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Background: Risk-reducing mastectomy is one option for women with hereditary breast and ovarian cancer to reduce the risk of breast cancer., Patients and Methods: We analyzed data of the Japanese Organization of Hereditary Breast and Ovarian Cancer on women who were diagnosed as hereditary breast and ovarian cancer by BRCA germline genetic testing between 2010 and 2019 to reveal the rate and likelihood of risk-reducing mastectomy., Results: There were 412 women with BRCA1, 271 with BRCA2 and 4 with both female pathogenic variants. Ninety (13.1%) received risk-reducing mastectomy. The rates of risk-reducing mastectomy were statistically significantly higher in women with BRCA1 pathogenic variants than BRCA2, in women who had breast cancer than those who did not, in women with a breast cancer family history than in those without, in mothers than in those without children, in women who were receiving surveillance with MRI than those who were not and in women who received risk-reducing salpingo-oophorectomy than in those who did not on univariate analyses. The ages when they received the genetic testing were statistically significantly younger in the women receiving risk-reducing mastectomy than those who did not receive it. The women with BRCA1 pathogenic variants, personal history of breast cancer, mothers, those receiving MRI surveillance and younger women were independently significantly more likely to receive risk-reducing mastectomy based on multivariate analysis., Conclusions: The rate of risk-reducing mastectomy was not high in Japan; however, risk-reducing surgery was approved by the Japanese National Medical Insurance for hereditary breast and ovarian cancer patients with breast and/or ovarian cancer in 2020, so this rate will increase., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In the global phase III IMpassion031 study, neoadjuvant atezolizumab plus nab-paclitaxel/anthracycline-based chemotherapy improved pathological complete response in patients with early stage triple-negative breast cancer. Here, we report primary analysis results from a subgroup of Japanese patients., Methods: Patients with histologically documented, previously untreated, stage cT2-cT4, cN0-cN3, cM0 triple-negative breast cancer were randomized 1:1 to receive intravenous atezolizumab 840 mg or placebo every 2 weeks in combination with chemotherapy consisting of nab-paclitaxel intravenous 125 mg/m2 once a week, followed by doxorubicin intravenous 60 mg/m2 and cyclophosphamide intravenous 600 mg/m2 every 2 weeks. Patients then underwent surgery. Pathological complete response (ypT0/is ypN0) in the intention-to-treat and PD-L1-positive (≥1% PD-L1-expressing tumor-infiltrating immune cells) populations were co-primary endpoints., Results: This subanalysis (data cutoff: 3 April 2020) included 36 patients from Japan (intention-to-treat; atezolizumab arm, n = 17; placebo arm, n = 19). Pathological complete response occurred in 41% (n = 7; 95% confidence interval, 18-67) of patients in the atezolizumab arm and 37% (n = 7; 95% confidence interval, 16-62) in the placebo arm. In the PD-L1-positive population, pathological complete response occurred in 50% (n = 5; 95% confidence interval, 19-81) of patients in the atezolizumab arm and 45% (n = 5; 95% confidence interval, 17-77) in the placebo arm. Treatment-related grade 3-4 adverse events occurred in 71% and 68% of patients in the respective arms., Conclusion: Atezolizumab added to neoadjuvant chemotherapy numerically improved pathological complete response versus placebo in this small exploratory analysis of Japanese patients with early stage triple-negative breast cancer, a trend directionally consistent with the global study results. No new safety signals were identified., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: It is critical to obtain informed consent from eligible patients to complete clinical trials. We investigated the factors that affect the participation rates of eligible patients., Patients and Methods: Patients with metastatic breast cancer who were eligible for SELECT BC or SELECT BC-CONFIRM trials, randomized controlled trials conducted for patients with chemotherapy-naive metastatic breast cancer were recruited to prospective studies, SELECT BC-FEEL and SELECT BC-FEEL II, respectively. SELECT BC FEEL and SELECT BC-FEEL II were conducted to identify the factors affecting the rates at which informed consent was obtained, using a self-administered questionnaire we developed., Results: In total, 232 patients participated in the studies. The patients who agreed to take part in the randomized trials were more likely than the refusers to answer that they decided to participate because: 'My doctor wanted me to participate in this trial' (P = 0.00000), ' My family or friends wanted me to participate in this trial' (P = 0.00000), 'Both treatment regimens used in the trial are suitable to me' (P = 0.00383), 'I know that the trial is conducted to determine which is a better treatment' (P = 0.01196), and ' I think that my participation in the trial will contribute to the benefit to future patients with the same disease' (P = 0.00756)., Conclusions: To enhance the consent rate in randomized trials of metastatic breast cancer patients, concepts of the trials must be considered important and acceptable not only by patients but also by doctors and their families., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The primary purpose of this large cohort study is to investigate the effects on breast cancer outcomes of modifiable lifestyle factors after breast cancer diagnosis. These factors include physical activity, smoking, alcohol consumption, obesity and weight gain after diagnosis, alternative medicine and dietary factors. Women diagnosed with Stage 0 to III breast cancer are eligible for participation to this study. Lifestyle, use of alternative medicine, psychosocial factors, reproductive factors and health-related quality of life will be assessed using a questionnaire at the time of breast cancer diagnosis (baseline), and 1, 2, 3 and 5 years after diagnosis. Clinical information and breast cancer outcomes will be obtained from a breast cancer database. The primary endpoint will be disease-free survival. Secondary endpoints are overall survival, health-related quality of life, breast cancer-related symptoms and adverse events. Patient recruitment commenced in February 2013. Enrollment of 2000 breast cancer patients is planned during the 5-year recruitment period. The concept of the study is described in this article., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

