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Background: Triple-negative breast cancer (TNBC) is the most fatal breast cancer subtype, which often shows aggressive progression, a high potential to metastasize, and resistance to chemotherapy. Comprehensive genomic profiling using next-generation sequencing (NGS) has been expected to identify gene alterations that are targetable by drugs. However, the significance of these genomic alterations in the cancer biology of TNBC patients has not yet been fully understood due to the lack of accurate clinical outcome data to compare with the genomic data. The aim of this study was to clarify the clinical impact of genomic profiling data, including copy number alterations (CNAs), in TNBC by comparing comprehensive genomic data with clinical outcomes. Methods: A total of 47 patients diagnosed with stage I-III TNBC (from the cohort reported in JCO Precis Oncol. 2018;2:PO.17.00211) were enrolled in this study. The genomic profiling of 435 known cancer genes by NGS with clinical outcomes were analyzed. Overall survival (OS) was evaluated for its association to gene alterations and distinctively CNAs. The cut-off values of CNA for OS were determined from the receiver operating characteristic curve using the Youden index for area under the curve (AUC). Kaplan-Meier plots and log-rank tests of OS were applied for each group. Univariate and multivariate analyses for OS were performed using a Cox proportional-hazards model to obtain the hazard ratio (HR) and 95% confidence intervals. Results: Utilizing NGS-based genomic profiling, at least one alteration was found in 82 of the 435 cancer-associated genes, and a total of 162 alterations were found in the 47 patients. Among the 82 genes with alterations, the presence or absence of TP53 and PTEN alterations was significantly associated with OS of TNBC patients; patients with TP53 alterations (n = 31) showed significantly shorter OS than those without TP53 alterations (n = 16, p = 0.023), and patients with PTEN alterations (n = 9) showed significantly shorter OS than those without PTEN alterations (n = 38, p = 0.023). The cut-off value of CNA for OS was set at 25 (AUC, 0.788; sensitivity, 0.727; specificity, 0.900). Interestingly, CNA-high patients (n = 20) showed significantly shorter OS than CNA-low patients (n = 27, p = 0.014). Univariate analysis revealed that TP53 alterations and CNAs were significant prognostic factors for OS (HR, 8.81; p = 0.008; and HR, 8.00; p = 0.014, respectively). Finally, multivariate analysis using background clinical data revealed that CNA was an independent prognostic factor for OS in TNBC patients (HR, 7.15; p = 0.044). Conclusion: Our data suggest that CNA is an independent prognostic marker in TNBC, and that can be estimated from comprehensive genomic profiling data by NGS. Further investigation is needed to clarify the mechanisms of how CNAs are associated with this lethal disease. Citation Format: Masayuki Nagahashi, Chie Toshikawa, YiWei Ling, Tetsu Hayashida, Yuko Kitagawa, Manabu Futamura, Takashi Kuwayama, Seigo Nakamura, Hideko Yamauchi, Teruo Yamauchi, Koji Kaneko, Chizuko Kanbayashi, Nobuaki Sato, Junko Tsuchida, Kazuki Moro, Masato Nakajima, Yoshifumi Shimada, Hiroshi Ichikawa, Stephen Lyle, Yasuo Miyoshi, Kazuaki Takabe, Shujiro Okuda, Toshifumi Wakai. Copy number alteration is an independent prognostic biomarker in triple-negative breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-28.

