Abstract Background Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disease that results in the development of more than 100 polyps, premalignant lesions, in the colorectum. Therefore, patients with FAP are a high-risk group for colorectal cancer (CRC). The only standard method of preventing CRC is total colectomy. Thus, alternative methods to prevent the development of CRC are desired by patients. Epidemiological and animal studies suggested that green tea and its extracts, such as (−)-epigallocatechin gallate, may have the potential to prevent cancer development. Results In the present study, we evaluated the suppressive effects of green tea extract (GTE) on suppress colorectal polyps in FAP and conducted a double-blind clinical trial. Eighty patients were randomly assigned to the GTE group (1.5 g/day for 2 years) and an equal number were assigned to the placebo group. The primary endpoint of colon polyp enlargement tended to be reduced in the GTE group compared with the placebo group, with a risk ratio of 0.43 (95% confidence interval 0.12–1.49; p = 0.16). Conclusions Given that the risk ratio was less than 0.5 and few adverse events were observed, we believe that further research using GTE after calculating the necessary sample size is calculated on the based of this study, should be considered in a future large-scale clinical trial.

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 with-out previous history of polyposis in the family pedigree. Some patients with JPS develop gastrointestinal le-sions in childhood and require continuous medical care until adulthood. JPS is classified into three catego-ries according to phenotypic features of polyp distributions, including generalized juvenile polyposis, juve-nile 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 car-diovascular 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, Assess-ment, 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, adoles-cent, and adult patients with JPS.

Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20s. This syndrome is occasionally diagnosed in childhood due to the occurrence of multiple gastrointestinal polyps, autism spectrum disorders, and intellectual disability. CS/PHTS can be diagnosed taking the opportunity of multigene panel testing in patients with cancer. Appropriate surveillance for early diagnosis of associated cancers is required because patients have a high risk of cancers including breast, thyroid, colorectal, endometrial, and renal cancers. Under these circumstances, there is growing concern regarding the management of CS/PHTS in Japan, but there are no available practice guidelines. To address this situation, the guideline committee, which included specialists from multiple academic societies, was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour, and Welfare, Japan. The present clinical guidelines explain the principles in the diagnosis and management of CS/PHTS, together with four clinical questions and the corresponding recommendations, incorporating the concept of the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we present an English version of the guideline, some of which have been updated, to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with CS/PHTS.

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.

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

We report a rare carcinoma of the permanent ileostomy site developing 20 years or more after total proctocolectomy (TPC)in a 65-year-old woman with familial adenomatous polyposis(FAP). She underwent TPC for rectal cancer associated with FAP in her 40th at other institution. She also underwent pancreas-sparing total duodenectomy for duodenal mucosal cancer associated with severe duodenal polyposis at 59 years at our institution. She was referred to our hospital again complaining of the mass of the ileostomy site, 10 cm in diameter. Though biopsy revealed no definite malignancy, serum CA19-9 was elevated(98 U/mL), leading to a preoperative diagnosis to be ileal carcinoma. The involved bowel was widely resected. Histological examination demonstrated Stage ⅡA ileal carcinoma. Postoperative course was uneventful and she is well without recurrence 7 months after the ileal resection. This case seems valuable in that long-term surveillance including ileal carcinoma is important in the management of FAP patients whose colorectal cancer and duodenal cancer have been already well controlled.

Lynch syndrome is a hereditary disease characterized by an increased risk of colorectal and other cancers. Germline variants in the mismatch repair (MMR) genes are responsible for this disease. Previously, we screened the MMR genes in colorectal cancer patients who fulfilled modified Amsterdam II criteria, and multiplex ligation-dependent probe amplification (MPLA) identified 11 structural variants (SVs) of MLH1 and MSH2 in 17 patients. In this study, we have tested the efficacy of long read-sequencing coupled with target enrichment for the determination of SVs and their breakpoints. DNA was captured by array probes designed to hybridize with target regions including four MMR genes and then sequenced using MinION, a nanopore sequencing platform. Approximately, 1000-fold coverage was obtained in the target regions compared with other regions. Application of this system to four test cases among the 17 patients correctly mapped the breakpoints. In addition, we newly found a deletion across an 84 kb region of MSH2 in a case without the pathogenic single nucleotide variants. These data suggest that long read-sequencing combined with hybridization-based enrichment is an efficient method to identify both SVs and their breakpoints. This strategy might replace MLPA for the screening of SVs in hereditary diseases.