To accelerate the completion of clinical trials, it is critical to obtain, at high rates, informed consent to participate from patients who are eligible. It is therefore important to know what factors affect the participation rates of eligible patients. Selection of effective chemotherapy for breast cancer and its successor selection of effective chemotherapy for breast cancer-CONFIRM are randomized controlled trials conducted for Japanese patients with chemotherapy-naïve metastatic breast cancer. These trials are intended to compare the current standard chemotherapeutic regimens in the first-line setting, which are taxanes for selection of effective chemotherapy for breast cancer and anthracyclines for selection of effective chemotherapy for breast cancer-CONFIRM, respectively, and an oral regimen of TS-1 in terms of overall survival. We are conducting prospective studies to identify the factors affecting the rates at which informed consent is obtained in selection of effective chemotherapy for breast cancer and breast cancer-CONFIRM. We are using a self-administered questionnaire that we have developed to collect information regarding patients' characteristics and attitude to clinical trials., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: The 7-year follow-up of the US oncology 9735 trial demonstrated the superiority of TC [docetaxel (DTX)/cyclophosphamide (CPA)] to doxorubicin/CPA therapy. To introduce TC therapy in Japan, the verification of the safety and tolerability is essential. We performed a collaborative prospective safety study with Okayama University to introduce TC therapy., Methods: The subjects were 53 patients aged from 33 to 67 years at intermediate risk based on the St Gallen risk classification who underwent radical surgery for primary breast cancer between August 2007 and December 2008. As post-operative adjuvant chemotherapy, four cycles of TC (DTX 75 mg/m(2) + CPA 600 mg/m(2)) were administered at 3-week intervals. Adverse events were evaluated based on National Cancer Institute-Common Terminology Criteria for Adverse Events ver. 3.0. The safety and completion rate were evaluated as the primary and secondary endpoints, respectively., Results: Regarding hematological toxicity, Grade (G) 4 neutropenia occurred in 71.7% and G3 in 26.4%. G3-4 leukopenia developed in 32.1% and 56.6%, respectively, G4 anemia in 1.9% and G1-2 anemia in 26.4%. Regarding non-hematological toxicity, systemic malaise, skin eruption, edema, myalgia, arthralgia and nausea were noted in most patients. The completion rate was 94.3%, dose reduction was necessary in 7.5% and granulocyte colony-stimulating factor (G-CSF) support was required in 17.0%. On comparison between patients aged 65 years or older and younger than 65 years, the completion rate, dose reduction and incidence of febrile neutropenia (FN) were higher in the elderly patients. G-CSF support was more often needed in this subgroup., Conclusions: TC therapy is tolerable for Japanese patients, but attention should be paid to the development of FN and neutropenia. The completion rate was lower in the elderly patients, showing that tolerability was not necessarily favorable.

