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Objective: Anaplastic thyroid carcinoma (ATC) is considered a very aggressive carcinoma and has been difficult to treat with therapeutic strategies. This study examines the landscape of genomic alteration in ATC, including the BRAF V600E mutation, and its clinical implications., Design, Patients and Mesurement: A retrospective observational study was conducted using collected at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan, utilizing comprehensive genomic profiling data from 102 ATC cases. Additionally, AACR-GENIE data from 267 cases were analysed for validation. Statistical methods, including the conditional Kendall tau statistic and χ 2 tests, were employed for survival analysis and gene mutation comparisons., Results: Among 102 ATCs, BRAF, RAS, and other driver mutations were found in 83 cases (81.2%). The prevalence of BRAF V600E mutations was as high as 60%. Co-mutation analysis identified different genomic profiles in the BRAF, RAS, and wild-type groups. Despite the diverse molecular backgrounds, no significant differences in clinical variables and overall survival were observed. The analysis considering left-side amputation suggested that RAS mutations had a poorer prognosis. In the BRAF/RAS wild-type group, FGFR1 and NF1 were identified as driver mutations, with an accumulation of copy number variations and less TERT promoter mutations. This molecular subgrouping was also supported by the AACR-GENIE data., Conclusions: Comprehensive genomic analysis of ATC in Japan revealed distinct molecular subgroups, highlighting the importance of BRAF V600E mutations, particularly V600E, as potential therapeutic targets and suggest the relevance of tailor-made therapeutic strategies based on genomic profiling., (© 2024 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)

In Japan, comprehensive genomic profiling (CGP) tests have been reimbursed under the national health care system for solid cancer patients who have finished standard treatment. More than 50,000 patients have taken the test since June 2019. We performed a nation-wide questionnaire survey between March 2021 and July 2022. Questionnaires were sent to 80 designated Cancer Genomic Medicine Hospitals. Of the 933 responses received, 370 (39.7%) were web based and 563 (60.3%) were paper based. Most patients (784, 84%) first learned about CGP tests from healthcare professionals, and 775 (83.1%) gave informed consent to their treating physician. At the time of informed consent, they were most worried about test results not leading to novel treatment (536, 57.4%). On a scale of 0-10, 702 respondents (75.2%) felt that the explanations of the test result were easy to understand (7 or higher). Ninety-one patients (9.8%) started their recommended treatment. Many patients could not receive recommended treatment because no approved drugs or clinical trials were available (102/177, 57.6%). Ninety-eight patients (10.5%) did not wish their findings to be disclosed. Overall satisfaction with the CGP test process was high, with 602 respondents (64.5%) giving a score of 7-10. The major reason for choosing 0-6 was that the CGP test result did not lead to new treatment (217/277, 78.3%). In conclusion, satisfaction with the CGP test process was high. Patients and family members need better access to information. More patients need to be treated with genomically matched therapy., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Stroke is a major cause of disability and mortality worldwide and requires long-term care, including rehabilitation. This study aims to elucidate the association between care-need levels after discharge and long-term outcomes in patients with stroke., Methods: We used a Japanese administrative database that covers both medical and long-term care insurance systems to retrospectively identify 7491 patients who underwent acute-phase in-hospital rehabilitation for stroke between June 2014 and February 2019. We investigated the association between nationally standardized care-need levels (support levels 1-2 and care-need levels 1-3) 6 months after discharge and long-term outcomes. Using the Fine-Gray model, we conducted multivariable survival analysis with adjustment for patient backgrounds and treatment courses to estimate hazard ratios (HR) for mortality and the incidence of being bedridden., Results: The median age was 82 (interquartile range [IQR], 76-87) years, 5418 patients (72%) had cerebral infarction, and 4009 patients (54%) had partial dependence after discharge. During a median follow-up of 580 (IQR, 189-925) days, 1668 patients (22%) became bedridden, and 2174 patients (29%) died. Compared with patients with support level 1, those with higher care-need levels showed significantly higher proportions of being bedridden-the subdistribution HR [95% confidence interval] were 1.52 [1.10-2.12], 2.85 [2.09-3.88], and 3.79 [2.79-5.15] in those with care-need levels 1, 2, and 3, respectively. Higher care-need levels were also significantly associated with higher mortality., Conclusions: This large-scale observational study demonstrated that a higher level of care-need after discharge was significantly associated with poorer functional outcomes and higher mortality., Competing Interests: Takaaki Konishi received grants from Pfizer Co. Ltd., Kanzawa Medical Research Foundation, and Japan Kampo Medicines Manufacturers Association outside the submitted work., (Copyright © Japan Medical Association.)

The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain-containing ion transport regulator 3 (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.

Mammography images contain a lot of information about not only the mammary glands but also the skin, adipose tissue, and stroma, which may reflect the risk of developing breast cancer. We aimed to establish a method to predict breast cancer risk using radiomics features of mammography images and to enable further examinations and prophylactic treatment to reduce breast cancer mortality. We used mammography images of 4000 women with breast cancer and 1000 healthy women from the 'starting point set' of the OPTIMAM dataset, a public dataset. We trained a Light Gradient Boosting Machine using radiomics features extracted from mammography images of women with breast cancer (only the healthy side) and healthy women. This model was a binary classifier that could discriminate whether a given mammography image was of the contralateral side of women with breast cancer or not, and its performance was evaluated using five-fold cross-validation. The average area under the curve for five folds was 0.60122. Some radiomics features, such as 'wavelet-H_glcm_Correlation' and 'wavelet-H_firstorder_Maximum', showed distribution differences between the malignant and normal groups. Therefore, a single radiomics feature might reflect the breast cancer risk. The odds ratio of breast cancer incidence was 7.38 in women whose estimated malignancy probability was ≥0.95. Radiomics features from mammography images can help predict breast cancer risk.

Background: Although functional outcomes are important in surgery for elderly patients, the long-term functional prognosis following oncologic surgery is unclear. We retrospectively investigated the long-term, functional and survival prognosis following major oncologic surgery according to age among elderly patients., Methods: We used a Japanese administrative database to identify 11,896 patients aged ≥ 65 years who underwent major oncological surgery between June 2014 and February 2019. We investigated the association between age at surgery and the postoperative incidence of bedridden status and mortality. Using the Fine-Gray model and restricted cubic spline functions, we conducted a multivariable, survival analysis with adjustments for patient background characteristics and treatment courses to estimate hazard ratios for the outcomes., Results: During a median follow-up of 588 (interquartile range, 267-997) days, 657 patients (5.5%) became bedridden and 1540 (13%) died. Patients aged ≥ 70 years had a significantly higher incidence of being bedridden than those aged 65-69 years; the subdistribution hazard ratios of the age groups of 70-74, 75-79, 80-84, and ≥ 85 years were 3.20 (95% confidence interval [CI], 1.53-6.71), 3.86 (95% CI 1.89-7.89), 6.26 (95% CI 3.06-12.8), and 8.60 (95% CI 4.19-17.7), respectively. Restricted cubic spline analysis demonstrated an increase in the incidence of bedridden status in patients aged ≥ 65 years, whereas mortality increased in patients aged ≥ 75 years., Conclusions: This large-scale, observational study revealed that older age at oncological surgery was associated with poorer functional outcomes and higher mortality among patients aged ≥ 65 years., (© 2023. The Author(s).)