Although the categorization of ultrasound using the Breast Imaging Reporting and Data System (BI-RADS) has become widespread worldwide, the problem of inter-observer variability remains. To maintain uniformity in diagnostic accuracy, we have developed a novel artificial intelligence (AI) system in which AI can distinguish whether a static image obtained using a breast ultrasound represents BI-RADS3 or lower, or BI-RADS4a or higher, to determine the medical management that should be performed on a patient whose breast ultrasound shows abnormalities. To establish and validate the AI system, a training dataset consisting of 4,028 images containing 5,014 lesions and a test dataset consisting of 3,166 images containing 3,656 lesions were collected and annotated. We selected a setting that maximized the area under the curve (AUC) and minimized the difference in sensitivity and specificity by adjusting the internal parameters of the AI system, achieving an AUC, sensitivity, and specificity of 0.95, 90.0%, and 88.5%, respectively. Furthermore, based on 30 images extracted from the test data, the diagnostic accuracy of 20 clinicians and the AI system was compared, and the AI system was found to be significantly superior to the clinicians (McNemar test, p < 0.001). Then, we conducted a trial to introduce the system for use in clinical practice. Physicians reviewed the images and determined whether they were BI-RADS3 or lower, or BI-RADS4a or higher. Next, the classification was performed again for the same images concerning the AI diagnosis. At this time, the initial judgment was allowed to be overturned. We checked whether there was any difference in the diagnostic accuracy, sensitivity, and specificity before and after reviewing to the AI diagnosis. Reviews by 24 physicians were evaluated: 4 Japanese Breast Cancer Society breast specialists, 5 non-specialists and physicians with experience treating more than 40 cases of breast cancer, and 15 non-specialists and physicians with no experience treating more than 40 cases of breast cancer. The average rate of accuracy before confirming the AI diagnosis increased to 73.1% after confirming the AI diagnosis (p=0.00548), compared to 69.3% on average before the AI diagnosis. Compared to practice experience, the accuracy increased from an average of 77.1% to 79.6% for the 9 physicians who were breast specialists or who had treated 40 or more cases of breast cancer. For the 15 physicians with less than 40 breast cancer cases, the average rate of accuracy increased from 64.7% to 69.2%. Furthermore, sensitivity increased significantly to an average of 99.7% after reviewing of the AI diagnosis from an average of 88.8% prior to reviewing the AI-diagnosis.(p< 0.01). Specificity increased from an average of 62.4% to 63.8% (p=0.433) after reviewing AI diagnosis. We showed that our AI system, when applied to clinical practice and used by physicians, contributes to the improvement of diagnostic accuracy. Our results indicated that our AI diagnostic system was sufficiently accurate to be used in the clinical practice. Citation Format: Erina Odani, Tetsu Hayashida, masayuki kikuchi, Aiko Nagayama, tomoko seki, maiko takahashi, Akiko Matsumoto, Takeshi Murata, Rurina Watanuki, Takamichi Yokoe, Ayako Nakashoji, Hinako Maeda, Tatsuya Onishi, Sota Asaga, Takashi Hojo, Hiromitsu Jinno, Keiichi Sotome, Akira Matsui, Akihiko Suto, Shigeru Imoto, Yuko Kitagawa. Establishment of the breast ultrasound support system using deep-learning system [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-06.

Although the categorization of ultrasound using the Breast Imaging Reporting and Data System (BI-RADS) has become widespread worldwide, the problem of inter-observer variability remains. To maintain uniformity in diagnostic accuracy, we have developed a system in which artificial intelligence (AI) can distinguish whether a static image obtained using a breast ultrasound represents BI-RADS3 or lower or BI-RADS4a or higher to determine the medical management that should be performed on a patient whose breast ultrasound shows abnormalities. To establish and validate the AI system, a training dataset consisting of 4028 images containing 5014 lesions and a test dataset consisting of 3166 images containing 3656 lesions were collected and annotated. We selected a setting that maximized the area under the curve (AUC) and minimized the difference in sensitivity and specificity by adjusting the internal parameters of the AI system, achieving an AUC, sensitivity, and specificity of 0.95, 91.2%, and 90.7%, respectively. Furthermore, based on 30 images extracted from the test data, the diagnostic accuracy of 20 clinicians and the AI system was compared, and the AI system was found to be significantly superior to the clinicians (McNemar test, p 0.001). Although deep-learning methods to categorize benign and malignant tumors using breast ultrasound have been extensively reported, our work represents the first attempt to establish an AI system to classify BI-RADS3 or lower and BI-RADS4a or higher successfully, providing important implications for clinical actions. These results suggest that the AI diagnostic system is sufficient to proceed to the next stage of clinical application.

Background Anthracyclines are commonly used for the treatment of solid tumors and hematological malignancies because of their inevitable dose-dependent cardiotoxic effects. The study aimed to assess the feasibility of applying a biomarker-based surveillance strategy according to European guidelines for the early prediction of anthracycline-induced cardiotoxicity in patients with breast cancer.Methods From April 2018 to December 2021, 45 women with breast cancer (53.9 ± 11.0 years) treated with anthracycline-based regimens were evaluated for 1 year. We measured and analyzed high-sensitivity cardiac troponin T (hsTnT), B-type natriuretic peptide (BNP), global longitudinal strain (GLS), and left ventricular ejection fraction (LVEF) at baseline, and 3 and 6 months after the initiation of anthracycline-based chemotherapy. Cardiotoxicity was defined as a reduction in LVEF > 10% compared with baseline to LVEF 15% from baseline.Results After initiating anthracycline treatment, hsTnT levels peaked at 3 months, whereas BNP levels were the highest at 6 months. Cardiotoxicity was detected in 18 (20.0%) patients (one patient with LVEF decline), where GLS declined over time yet became significant only after 6 months. Elevated hsTnT at 3 months were significantly associated with a GLS decline at 6 months (P Conclusions Among patients with early-stage breast cancer, an increase in hsTnT at 3 months after initiation of the anthracycline-based regimen predicted a subsequent decline in GLS with high sensitivity and moderate specificity.

