical T1 (n = 190) and T2 (n = 51) gastric cancer by two experienced surgeons. All nodes that stained green (green node, GN), representing SNs, were excised before gastrectomy and were sliced into 2-mm sections for intraoperative histological examinations with hematoxylin and eosin staining. The sliced GNs were also examined simultaneously by imprint cytology. RESULTS: The GNs were detectable in 240 patients (3.8 ± 2.4 nodes per patient; range 1-17 nodes; median 3 nodes), and the success rate of detection was 99.6 % (240 of 241). Of 240 patients with a successful detection, 29 were found to have lymph node (LN) metastases; 16 were diagnosed with LN metastases in both GNs and non-GNs, 12 in GNs alone, and 1 in non-GNs alone. The false-negative rate based on the SN concept was 3.4 % (1 of 29). However, two patients with cT1 gastric cancer were diagnosed as intraoperative GN negative but were later confirmed as GN positive by histological examinations of paraffin sections. As an intraoperative diagnosis, the false-negative rate was 10.3 % (3 of 29). CONCLUSIONS: Sentinel node biopsy using ICG could be performed intraoperatively within reasonable limits under certain conditions, such as multiplanes for detection, combination use of imprint cytology, and open surgery by experienced surgeons.

CD34 expression in noncancerous liver tissue predicts multicentric recurrence of hepatocellular carcinoma.

BACKGROUND: Metachronous multicentric recurrence of hepatocellular carcinoma (HCC) is a common cause of morbidity and mortality following curative surgical resection. Clinical and laboratory predictors of these processes can markedly aid in managing these patients. Capillarization of hepatic sinusoids is also a well-known phenomenon in many liver diseases, especially in neoplastic liver diseases. Here, we investigated the clinical features, fibrosis scores and distribution of CD34 in noncancerous hepatic tissues of postresection patients with and without multicentric recurrence. METHODS: Eighteen patients with multicentric recurrence of HCC diagnosed by histological examination of repeated hepatectomy specimens and 72 HCC patients with more than 5-year disease-free survival postresection participated in the study. We compared the clinicopathological features of these two groups. We examined noncancerous hepatic tissues for iron deposition by Prussian blue staining and computed the CD34-labeling index (LI) through immunohistochemistry using anti-CD34 antibody. RESULTS: CD34-LI was significantly higher in the multicentric recurrence group (p < 0.001) and staging scores of fibrosis were also significantly higher in the recurrence group (p = 0.035). A high histological activity grade (p = 0.057) and a high alanine aminotransferase level (p = 0.060) were also associated with recurrence. There were no significant differences between the two groups in age, sex, hepatitis B virus surface antigen and anti-hepatitis C virus antibody levels, or grade of iron deposition. On multivariate analysis, high CD34-LI was the only independent risk factor (p = 0.001) for metachronous multicentric recurrence. CONCLUSION: CD34 expression in the capillaries and sinusoids of noncancerous hepatic tissue is a risk factor for multicentric recurrence of HCC. Histologic assessment of hepatic tissue with CD34 immunohistochemistry might be useful for the prognostic evaluation of HCC patients after surgery.

Histological features responsible for brownish epithelium in squamous neoplasia of the esophagus by narrow band imaging.

BACKGROUND AND AIM: Esophageal squamous neoplasias usually appear brown under narrow band imaging as a result of microvascular proliferation, and brownish color changes in the areas between vessels, referred to as brownish epithelium. However, the reasons for the development of this brownish epithelium and its clinical implications have not been fully investigated. METHODS: Patients with superficial esophageal neoplasias treated by endoscopic resection were included in the study. Areas of mucosa with brownish and non-brownish epithelia were evaluated histologically. RESULTS: A total of 68 superficial esophageal neoplasias in 58 patients were included in the analysis. Of the 68 lesions, 32 were classified in the brownish epithelium group, and 36 in the non-brownish epithelium group. Brownish epithelium was significantly associated with a diagnosis of high-grade intraepithelial neoplasia or invasive cancer (P < 0.0001). Thinning of the keratinous layer, thinning of the epithelium, and cellular atypia were significantly associated with brownish epithelium by univariate analysis, and thinning of the keratinous layer and thinning of the epithelium were confirmed to be independent factors by multivariate analysis. The odds ratios were 9.6 (95% confidence interval: 2.0-46.3) for thinning of the keratinous layer, and 4.6 (95% confidence interval: 1.1-19.4) for thinning of the epithelium. CONCLUSIONS: Brownish epithelium is an important finding in the diagnosis of esophageal squamous neoplasia, and may be related to thinning of the keratinous layer, caused by neoplastic cell proliferation, and thinning of the epithelium.

[Russell body gastritis].

