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The diagnostic criteria for adult-onset Alzheimer's disease (AD) in patients with Down syndrome (DS) have not been standardised. This study investigated the specific symptoms of AD in the prodromal stage of DS, the mean age at diagnosis at each stage of dementia, and the relationship between intellectual disability (ID) and dementia. PubMed, Web of Science, and Embase were searched for studies on DS, AD, early-stage disease, initial symptoms, and prodromal dementia registered between January 2012 and January 2022. We also performed a meta-analysis of the differences between the mean age at prodromal symptoms and AD diagnosis and the proportion of mild cognitive impairment in patients with mild and moderately abnormal ID. We selected 14 articles reporting the behavioural and psychological symptoms of dementia (BPSD) and memory- and language-related impairments as early symptoms of AD in patients with DS. The specific symptoms of BPSD were classified into five categories: irritability (agitation), apathy, abnormal behaviour, adaptive functioning, and sleep disturbance. The mean age at the diagnosis of prodromal symptoms and AD dementia was 52.7 and 56.2 years, respectively (mean difference, + 3.11 years; 95% CI 1.82–4.40) in the meta-analysis. The diagnosis of mild dementia tended to correlate with ID severity (odds ratio [OR], 1.38; 95% CI 0.87–2.18). The features of behaviour-variant frontotemporal dementia may be clinically confirmed in diagnosing early symptoms of DS-associated AD (DSAD). Moreover, age-appropriate cognitive assessment is important. Further studies are required to evaluate DSAD using a combination of biomarkers and ID-related data. [ABSTRACT FROM AUTHOR]

The Japanese Breast Cancer Society Clinical Practice Guidelines for Epidemiology and Prevention of Breast Cancer, 2022 Edition. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer often metastasizes to the central nervous system. Although the prognosis of brain metastases from breast cancer has been considered poor, and systemic therapy has not contributed to an improved prognosis, newer agents are expected to be more effective. BRCAness is defined as the status of homologous recombination deficiency (HRD) in tumor tissue, regardless of the presence of pathogenic germline BRCA1/2 variants. A study employing next-generation sequencing analysis showed that HRD was found relatively frequently in brain metastases of breast cancer patients. However, there have been no studies evaluating BRCAness in brain metastases of breast cancer with more efficient, rapid, and cost-effective methods. Methods: We retrospectively investigated 17 brain metastases of breast cancer that were surgically resected at our hospital from January 2007 to December 2022. Of these, samples from 15 patients were evaluable for BRCAness by employing multiplex ligation-dependent probe amplification (MLPA) assay. Results: Of the 15 patients, five patients (33%) had tumors with BRCAness. Clinicopathological factors of patients with brain metastases with BRCAness were not statistically different from those of patients who possessed tumors without BRCAness. Patients with brain metastases with BRCAness had shorter overall survival compared to those without BRCAness (BRCAness, median 15 months (95% CI 2–30) vs. non-BRCAness, median 28.5 months (95% CI 10–60); P = 0.013). Conclusion: In this study, we evaluated BRCAness in brain metastases of breast cancer with the MLPA method, and found that about one-third of patients had BRCAness-positive tumors. The analysis of BRCAness using MLPA has the potential for practical clinical use. [ABSTRACT FROM AUTHOR]