Objective: To determine if health-related quality-of-life (QOL) differences existed between breast cancer (BC) survivors receiving mastectomy and those receiving breast-conserving treatment (BCT). Factors associated with QOL in long-term BC survivors were also identified., Methods: One hundred patients who had previously undergone BC surgery and were alive without recurrence for >5 years were asked to answer the patient-administered questionnaires to assess their QOL (Functional Assessment of Cancer Therapy scale-Breast: FACT-B) and psychological distress (Hospital Anxiety and Depression Scale: HADS). Of them, 93 responded to the questionnaires affirmatively., Results: Although none of the QOL scores were related to the surgical procedures, statistically significant relationships were found between age and the scores of FACT-General and social/family well-being (SWB), and between the educational status and scores of SWB in univariate analyses. There was no statistically significant relationship between psychological distress and each factor examined. In multivariate analyses, significant correlations were established between scores of the FACT-BC subscale (FACT-BCS) and the type of surgery and between those on the FACT SWB subscale and age at study or educational status. Namely, patients who had undergone BCT, younger patients and patients with higher educational background scored higher QOL., Conclusions: Among the BC survivors, those who underwent BCT experienced significantly but slightly better QOL than those who received mastectomy in FACT-BCS assessments. Younger patients and patients with higher educational backgrounds experienced significantly better SWB.

Objective: Sentinel node biopsy (SNB) is indicated for axillary lymph node metastasis-negative cases (N0), but clarification of the indication may increase treatment efficiency. Fluorine-18-labeled 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) may have a high positive predictive value in diagnosis of axillary lymph node metastasis., Methods: Ninety-two breasts/axillae were analyzed retrospectively in 90 patients (median age 54.6-year old, median primary tumor 1.7 cm). FDG-PET/computed tomography was used to indicate SNB in N0 cases. Axillary lymph node dissection (ALND) was performed in cases that were axillary lymph node metastasis-positive (PET N+) on FDG-PET/CT., Results: Seventy-four (80.4%) and 18 (19.6%) of the 92 axillae were diagnosed as metastasis-negative (PET N0) and PET N+, respectively, by FDG-PET/CT. SNB was performed in 51 of the 74 PET N0 axillae. ALND was performed in 23 PET N0 axillae (at the patients' request) and in all 18 PET N+ axillae. Of the 74 PET N0 axillae, 14 were metastasis-positive (pN+) and 60 were pN0 pathologically, and of the 18 PET N+ axillae, 13 were pN+ and five were pN0. The sensitivity and specificity of FDG-PET/CT for diagnosis of axillary metastasis were 48.1 and 92.3%, respectively, and the positive and negative predictive values were 72.2 and 81.1%, respectively., Conclusion: The positive detection rate on FDG-PET/CT was insufficient for determining an indication of SNB. However, use of an appropriate cut-off for SUV(max) (the positive rate was 90.9% with a cut-off of 2.0) and exclusion of surgically biopsied cases may achieve a clinically applicable positive detection rate.

Objective: Since there is now growing interest in the incorporation of patient-reported outcome measures in cancer clinical trials, a patient-based questionnaire, the Patient Neurotoxicity Questionnaire (PNQ) was developed to quantify the symptoms and severity of chemotherapy-induced peripheral neuropathy (CIPN). The aim of this study was to evaluate the physicians' perspectives regarding the utility and diagnostic value of PNQ., Methods: A questionnaire was sent to 61 physicians who participated in a Phase III randomized trial of adjuvant chemotherapy in breast cancer (AC followed by taxane versus taxane alone) that used the PNQ to assess CIPN., Results: Forty-seven out of 61 physicians (77%) responded. The majority considered neurosensory symptoms the diagnostic hallmark for CIPN and most regarded interference with activities of daily living (ADLs) as definite justification for treatment modifications. For neurosensory disturbance, the majority of physicians indicated that Grade D severity (moderate to severe symptoms interfering with ADLs) should result in treatment postponement and Grade E severity (severe symptoms preventing most ADLs) should result in treatment discontinuation. Similarly, for neuromotor disturbance, over half of the physicians replied that Grade C (moderate symptoms not interfering with ADLs), D and E severity should result in dose reduction, treatment postponement and treatment discontinuation, respectively. Eighty-four percentage of the physicians reported that the use of the PNQ was helpful in the diagnosis and assessment of patients at risk of CIPN., Conclusions: The PNQ appears to be a useful instrument for the diagnosis and grading of CIPN, as well as for clinical decision-making regarding treatment modifications secondary to CIPN.