Purpose: This study aimed to clarify the characteristics of post-traumatic growth (PTG) among adolescents having mothers diagnosed with breast cancer and the relationship between PTG and cancer-related communication with breast cancer survivors., Methods: A cross-sectional study was conducted using anonymous self-report questionnaires with breast cancer survivors and adolescent children. PTG in adolescents was measured using the Japanese version of the revised PTG Inventory for Children (PTGI-C-R-J). Furthermore, hierarchical multiple regression analysis was implemented. To evaluate the impact of cancer-related communication on each subscale, the total score of cancer-related communication was switched with other subscales individually within the constructed model., Results: A total of 97 breast cancer survivors and their adolescent children were included. The mean scores of the total PTGI-C-R-J and subscale scores for "personal strength," "new possibilities," "relating to others," "appreciation of life," and "spiritual change" were 9.0, 1.7, 1.8, 2.3, 2.4, and 0.9, respectively. The connection between PTG and cancer-related communication was partially clarified. The PTGI-C-R-J score was higher when adolescents shared more information regarding breast cancer with their mothers and lower when adolescents expressed more negative feelings toward their mothers. Communication regarding relationships with mothers was not correlated with PTG., Conclusions: Of all PTG domains, "relating to others" and "appreciation of life" were comparatively higher in adolescents. Health professionals should support breast cancer survivors to ensure that they convey appropriate information regarding their treatment plans and side effects to their adolescent children. Health professionals should help adolescent children express their negative feelings calmly and clearly., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Comprehensive genomic profiling (CGP) tests have been nationally reimbursed in Japan since June 2019 under strict restrictions, and over 46,000 patients have taken the test. Core Hospitals and Designated Hospitals host molecular tumor boards, which is more time-consuming than simply participating in them. We sent a questionnaire to government-designated Cancer Genomic Medicine Hospitals, including all 12 Core Hospitals, all 33 Designated Hospitals, and 117 of 188 Cooperative Hospitals. The questionnaire asked how much time physicians and nonphysicians spent on administrative work for cancer genomic medicine. For every CGP test, 7.6 h of administrative work was needed. Physicians spent 2.7 h/patient, while nonphysicians spent 4.9 h/patient. Time spent preparing for molecular tumor boards, called Expert Panels, was the longest, followed by time spent participating in Expert Panels. Assuming an hourly wage of ¥24,000/h for physicians and ¥2800/h for nonphysicians, mean labor cost was ¥78,071/patient. On a monthly basis, more time was spent on administrative work at Core Hospitals compared with Designated Hospitals and Cooperative Hospitals (385 vs. 166 vs. 51 h/month, respectively, p < 0.001). Consequently, labor cost per month was higher at Core Hospitals than at Designated Hospitals and Cooperative Hospitals (¥3,951,854 vs. ¥1,687,167 vs. ¥487,279/month, respectively, p < 0.001). Completing a CGP test for a cancer patient in Japan is associated with significant labor at each hospital, especially at Core Hospitals. Streamlining the exchange of information and simplifying Expert Panels will likely alleviate this burden., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on disease-free survival (DFS)., Patients and Methods: This prospective, randomized, multicenter open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients who were disease-free after treatment with either 5 years of anastrozole alone or 2-3 years of tamoxifen followed by 2-3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole for an additional 5 years or stop anastrozole. The primary end point was DFS, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with University Hospital Medical Information Network, Japan (UMIN) clinical trials registry (UMIN000000818)., Results: We enrolled 1,697 patients from 117 facilities between November 2007 and November 2012. Follow-up information was available for 1,593 patients (n = 787 in the continue group, n = 806 in the stop group), who were defined as the full analysis set, including 144 patients previously treated with tamoxifen and 259 patients who underwent breast-conserving surgery without irradiation. The 5-year DFS rates were 91% (95% CI, 89 to 93) in the continue group and 86% (95% CI, 83 to 88) in the stop group (hazard ratio, 0.61; 95% CI, 0.46 to 0.82; P < .0010). Notably, extended anastrozole treatment reduced the incidence of local recurrence (continue group, n = 10; stop group, n = 27) and second primary cancers (continue group, n = 27; stop group, n = 52). There was no significant difference in overall or distant DFS. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than those in the stop group, but the incidence of grade ≥3 adverse events was <1% in both groups., Conclusion: Continuing adjuvant anastrozole for an additional 5 years after 5 years of initial treatment with anastrozole or tamoxifen followed by anastrozole was well tolerated and improved DFS. Although no difference in overall survival was observed as in other trials, extended anastrozole therapy could be one treatment choice in postmenopausal patients with hormone receptor-positive breast cancer.

Introduction: Mastitis is the inflammation of the mammary gland that mainly occurs during the lactation period and requires antibiotic treatment with little evidence for its efficacy. We investigated the effect of the National Action Plan for antimicrobial resistance aiming for appropriate antimicrobial stewardship on broad-spectrum antibiotics administration for mastitis despite the lack of a disease-specific antimicrobial agents manual., Methods: Using a large nationwide database, an interrupted time-series analysis was performed using data from 34,340 female patients who received antibiotics for mastitis between April 2012 and March 2020. This study compared the trend of outcomes before and after the publication date of the National Action Plan (April 2016). The outcomes were the proportion of broad-spectrum and first-choice narrow-spectrum antibiotic administration and surgical drainage within 30 days after the administration., Results: Broad-spectrum antibiotics were administered in 70% of the cases before and 67% of the cases after the National Action Plan publication date. The trend of broad-spectrum antibiotics administration significantly changed at the publication (-2.6% [95% confidence interval, -3.9% to -1.3%], p < 0.001) and the administration decreased after the publication (1.9% annual decrease, P trend < 0.001). The trend of first-choice antibiotics administration also changed at the publication (1.3% [0.1-2.4%], p = 0.028) and the administration increased after the publication (1.3% annual increase, P trend < 0.001). The occurrence of surgical drainage was stable during the study period., Conclusion: Despite the lack of a disease-specific antimicrobial manual, the publication of the National Action Plan improved antimicrobial stewardship for mastitis without any impact on a surgical treatment course., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 by The Author(s). Published by S. Karger AG, Basel.)

Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent TOP as part of Advanced Medical Care B with approval from the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were carried out in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those 30 transcripts, 6 had treatment implications and 4 had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647)., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: Although parapharyngeal and retropharyngeal abscesses are potentially fatal deep neck abscesses, there is limited evidence for the treatment courses for adult patients with these abscesses. We aimed to describe the practice patterns and clinical outcomes of adult patients undergoing an emergency surgery for parapharyngeal or retropharyngeal abscesses using a nationwide database., Materials and Methods: We identified patients aged ≥18 years who underwent emergency surgery for parapharyngeal (para group, n = 1148) or retropharyngeal (retro group, n = 734) abscesses from July 2010 to March 2020, using a nationwide inpatient database. We performed between-group comparisons of the baseline characteristics, treatment course, and outcomes., Results: Compared with the retro group, the para group was more likely to be older (median, 66 vs. 60 years; P < 0.001) and have several comorbidities, such as diabetes (21 % vs 16 %; P = 0.010) and epiglottitis (33 % vs. 26 %; P = 0.002), except for peritonsillar abscess (14 % vs. 22 %; P < 0.001) and tonsillitis (2.1 % vs. 13 %; P < 0.001). Regarding intravenous drugs administered within 2 days of admission, approximately half of the patients received steroids, non-antipseudomonal penicillins, and lincomycins. The para group received more comprehensive treatments, such as tracheostomy, intensive care unit admissions, and swallowing rehabilitation, within total hospitalization than the retro group. Moreover, it demonstrated higher in-hospital mortality (2.7 % vs. 1.1 %; P = 0.017) and morbidity (16 % vs. 9.7 %; P < 0.001), and longer length of hospitalization than the retro group., Conclusion: The current nationwide study provided an overview of the characteristics, treatments, and outcomes for patients who underwent an emergency surgery for parapharyngeal or retropharyngeal abscess., Competing Interests: Conflict of interest The authors have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Pertuzumab and trastuzumab are monoclonal antibodies used for treating HER2-positive breast cancer. These anti-HER2 antibodies may induce infusion reactions (IR), mainly upon first administration. We investigated factors predicting IR in the initial pertuzumab treatment for HER2-positive breast cancer., Methods: We retrospectively reviewed the medical records of 57 patients who first received pertuzumab-containing treatment in our hospital from January 2014 to February 2021. The frequency of IR during or immediately after pertuzumab administration was examined. We also analyzed patient characteristics that may represent possible risk factors for IR., Results: The incidence rate of IR was 44% (25/57). Red blood cell count (P < 0.001), hemoglobin (Hb) concentration (P = 0.0011), and hematocrit (P < 0.001) immediately before pertuzumab administration were significantly lower in patients with IR than in those without. In patients with IR, erythrocyte levels immediately before pertuzumab treatment were significantly lower than baseline when having received anthracycline-containing chemotherapy within three months. Logistic regression analysis showed that a decrease in Hb levels was a significant risk factor for IR (log odds ratio = -17). According to the receiver-operating characteristic analysis, a 10% decrease in Hb after anthracycline-containing treatment was the best cut-off value for predicting IR (sensitivity: 88%; specificity: 77%; area under the curve: 0.87)., Conclusions: Our study showed a higher incidence of IR after pertuzumab treatment than in clinical trials. There was a strong association between IR occurrence and erythrocyte levels lower than baseline in the group that received anthracycline-containing chemotherapy immediately before., Competing Interests: None, (Copyright © Japan Medical Association.)