Alcohol consumption is internationally recognized as one of the compelling risk factors for breast cancer, but it does not necessarily correlate with the prognosis of breast cancer patients. Alcohol consumption in breast cancer patients was addressed in the 2022 Breast Cancer Clinical Practice Guidelines. A systematic review and meta-analysis of epidemiological studies on alcohol consumption and breast cancer recurrence, breast cancer-related mortality, all-cause mortality, and cardiovascular disease mortality in breast cancer patients was performed. The PubMed, Cochrane Library, and Ichushi-Web databases were searched for relevant publications reporting cohort or case–control studies published until March 2021. A total of 33 studies (32 cohort studies and 1 case–control study) met the eligibility criteria; 4638 cases of recurrence, 12,209 cases of breast cancer-specific mortality, and 21,945 cases of all-cause mortality were observed. With regard to breast cancer recurrence, 7 studies assessed pre-diagnosis alcohol consumption (relative risk (RR) 1.02, 95% confidence interval (95% CI) 0.77–1.37, p = 0.88) and 3 studies assessed post-diagnosis alcohol consumption (RR 0.96, 95% CI 0.85–1.10, p = 0.57), and no significant increase or decrease in risk was observed. With regard to breast cancer-related mortality, 19 studies assessed pre-diagnosis alcohol consumption (RR 1.02, 95% CI 0.93–1.11, p = 0.69), 9 studies assessed post-diagnosis alcohol consumption (RR 0.96, 95% CI 0.77–1.19, p = 0.70), and no significant increase or decrease in risk was observed. With regard to all-cause mortality, 18 studies assessed pre-diagnosis alcohol consumption (RR 0.90, 95% CI 0.82–0.99, p = 0.02), 8 studies assessed post-diagnosis alcohol consumption (RR 0.88, 95% CI 0.74–1.02, p = 0.08), and pre-diagnosis alcohol consumption was associated with a significantly decreased risk. With regard to cardiovascular disease mortality and alcohol consumption, 2 studies assessed it, and the RRwas 0.47 (95% CI 0.28–0.79, p = 0.005), showing that alcohol consumption was associated with a significantly decreased risk. The limitations of this study are that drinking status was mainly based on a questionnaire survey, which is somewhat inaccurate and has many confounding factors, and the cut-off value for the maximum alcohol intake in many studies was low, and it is possible that the actual intake was only an appropriate amount. In many countries, a standard drinking amount is set, and wise decisions are required. [ABSTRACT FROM AUTHOR]

Individuals carrying pathogenic BRCA1 or BRCA2 mutations have an increased lifetime risk of breast and/or ovarian cancer. The incidence of breast cancer amongst disease-free BRCA mutation carriers under surveillance and the clinical and pathological characteristics of those who subsequently develop the disease remain unclear in Japan. We reviewed the records of 155 individuals with BRCA1 or BRCA2 mutations identified by genetic testing between January 2000 and December 2016. At the time of genetic testing, 26 individuals with one of these mutations had no history of breast cancer and were therefore enrolled in a surveillance program that included biannual ultrasonography, clinical breast examination, annual mammography, and conditional magnetic resonance imaging for the early detection of primary breast cancer. During the surveillance period, 5 individuals with BRCA1 or BRCA2 mutations were diagnosed with primary breast cancer. The mean surveillance duration until breast cancer diagnosis was 48 months. The incidence of primary breast cancer during surveillance in initially disease-free BRCA mutation carriers was 4.23%/year. In two cases, the tumors were only detectable on MRI. The case 5 patient who presented with a tumor that was detected by self-examination, which then grew rapidly, had stage IIB triple-negative breast cancer. In conclusion, our results show that some challenges exist in the early detection of breast cancers in BRCA1 or BRCA2 mutation carriers. There are also some difficulties in approaching those individuals in Japanese society. [ABSTRACT FROM AUTHOR]

Background: This study aimed to identify the clinical background and treatment outcomes of risk-reducing salpingo-oophorectomy (RRSO) in Japan for women with hereditary breast and ovarian cancer (HBOC). Methods: In the present retrospective observational study, we examined the Japanese HBOC Consortium's (JHC) database. This database contains 11,711 probands who received BRCA genetic testing, or their relatives, with any cancer in 2433 pedigrees. This study was supported by the registration committee of the JHC. Results: We analyzed 488 individuals diagnosed with HBOC, of which 153 (31.4%) underwent RRSO. Of the latter patients, 88 carried BRCA1 mutation (B1); 62 carried BRCA2 mutation (B2); and 3 carried both mutations. During a mean follow-up period of 2.6 years (range 0–12.6), one patient developed a primary peritoneal cancer (PPC). Clinical background comparison for individuals who underwent RRSO vs. those > 45 years of age who did not undergo RRSO revealed that significant factors were represented by B1 (p < 0.0001); child bearing (p < 0.00001); and breast cancer history (p < 0.01). However, family history of ovarian cancer and menopause status were not significantly different. Conclusion: Over 30% HBOC's in Japan underwent RRSO. In Japan, individuals with breast cancer history and B1 generally underwent RRSO, whereas those who did not bear a child mostly avoided RRSO. [ABSTRACT FROM AUTHOR]

