Case series of Li-Fraumeni syndrome: carcinogenic mechanisms in breast cancer with TP53 pathogenic variant carriers.

BACKGROUND: Li-Fraumeni syndrome (LFS), a hereditary condition attributed to TP53 pathogenic variants,(PV), is associated with high risks for various malignant tumors, including breast cancer. Notably, individuals harboring TP53 PVs are more likely (67-83%) to develop HER2 + breast cancer than noncarriers (16-25%). In this retrospective study, we evaluated the associations between TP53 variants and breast cancer phenotype. METHODS: We conducted a retrospective review of the medical records of patients with LFS treated at a single institution and reviewed the literature on TP53 functions and the mechanisms underlying HER2 + breast cancer development in LFS. RESULTS: We analyzed data for 10 patients with LFS from 8 families. The median age at the onset of the first tumor was 35.5 years. Only case 2 met the classic criteria; this patient harbored a nonsense variant, whereas the other patients carried missense variants. We observed that 9 of 10 patients developed breast cancer. Immunohistochemical analyses revealed that 40% of breast cancers in patients with LFS were HR - /HER2 + . The median age at the onset of breast cancer was slightly younger in HR - /HER2 + tumors than in HR + /HER2 - tumors (31 years and 35.5 years, respectively). CONCLUSIONS: The occurrence of HER2 + breast cancer subtype was 40% in our LFS case series, which is greater than that in the general population (16-25%). Some TP53 PVs may facilitate HER2-derived oncogenesis in breast cancer. However, further studies with larger sample sizes are warranted to clarify the oncogenic mechanisms underlying each subtype of breast cancer in TP53 PV carriers.

Risk-reducing decisions regarding germline BRCA pathogenic variant: focusing on the timing of genetic testing and RRSO.

BACKGROUND: In Japan, the public insurance policy was revised in 2020 to cover hereditary breast and ovarian cancer (HBOC), including genetic testing and surveillance, for patients with breast cancer (BC). Consequently, the demand for risk-reducing salpingo-oophorectomy (RRSO) has increased. This study aimed to clarify the changes in the demand and timing of genetic testing and RRSO associated with public insurance coverage for HBOC in Japan. METHODS: This retrospective analysis included 350 women with germline BRCA (gBRCA) pathogenic variants (PVs) who had visited gynaecologists; they received gBRCA genetic testing at 45.1±10.6 (20-74) years. The use of medical testing and preventive treatment was compared between the preinsurance and postinsurance groups using Mann-Whitney U and Fisher's exact tests. RESULTS: The findings indicate that RRSO rates doubled from 31.4% to 62.6% among patients with gBRCA-PV. The implementation rate was 32.4% among unaffected carriers and 70.3% among BC-affected patients. Younger patients received genetic testing with significantly shorter intervals between BC diagnosis and genetic testing and between genetic testing and RRSO. CONCLUSION: Overall, the insurance coverage for HBOC patients with BC has increased the frequency of RRSO in Japan. However, a comparison between the number of probands and family members indicated that the diagnosis among family members is inadequate. The inequality in the use of genetic services by socioeconomic groups is an issue of further concern.

Impact of the coverage of risk-reducing salpingo-oophorectomy by the national insurance system for women with BRCA pathogenic variants in Japan.

To determine the impact of the coverage of risk-reducing salpingo-oophorectomy (RRSO) and mastectomy (RRM) as well as genetic testing for BRCA pathogenic variants by the national insurance system in Japan. We compared the clinical background of women who underwent RRSO at our institution before and after its coverage by the national insurance system. Those who underwent RRSO between January 2017 and December 2019 and between April 2020 and March 2022 were classified as Period. A and B, respectively. Overall, 134 women underwent RRSO during the study period. In Period A and B, 45 and 89 women underwent RRSO for the study period was 36 and 24 months, respectively. Compared with Period A, the number of women who underwent RRSO per month increased by threefold in Period B (p < 0.01). In addition, the number of women who underwent surgery for breast cancer along with RRSO increased in Period B (p < 0.01). Although the number of women who underwent concurrent RRM with RRSO in Period B increased, the difference was not statistically significant. Compared with Period A, the number of women diagnosed with BRCA pathogenic variant increased by 3.9-fold, and the proportion of women who underwent concurrent hysterectomy at the time of RRSO decreased from 66 to 7.9% in Period B (p < 0.01). Owing to the introduction of the national insurance system, the number of women who underwent RRSO and concurrent surgery for breast cancer at the time of RRSO increased in Japan.

Detection of BRCA1 Pathogenic Variant in a 24-Year-Old Endometrial Cancer Patient: Risks of Several Hereditary Tumor Syndromes Assessed Using Germline Multigene Panel Testing.

A 24-year-old woman suspected of Lynch syndrome was found to carry a BRCA1 pathogenic variant, based on germline multigene panel testing (MGPT). The patient was diagnosed with endometrial carcinoma and underwent modified radical hysterectomy, bilateral salpingo-oophorectomy, pelvic lymphadenectomy, and omentectomy at the age of 23. Based on her father's history of colorectal cancer and her history of early onset endometrial cancer, mismatch repair protein immunohistochemistry analysis was performed. However, no loss of expression for mismatch repair proteins was found. Given her family history of ovarian and breast cancers, MGPT was recommended to identify the presence of any hereditary tumor syndromes. This testing revealed a BRCA1 pathogenic variant (exon13: c.1016delA, p.Lys339ArgfsX2) and diagnosed as hereditary breast and ovarian cancer syndrome (HBOC). Subsequently, the patient's mother also underwent single-site analysis for this variant, and the same pathogenic variant was detected. The patient and her mother are at high risk of developing BRCA1-associated HBOC-related cancers. Based on family history, clinical surveillance is currently underway for this patient and her mother. Currently, MGPT offers the potential for comprehensive genetic cancer risk assessment and may provide a more rational approach for the genetic assessment of those individuals whose personal and family cancer histories do not fit neatly into a single syndrome. This case suggests that if a patient is at high risk for hereditary tumor syndromes, MGPT should be considered to improve disease management strategies in clinical settings.