Background and study aims  Despite the widespread use of direct oral anticoagulants (DOACs), the association between DOAC use and complications (e. g., bleeding) following gastrointestinal endoscopic biopsy remains unclear. This study aimed to evaluate complications after biopsy in patients treated with DOACs in Japan, where biopsies would be generally performed without DOAC withdrawal based on guideline recommendations. Patients and methods  Using a Japanese nationwide database, we identified patients taking DOACs who underwent gastrointestinal endoscopic biopsy (n  = 2,769, DOAC group) and those not taking DOACs (n = 129,357, control group) from April 2015 to November 2020. We conducted 1:4 propensity score (PS) matching and overlap PS-weighting analyses with adjustment for background characteristics to compare occurrence of post-procedure hemorrhage and stroke within 1 week after biopsy, and thrombin use on the day of biopsy without a diagnosis of hemorrhage. Results  In total, 578 patients (0.44 %) developed post-procedure hemorrhage, and 13 patients (0.01 %) developed stroke. The DOAC group had more comorbidities than the control group. The PS matching analysis revealed no significant differences in post-procedure hemorrhage (odds ratio, 1.52 [95 % confidential interval, 0.96-2.41]) or stroke (1.00 [0.21-4.71]), whereas the DOAC group received thrombin more often than the control group (1.60 [1.30-1.95]). The results were equivalent in the overlap PS-weighting analysis. Conclusions  The PS analyses showed no significant differences in complications following gastrointestinal endoscopic biopsy between DOAC users and non-users. These results suggest the safety of endoscopic biopsy without DOAC withdrawal although the need for careful hemostasis remains., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Although arm lymphedema is a well-known complication following breast cancer surgery, previous studies involving a small population showed inconsistent results regarding the risk. Therefore, we examined the risk factors using a Japanese nationwide database., Methods: Female patients who underwent breast cancer surgery from April, 2016, to March, 2020, were identified from a Japanese nationwide database. Multivariable survival analyses for 19 baseline factors (12 patient characteristics, four tumor characteristics, and three surgical procedures) were conducted to investigate risk factors associated with treatments for postoperative lymphedema (such as lymphatic bypass, compositive drainage therapy, hospitalization, and Kampo use) with a multilevel model to adjust for within-hospital clustering. We also conducted multivariable analysis for five postoperative factors (two local complications and three postoperative therapies) with adjustment for 19 baseline factors., Results: The study included 84,022 patients; 1547 (1.8%) received treatments for lymphedema during a median follow-up of 119 weeks (interquartile range, 59-187 weeks). Young age, obesity, smoking, collagen diseases, advanced cancer stage, total mastectomy, axillary dissection, postoperative bleeding, chemotherapy, and radiotherapy were identified as risk factors. Postoperative chemotherapy (hazard ratio, 3.78 [95% confidence interval, 3.35-4.26]) and axillary dissection (2.46 [1.95-3.11]) showed the highest odds ratio among the risk factors. The cumulative probabilities in high-risk patients reached approximately 3% at 1 year and 6% at 4 years after surgery., Conclusions: This study identified several risk factors for postoperative lymphedema in breast cancer surgery. The treatment initiation increased markedly within the first year and gradually after 1 year post-surgery., (© 2022. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Background: Although postoperative bleeding is a common and serious complication in breast cancer surgery, the risk factors remain unclear. Therefore, we examined the risk factors using a Japanese nationwide database., Methods: Patients who underwent breast cancer surgery between July 2010 and March 2020 were identified from a Japanese nationwide database. Multivariable analyses for 47 candidate risk factors (4 patient characteristics, 32 comorbidities, 5 tumor characteristics, 3 preoperative drug uses, and 3 surgical procedures) were conducted to investigate risk factors associated with postoperative bleeding requiring reoperation. Two sensitivity analyses were conducted: an analysis for postoperative bleeding with or without reoperation and an analysis for patients who underwent total mastectomy without breast reconstruction., Results: Among the 477,108 patients included, 7048 (1.5%) developed postoperative bleeding and 2357 (0.5%) underwent reoperation for postoperative bleeding. Male sex, old age, body mass index ≥ 25.0 kg/m 2 , several comorbidities (deficiency anemia, cardiac arrhythmias, hypertension, liver disease, psychoses, and valvular disease), preoperative heparin use, and several procedures were identified as risk factors. Deficiency anemia showed the highest odds ratio among the risk factors (4.41 [95% confidence interval, 3.63-5.36]). High odds ratios were also observed in total mastectomy (2.32 [2.10-2.56]), flap reconstruction (1.93 [1.55-2.40]), and preoperative heparin use (1.64 [1.26-2.14]). The results corresponded with the sensitivity analyses., Conclusions: This study identified several risk factors for postoperative bleeding in breast cancer surgery, such as high body mass index, anemia, cardiovascular diseases, liver diseases, psychoses, preoperative heparin use, and surgical procedures., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: In elderly patients with human epidermal growth factor 2-positive breast cancer, adjuvant chemotherapy was associated with decreased quality of life, with relatively small benefits for prognosis. We examined the cost-effectiveness of trastuzumab monotherapy versus adjuvant chemotherapy plus trastuzumab in elderly patients with human epidermal growth factor 2-positive breast cancer., Methods: A Markov model was developed to evaluate the costs and benefits of trastuzumab monotherapy over adjuvant chemotherapy plus trastuzumab for elderly patients with human epidermal growth factor 2-positive breast cancer. We built the model with a yearly cycle over a 20-year time horizon and five health states: disease-free, relapse, post-relapse, metastasis and death. The parameters in the model were based on a previous randomized controlled trial and a nationwide administrative database in Japan. The incremental cost-effectiveness ratio, expressed as Japanese yen per the quality-adjusted life-years, was estimated from the perspective of health care payers. One-way deterministic sensitivity analysis and probabilistic sensitivity analysis with Monte-Carlo simulations of 10 000 samples were conducted., Results: The incremental cost-effectiveness ratio of trastuzumab monotherapy over adjuvant chemotherapy plus trastuzumab was $\sim$1.8 million Japanese yen /quality-adjusted life-year. The one-way deterministic sensitivity analysis showed that transition probability from disease-free to metastasis status and cost of metastasis status had the greatest influence on the incremental cost-effectiveness ratio. More than half the estimates in the probabilistic sensitivity analysis were located below a threshold of willingness-to-pay of 5 million Japanese yen /quality-adjusted life-year., Conclusion: In this first comparative cost-effectiveness analysis of adjuvant chemotherapy plus trastuzumab versus trastuzumab monotherapy in the elderly, the latter was found favorable for elderly patients with human epidermal growth factor 2-positive breast cancer., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Purpose: To evaluate the validity of operative information recorded in the Diagnosis Procedure Combination (DPC) database, a national inpatient database including administrative claims data., Methods: We reviewed the medical charts of 1221 patients who underwent one of six surgeries (breast, esophageal, gastric, thyroid cancer surgery, appendectomy, or inguinal hernia repair) at a surgery department of a university hospital from April 2016 to March 2019. We compared operative information (type, date, laterality of procedure; type of anesthesia; transfusion; and duration of anesthesia) recorded in the DPC database with the information recorded in the medical charts., Results: The DPC data for type, date, laterality of surgery, and type of anesthesia were accurate in 99% of the reviewed patients. The sensitivity and specificity for identifying whether a patient received a transfusion procedure were 97.5% and 99.6%, respectively. Data regarding the duration of anesthesia in the DPC database were identical to those in medical chart records in 1114 of 1216 cases that received general or spinal anesthesia (91.5%). The duration of anesthesia in the DPC data was 53 min longer on average than the recorded operative time in the medical charts., Conclusion: The DPC database had high validity for operative information., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Purpose: Although the incidence of breast cancer during pregnancy is increasing, little is known about short-term outcomes following breast cancer surgery during pregnancy. We aimed to compare the characteristics and outcomes of breast cancer surgery with and without pregnancy, and describe the obstetric outcomes following surgery., Methods: The data of 249,257 female patients aged < 60 years who underwent breast cancer surgery between July 2010 and March 2020 were analyzed using a nationwide Japanese database; we generated a 1:10 matched-pair cohort (260 and 2597 patients with and without pregnancy, respectively) matched according to age and treatment year. We conducted multivariable analyses to compare surgical procedures and outcomes, adjusting for potential confounders in the matched-pair cohort. Additionally, we described the obstetric outcomes of patients with pregnancy., Results: Patients with pregnancy were more likely to undergo total mastectomy [odds ratio: 1.48 (95% confidence interval: 1.13-1.94)] and axillary dissection [1.62 (1.17-2.24)], but less likely to undergo reconstruction [0.14 (0.07-0.31)], than patients without; however, postoperative complications, postoperative length of stay, and total hospitalization costs did not differ significantly with pregnancy. Additionally, some pregnant patients experienced premature delivery [n = 18 (6.9%)] and miscarriage [n = 4 (1.5%)], and 31 of 101 patients in the third trimester at breast cancer surgery underwent a cesarean section., Conclusion: This study demonstrated significant differences regarding surgical procedures; however, there were no significant differences regarding surgical outcomes between patients who underwent breast cancer surgery with and without pregnancy. Obstetric outcomes following breast cancer surgery were also reported., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Epithelioid hemangioendothelioma (EHE) is a rare and slow-growing malignant vascular neoplasm composed of epithelioid endothelial cells within a distinctive myxohyaline stroma. It most commonly involves somatic soft tissue, lungs, liver and bone. Herein, we describe a case of EHE arising in the axillary region., Case Presentation: A 61-year-old man was under observation for multiple hepatic hemangiomas. Fluorodeoxyglucose-positron emission tomography/computed tomography showed specific uptake in a right axillary tumor. The patient was referred to our department for further investigation of the axillary tumor. An elastic-soft and poorly mobile tumor was palpable in the right axilla. Contrast-enhanced computed tomography showed a right axillary tumor and enlarged hepatic hemangiomas. In addition, multiple nodules in both lungs, a left renal angiomyolipoma, and left adrenal adenoma were revealed. Ultrasonography showed masses in both lobes of the thyroid gland, and a 30-mm lobulated hypoechoic mass in the axilla with well-defined and rough borders, showing internal heterogeneity. Fine-needle aspiration cytology was performed on the thyroid and axillary tumors: the thyroid tumor was class V, raising suspicion of papillary thyroid cancer (PTC); the left superior internal jugular node was class V, raising suspicion of metastasis of PTC; and the axillary tumor was class III, raising suspicion of a mesenchymal tumor with few epithelioid cells. The multiple lung nodules were diagnosed as metastatic tumors derived from thyroid cancer. We diagnosed these diseases as PTC of T1b(m)N1bM1(lung) Stage IVB and a right axillary tumor of unclear origin. However, it was assumed to be a primary mesenchymal tumor or a lymph node metastasis from lung cancer or occult breast cancer. We performed total thyroidectomy, left cervical lymph node dissection, and right axillary tumor excision. Histopathologic examination revealed the thyroid tumor as a PTC and the axillary tumor as an EHE. The EHE showed nuclear atypia, necrosis and high mitotic figures. Hence, it was considered to be a high-risk EHE., Conclusions: We experienced a rare primary subcutaneous axillary EHE with metastatic thyroid cancer in the lung. Since our case was classified as a high-risk EHE, a close follow-up would be appropriate., (© 2022. The Author(s).)