Purpose: Prophylactic surgery is a preemptive strategy for hereditary breast and ovarian cancer (HBOC). Prophylactic mastectomy (PM) reduces breast cancer risk by > 90%. The aim of our study is to analyze the information of the Japanese pedigrees and to utilize the results for clinical practice.Methods: We statistically analyzed records of HBOC registrees who had undergone BRCA1/2 genetic testing at seven medical institutions up until 2016. In the cases of PM, we examined breasts with the use of mammography (MMG), ultrasound (US), and magnetic resonance imaging (MRI) before surgery. After PM, the specimens were divided about 1 cm serially and examined in their entirety.Results: Of 1527 registrees who underwent BRCA testing, 1125 (73.7%) were negative for BRCA1/2 mutation, 297 (19.5%) were positive for BRCA1/2 mutation (BRCA1/2MUT+), and 105 (6.9%) had uncertain results. To decide whether to undergo total mastectomy vs. breast-conserving surgery (BCS), 370 registrees underwent presurgical genetic testing. During the follow-up period, four new-onset breast cancers were found among the 55 non-affected BRCA carriers. Among the 73 BRCA1/2MUT+ carriers who underwent BCS, 3 were found to have ipsilateral breast cancer. Of 189 BRCA1/2MUT+ carriers with unilateral breast cancer, 8 were found to have contralateral breast cancer. Of 53 PM specimens, 6 (11.3%) were found to have occult breast cancer despite using MMG, US, and MRI.Conclusions: Our report showed a relatively higher incidence rate of occult cancer at 11.3% in PM specimens despite thorough pre-operative radiological evaluations, which included a breast MRI. Considering the occult cancer rates and the various pathological methods of our study and published studies, we propose the necessity of a histopathological protocol. [ABSTRACT FROM AUTHOR]

We conducted this study to establish whether drinking alcohol alters the risk of early-onset colorectal cancer (CRC) in Japanese patients with Lynch syndrome (LS). The subjects were 66 LS patients with pathogenic mutation of mismatch repair genes (MLH1, MSH2, and MSH6) from the nationwide Japanese retrospective multicenter study. Cox proportional hazards modeling was used to investigate the factors correlating with early-onset CRC diagnosis, using clinical data such as gender, tobacco use, alcohol consumption, body mass index, gene mutation (MLH1, MSH2 vs MSH6), and family cancer history. Alcohol was significantly correlated with an increased risk of early-onset CRC [HR 2.44, 95% CI 1.13-5.16 (p = 0.02)], but tobacco use was not [HR 0.8, 95%CI 0.38-1.62 (p = 0.53)]. These findings suggest that alcohol consumption is correlated with an earlier onset of CRC in Japanese patients with LS [ABSTRACT FROM AUTHOR]

