Clinical features of biliary tract cancer in Japanese individuals with Lynch syndrome.

Background: Biliary tract cancer (BTC) is a Lynch syndrome (LS)-associated cancer with a high mortality rate. This study aimed to clarify the clinical features of BTC in individuals with LS and to discuss its management. Methods: We obtained data from genetically verified Japanese individuals with LS who were diagnosed at a single institution, between January 2003 and April 2021. Moreover, 21 individuals with sporadic BTC (n=15) and LS associated BTC (n=6) underwent microsatellite instability (MSI) testing. Results: Among 92 individuals with LS, 6 individuals with MLH1 variants developed BTCs (10 lesions, male/female, 2:1). The median age at diagnosis of initial BTC was 69 years (range, 34-78 years). Histological examination revealed a predominance of differentiated adenocarcinoma (89%). Then, 2 individuals had multiple BTCs. All available 7 BTC lesions showed high-frequency of microsatellite instability (MSI-H). MLH1 carriers showed a 7.2% cumulative risk of BTC development at an age of 70 years. Five of the six individuals died of BTC. Conclusions: MSI analysis could facilitate LS identification in individuals with BTC. Surveillance for BTC should be considered for MLH1 carriers in Japan.

Medical guidelines for Li-Fraumeni syndrome 2019, version 1.1.

Li-Fraumeni syndrome (LFS) is a hereditary tumor that exhibits autosomal dominant inheritance. LFS develops in individuals with a pathogenic germline variant of the cancer-suppressor gene, TP53 (individuals with TP53 pathogenic variant). The number of individuals with TP53 pathogenic variant among the general population is said to be 1 in 500 to 20,000. Meanwhile, it is found in 1.6% (median value, range of 0-6.7%) of patients with pediatric cancer and 0.2% of adult patients with cancer. LFS is diagnosed by the presence of germline TP53 pathogenic variants. However, patients can still be diagnosed with LFS even in the absence of a TP53 pathogenic variant if the familial history of cancers fit the classic LFS diagnostic criteria. It is recommended that TP53 genetic testing be promptly performed if LFS is suspected. Chompret criteria are widely used for the TP53 genetic test. However, as there are a certain number of cases of LFS that do not fit the criteria, if LFS is suspected, TP53 genetic testing should be performed regardless of the criteria. The probability of individuals with TP53 pathogenic variant developing cancer in their lifetime (penetrance) is 75% for men and almost 100% for women. The LFS core tumors (breast cancer, osteosarcoma, soft tissue sarcoma, brain tumor, and adrenocortical cancer) constitute the majority of cases; however, various types of cancers, such as hematological malignancy, epithelial cancer, and pediatric cancers, such as neuroblastoma, can also develop. Furthermore, approximately half of the cases develop simultaneous or metachronous multiple cancers. The types of TP53 pathogenic variants and factors that modify the functions of TP53 have an impact on the clinical presentation, although there are currently no definitive findings. There is currently no cancer preventive agent for individuals with TP53 pathogenic variant. Surgical treatments, such as risk-reducing bilateral mastectomy warrant further investigation. Theoretically, exposure to radiation could induce the onset of secondary cancer; therefore, imaging and treatments that use radiation should be avoided as much as possible. As a method to follow-up LFS, routine cancer surveillance comprising whole-body MRI scan, brain MRI scan, breast MRI scan, and abdominal ultrasonography (US) should be performed immediately after the diagnosis. However, the effectiveness of this surveillance is unknown, and there are problems, such as adverse events associated with a high rate of false positives, overdiagnosis, and sedation used during imaging as well as negative psychological impact. The detection rate of cancer through cancer surveillance is extremely high. Many cases are detected at an early stage, and treatments are low intensity; thus, cancer surveillance could contribute to an improvement in QOL, or at least, a reduction in complications associated with treatment. With the widespread use of genomic medicine, the diagnosis of LFS is unavoidable, and a comprehensive medical care system for LFS is necessary. Therefore, clinical trials that verify the feasibility and effectiveness of the program, comprising LFS registry, genetic counseling, and cancer surveillance, need to be prepared.

Ethical, legal and social implications of human genome studies in radiation research: a workshop report for studies on atomic bomb survivors at the Radiation Effects Research Foundation.