Background: Although the laparoscopic approach has been applied to distal pancreatectomy, its benefits with regard to the short-term outcomes of distal pancreatectomy remain unclear., Materials and Methods: Using a Japanese nationwide inpatient database, we identified patients who underwent laparoscopic (n = 6647) and open (n = 21,843) distal pancreatectomy between July 2012 and March 2020. We conducted a 1:2 propensity score-matched analysis with adjustment for background characteristics (e.g., comorbidities, preoperative diagnosis, and hospital background) to compare in-hospital morbidity and mortality, reoperation requirement, duration of anesthesia and drainage, postoperative length of stay, and total hospitalization costs. For sensitivity analyses, we performed overlap propensity score-weighted analysis, instrumental variable analysis, and subgroup analyses for hospital volume, patients with benign tumors, and those with malignant tumors that required splenectomy., Results: In-hospital morbidity and mortality were 27% and 0.7%, respectively. The 1:2 propensity score-matched analysis showed that compared to open surgery, laparoscopic surgery was significantly associated with lower in-hospital morbidity (odds ratio [95% confidence interval]: 0.78 [0.73 to 0.84]) and mortality (0.26 [0.14 to 0.50]), lower occurrence of postoperative pancreatic fistula (0.78 [0.72 to 0.85]), postoperative bleeding (0.59 [0.51 to 0.69]), and reoperation (0.65 [0.58 to 0.75]), longer duration of anesthesia (difference, 59 [56 to 63] minutes), shorter duration of drainage (difference, -4.0 [-4.5 to -3.6] days) and postoperative length of stay (difference, -4.4 [-4.9 to -3.9] days), and lower total hospitalization costs (difference, -1510 [-1776 to -1243] US dollars). The sensitivity analyses showed compatible results with those from the main analysis., Conclusion: In this large nationwide cohort, laparoscopic distal pancreatectomy showed lower in-hospital morbidity, mortality, and total hospitalization costs than open distal pancreatectomy. Laparoscopic distal pancreatectomy may be a favorable procedure in terms of both complications and costs., (Copyright © 2022 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Introduction: Length of stay (LOS) is a major concern while optimizing medical resources and costs. Hence, factors influencing LOS should be investigated. In Japan, breast cancer surgery generally involves several days of hospitalization for observation, despite few complications. We hypothesized that the day of surgery (weekday; Monday-Friday) affects LOS., Methods: Using a Japanese nationwide database, we retrospectively identified 146,610 patients who underwent partial mastectomy for stage 0-III breast cancer from July 2010 to March 2017. We conducted multivariable linear and logistic regression analyses adjusting for background characteristics (such as comorbidities and hospital characteristics) with a generalized estimating equation for within-hospital clustering to compare postoperative and total LOS, total hospitalization costs, and postoperative complications between the groups for whom the surgery was performed on different days of the week., Results: In total, whereas the median postoperative LOS was 4 days (interquartile range, 3-6 days), the median total LOS was 6 days (5-8 days). The median total hospitalization cost was 6,189 US dollars (5,609-6,668 US dollars), and postoperative complications occurred in 3.3% of cases. Despite no significant difference in postoperative complications, Monday-Wednesday surgeries showed significantly shorter postoperative LOS than Friday surgeries (-0.11 days [95% confidence interval, -0.14 to -0.07] on Monday with reference to Friday). Nevertheless, Monday surgeries showed significantly increased total LOS (0.69 days [0.64-0.74]) and hospitalization costs (93 US dollars [71-116]) in comparison with Friday surgeries., Conclusions: The operative day of the week was associated with increased LOS and cost, with no difference in postoperative complications after partial mastectomy. Surgeries on Monday involved longer preoperative hospital stays and higher total hospitalization costs than those on other weekdays., Competing Interests: None, (Copyright © Japan Medical Association.)

Background: Hormonal therapy and radiotherapy are conducted concurrently or sequentially after breast cancer surgery. It remains unclear whether concurrent or sequential treatment is safer in terms of lung complications. Using a Japanese nationwide database, this study aimed to compare the occurrence of severe lung complications between concurrent and sequential treatments., Methods: We identified patients who underwent partial mastectomy for stage 0-III breast cancer from July 2010 to March 2020 and received adjuvant hormonal therapy and radiotherapy concurrently (n = 1851) or sequentially (n = 18,429). Two propensity score analyses (1:4 matching and overlap weighting) were conducted to compare hospitalization for radiation pneumonitis and pneumonia within 1 year after surgery, and intensive care unit admission and mortality during the hospitalization. We conducted additional analyses stratified by hormonal drugs (aromatase inhibitors and tamoxifen)., Results: The propensity score-matched analysis showed no significant differences in occurrence of hospitalization for radiation pneumonitis (0.27 vs. 0.58%, p = 0.10) and pneumonia (0.16 vs. 0.58%, p = 0.05) between the concurrent and sequential treatments. The overlap propensity score-weighted analysis also showed no significant differences (0.25 vs. 0.56%, p = 0.08 and 0.15 vs. 0.44%, p = 0.06, respectively). Intensive care unit admission and in-hospital mortality did not differ significantly between the two treatments. The stratified analysis showed similar results., Conclusion: Our propensity score analyses revealed no significant differences in severe lung complications between concurrent and sequential hormonal therapy with radiotherapy following breast cancer surgery, regardless of the type of hormonal drugs. Clinicians can provide concurrent or sequential treatment with equivalent attention to early lung complications., (© 2022. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Purpose: The association between body mass index (BMI) and the incidence of premenopausal breast cancer in the Asian population remains unclear. We investigated this association using data from a Japanese nationwide administrative database., Methods: We retrospectively identified 785,703 females aged < 45 years with available health checkup data on BMI from January 2005 and April 2020 from a Japanese nationwide database. Cox proportional hazards model was used to estimate hazard ratios for breast cancer (total breast cancer, breast cancer with hormonal drug and trastuzumab administration, and breast cancer by age ≤ 45 years) associated with BMI recorded at the first health checkup. We conducted restricted cubic spline analysis without BMI categorization to investigate potential nonlinear associations with adjustment for backgrounds such as smoking and alcohol consumption., Results: Overall, the median BMI was 20.5 (interquartile range [IQR], 18.9-22.7) kg/m 2 , and the median age was 37 (IQR, 29-41) years. Breast cancer occurred in 5597 participants (0.71%) at a median age of 44 (IQR, 42-46) years during a median follow-up of 1034 (IQR, 634-1779) days. A BMI of ≥ 22.0 kg/m 2 was significantly associated with lower incidences of total breast cancer, breast cancer with hormonal drug administration, and breast cancer by age ≤ 45 years, whereas no significant associations were observed for breast cancer with trastuzumab administration., Conclusion: This study, which used a Japanese nationwide database, demonstrated that BMI was inversely associated with premenopausal breast cancer development in Japanese women, similar to that observed in Western women., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Although neoadjuvant chemotherapy (NAC) has become common for breast cancer, its impact on short-term surgical outcomes and the feasible chemotherapy-surgery interval remain unclear. Using a Japanese nationwide database, this study investigated the impact of NAC on short-term outcomes following breast cancer surgery., Methods: In this study of 11,722 patients with NAC and 120,538 patients without NAC who underwent surgery for stage 0-III breast cancer July 2010-March 2017, to cancel out site-specific effects, we generated a 1:4 matched-pair cohort matched for age, institution, and fiscal year of admission. We then conducted multivariable analyses adjusting for potential confounders to compare postoperative complications, duration of anesthesia, and total hospitalization costs. Additionally, we conducted three sensitivity analyses for patients with a short interval from NAC to surgery, patients receiving a particular NAC regimen, and patients undergoing a particular surgical procedure., Results: In total, the occurrence of postoperative complications was 6.0%, and the median interval from NAC to surgery was 31 (interquartile range, 24-39) days. The two groups did not differ significantly in terms of complications (odds ratio, 0.95; 95% confidence interval, 0.88-1.04), including local and general complications. NAC was significantly associated with shorter duration of anesthesia and lower total hospitalization costs. The sensitivity analyses showed similar results., Conclusions: Our matched-pair cohort analyses revealed no significant differences in postoperative complications between patients with and without NAC for breast cancer, regardless of the interval, regimen, and surgical procedure. Patients can safely receive surgery and NAC without a lengthened interval., (© 2021. Society of Surgical Oncology.)