Background: Cost-effectiveness analysis is an important aspect of healthcare, including in Japan, where preventive measures for BRCA1/2 mutation carriers are not covered by health insurance.Methods: We developed Markov models in a simulated cohort of women aged 35–70 years, and compared outcomes of surveillance with risk-reducing mastectomy (RRM) at age 35, risk-reducing salpingo-oophorectomy (RRSO) at age 45, and both (RRM&RRSO). We used breast and ovarian cancer incidences and adverse event rates from the previous studies, adjuvant chemotherapy, and hormonal therapy rates from the Hereditary Breast and Ovarian Cancer Registration 2015 in Japan, mortality rates from the National Cancer Center Hospital, Japan Society of Clinical Oncology, and Ministry of Health, Labour and Welfare, and direct costs from St. Luke’s International Hospital and Keio University Hospital. We used previously published preference ratings of women without known high risk to adjust survival for quality of life. The discount rate was 2%.Results: Compared with surveillance, RRSO and RRM&RRSO were dominant (both cost-saving and more effective), and RRM was cost-effective in BRCA1 mutation carriers, while RRM and RRM&RRSO were dominant and RRSO was cost-effective in BRCA2. Among the four strategies including surveillance, RRM&RRSO and RRM were the most cost-effective in BRCA1 and BRCA2 mutation carriers, respectively.Conclusions: With quality adjustment, RRM, RRSO, and RRM&RRSO were all cost-effective preventive strategies in BRCA1/2 mutation carriers, with RRM&RRSO being the most cost-effective in BRCA1 and RRM in BRCA2. This result supports the inclusion of insurance coverage for BRCA mutation carriers in Japan. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the clinicopathological features of and prognosis associated with sporadic colorectal cancer (CRC) in Japanese patients younger than 40 years old. Methods: The subjects of this study were patients with sporadic stage 0-III CRC, who underwent curative resection between 2004 and 2012 at the Cancer Institute Hospital. Clinicopathological characteristics and survival were compared between the young (<40 years; n = 81) and older groups (≥40 years; n = 2257). Results: The median age was 36 years in the young group and 64 years in the older group. Young patients had a lower incidence of right-sided colon cancer (14 vs 28 %) and a higher incidence of rectal cancer (47 vs 32 %; P < 0.0001). The number of retrieved lymph nodes was significantly higher in the young group than in the older group ( P = 0.0049). The young patients had similar overall survival and relapse-free survival to their older counterparts, except for overall survival in stage II patients ( P = 0.0229). However, multivariate analysis indicated that age was not an independent prognostic factor for overall survival in patients with stage II CRC. Conclusions: Young Japanese patients with sporadic CRC have unique characteristics such as a high incidence of rectal cancer and similar pathological features; however, they appear to have comparable survival to older patients. [ABSTRACT FROM AUTHOR]

Germline MUTYH mutations were investigated in 14 Japanese colorectal polyposis patients without germ line adenomatous polyposis coli ( APC) gene mutations. Three patients had a heterozygous IVS10-2A>G MUTYH mutation. The onset of MUTYH-associated polyposis (MAP) occurs later than that of familial adenomatous polyposis with germline APC mutation. Thus, we compared the carrier frequency of MUTYH IVS10-2A>G heterozygote in the APC mutation negative cases with that in 115 controls over 70 years of age who showed no apparent clinical manifestations of cancer and claimed that they had no history of cancer at the time of enrollment. The frequency of IVS10-2A>G heterozygote in APC germline mutation negative polyposis patients was significantly higher than control subject ( p = 0.012, Chi square test). Although the sample size is still too small to conclude, the IVS10-2A>G MUTYH heterozygote might add to the risk of developing germline APC mutation negative polyposis. [ABSTRACT FROM AUTHOR]

Purpose: This study assessed the feasibility and safety of laparoscopic surgery for metachronous colorectal cancer in patients who had previously undergone surgery for primary colorectal cancer. Methods: Of the 52 patients who underwent curative resection for metachronous colorectal cancer from August 2004 to April 2013, 26 each underwent laparoscopic and open surgery. Their clinical characteristics and surgical and postoperative outcomes were compared. Results: The percentage of patients who underwent previous open surgery was significantly higher in the open group than in the laparoscopic group (92.3 vs. 65.4 %). The body mass index was higher in the laparoscopic group than in the open group (23.8 vs. 21.1 kg/m), and the amount of blood loss was significantly smaller in the laparoscopic than in the open group (30 vs. 195 ml); however, the mean operative time did not differ significantly. The time to first flatus (1 vs. 3 days) and first stool (2 vs. 3.5 days), as well as the length of postoperative hospital stay (10 vs. 16 days), was significantly shorter in the laparoscopic group than in the open group, although the rates of postoperative complications did not differ (15.4 vs. 23.1 %). Conclusions: Laparoscopic surgery for metachronous colorectal cancer shows short-term benefits compared with open surgery and should be considered as a treatment option in these patients. [ABSTRACT FROM AUTHOR]