The effect of an experiential learning program on motivations and activity involvement among dementia supporters in Japan.

PURPOSE: The purpose of this study was to examine the effectiveness of an experiential learning program based on Kolb's theory in increasing dementia supporters' motivation and activity involvement within the community. METHOD: In this interventional study, the sample was divided into two groups. The intervention group underwent dementia supporter training and participated in an experiential learning program, which was conducted two weeks after the initial training session. The control group underwent only the dementia supporter training. RESULTS: Kolb's experiential learning model consists of four stages: concrete experience, reflective observation, conceptualization, and active experimentation. A total of 37 and 44 individuals constituted the intervention and control groups, respectively. The Wilcoxon signed-rank test revealed that there was a significant increase in motivation among the intervention group participants, when compared to the control group participants. Moreover, the activity rate was higher among the intervention group participants. DISCUSSION: The experiential learning program was effective in increasing motivation levels and activity involvement among the dementia supporters. CONCLUSIONS: The experiential learning program for dementia supporters can be used to improve other volunteer and professional programs. Moreover, Kolb's theory can be used to support individuals with dementia within the community.

Outcome of the fetuses with severely increased nuchal translucency thickness in the first trimester.

AIM: To study the outcome of pregnancies with severely increased nuchal translucency (NT) thickness at the 11-13-week scan. METHODS: This study included 162 singleton pregnancies whose fetuses had increased NT thickness ≥ 5.5 mm between September 2013 and August 2018. The cases were divided into two groups: NT ≥ 6.5 mm (n = 112) (group A); and 6.5 mm > NT ≥ 5.5 mm (n = 50) (group B). Fetal (amniotic fluid) or placental (chorionic villous) chromosome analyses were conducted. Subsequent ultrasound findings, pregnancy outcome and structural defects in the neonates were recorded and analyzed. RESULTS: Abnormal karyotype was found in 71% (60/84) (group A) and 57% (21/37) (group B) of the cases respectively. In group A, 15 cases out of 24 with normal karyotype were born. Among these 15 cases, one case died soon after birth and 5 cases had associated abnormalities. In group B, 13 cases out of 18 with normal karyotype or negative noninvasive prenatal testing results and 1 case out of 2 cases with 47,XXY were born. All of them survived with no major anomaly. CONCLUSION: Incidence of chromosomal aberrations was high in the cases with severely increased NT thickness. But favorable outcome could be expected if the fetus had no chromosomal abnormality and no abnormal findings were found in second trimester ultrasound scan especially in a fetus with increased NT < 6.5 mm.

The reliability and validity of the Japanese version of the Levels of Emotional Awareness Scale (LEAS-J).

BACKGROUND: The Levels of Emotional Awareness Scale (LEAS) was developed to assess five levels of emotional awareness: bodily sensations, action tendencies, single emotions, blends of emotion, and combinations of blends. It is a paper and pencil performance questionnaire that presents 20 emotion-evoking scenes. We developed a Japanese version of the LEAS (LEAS-J), and its reliability and validity were examined. METHODS: The LEAS-J level was independently assessed by two researchers who scored each response according to the LEAS scoring manual. High inter-rater reliability and internal consistency were obtained for the LEAS-J. Measures were socioeconomic status, LEAS-J, Toronto Alexithymia Scale-20 (TAS-20), Interpersonal Reactivity Index (IRI), and NEO Five-Factor Inventory (NEO-FFI). TAS-20, IRI and NEO-FFI were the measures used to explore the construct validity of LEAS-J, as it was predicted that higher scores on the LEAS-J would be related to fewer alexithymic features, greater empathetic ability, and a greater sense of cooperation with others. Questionnaires were completed by 344 university students. RESULTS: The criterion-referenced validity was determined: a significant negative relationship was found with the externally-oriented thinking scores of TAS-20, and positive relationships were found with fantasy, perspective taking, and empathic concern on IRI and with extraversion, openness to experience, and agreeableness on NEO-FFI. CONCLUSIONS: Consistent with our expectations, the findings provide evidence that the LEAS-J has good reliability and validity. In addition, women had significantly higher scores than men on LEAS-J, showing that the gender difference identified in the original LEAS was cross-culturally consistent.

Structure-activity relationship of an antibacterial peptide, maculatin 1.1, from the skin glands of the tree frog, Litoria genimaculata.

Maculatin 1.1 (Mac) is a cationic antibacterial peptide isolated from the dorsal glands of the tree frog, Litoria genimaculata, and has a sequence of GLFGVLAKVAAHVVPAIAEHF-NH2. A short peptide lacking the N-terminal two residues of Mac was reported to have no activity. To investigate the structure-activity relationship in detail, several analogs and related short peptides of Mac were synthesized. CD measurement showed that all the peptides took more or less an alpha-helical structure in the presence of anionic lipid vesicles. Analogs which are more basic than Mac had strong antibacterial and hemolytic activities, while short peptides lacking one or two terminal residues exhibited weak or no activity. Outer and inner membrane permeabilization activities of the peptides were also reduced with shortening of the peptide chain. These results indicate that the entire chain length of Mac is necessary for full activity, and the basicity of the peptides greatly affects the activity.