Background: Conventional prediction models for estimating risk of postoperative mortality in gastroduodenal ulcer perforation have suboptimal prediction ability. We aimed to develop and validate new machine learning models and an integer-based score for predicting the postoperative mortality., Methods: We retrospectively identified patients with gastroduodenal ulcer perforation who underwent surgical repair, using a nationwide Japanese inpatient database. In a derivation cohort from July 2010 to March 2016, we developed 2 machine learning-based models, Lasso and XGBoost, using 45 candidate predictors, and also developed an integer-based score for clinical use by including important variables in Lasso. In a validation cohort from April 2016 to March 2017, we measured the prediction performances of the models by computing area under the curve and comparing it to the conventional American Society of Anesthesiology risk score., Results: Of 25,886 patients, 1,176 (4.5%) died after surgical repair. For the validation cohort, Lasso and XGBoost had significantly higher prediction abilities than the American Society of Anesthesiology score (Lasso area under the curve = 0.84; 95% confidence interval 0.81-0.86; American Society of Anesthesiology score area under the curve = 0.70; 95% confidence interval 0.65-0.74, P < .001). The integer-based risk score, which had 13 factors, had a prediction ability similar to those of Lasso and XGBoost (area under the curve = 0.83; 95% confidence interval 0.81-0.86). According to the integer-based score, the mortalities were 0.1%, 2.3%, 9.3%, and 29.0% for the low (score, 0), moderate (1-2), high (3-4), and very high (≥5) score groups, respectively., Conclusion: Machine learning models and the integer-based risk score performed well in predicting risk of postoperative mortality in gastroduodenal ulcer perforation. These models will help in decision making., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Vigabatrin (VGB) is an effective antiseizure medication for West syndrome. It works by irreversibly inhibiting gamma-aminobutyric acid (GABA) transaminase and increasing central GABA levels. Vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM) are an adverse effect of VGB that has only been reported in children, but the pathophysiology of this effect is unknown. In this study, we evaluated the relationship of VGB and brain GABA levels as well as the association between VABAM and GABA., Methods: For the 15 consecutive pediatric patients treated with VGB, free GABA, glutamine, and glutamate in cerebrospinal fluid (CSF) and plasma, GABA to creatine and phosphocreatine (Cr) peak ratio (GABA/Cr), glutamine (Gln)/Cr, and glutamate (Glu)/Cr as quantified by proton MR spectroscopy ( 1 H-MRS) were retrospectively examined. GABA/Cr was compared with in-house normal pediatric controls. Differences in the levels of each metabolite in VABAM and non-VABAM cases were also examined., Results: Thirteen of the included subjects underwent magnetic resonance imaging (MRI) and 1 H-MRS, and two of them presented VABAM; both cases were very-low-birth-weight preterm infants with post-hemorrhagic hydrocephalus. CSF levels of free GABA were significantly higher in VABAM (5.26 ± 1.95 μmol/L) than in non-VABAM (0.59 ± 0.63 μmol/L) cases (P = 0.03). The GABA/Cr was significantly higher in patients with VGB (0.34 ± 0.16) than in pediatric controls (0.20 ± 0.05) (P = 0.02). The GABA/Cr tended to be higher in VABAM (0.48 ± 0.10) than in non-VABAM cases (0.31 ± 0.15) (P = 0.31)., Significance: Elevated brain GABA levels were observed in VABAM patients, suggesting its involvement in the pathogenesis of this condition. In particular, a marked increase in CSF-free GABA was characteristic. Although the elevation of the GABA/Cr is mild, it may be useful for early identification of patients with risk of VABAM., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Recent studies have shown worse post-operative outcomes following several surgeries in underweight or obese patients. However, the association between body mass index (BMI) and short-term outcomes following thyroid cancer surgery remains unclear because of the small number of patients, deficits in background data known as risk factors (e.g. cancer stage, operative procedure, intraoperative device use and hospital volume) and categorisation of BMI., Methods: We identified patients who underwent thyroidectomy for differentiated thyroid cancer from July 2010 to March 2017 using a Japanese nationwide inpatient database. We used restricted cubic spline (RCS) analyses to investigate potential non-linear associations between BMI (without categorisation) and outcomes: post-operative complications (local and general), duration of anaesthesia, post-operative length of hospital stay and hospitalisation costs. The analyses were adjusted for demographic and clinical backgrounds including the above-stated factors. We also performed multivariable regression analyses for the outcomes with categorisation of BMI., Results: Among 59,671 eligible patients, the median BMI was 22.9 kg/m2 (interquartile range (IQR), 20.7-25.6 kg/m2). In total, 3860 patients (6.5%) had local complications and 787 patients (1.3%) had general complications. Although there were no significant associations with local complications, such as bleeding, recurrent laryngeal nerve paralysis and surgical site infection, the occurrence of general complications was significantly associated with higher BMI. BMI showed a linear association with the duration of anaesthesia and U-shaped associations with post-operative length of stay and hospitalisation costs. The lowest points of the U-shaped curves occurred at a BMI of approximately 24 kg/m2. The multivariate regression analyses showed consistent results with the RCS analyses., Discussion/conclusion: Whereas RCS analyses revealed no significant associations between BMI and post-operative local complications, obesity was significantly associated with the occurrence of general complications. The linear association between BMI and duration of anaesthesia corresponds to previous studies. Although post-operative length of stay and total hospitalisation costs demonstrated U-shaped associations, the slight differences would not be clinically important. Even if surgeons must pay attention to general complications in obese patients undergoing thyroid cancer surgery as well as other surgeries, underweight and overweight patients can undergo thyroidectomy as safely as patients with normal BMI.

Background: The significance of circulating tumor DNA (ctDNA) in primary papillary thyroid cancer (PTC) is yet to be well established. This study aimed to clarify whether ctDNA carrying the BRAF V600E mutation in plasma from primary PTC patients before and after surgery can predict outcomes. Methods: Twenty-two primary PTC patients without distant metastasis, who underwent surgical resection at the University of Tokyo Hospital, were eligible for this study. Genomic DNA of the primary tumor was extracted from formalin-fixed and paraffin-embedded specimens, and the BRAF V600E mutation was detected by droplet digital polymerase chain reaction (ddPCR). Pre- and postsurgery ctDNAs were extracted from matched plasma samples obtained from 22 patients and analyzed for the BRAF V600E mutation using ddPCR. Results: The BRAF V600E mutation was detected in 16 of 22 (73%) primary tumors. Five of 16 (31%) cases carrying the BRAF V600E mutation in their tumors showed the identical mutation in presurgery plasma. Extrathyroidal extension of the primary tumor correlated significantly with the BRAF V600E mutation in presurgery ctDNA ( p  = 0.025). In the five patients carrying the BRAF V600E mutation in presurgery ctDNA, the fractional abundance of the BRAF V600E alleles to the total BRAF alleles in the primary tumor was significantly higher than that in the 11 patients without mutated BRAF in presurgery ctDNA (mean, 34% vs. 17%) ( p  < 0.01). Moreover, one patient with the mutated BRAF V600E in the primary tumor showed the identical mutation not in presurgery ctDNA but in postsurgery ctDNA. This patient had regional lymph node recurrence six months after surgery. Conclusions: Presurgery ctDNA with the BRAF V600E mutation was detected in 31% of cases with primary PTCs carrying the identical mutation. Detection of the BRAF V600E mutation in presurgery plasma can provide information on the increased fractional abundance of the mutated BRAF V600E alleles and local progression of the primary tumor. Furthermore, the fractional abundance of the mutated BRAF V600E in postsurgery ctDNA might predict PTC recurrence.