Background: Magnetic resonance imaging mammography is performed to determine the extent of lesions and to detect occult lesions, but preoperative diagnosis by breast computed tomography (CT) is less common., Methods: We performed a retrospective study of detection of mammographically occult multiple lesions using breast CT. The subjects were 407 female patients (median age: 56 years old; median tumor size: 1.9 cm) with breast cancer who underwent preoperative, contrast-enhanced breast CT., Results: CT detected 73 incidental-enhanced breast nodules (median size: 0.8 cm) in 73 patients that were undetectable by conventional methods. Age, size of the main lesion or laterality of lesions did not differ between patients with and without incidental nodules, but the frequency of mastectomy was significantly higher in those with incidental nodules. Of the 73 incidental nodules, 22 (30%) were in the same quadrant as the main lesion, 26 (36%) were in other quadrants and 25 (34%) were in the opposite breast. On qualitative diagnosis by CT, 48 were suspected to be malignant (66%), 17 benign (23%) and eight non-specific (11%). In histological evaluation of 44 of the 48 nodules suspected to be malignant, 24 were malignant (invasive carcinoma: 22, non-invasive carcinoma: 2); of seven of the 17 nodules suspected to be benign, all were benign; and of three of the eight non-specific nodules, one was non-invasive carcinoma. The discovery rate of clinically and mammographically occult multiple lesions by preoperative breast CT was 6%., Conclusion: We conclude that breast CT is useful for the detection of occult lesions and choice of surgical procedure.

Background: The local recurrence rate of phyllodes tumors is high and ensuring a sufficient surgical margin is considered important for local control. However, the preoperative diagnosis rate of phyllodes tumors is low and we often encounter cases in which a sufficient surgical margin is not achieved, since in routine medical practice the lesion may not be diagnosed as phyllodes tumor until postoperative biopsy of a mammary mass. Furthermore, there are no established therapeutic guidelines for surgical stump-positive phyllodes tumors. We reviewed the outcomes of excision of phyllodes tumors to investigate factors involved in local recurrence and to determine the indication for re-excision in stump-positive cases., Methods: The subjects were 45 patients treated for phyllodes tumors at our institution from January 1980 to July 2005. Age, tumor size, surgical method, stromal cellular atypia, mitotic activity, stromal overgrowth, histological classification and surgical stump status were analyzed., Results: Median age was 45 years old (range 28-75) and tumor size was 1-17 cm (median 3.5 cm). Pathologic diagnoses were benign, borderline and malignant in 31, five and nine cases, respectively, and the surgical stump was negative in 27 lesions and positive in 15. Median follow-up was 101 months (range 1-273), with local recurrence in six cases and distant metastasis in one. The local recurrence-free rate was 88, 88 and 84% and the disease-free rate was 85, 85 and 81% after 5, 10 and 15 years, respectively. Overall 10-year survival was 97%. In univariate analysis, a positive surgical margin, stromal overgrowth and histological classification were predictive factors for local recurrence after breast-conservation surgery (P = 0.0034, 0.0003, 0.026). A positive surgical stump was the only independent predictor of local recurrence in multivariate analysis (RR 0.086; 95% CI 0.01-0.743, P = 0.012). Stromal overgrowth was a predictive factor for local recurrence in cases with a positive surgical margin (P = 0.0139)., Conclusion: Wide excision is the preferred therapy for phyllodes tumor and preoperative diagnosis is important for good local control. Re-excision is recommended in cases with a positive surgical margin and stromal overgrowth and malignancy.