A 63-year-old woman who presented with chest and back pain underwent an upper gastrointestinal endoscopy which revealed elevated legion in the antrum mucosa. Histologic examinations of gastric biopsies were showing monoclonal proliferation plasma cells containing Russell bodies. Differential diagnosis from B-cell lymphoma and plasmacytoma is difficult, because of monoclonality. Molecular analyses of immunoglobulin heavy chain (IgH) gene demonstrated that gene rearrangement was negative. Thus, diagnosis of Russell body gastritis was made. The Giemsa stains were also showing infection of Helicobacter pylori (H.pylori). After eradication therapy for H.pylori, follow-up upper gastrointestinal endoscopy was performed. She then recovered.

Promotion Effects of Smoking in Polyp Development in Monozygotic Twins with Atypical Colorectal Polyposis.

Smoking is a known risk factor for the development of colorectal polyps. Even in familial adenomatous polyposis and serrated polyposis syndrome, smoking is a risk factor of the development of polyps. Here, we report a case of monozygotic twins with atypical colorectal polyposis showing lots of hyperplastic polyps and adenomas and describe how the polyposis developed differently in the brothers based on the presence or absence of smoking. The case was of a set of monozygotic male twins, and the twins were in their 50s. The younger brother smoked 40 cigarettes a day since he was 16 years old. The older brother had smoked about 25 cigarettes a day since he was 16 years old but stopped smoking after he was diagnosed with polyposis. As we previously reported, we managed to remove polyps as much as possible from both twins without surgery. The median number of removed polyps (IQR: 25-75%) per colonoscopy for 20 years was 9.0 (3.5-14.8) in the older brother and 20.5 (7.5-35.5) in the younger brother. There was a significant difference between the twins (p < 0.01). Additionally, genetic tests found that the twins carried a rare missense variant of BRCA2, and this variation has not been previously reported. In conclusion, these monozygotic twins with atypical colorectal polyposis showing a new variant of BRCA2 suggest that smoking is related to the development of colorectal polyps. Further analysis will be required for the identified BRCA2 variant in possible involvement in the development of atypical polyposis.

Importance of sessile serrated lesions in a patient with familial adenomatous polyposis.

A 28-year-old male visited hospital because his mother had been diagnosed with familial adenomatous polyposis (FAP) with a pathological variant of the APC gene. Total colonoscopy showed that he has more than 100 polyps distributed throughout the colorectum, and the APC gene variant was also detected. After he was diagnosed with FAP, he received information that surgery was currently the only way to prevent the development of colorectal cancer. However, he firmly declined to undergo surgical procedures and decided to have strict follow-up with frequent endoscopic polypectomy to prevent the development of colorectal cancer. At the first endoscopy, polypectomy was performed on 52 polyps. Histological analysis of the dissected polyps showed that they were all adenomas, but adenocarcinoma was not detected. The second endoscopic polypectomy was performed after 4 months later. We found a pale 20 mm wide flat, elevated type polyp in the ascending colon with an adherent mucus cap that was resistant to washing off. After endoscopic mucosal resection, histological analysis revealed that there were two lesions in the polyps, a sessile serrated lesion (SSL) and SSL with dysplasia. SSL is a high-risk lesion for colorectal cancer, but it was reported to be rare in patients with FAP, and the existence of SSL suggested another carcinogenesis pathway in patients with FAP in addition to the adenoma-carcinoma sequence. Our report may be significant not only in consideration of the pathogenesis of FAP but also useful to raise awareness of SSL for clinicians who perform endoscopic polypectomy to prevent the development of colorectal cancer in patients with FAP.

Excessive fat restriction might promote the recurrence of colorectal tumors.

The incidence of colorectal cancer is rapidly increasing in Japan. This trend has been suggested to be caused by an increasing fat intake as a result of the Westernized diet among Japanese. We investigated whether dietary instruction optimizing the fat energy ratio suppresses the recurrence of colorectal tumors. The subjects, 373 men and women, were the participants in a randomized clinical trial of colorectal cancer prophylaxis. At entry, each participant completed a 3-consecutive-day food record on which dietary instruction was given to restrict fat energy ratio to 18-22%. Data obtained before and after the intervention were examined by cohort analysis. The primary endpoint was the presence or absence of colorectal tumor(s) at colonoscopy after 4 yr. Unexpectedly, the recurrence of tumor increased as the subjects reduced their fat intake. The lowest tumor recurrence among the men was observed in the group with 23.8-26.4% fat energy ratio after the intervention. Furthermore, in men, the risk of tumors decreased significantly as the intake of linoleic acids per body weight increased. For women, similar trends were observed. These results suggest that extreme fat restriction is highly likely to promote the recurrence of colorectal tumors, which may be partly attributable to linoleic acid deficiency.