Purpose: The sequence of taxanes (T) followed by anthracyclines (A) as neoadjuvant chemotherapy has been the standard of care for almost 20 years for locally advanced breast cancer (LABC). Sequential administration of eribulin (E) following A/T could provide a greater response rate for women with LABC., Methods: In this single-arm, multicenter, Phase II prospective study, the patients received 4 cycles of the FEC regimen and 4 cycles of taxane. After the A/T-regimen, 4 cycles of E were administered followed by surgical resection. The primary endpoint was the clinical response rate. Eligible patients were women aged 20 years or older, with histologically confirmed invasive breast cancer, clinical Stage IIIA (T2-3 and N2 only), Stage IIIB, and Stage IIIC, HER2-negative., Results: A preplanned interim analysis aimed to validate the trial assumptions was conducted after treatment of 20 patients and demonstrated that clinical progressive disease rates in the E phase were significantly higher (30%) than assumed. Therefore, the Independent Data Monitoring Committee recommended stopping the study. Finally, 53 patients were enrolled, and 26 patients received the A/T/E-regimen. The overall observed clinical response rate (RR) was 73% (19/26); RRs were 77% (20/26) in the AT phase and 23% (6/26) in the E phase. Thirty percent (8/26) of patients had PD in the E phase, 6 of whom had achieved cCR/PR in the AT phase. Reported grade ≥ 3 AEs related to E were neutropenia (42%), white blood cell count decrease (27%), febrile neutropenia (7.6%), weight gain (3.8%), and weight loss (3.8%)., Conclusion: Sequential administration of eribulin after the A/T-regimen provided no additional effect for LABC patients. Future research should continue to focus on identifying specific molecular biomarkers that can improve response rates., (© 2021. The Author(s).)

Background: Gastroduodenal ulcer perforation is a common abdominal emergency that may be curable without surgical repair in non-elderly patients with localized and stable symptoms. However, the outcomes of nonoperative approaches have rarely been described., Methods: Using a Japanese national inpatient database, we identified 14,918 patients with gastroduodenal ulcer perforation who were hospitalized and received nonoperative treatment from July 2010 to March 2017. We categorized these patients into three groups according to age: 18 to 64 years (young group, n=8407), 65 to 74 years (old group, n=2616), and ≥75 years (old-old group, n=3895). We investigated the characteristics, treatments, and outcomes in each group., Results: Most of the patients were men (71%), and the median patient age was 62 years (interquartile range, 47-75 years). The old and old-old groups had more comorbidities than the young group. Whereas most patients were administered proton pump inhibitors and various antibiotics (96% and 90%, respectively), only 58% of patients underwent gastric tube placement. Surgical repair >3 days after admission was performed in 7.1% of all patients (6.3% vs. 7.9% vs. 5.5%, P<0.001). The old and old-old groups showed higher mortality (1.4% vs. 8.3% vs. 18%, P<0.001) and morbidity (6.6% vs. 15% vs. 17%, P<0.001) than the young group. The median length of stay was almost 2 weeks (13 vs. 17 vs. 20 days, P<0.001)., Discussion: Unlike previous studies, many patients aged >65 years received nonoperative treatment in this nationwide cohort. Our findings provide useful information for clinicians and patients hospitalized for gastric ulcer perforation., (© 2021. The Society for Surgery of the Alimentary Tract.)

Background: Although patients receiving renal replacement therapy (RRT) have more comorbidities and higher mortality and morbidity risks than the general population, surgery during breast cancer treatment is crucial because of limitations in anticancer agents for patients with renal insufficiency. We aimed to compare the short-term postoperative outcomes between patients with and without RRT., Methods: Patients who underwent surgery for stages 0-III breast cancer between July 2010 and March 2017 were retrospectively identified in a Japanese nationwide inpatient database and divided into those with RRT (RRT group, n = 1547) and those without RRT (control group, n = 364,047). We generated a 1:4 matched-pair cohort matched for age, institution, and fiscal year at admission. We conducted multivariable regression analyses to compare postoperative complications, 30-day readmission, and anesthesia duration between the two groups., Results: The RRT group was more likely to have comorbidities (95.0% vs. 24.1%) and undergo total mastectomy (64.2% vs. 47.0%) than the control group. The RRT group was not significantly associated with complications (odds ratio 1.18; 95% confidence interval [CI] 0.89-1.56) and 30-day readmission (odds ratio 0.88; 95% CI 0.65-1.18), but was associated with shorter anesthesia duration (difference, - 6.8 min; 95% CI - 10.7 to - 3.0 min) compared with the control group., Conclusions: The matched-pair cohort analyses revealed no significant differences in postoperative complications after breast cancer surgery between patients with and without RRT. Breast cancer surgery in patients with RRT may be as safe as that in patients without RRT, if comorbidities other than chronic renal failure are adequately addressed., (© 2021. The Japanese Breast Cancer Society.)

Aberrant DNA methylation in the BRCA1 promoter region causes epigenetic silencing of BRCA1 gene expression, which is critical for breast cancer development. However, how BRCA1 promoter methylation status alters histological features remains poorly understood. Here, we investigated the possibility to predict BRCA1 promoter methylation status based on the morphological and immunohistochemical features of triple-negative breast cancers (TNBCs). The morphological features of 53 TNBCs were evaluated with hematoxylin-eosin staining, with immunohistochemical staining of BRCA1, androgen receptor, p53, cytokeratin 5/6, and epidermal growth factor receptor. BRCA1 promoter methylation status was used to distinguish BRCA1 promoter-methylated tumors (BPMTs) from BRCA1 promoter-unmethylated tumors (BPUTs) dependent on pathological characteristics. BPMTs comprised approximately 26% of the TNBCs. Immunohistochemical analysis found that BRCA1 protein expression was significantly lower in BPMT compared with BPUT (p = 0.016). Morphologically, BPMTs were associated with high mitotic index (p = 0.017), pushing margin (p = 0.017), a circumscribed growth pattern (p = 0.014), and a syncytial growth pattern (p = 0.034) compared with BPUTs. We then assessed the potential of predicting BRCA1 promoter methylation status by using published score systems based on these morphological characteristics. A receiver operating characteristic analysis showed an area under the curve of 0.80. This study found that BRCA1 promoter methylation status could be derived from morphological features and lower BRCA1 expression of TNBCs, which may help identify suitable cases for target treatment with PARP inhibitors., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

We previously reported the usefulness of droplet digital polymerase chain reaction (ddPCR) for the assessment of Human epithelial growth factor receptor 2 (HER2) gene amplification in breast cancer using formalin-fixed and paraffin-embedded sections. In our previous study, we combined HER2/CEP17 ratio (HER2 gene signals to chromosome 17 signals) with ddPCR and tumor content ratio (TCR) of each sample and determined the HER2 status by adopting a two-dimensional chart. This "ddPCR-TCR method" showed a high concordance with conventional HER2 status. In this study, we updated our method to assess the HER2 status of breast cancer in a more quantitative manner. We combined obtained data of the ddPCR ratio [R x ] and TCR [x]; we calculated "(R x  - 1)/x + 1" for 41 samples with primary breast cancer and named the value led by this formula as "eHER2 (estimated HER2/CEP17 ratio of a tumor cell)". eHER2 was equivalent to conventional in situ hybridization (ISH) HER2/CEP17 ratio in most cases. eHER2 and ISH ratio showed a strong correlation (Spearman rank correlation ρ = 0.70, p < 0.0001). The obtained results indicated that eHER2 is a potential tool for HER2 status diagnosis in breast cancer., (© 2021 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Introduction: Some clinicians administer antibiotics in adhesive SBO treatment to prevent bacterial translocation without evidence confirming reduced sepsis and mortality. We aimed to evaluate the effectiveness of preventive antibiotic administration in nonoperative treatment of adhesive small bowel obstruction (SBO) in a retrospective study., Methods: Using a Japanese national inpatient database, we identified 114,786 eligible patients with adhesive SBO and divided patients into a group who did not receive intravenous antibiotics in the initial 2 consecutive days after admission (control group, n = 71,666) and a group who received intravenous antibiotics ≥2 days after admission (antibiotic group, n = 43,120). To compare the in-hospital mortality, occurrence of sepsis, septic shock, Clostridioides difficile colitis, length of stay, and total costs between the two groups, we performed instrumental variable analyses to adjust for measured and unmeasured confounding factors., Results: Overall, in-hospital mortality was 2.2%, and the occurrence of sepsis was 0.8%. In the instrumental variable analyses, no significant differences were found for in-hospital mortality, occurrence of sepsis, septic shock, Clostridioides difficile colitis, or total hospitalization costs. The antibiotic group showed a longer length of stay than the control group (coefficient, 1.9 days; 95% confidence interval, 0.6-3.2)., Conclusions: In this large nationwide cohort of patients with adhesive SBO, we found no benefit regarding preventive antibiotic administration in nonoperative treatment; however, antibiotic administration was associated with a longer hospital stay. These results did not support routine administration of antibiotics at admission to prevent bacterial translocation., Competing Interests: Declaration of competing interest The authors declare no conflicts of interests., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Purpose: Although long-term survival is similar between men and women, little is known about the short-term outcomes following breast cancer surgery in men. This study was performed to compare postoperative outcomes adjusted for background factors between men and women with breast cancer using a Japanese nationwide inpatient database., Methods: This study included 2126 men and 363,468 women who underwent surgery for stage 0-III breast cancer from July 2010 to March 2017. We generated a 1:4 matched-pair cohort matched for age, institution, and fiscal year at admission. We then conducted multivariable regression analyses to compare postoperative complications, 30-day readmission, duration of anesthesia, length of hospitalization, and total hospitalization costs between the sexes., Results: Men were older, more likely to have comorbidities and advanced cancer, and more likely to undergo total mastectomy and axillary dissection than women. There were no significant differences in postoperative complications between the sexes, but men showed a lower risk of 30-day readmission (odds ratio 0.74; 95% confidence interval [CI] 0.57-0.95), shorter duration of anesthesia (difference - 22.0 min; 95% CI - 2.1 to - 0.5), shorter length of hospitalization (difference - 1.3 days; 95% CI - 2.1 to - 0.5), and lower total hospitalization costs (difference - 506 US dollars; 95% CI - 668 to - 334) than women., Conclusions: The matched-pair cohort analyses revealed no significant differences in postoperative complications between men and women with breast cancer. However, men showed better outcomes than women in terms of 30-day readmission, duration of anesthesia, length of hospitalization, and total hospitalization costs.