Background: Seroma is a common problem in breast surgery. The aim of this systematic review was to identify risk factors for seroma formation., Methods: Articles published in English were obtained from searches of Medline and additional references were found in the bibliographies of these articles. Risk factors were graded according to the quality and strength of evidence and to the direction of association., Results: One meta-analysis, 51 randomized controlled trials, 7 prospective studies and 7 retrospective studies were identified. There was no risk factor supported by strong evidence, but there was moderate evidence to support a risk for seroma formation in individuals with heavier body weight, extended radical mastectomy as compared with simple mastectomy, and greater drainage volume in the initial 3 days. On the other hand, the following factors did not have a significant influence on seroma formation: duration of drainage; hormone receptor status; immobilization of the shoulder; intensity of negative suction pressure; lymph node status or lymph node positivity; number of drains; number of removed lymph nodes; previous biopsy; removal of drains on the fifth postoperative day versus when daily drainage volume fell to minimal; stage; type of drainage (closed suction versus static drainage); and use of fibrinolysis inhibitor. In contrast, sentinel lymph node biopsy reduced seroma formation. Evidence was weak, or unproven, for other factors that were commonly cited in the literature., Conclusions: Although a number of factors have been correlated with seroma formation, strong evidence is still scarce. However, there is evidence showing that sentinel lymph node biopsy reduces seroma formation.

Background: Although many clinical data regarding breast-conserving treatment have already been reported from European and North American countries, few clinical data with long-term follow-up have been reported from Japan., Method: We collected information on therapeutic and possible or developed prognostic factors and follow-up data for Japanese women who had received breast-conserving treatment consisting of wide excision of the primary tumor, axillary dissection and radiotherapy for unilateral breast cancer considered suitable for breast-conserving treatment from 18 Japanese major breast cancer treating hospitals; 1561 patients were registered., Results: The median follow-up period was 77 months. Five-year disease-free and overall survival rates were 89.4 and 95.9%, respectively. The 5-year local recurrence-free rate was 96.3%. The patients with histologically positive margins (P < 0.0001) or estrogen receptor negative tumor (P = 0.0340) or younger than 40 years old (P < 0.0001) developed statistically significantly more local recurrences. Adjuvant endocrine therapy was essential for the estrogen receptor positive patients to have a lower local recurrence rate. Endocrine therapy did not change the local recurrence rate among estrogen receptor negative patients at all. Multivariate analysis showed histological margin status and the combination of estrogen receptor status and endocrine therapy were independent prognostic factors for local recurrence., Conclusion: The 5-year local recurrence rate of Japanese breast cancer patients who were treated with breast-conserving treatment using radiotherapy was 3.7%. Independent prognostic factors for local recurrence were histological margin status and the combination of estrogen receptor status and adjuvant endocrine therapy.

Background: It is planned to start screening mammography throughout Japan in the near future. However, a minimally invasive biopsy procedure for mammographically detected non-palpable breast lesions is not available in almost all Japanese hospitals. It is crucial to develop a useful minimally invasive biopsy method which can be applied without difficulty., Methods: Eighty-nine biopsies for 88 mammographically detected non-palpable breast lesions, consisting of 70 lesions with microcalcifications alone, eight masses without calcifications and 10 with both masses and microcalcifications, were performed using the combination of a vacuum-assisted biopsy device (Mammotome) and an upright-type stereotactic mammography unit., Results: Microcalcifications were confirmed radiographically in the tissue obtained from 78 biopsies among 81 biopsies for the lesions with microcalcifications (96.3%). All the lesions without calcifications were considered to be biopsied successfully. Five patients complained of nausea or fainted during the localization or biopsy procedure and an additional patient suffered from hyperventilation syndrome. Five cases experienced mild subcutaneous bleeding in the breasts., Conclusions: The biopsy technique using the combination of a vacuum-assisted biopsy device and an upright-type stereotactic mammography unit is a cost-effective, safe and very useful method for mammographically detected non-palpable breast lesions. It is expected to be a standard method of biopsy for such lesions in many developed countries other than the USA. However, it is important to make the patients relaxed during the biopsy to prevent mental strain.