Lynch syndrome (LS) is an autosomal dominantly inherited disease predisposed to not only colorectal cancer but also other LS-related tumors. Although the clinical and genetic characteristics of LS in Western countries have been well characterized, the information of Japanese LS is limited. As a collaborative study of Japanese Society for Cancer of the Colon and Rectum (JSCCR), we registered colorectal cancer (CRC) patients who fulfilled the modified Amsterdam II criteria including gastric cancer as an LS-related tumor. Among 4030 CRC patients initially registered in this project, 85 patients (2.1%) fulfilled the modified criteria. An additional 26 patients who met the same criteria were enrolled in the analysis. We analyzed three major responsible genes, MLH1 , MSH2 , and MSH6 by direct sequencing, and further performed multiplex ligation-dependent probe amplification for MLH1 and MSH2 . Consequently, we identified pathogenic variants in 64 of the 111 patients comprising of 34 patients in MLH1 , 28 in MSH2 , and 2 in MSH6 . It is of note that large structural alterations were found in 17 patients. Among the 64 patients, 11 patients would not have been enrolled in the analysis if gastric cancer were not included in the modified criteria. In addition, 10 of the 64 variant carriers (15.6%) had medical history of gastric cancer. Furthermore, the standardized incidence ratio of gastric cancer in the LS patients to the Japanese population is estimated to be as high as 20.2. These data underscore the importance of gastric cancer in the diagnosis and healthcare of Japanese LS patients.

The proband was a 49-year-old woman who had undergone total colectomy, ileorectostomy, and bilateral ovariectomy for the treatment of cecal(T3N0)and sigmoid colon(T4a, N2b, M1c2[Ova], Stage Ⅳc)cancers. Pathological findings revealed 6 adenomas and 2 adenocarcinoma-in-adenomas in the right colon, other than advanced colon cancers. She had a family history of colorectal cancer meeting the Amsterdam Criteria I, but none of her relatives had definite polyposis. Considering the possibility of Lynch syndrome, the microsatellite-instability test and immunohistochemistry(IHC)examination of the mismatch repair protein were performed, leading to the results of microsatellite stable and proficient mismatch repair protein expression. Therefore, we performed the multigene panel test containing 26 genes using the next-generation sequencing technology. In the APC(5q22.2)gene, a pathogenic variant(exon 12 c.994C>T/p.Arg332*)was identified, leading to a diagnosis of attenuated familial adenomatous polyposis(AFAP). After disclosure of the results to the proband, the single-site variant analysis was performed on her 3 daughters. In her second and third daughters, the same variant was confirmed, and laparoscopic total colectomy was performed 23 and 35 months after the disclosure of the genetic analysis results, respectively. Currently, we are conducting periodical surveillance for the residual rectum.

The proband was a 77-year-old man who had been admitted to a local hospital for fecal occult blood. He was diagnosed with descending colon carcinoma, T4a, N1, M0, Stage Ⅲb, and rectal adenoma. He had undergone surgeries for rectal cancer at 52 years of age and cecum colon cancer at 57 years of age. Regarding his family history, 5 first-degree and 3 second- degree relatives had a history of gastrointestinal and gynecological cancers, thus meeting 2 of the 5 criteria of the revised Bethesda guidelines. The microsatellite-instability(MSI)test performed using preoperative biopsy tissues demonstrated high-frequency MSI(MSI-H). Hartmann's procedure was performed for MSI-H colon cancer under a strong suspicion of Lynch syndrome. Pathological findings were consistent with descending colon carcinoma, tub2, pT3, pN0, M0, pStage Ⅱa. He was then referred to our hospital. We performed the immunohistochemistry(IHC)analysis of the mismatch repair protein using surgical specimens. The IHC analysis revealed defective expression of the MSH2/MSH6 protein. We found a pathogenic variant in the mismatch repair gene, MSH2(c.1510+2T>G), through genetic testing and finally diagnosed the patient with Lynch syndrome. After disclosure of the results to the proband, 7 relatives underwent genetic testing for the MSH2 variant. Four relatives had the same variant and were also diagnosed with Lynch syndrome. They subsequently underwent surveillance for Lynch syndrome-associated cancers. In 2 variant carriers with a history of early colorectal cancer, an early colon cancer was identified and successfully resected endoscopically. Surveillance for Lynch syndrome-associated cancer is ongoing for the proband and variant carriers.

The risk of malignant tumors developing in association with juvenile polyposis syndrome (JPS) was evaluated to explore the optimal treatment for this rare disease.