Cancer stem-like cells (CSCs) induce drug resistance and recurrence of tumors when they experience DNA replication stress. However, the mechanisms underlying DNA replication stress in CSCs and its compensation remain unclear. Here, we demonstrate that upregulated c-Myc expression induces stronger DNA replication stress in patient-derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini-chromosome maintenance protein 10 (MCM10), a firing (activating) factor of DNA replication origins, to compensate for DNA replication stress in CSCs. MCM10 expression is upregulated in CSCs and is maintained by c-Myc. c-Myc-dependent collisions between RNA transcription and DNA replication machinery may occur in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to these collisions to ensure the progression of replication. Moreover, patient-derived breast CSCs were found to be dependent on MCM10 for their maintenance, even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. Further, MCM10 depletion decreased the growth of cancer cells, but not of normal cells. Therefore, MCM10 may robustly compensate for DNA replication stress and facilitate genome duplication in cancer cells in the S-phase, which is more pronounced in CSCs. Overall, we provide a preclinical rationale to target the c-Myc-MCM10 axis for preventing drug resistance and recurrence of tumors., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Breast fibroadenoma (FA) and phyllodes tumour (PT) often have variations of gene mediator complex subunit 12 (MED12) and mutations in the telomerase reverse transcriptase promoter region (TERTp). TERTp mutation is usually tested by Sanger sequencing. In this study, we compared Sanger sequencing and droplet-digital PCR (ddPCR) to measure TERTp mutations in FA and PT samples., Methods: FA and PT samples were collected from 82 patients who underwent surgery at our institution from 2005 to 2016. MED12 mutations for all cases and TERTp mutations for 17 tumours were detected by Sanger sequencing. ddPCR was performed to analyse TERTp mutation in all cases., Results: A total of 75 samples were eligible for analysis. Sanger sequencing detected MED12 mutations in 19/44 FA (42%) and 21/31 PT (68%). Among 17 Sanger sequencing-tested samples, 2/17 (12%) were TERTp mutation-positive. In ddPCR analyses, a significantly greater percentage of PT (19/31, 61%) was TERTp mutation-positive than was FA (13/44, 30%; P = 0.0046). The mutation positivity of TERTp and MED12 did not correlate, in either FA or PT., Conclusions: ddPCR was more sensitive for detecting TERTp mutation than Sanger sequencing, being able to elucidate tumorigenesis in FA and PT.

Purpose: Although both localization of breast cancer and body mass index (BMI) are associated with prognosis, the association between localization of breast cancer and BMI remains unclear. This study aimed to investigate the association between localization of breast cancer and BMI at diagnosis., Methods: Patients who underwent surgery for stage 0-III breast cancer July 2010-March 2017 were identified retrospectively in a Japanese nationwide inpatient database. Multinomial logistic regression analyses adjusting for patient's age were conducted to compare the outcomes among five BMI groups: < 18.5 kg/m 2 (n = 31,724; 9.3%), 18.5-24.9 kg/m 2 (n = 218,244; 64.3%), 25.0-29.9 kg/m 2 (n = 69,813; 20.6%), 30.0-34.9 kg/m 2 (n = 16,052; 4.7%), and ≥ 35.0 kg/m 2 (n = 3716; 1.1%). The outcomes were the quadrant and side of the breast where tumors were detected., Results: In total, about half of the patients had breast cancer in the upper-outer quadrant (49.7%) and in the left breast (51.1%). In the multinomial analysis, BMI ≥ 25.0 kg/m 2 was associated with the occurrence of breast cancer in the upper-inner and lower-outer quadrants and in the central area, whereas BMI < 18.5 kg/m 2 was associated with the occurrence of breast cancer in the central area only. The side of breast cancer did not differ significantly among the five BMI groups., Conclusions: Localization of breast cancer was associated with BMI in this large nationwide cohort. The findings may benefit patients' self-checks and doctors' examinations, potentially resulting in early detection and treatment.

Purpose: Strain elastography for imaging lesion stiffness is being used as a diagnostic aid in the malignant/benign discrimination of breast diseases. While acquiring elastography in addition to B-mode images has been reported to help avoid performing unnecessary biopsies, intraductal lesions are difficult to discriminate whether they are malignant or benign using elastography. An objective evaluation of strain in lesions was performed in this study by measuring the elasticity index (E-index) and elasticity ratio (E-ratio) of lesions as semi-quantitative numerical indicators of the color distribution of strain. We examined whether ductal carcinoma in situ (DCIS) and intraductal papilloma could be distinguished using these semi-quantitative numerical indicators., Methods: In this study, 170 ultrasonographically detected mass lesions in 162 cases (106 malignant lesions and 64 benign lesions)-in which tissue biopsy by core needle biopsy and vacuum-assisted biopsy, or surgically performed histopathological diagnosis, was performed-were selected as subjects from among 1978 consecutive cases (from January 2014 to December 2016) in which strain elastography images were acquired, in addition to standard B-mode breast ultrasonography, by measuring the E-index and E-ratio., Results: The cut-off values for E-index and E-ratio in the malignant/benign discrimination of breast lesions were determined to be optimal values at 3.5 and 4.2, respectively, based on receiver operating characteristic (ROC) curve analysis. E-index sensitivity, specificity, accuracy, and AUC value (area under the curve) were 85%, 86%, 85%, and 0.860, respectively, while those for E-ratio were 78%, 74%, 74%, and 0.780, respectively. E-index yielded superior results in all aspects of sensitivity, specificity, accuracy, and AUC values, compared to those of E-ratio. The mean E-index values for malignant tumors and benign tumors were 4.46 and 2.63, respectively, indicating a significant difference (P < 0.001). E-index values of 24 DCIS lesions and 25 intraductal papillomas were 3.88 and 3.35, respectively, which showed a considerably close value, while the false-negative rate for DCIS was 29.2%, and the false-positive rate for intraductal papilloma was as high as 32.0%., Conclusion: E-index in strain elastography yielded better results than E-ratio in the malignant/benign discrimination of breast diseases. On the other hand, E-index has a high false-negative rate and false-positive rate for intraductal lesions, a factor which should be taken into account when making ultrasound diagnoses.