The Radiation Effects Research Foundation (RERF) is the primary organization in Japan dedicated to studying the health consequences of the Hiroshima and Nagasaki atomic bombings in World War II. In December 2020, RERF held a virtual international workshop on the ethical, legal and social implications (ELSI) of genome studies. In this workshop, the ELSI considerations of future human genome studies on radiation research including atomic bomb survivors and their families were discussed. Since genome sequencing (GS) is now practical and affordable, RERF now plans GS of parents/child trios to examine genetic effects of atomic bomb radiation. As such studies may engender some novel risks and benefits, ethics review and engagement with families (including consent) need to be considered. These include protection of individual privacy, use of samples from deceased prior participants, return of results to the participants, public sharing of genome data and advance science and social welfare. Specifically with regard to social welfare, the results of such studies may have implications for public and government decision-making regarding social benefits of victims and other important questions. Based on these broad-ranging discussions we have developed the following concepts to guide this work: "trust," "compromise" and "relationship building," inclusive of the concerned stakeholders, scientific aims and Japanese society at large. We conclude that in order to realize, establish and maintain these concepts, it is essential to put procedures into place to ensure the successful, consensus-based implementation of the RERF studies.

Characteristics of Li-Fraumeni Syndrome in Japan; A Review Study by the Special Committee of JSHT.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome, and the majority of patients with LFS have been identified with germline variants in the p53 tumor suppressor (TP53) gene. In the past three decades, considerable case reports of TP53 germline variants have been published in Japan. To the best of our knowledge, there have been no large-scale studies of Japanese patients with LFS. In this study, we aimed to identify Japanese patients with TP53 germline variants and to reveal the characteristics of LFS in Japan. We collected reported cases by reviewing the medical literature and cases diagnosed at the institutions of the authors. We identified 68 individuals from 48 families with TP53 germline pathogenic or likely pathogenic variants. Of the 48 families, 35 (72.9%) had missense variants, most of which were located within the DNA-binding loop. A total of 128 tumors were identified in the 68 affected individuals. The 128 tumor sites were as follows: breast, 25; bones, 16; brain, 12; hematological, 11; soft tissues, 10; stomach, 10; lung, 10; colorectum, 10; adrenal gland, 9; liver, 4; and others, 11. Unique phenotype patterns of LFS were shown in Japan in comparison to those in a large national LFS cohort study in France. Above all, a higher frequency of patients with stomach cancer was observed in Japanese TP53 germline variant carriers. These results may provide useful information for the clinical management of LFS in Japan.

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Pathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer. Large-scale studies are needed to inform future testing and variant classification processes in Japanese. We performed a case-control association study for variants in coding regions of 11 hereditary breast cancer genes in 7051 unselected breast cancer patients and 11,241 female controls of Japanese ancestry. Here, we identify 244 germline pathogenic variants. Pathogenic variants are found in 5.7% of patients, ranging from 15% in women diagnosed <40 years to 3.2% in patients ≥80 years, with BRCA1/2, explaining two-thirds of pathogenic variants identified at all ages. BRCA1/2, PALB2, and TP53 are significant causative genes. Patients with pathogenic variants in BRCA1/2 or PTEN have significantly younger age at diagnosis. In conclusion, BRCA1/2, PALB2, and TP53 are the major hereditary breast cancer genes, irrespective of age at diagnosis, in Japanese women.

[Complete Response Achieved with Oral Anticancer Monotherapy for Unresectable Lymph Node Metastasis after Cecal Cancer Surgery - A Case Report].

We herein report an interesting case in which a complete response was achieved with oral anticancer monotherapy for unresectable lymph node metastasis after surgery for cecal cancer. A 78-year-old woman was referred to our hospital to undergo a detailed examination for anemia. The examination led to a diagnosis of cecal cancer. She underwent open right hemicolectomy combined with adjacent abdominal wall resection and reconstruction of abdominal wall defects the next month. During follow-up without adjuvant therapy at her request, right iliac lymph node metastasis was detected 5 months later. A lymphadenectomy by laparotomy was attempted 6 months later but ended as only an exploratory laparotomy because the metastatic lymph node was difficult to detach from the vascular wall. Starting the next month, oral anticancer monothera- py(TS-1, 80mg/day for 2weeks followed by 1week of rest)was started at the patient's request. Abdominal ultrasonography performed in March 2011 revealed no evidence of lymphadenopathy, and subsequent imaging tests also confirmed the absence of lymphadenopathy. The anticancer monotherapy was discontinued after 4 years of medication. The patient remains alive, after 3 years and 5 months of medication to date, without recurrence.

[A Case in Which Eating Ability Was Restored after Chemotherapy for Gastric Metastasis Following Colon Cancer Resection].