Lynch syndrome (HNPCC) is an autosomal dominant hereditary cancer syndrome, and members of affected families are at-risk for developing colorectal and other associated tumors. Such individuals should disseminate familial genetic information, so they can seek specific medical assessment or genetic testing to reduce mortality and morbidity rates by early detection. Since published results have been encouraging, we explored which factors influence the likelihood of good communication within families regarding medical assessment. We studied 40 individuals from 33 families who satisfied the Japanese clinical criteria for Lynch syndrome and their relatives at our hospital. We determined the status of relatives of the 40 individuals after genetic counseling and testing using questionnaires and semi-structured interviews based on pedigree charts. We also examined their knowledge or perception of colorectal cancer syndrome, levels of intimacy and whether or not they encouraged their relatives to have specific medical assessments. We found that 75% of the individuals advised their relatives to seek medical assessment, and any significant background factors that promoted such encouragement were observed. They tended to encourage first degree relatives and discuss the issue with other family members such as spouses before undertaking such attempts at encouragement. The reasons and methods of imparting encouragement were essentially identical. We also found that genetic testing for at-risk or more distant relatives was not encouraged so often. Therefore, providing individuals who have been tested for Lynch syndrome with opportunities for disseminating familial genetic information through appropriate genetic counseling is important. [ABSTRACT FROM AUTHOR]

Objective: PET cancer screening is performed widely in Japan as opportunistic screening, but no study has focused on the correlation with various cancer risk factors and the seeking bias of examinees and cancer detection rate. Analyzing our large series of PET cancer screening data, correlations with cancer detection rates according to general cancer risk factors and PET detection survey were reviewed, and the selection bias of the medical examinees was determined. Methods: 19189 examinees who underwent PET cancer screening were enrolled. Using logistic-regression analysis, we analyzed correlations between smoking history/drinking history/cancer family history and detection rates of thyroid cancer/breast cancer/colorectal cancer/lung cancer, which are the main malignancies detected in PET cancer screening. In addition, we evaluated seeking bias of examinees, analyzing correlations between the presence of cancer risk factors and prior screening checkups at other institutions to our PET cancer screening using a matched case-control study. Results: Cancer detection rates by FDG-PET were 1.17% (224/19189), being much higher than those of standard cancer mass screenings. In males, statistically significant correlations were seen between lung cancer and smoking, and between prostate cancer and a family history of prostate cancer, but not between the detection rates of three other types of cancer (thyroid cancer/lung cancer/colorectal cancer) and other cancer risk factors. In females, detection rates of four types of cancer (thyroid cancer/lung cancer/colorectal cancer/breast cancer) were significantly higher in the examinees without cancer risks, and subgroup analysis according to types of cancer did not indicate significant correlations either. The matched case-control study evaluating seeking bias indicated that a significant proportion of the examinees with cancer risks had undergone prior cancer screening at other institutions. Conclusions: Our study indicated that there was significant seeking bias for prior screening of examinees, with this accounting for the fact that this study did not find a significant correlation between cancer risks and cancer detection rates. The results of our study indicated that PET cancer screening can provide high cancer detection rates. [ABSTRACT FROM AUTHOR]