INTRODUCTION The characteristics of desmoid tumors(DTs)associated with familial adenomatous polyposis(FAP)and relationships between the development of DTs and the sites of APC germline mutation have not closely been examined Japan. PATIENTS AND METHODS This retrospective study was performed to address these issues by examining patients with FAP who underwent proctocolectomy between 1981 and 2015. RESULTS The cumulative 2-year incidence of DT development was 50%. The DTs developed in the abdominal wall only in 2, in the abdominal wall plus intra-abdominally in 4, and intra-abdominally in 2. Clinical stages according to the Church's classification included Stage I in 3, Stage II in 2, Stage III in 1, and Stage IV in 2. Among 31 patients with a confirmed pathogenic germline APC mutation, patients with mutation in 3' site of codon 1400 (n=7)tended to develop DTs more frequently than those with mutation in 5' site of codon 1400(n=24)(p=0.08). The cumulative 5-year survival rate in patients with DT development was 73.3%. Including 2 patients undergoing initial colectomy at other institutions, the therapeutic efficacy in 4 patients with severe intraabdominal DTs(Stage III /Stage IV )who were given chemotherapy comprising doxorubicin plus dacarbazine(DOX plus DTIC)revealed partial response in 3 and complete response in 1. Febrile neutropenia was recorded in 2 of these patients. CONCLUSION The frequency of DTs development and genotype-phenotype relationship of FAP patients seems to concur with those reported from Western countries. Since the DOX plus DTIC therapy for severe DTs is valid but toxicity is high, the development of less toxic regimens are warranted.

The aim of this study was to investigate the prevalence of Lynch syndrome among Japanese patients with surgically resected colorectal cancer at a single institution.

Hereditary colorectal cancers comprise less than 5 % of all colorectal cancers and are defined as heritable conditions characterized by an apparently increased risk of colorectal cancer in individuals (mutant carriers in the germline), compared with the risk in the general population. Among the various known hereditary colorectal cancers, Lynch syndrome is the most common, followed by familial adenomatous polyposis. Other rarer diseases have been described, such as MUTYH-associated polyposis, polymerase proofreading-associated polyposis, hamartomatous polyposis syndromes (Peutz-Jeghers syndrome, juvenile polyposis syndrome, and PTEN hamartomatous syndrome). The early-onset of colorectal cancer and the development of other malignant neoplasms in various organs are characteristics that are common to these diseases. We herein document the epidemiologic characteristics of these rare diseases.

Genetic testing for hereditary colorectal polyposis/cancers has become increasingly important. Therefore, the development of a timesaving diagnostic platform is indispensable for clinical practice. We designed and validated target enrichment sequencing for 20 genes implicated in familial gastrointestinal polyposis/cancers in 32 cases with previously confirmed mutations using the HaloPlex enrichment system and MiSeq. We demonstrated that HaloPlex captured the targeted regions with a high efficiency (99.66 % for covered target regions, and 99.998 % for breadth of coverage), and MiSeq achieved a high sequencing accuracy (98.6 % for the concordant rate with SNP arrays). Using this approach, we correctly identified 33/33 (100 %) confirmed alterations including SNV, small INDELs and large deletions, and insertions in APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, PMS2, and SKT11. Our approach yielded the sequences of 20 target genes in a single experiment, and correctly identified all previously known mutations. Our results indicate that our approach successfully detected a wide range of genetic variations in a short turnaround time and with a small sample size for the rapid screening of known causative gene mutations of inherited colon cancer, such as familial adenomatous polyposis, Lynch syndrome, Peutz–Jeghers syndrome, and Juvenile polyposis syndrome.

BACKGROUND AND AIMS:It is not possible to accurately count adenomas in many patients with familial adenomatous polyposis (FAP). Nevertheless, polyp counts are critical in evaluating each patient's response to interventions. However, the U.S. Food and Drug Administration no longer recognizes the decrease in polyp burden as a sufficient chemoprevention trial treatment endpoint requiring a measure of "clinical benefit." To develop endpoints for future industry-sponsored chemopreventive trials, the International Society for Gastrointestinal Hereditary Tumors (InSIGHT) developed an FAP staging and intervention classification scheme for lower-GI tract polyposis.METHODS:Twenty-four colonoscopy or sigmoidoscopy videos were reviewed by 26 clinicians familiar with diagnosis and treatment of FAP. The reviewers independently assigned a stage to a case by using the proposed system and chose a stage-specific intervention for each case. Our endpoint was the degree of concordance among reviewers staging and intervention assessments.RESULTS:The staging and intervention ratings of the 26 reviewers were highly concordant (ρ = 0.710; 95% credible interval, 0.651-0.759). Sixty-two percent of reviewers agreed on the FAP stage, and 90% of scores were within ±1 stage of the mode. Sixty percent of reviewers agreed on the intervention, and 86% chose an intervention within ±1 level of the mode.CONCLUSIONS:The proposed FAP colon polyposis staging system and stage-specific intervention are based on a high degree of agreement on the part of experts in the review of individual cases of polyposis. Therefore, reliable and clinically relevant means for measuring trial outcomes can be developed. Outlier cases showing wide scatter in stage assignment call for individualized attention and may be inappropriate for enrollment in clinical trials for this reason.