We report here a rare case of gastric metastasis after resection ofa transverse colon cancer in which eating ability was restored following mFOLFOX6 (folinic acid plus fluorouracil plus oxaliplatin) plus cetuximab (Cet) chemotherapy. A 56-year-old man with chief complaints of constipation and abdominal fullness was referred to our hospital. In February 2013, he was diagnosed with transverse colon cancer via enema and colonoscopy. We performed transverse colon cancer resection followed by a 6-month course of capecitabine chemotherapy. In July 2014, the patient's serum carcinoembryonic antigen level increased, in October, he was again referred to our hospital with complaints of appetite loss and vomiting. He was diagnosed with multiple lymph node and gastric metastases via ultrasonography, computed tomography, and endoscopy, as well as multiple lung metastases via computed tomography. As the gastric metastases and vomiting rendered him unable to eat, a nasogastric tube was inserted and was administered mFOLFOX6 plus Cet chemotherapy. After 2 courses of chemotherapy his ability to eat was restored. As of March 2015, the patient remains alive following 12 courses of chemotherapy.

[A case of long-term survival following chemotherapy after laparoscopic resection of sigmoid colon cancer with multiple liver metastases].

We report a rare case of long -term survival after laparoscopic resection of sigmoid colon cancer with multiple liver metastases, followed by 5-fluorouracil Leucovorin irinotecan with bevacizumab (FOLFIRI+Bev) chemotherapy. A 61-year-old woman was referred to our hospital with a principal complaint of bloody stools. She was diagnosed with sigmoid colon cancer by colonoscopy and multiple liver metastases by ultrasonography. In October 2008, we performed laparoscopic resection of the sigmoid colon cancer with multiple liver metastases, followed by 4 courses of modified 5-fluorouracil Leucovorin oxaliplatin ( mFOLFOX6) chemotherapy. In February 2009, abdominal ultrasonography showed progressive disease, and as a result the patient was administered 73 courses of FOLFIRI +Bev chemotherapy. As of March 2014, the patient has survived for more than 5 years following treatment, but still has liver metastases. The possibility of resecting multiple liver metastases from colorectal cancer should be considered, and in some cases, chemotherapy may enhance survival.

[A patient with multiple liver metastases of gastric and rectal cancers after laparoscopic sigmoidectomy who responded completely to S-1 therapy followed by open gastrectomy].

We report a rare case of a patient with multiple liver metastases of gastric and rectal cancers after laparoscopic sigmoidectomy, who responded completely to S-1 therapy followed by open gastrectomy. A 72-year-old man with a chief complaint of occult blood in the feces was referred to our hospital and was diagnosed with rectal cancer by colonoscopy. In addition, we found concomitant gastric cancer by gastrointestinal fiberscopy. Abdominal plain computed tomography showed no liver metastasis. In August 2010, we performed laparoscopic resection of the rectal cancer. However, at the time of discharge, abdominal enhanced computed tomography showed multiple liver metastases. Then, we administered 4 courses of S-1 therapy. In December 2010, abdominal enhanced computed tomography showed no liver metastasis. In March 2011, because no other lesion without residual gastric cancer was detected, the patient underwent gastrectomy followed by S-1 therapy. As of January 2012, the patient is alive and disease free. S-1 therapy with laparoscopic resection for rectal cancer and gastrectomy may help prolong the survival of patients with multiple liver metastases of gastric and rectal cancers.

[A case of lung resection after chemotherapy due to lung metastases derived from esophageal cancer resection].

We report a rare case of esophageal cancer resection in which lung metastases was resected after chemotherapy with paclitaxel. A 59-year-old man with epigastralgia as a chief concern was referred to our hospital and was diagnosed with esophageal cancer by gastrointestinal fiber. In June 2007, the cancer was resected and followed by 3 courses of weekly chemotherapy with paclitaxel. In January 2009, chest computed tomography showed lung nodules (Rt-S1 and Rt-S5), and positron emission tomography (PET) showed uptake (Rt-S1); a final diagnosis of multiple lung metastases was made. Thereafter, the patient underwent 8 courses of weekly chemotherapy with paclitaxel. In December 2009, the growing Rt-S1 nodule was detected but no other lesion. The patient underwent a resection of lung metastases followed by 5 courses of weekly chemotherapy with paclitaxel. As of June 2011, the patient was alive and disease free. In conclusion, the resection of solitary lung metastases derived from esophageal cancer should be considered because it may improve survival.