Lynch syndrome (hereditary non-polyposis colorectal cancer) is an inherited disease caused by germ-line mutation in mismatch repair genes such as MLH1, MSH2, and MSH6. The mutations include missense and nonsense mutations, small insertions and deletions, and gross genetic alterations including large deletions and duplications. In addition to these genetic changes, mutations in introns are also involved in the pathogenesis. However, it is sometimes difficult to interpret correctly the pathogenicity of variants in exons as well as introns. To evaluate the effect of splice-site mutations in two Lynch syndrome patients, we carried out a functional splicing assay using minigenes. Consequently, this assay showed that the mutation of c.1731+5G>A in MLH1 led to exon15 skipping, and that the mutation of c.211+1G>C in MSH2 created an activated cryptic splice-site 17-nucleotides upstream in exon1. These aberrant splicing patterns were not observed when wild type sequence was used for the assay. We also obtained concordant results by RT-PCR experiments with transcripts from the patients. Furthermore, additional functional splicing assays using two different intronic mutations described in earlier studies revealed splicing alterations that were in complete agreement with the reports. Therefore, functional splicing assay is helpful for evaluating the effects of genetic variants on splicing. [ABSTRACT FROM AUTHOR]

We describe a patient who had nine primary malignant tumors and a germline mutation in the p53 tumor-suppressor gene, characteristically found in the Li-Fraumeni syndrome (LFS). A 15-year-old girl with no family history of cancer was referred to our hospital because of pain and swelling of the right knee. Osteosarcoma was diagnosed. The patient received chemotherapy followed by surgery and had a remission. After the age of 28 years, nine primary malignant tumors developed successively, including right breast cancer, colon cancer, malignant fibrous histiocytoma (MFH) of the abdominal wall, right lung double cancers, bilateral breast cancers, and MFH of the left thigh. This is the second highest number of types of primary malignant tumors to be reported in LFS. All tumors were treated by a multidisciplinary approach, including surgery. Genetic analysis revealed a germline missense mutation in the p53 gene (c.659 A > G), resulting in Y220C, which has been reported in three families with LFS. The patient died of lung metastasis from MFH at the age of 37 years. Despite the multiple tumors, repeated induction of remissions resulted in long survival. Our findings suggest that a multidisciplinary approach to treatment, including surgery, is beneficial in patients with LFS. [ABSTRACT FROM AUTHOR]

About 60% of familial breast and ovarian cancers in Japan involve germline mutations of the BRCA1 or BRCA2 (BRCA½) genes. These genes contribute to genetic stability and DNA repair and act as tumor suppressor genes. Mutation analysis of the BRCA½ genes has improved our understanding of both common mutation patterns in Japanese patients and the clinicopathological features of BRCA½-related cancers. BRCA1-related breast cancers are characterized by poor prognosis, a low rate of estrogen receptor positivity, and histological predominance of solid-tubular carcinoma. BRCA1-related ovarian cancers are associated with a high frequency of serous adenocarcinoma and a good outcome. Further largescale studies are needed to delineate genotype-phenotype relations and penetrance in BRCA½-related breast and ovarian cancers in Japan. The development of systems for clinical genetics in Japan, including genetic counseling, has led to the increased use of genetic testing for the clinical management of BRCA½-related cancers. Three options are available for carriers of BRCA½ mutations: intensive surveillance, chemoprevention, and prophylactic surgery. Studies done in other countries indicate that prophylactic surgery effectively prevents the development of breast and ovarian cancers in carriers of BRCA½ mutations. However, prophylactic mastectomy remains controversial in Japan, and now systematic intensive surveillance is generally performed for the prevention of breast cancer in women at high risk. Early detection of ovarian cancer remains challenging, resulting in increased acceptance of the need for prophylactic oophorectomy in women at risk. This review summarizes experimental and clinical findings about familial breast and ovarian cancers, including data on Japanese patients. [ABSTRACT FROM AUTHOR]

Provides a historical perspective on familial cancer in Japan. Results and vision of the Polyposis Center Project; Prelude to cancer molecular genetics and medicine; Comments on the role of familial cancer approach in genomic medicine.