Minke whale (Balaenoptera acutorostrata) follicular oocytes were cryopreserved by a slow-step freezing procedure using ethylene glycol. The morphologically viable proportion of postthawed minke whale follicular oocytes was 39.7%. The maturity of the animals (immature and mature whales) or the presence or absence of cumulus cells (CC) did not affect the proportion of morphologically viable oocytes. Postthawed oocytes were examined for nuclear status after in vitro maturation. The presence of CC (29.1%) significantly enhanced (P < 0.05) the proportion of oocytes at metaphase I/anaphase I/telophase I stages compared to results with the absence of CC (13.5%). A total of 4 of 194 postthawed oocytes matured to the second metaphase stage after culture for 5.5 days with or without CC. The cryopreserved immature oocytes obtained from immature and mature whales were processed to examine the ultrastructure by transmission electron microscopy. Varying ultrastructural damage to the cytoplasm was observed as a result of the cryopreservation procedures. These results show that 20-30% of cryopreserved minke whale follicular oocytes can resume meiosis in vitro, but damage induced by the freezing and thawing procedures was observed.

Factors affecting in vitro maturation (IVM) of minke whale (Balaenopetra acutorostrata) follicular oocytes were investigated. In experiment 1, recovery rates for oocytes from follicles of different sizes (small, 1-5 mm; medium, 6-10 mm; large, > or = 11 mm) were similar in both immature (54.7%) and mature (53.5%) females, and the follicular sizes did not affect recovery rate. Approximately half the oocytes recovered from small follicles in immature (55.5%) and mature (52.1%) whales were surrounded by at least a few layers of cumulus cells. Before culture, 71.7% and 61.2% of oocytes from immature and mature whales, respectively, were at the germinal vesicle stage. For IVM, effects of serum type, hormones, and additional cumulus cells (experiment 2) and effects of culture durations (24-120 h, experiment 3) were investigated. The three factors investigated in experiment 2 did not affect maturation rates. TCM199 supplemented with fetal whale serum, hormones, and additional cumulus cells showed the highest rate (21.6%) of matured oocytes and resulted in a significant difference from the rate in medium with only fetal calf serum added (6.6%). The first oocyte with an extruded polar body was observed after 84 h of culture. The maximum rate (27.3%) of matured oocytes was obtained by 96 h of culture, but there was no significant difference in the proportions of matured oocytes between 90 and 120 h in culture. These results indicate that in vitro nuclear maturation of immature follicular oocytes in minke whales can be induced.

Products formed from defined oligodeoxyribonucleotide tetramers (oligonucleotides) by depurination at pH 5.0 and 90 degrees C followed by chain breakage at the resulting apurinic sites (AP sites) were assigned by reversed phase HPLC. Through kinetic analysis, rate constants of depurination and subsequent chain breakage reactions were measured. Depurination of the oligonucleotides with purine bases locating at the terminal positions was several times faster than those with purines at the internal ones. The pKa values for the N7 of the G residues and the activation energies of the depurination were essentially independent of the position of the bases. The frequency factor was found to be responsible for the observed difference of the depurination rates. In contrast, the chain breakage by beta-elimination was several times faster for the AP sites formed at the internal positions than those at the 5'-terminal positions. It is suggested that an electron withdrawing phosphate group attached to the 5'-side of an AP site facilitates the chain cleavage.

A strong NOESY cross peak was observed between G1H8 and G4H8 for a single-stranded tetradeoxyoligonucleotide dGTTG in aqueous solution. If dGTTG is in an expanded form, NOE should not be observed because the distance between G1H8 and G4H8 is estimated to be about 13 A. This NOESY cross peak shows that the guanine residues of the both ends of dGTTG exist with short distance (< 5 A), and that dGTTG has a distorted loop-like structure in aqueous solution. This is the shortest single-stranded oligodeoxynucleotide that has a rigid structure in solution.