Background: Recent studies have shown better postoperative outcomes in mildly obese patients, a phenomenon called the obesity paradox. In the field of breast cancer surgery, however, previous studies have only shown an association between obesity and worse postoperative outcomes using multivariable analysis; the obesity paradox has not been investigated in patients undergoing breast cancer surgery., Patients and Methods: We identified patients who underwent mastectomy for stage 0 to III breast cancer from July 2010 to March 2017 using a Japanese nationwide inpatient database. We used restricted cubic spline analyses to investigate potential nonlinear associations between body mass index (BMI) and outcomes (postoperative complications, 30-day readmission, duration of anesthesia, length of hospital stay, and hospitalization costs). We also performed multivariable regression analyses for the outcomes., Results: Among 239,108 eligible patients, 25.6% had a BMI of > 25.0 kg/m 2 . BMI showed U-shaped associations with postoperative complications, length of stay, and hospitalization costs, and a linear association with duration of anesthesia. The proportion of postoperative complications was lowest at a BMI of around 22.0 kg/m 2 , while the length of stay was shortest and total costs were lowest at a BMI of around 20.0 kg/m 2 . Compared to a BMI of 22.0 kg/m 2 , a BMI of > 30.0 kg/m 2 was significantly associated with greater postoperative complications, 30-day readmission, duration of anesthesia, length of stay, and hospitalization costs., Conclusion: Restricted cubic spline analyses displayed U-shaped associations between BMI and in-hospital complications, length of stay, and hospitalization costs, but none of the associations showed the obesity paradox., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The number of patients undergoing renal replacement therapy is increasing. We evaluated the practice patterns and outcomes of encapsulating peritoneal sclerosis (EPS) in patients undergoing peritoneal dialysis., Methods: Using a Japanese national inpatient database, we identified 295 patients with EPS who were hospitalized from July 2010 to March 2017. We categorized them into four groups: those who underwent surgery only ( n = 39), those who received corticosteroid treatment only ( n = 70), those who underwent both ( n = 30), and those who underwent neither ( n = 156). We investigated their characteristics, treatments, and outcomes., Results: More than half of patients were males and never-smokers and had a normal body mass index. Patients tended to undergo parenteral nutrition for 2 months. The proportions of emergency admission, intensive care unit (ICU) admission, central venous catheterization, catecholamine use, mechanical ventilation, and continuous hemodiafiltration were significantly different among the four groups (61%, 8.1%, 37.0%, 44.0%, 8.8%, and 5.8%, respectively). The both-treatment group had a significantly longer hospital stay (37.0 vs. 37.5 vs. 72.5 vs. 31.0 days, p < 0.001) and higher costs (US$16,554 vs. US$17,029 vs. US$33,757 vs. US$13,983, p < 0.001) than the other groups. In total, 52 patients (18%) died during hospitalization. There was no significant difference in inhospital complications and death, discharge status, 30-day readmission, or length of ICU stay among the four groups., Conclusions: Our findings provide useful information for clinicians and patients hospitalized for treatment of EPS.

Background: The benefits of using energy devices (EDs) such as ultrasonic coagulating shears or electrothermal bipolar vessel sealing devices for thyroid cancer surgery have been evaluated only with limited data obtained from small samples., Materials and Methods: Using a Japanese national inpatient database, we identified 59,394 patients with thyroid cancer who underwent thyroidectomy without EDs (without-ED group, n = 32,360) and with EDs (with-ED group, n = 26,764) from July 2010 to March 2017. One-to-one propensity score matching was performed to compare the occurrence of postoperative complications including recurrent laryngeal nerve paralysis and chyle leakage, duration of anesthesia, length of stay, total costs, in-hospital mortality rate between the two groups. We also performed multivariate regression analyses using a generalized estimating equation and multiple imputation as a sensitivity analysis., Results: In the propensity-matched analysis involving 22,108 pairs, no significant differences were found in any postoperative complications (7.4% vs. 7.3%, p = 0.73), duration of anesthesia (217 min vs. 218 min, p = 0.54), length of stay (8.7 days vs. 8.2 days, p = 0.07) and in-hospital mortality rate (0.07% vs. 0.09%, p = 0.61). Compared with the without-ED group, the with-ED group showed a lower occurrence of postoperative recurrent laryngeal nerve paralysis (2.3% vs. 2.7%, p = 0.01) but a higher occurrence of postoperative chyle leakage (0.3% vs. 0.1%, p < 0.001) and total cost (US $7246 vs. US $6937, p < 0.001). The multivariate regression analysis showed compatible results with the propensity-matched analysis., Conclusion: In this large nationwide cohort of patients with thyroid cancer, no significant difference was detected in the proportions of any complications. The use of EDs was associated with a lower occurrence of postoperative recurrent laryngeal nerve paralysis but a higher occurrence of postoperative chylothorax and higher cost., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Angiosarcoma of the breast is rare. It carries a poor prognosis because of its high risk of local recurrence and distant metastases. Presently, there are still no established systemic therapies. Thus, the main treatment strategy for breast angiosarcoma is complete resection. This underscores the importance of closely monitoring the spread of the tumor lesion, particularly for multifocal angiosarcoma, and to plan an optimal operative procedure. We herein present the successful surgical treatment of a rare case of multifocal primary breast angiosarcoma., Case Presentation: A 43-year-old woman visited our hospital with a growing lump on her right breast accompanied by pain. Clinical and radiological examinations revealed a well-circumscribed 40-mm-diameter tumor at the inner lower quadrant of her right breast. Histological examination of a needle biopsy specimen revealed angiosarcoma. Based on a precise evaluation of the tumor by contrast-enhanced MRI and contrast-enhanced CT scan, a wide local excision with sufficient margins was performed. In the resected specimen, three discontinuous small lesions of angiosarcoma were observed around the main tumor. Therefore, total mastectomy was additionally performed. Pathological examination revealed two other small nodules of angiosarcoma in the remnant right breast, which appeared to be close but not continuous to the defective part of the initial resection. Postoperative follow-up at 1 year showed no signs of recurrence or distant metastasis. Multifocal primary breast angiosarcoma is extremely rare with only two previous reports describing its multifocality., Conclusions: Owing to its rarity, a standardized surgical treatment for breast angiosarcoma remains controversial. Our case suggests that primary breast angiosarcoma may occasionally present with multifocal tumor. Thus, it is important to keep in mind the multifocality of breast angiosarcoma when assessing its spread by diagnostic imaging and when planning the surgical strategy.

Background: This study aimed to evaluate the impact of previous local treatment on lymphatic drainage patterns in ipsilateral breast tumor recurrence (IBTR) based on our data on re-operative sentinel lymph node biopsy (re-SLNB) for IBTR., Methods: Between April 2005 and December 2016, re-SLNB using lymphoscintigraphy with Tc-99 m phytate was performed in 136 patients with cN0 IBTR. Patients were categorized into two groups: the AX group included 55 patients with previous axillary lymph node dissection; the non-AX group included 69 patients with previous SLNB and 12 patients with no axillary surgery. The whole breast irradiation (RT) after initial surgery had performed in 17 patients in the AX group and 27 patients in the non-AX group., Results: Lymphatic drainage was visualized in 80% of the AX group and 95% of the non-AX group (P < 0.01). The visualization rate of lymphatic drainage was associated with the number of removed lymph nodes in prior surgery. In the non-AX group, lymphatic drainage was visualized in 96% of patients without RT and 93% with RT. Lymphatic drainage was observed at the ipsilateral axilla in 98% of patients without RT and in 64% with RT (P < 0.0001). Aberrant drainage was significantly more common in patients with RT than without RT (60% vs. 19%, P < 0.001); it was observed mostly to the contralateral axilla (52% vs. 2%, P < 0.0001). In the AX group, patients with previous RT showed decreased lymphatic drainage to the ipsilateral axilla compared to those without RT (29% vs. 63%, P < 0.05) and increased aberrant drainage to the contralateral axilla (64% vs. 5%, P < 0.0001)., Conclusion: Lymphatic drainage patterns altered in re-SLNB in patients with IBTR and previous ALND and RT were associated with alterations in lymphatic drainage patterns.

Overexpression of human epidermal growth factor receptor 2 (HER2) protein is well known to be more frequent in ductal carcinoma in situ (DCIS) than in invasive ductal carcinoma (IDC). However, the reasons for this difference are poorly understood. On the basis of the high frequency of estrogen receptor-positive (ER+) and HER2-positive (HER2+) DCIS, we hypothesized that this tumor type overexpresses HER2 protein without gene amplification and retrospectively investigated the HER2/neu gene status of 71 ER(+)HER2(+) DCIS, surgically removed during the 2007 to 2017 period, employing fluorescence in situ hybridization (FISH). To compare HER2 protein expressions between in situ and invasive components of individual tumors, 86 pT1mi/1a IDC with predominantly in situ disease were also examined. Furthermore, for comparison of FISH status between in situ and coexisting invasive components, another patient cohort, 78 FISH-positive IDC cases, were employed. To elucidate biological differences among DCIS with various combinations of ER and HER2 protein expressions, we also analyzed public microarray data of mRNA. HER2 gene amplification was observed in 35% of ER(+) and HER2 protein-overexpressing specimens, significantly lower than the 94% in ER-negative (ER-) and HER2 protein-overexpressing specimens (P<0.001). HER2 protein expression was decreased in the invasive component as compared with coexisting in situ portions in 40% of individual tumors, whereas the FISH status of these 2 components was well preserved. Moreover, ER(+) and HER2 protein-overexpressing DCIS showed significantly higher hypoxia-inducible factor-1α protein expression than the ER(+) and HER2 protein-nonoverexpressing tumors (P=0.016). We revealed that ER(+) and HER2 protein-overexpressing DCIS, especially ER-high tumors, frequently overexpress HER2 protein without gene amplification. Our data may provide novel insights for understanding the biology of DCIS.