Duodenal cancer is a leading cause of death in patients with familial adenomatous polyposis (FAP). In patients with Spigelman’s classification (SC) stage IV duodenal polyposis (DP), careful endoscopic surveillance by specialists or surgical intervention is mandatory. We herein report the surgical and pathological outcomes of FAP patients with SC stage duodenal polyposis undergoing pancreas-sparing total duodenectomy (PSTD), which has been rarely reported but seems optimal in such patients. PSTD and distal gastrectomy with Billroth-I type reconstruction in ten consecutive FAP patients with SC stage IV DP are reported. The median duration of surgery was 396 min (range 314–571 min) and the median estimated blood loss was 480 mL (range 100–975 mL). Significant postoperative complications included wound infection in 1 patient, pancreatic fistula [International Study Group on Pancreatic Fistula definition (ISGPF) grade B] in 4 patients. Histopathologic examinations revealed a well-differentiated carcinoma in situ in 3 patients and others were all adenomas. Over a median follow-up period of 15 months (range 9–29 months), 1 patient developed a stomal ulcer which improved with medical treatment. There were no patients with a body weight loss of ≥10 % relative to the preoperative body weight. No recurrence were experienced during the follow up period. Patients were free from postoperative diabetes mellitus. PSTD is a feasible and acceptable procedure in FAP patients with SC stage IV DP, in terms of surgical, pathological and clinical outcome. However, accumulation of the patients and long-term follow up study is necessary.

Background and study aims: Colectomy protects against colorectal cancer in familial adenomatous polyposis (FAP); however, some patients with FAP refuse surgery. The aim of this study was to evaluate the feasibility and safety of endoscopic management of these patients.Patients and methods: A retrospective review of medical records was performed to identify adult patients with FAP who refused colectomy and were managed by repeated colonoscopies to remove numerous polyps between 2001 and 2012. Polyps were removed by hot snare polypectomy or endoscopic mucosal resection. Polyps of <10 mm in size and without endoscopic features suggesting cancer were discarded without histological examination; the remaining polyps were examined histologically.Results: Of the 95 eligible patients, five (5.3 %) were excluded. The remaining 90 patients (median age at first visit 29 years [range 16-68 years]; 46 males) were followed for a median of 5.1 years (interquartile range [IQR] 3.3-7.3 years). During this period, a total of 55701 polyps were resected without adverse events such as bleeding or perforation. The median numbers of endoscopic treatment sessions and polyps removed per patient were 8 (IQR 6-11) and 475 (IQR 211-945), respectively. Five patients had noninvasive carcinoma (Category 4.2 according to the revised Vienna classification), detected within 10 months from the start of the follow-up period. All of these patients were treated endoscopically, without signs of recurrence during a median follow-up of 4.3 years (IQR 2.0-7.1 years). No invasive colorectal cancer was recorded during the study period. Two patients (2.2 %) underwent colectomy because the polyposis phenotype had changed to dense polyposis.Conclusion: Endoscopic management of FAP is feasible and safe in the medium term.

To investigate the recent incidence of malignant tumors associated with Peutz–Jeghers syndrome (PJS) in Japan to clarify if there are any differences in malignant tumor risk and the spectrum of malignancies by reviewing the literature on this subject.

When we perform stapled ileal pouch anal anastomosis (IPAA) for familial adenomatous polyposis (FAP), some rectal mucosa persists. There is no consensus on surgical treatment when cancer develops at the residual mucosa. We report the case of a 43-year-old woman who repeatedly underwent endoscopic resection for intramucosal cancer that developed in the residual rectal mucosa 6 years after stapled IPAA, which she received at age 33. She was referred to our department for surgical treatment. We performed mucosectomy for the residual rectum mucosa, including a 0-Ⅱa lesion at the anterior wall. Two months later, stenosis was observed at the anastomotic site. We repeatedly conducted balloon expansion of the stenotic lesion. Six months later, the resected lesion was covered with white epithelium, and columnar epithelium was confirmed by step biopsy of the epithelium from the dentate line to the ileoanal pouch anastomotic site. This finding indicated that the regenerating epithelium was derived from the epithelium from the anal side. The patient remains well after 2 year 4 months with no complaints.