Due to the increasing complexity of cancer treatment, ensuring safety and maintaining the quality of life during treatment are important issues. Patient-reported outcomes (PROs) in oncology are essential for assessing patient symptoms. A feasibility study was undertaken on breast cancer patients by building a PRO data collection system based on LINE, one of the most popular social network service applications in Japan. In this study, one or more predefined PRO questions for each breast cancer patient's clinical situation were sent to the patient's LINE application daily. The patient selected a predefined answer by tapping the screen, but no free-text answers were allowed. Seventy-three patients were enrolled. The median observation period was 435 days (84-656 days), and the total number of PROs collected was 16,417, with a mean of 224.9 reports per patient. Patients on adjuvant endocrine therapy were notified of 2.5 questions per week, and the median number of responses per week and response rate were 2.387 (1.687-11.627) and 95.5%, respectively. Analyzing the results by age group, the number of responses from those aged 60 and above was equal to or higher than that of the younger age group. It was also possible to track each patient's PROs accurately. These results suggested that the design of the system, based on an application used daily, instead of using specifically prepared applications for collecting electronic PROs, was the reason for the favorable acceptance from patients and the satisfactory response rate from all age groups, including the elderly.

Supplementary Methods from The Integrin αvβ3-5 Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions in ER+ and erbB2+ Breast Cancers

Supplementary Figure 2 from The Integrin αvβ3-5 Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions in ER+ and erbB2+ Breast Cancers

Supplementary Figure Legends 1-2 from The Integrin αvβ3-5 Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions in ER+ and erbB2+ Breast Cancers

Supplementary Figure 1 from The Integrin αvβ3-5 Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions in ER+ and erbB2+ Breast Cancers

Comprehensive genomic profiling (CGP) is being increasingly used for the routine clinical management of solid cancers. In July 2018, the use of tumor tissue‐based CGP assays became available for all solid cancers under the universal health insurance system in Japan. Several restrictions presently exist, such as patient eligibility and limitations on the opportunities to perform such assays. The clinical implementation of CGP based on plasma circulating tumor DNA (ctDNA) is also expected to raise issues regarding the selection and use of tissue DNA and ctDNA CGP. A Joint Task Force for the Promotion of Cancer Genome Medicine comprised of three Japanese cancer‐related societies has formulated a policy proposal for the appropriate use of plasma CGP (in Japanese), available at https://www.jca.gr.jp/researcher/topics/2021/files/20210120.pdf, http://www.jsco.or.jp/jpn/user_data/upload/File/20210120.pdf, and https://www.jsmo.or.jp/file/dl/newsj/2765.pdf. Based on these recommendations, the working group has summarized the respective advantages and cautions regarding the use of tissue DNA CGP and ctDNA CGP with reference to the advice of a multidisciplinary expert panel, the preferred use of plasma specimens over tissue, and multiple ctDNA testing. These recommendations have been prepared to maximize the benefits of performing CGP assays and might be applicable in other countries and regions.

Recording surgery is an important technique for education and the evaluation of medical treatments. However, capturing targets such as the surgical field, surgical tools, and the surgeon’s hands, is almost impossible since these targets are heavily occluded by the surgeon’s head and body during a surgery. We used a recording system in which multiple cameras are installed in the surgical lump, supposing at least one camera would capture the target without occlusion. As this system records multiple video sequences, we address the task to select a best view camera automatically. Recently, learning-based approaches in a fully supervised manner have been proposed for this task, but these previous approaches completely rely on manual annotation of the training data. In this paper, we focus on the eye tracker mounted on the surgeon’s head, which can capture the recording targets without occlusion. Employing this first-person-view video synchronized with multiple videos of the surgical lump, we propose a novel camera selection approach using a self-supervised learning framework. In experiments, we created a dataset composed of four different breast surgery. Our extended experiments showed that our approach successfully switched to the best camera view without manual annotation and achieved competitive accuracy compared with conventional supervised methods. Also, our approach yielded effective visual representations comparable to state-of-the-art self-supervised learning frameworks.

Purpose Male breast cancer (MBC) is a rare cancer accounting for only 1% of all male cancers and is, therefore, poorly studied. We aimed to characterize the subtypes of MBC in Japanese patients based on genetic profiling, the presence of tumor-infiltrating cells, and the expression of immunohistochemical markers. Methods This retrospective study included 103 patients with MBC diagnosed between January 2009 and December 2019 at various hospitals in Japan. Clinicopathological patient characteristics were obtained from medical records, and formalin-fixed paraffin-embedded tissue specimens were analyzed for histological markers, mutations of 126 genes, BRCA1 methylation, and stromal tumor-infiltrating lymphocytes. Results The median patient age was 71 (range 31–92) years. T1-stage tumors were the most frequent (47.6%), and most were node negative (77.7%). The majority of tumors were positive for estrogen receptor (98.1%), progesterone receptor (95.1%), and androgen receptor (96.1%), and BRCA2 was the most frequently mutated gene (12.6%). The most common treatment was surgery (99.0%), either total mastectomy (91.1%) or partial mastectomy (7.0%). Survival analysis showed a 5-year recurrence-free survival rate of 64.4% (95% confidence interval [CI] 46.7–88.8) and a 5-year overall survival rate of 54.3% (95% CI 24.1–100.0). Conclusion Japanese MBC is characterized by a high rate of hormonal receptor positivity and BRCA2 somatic mutation. Due to the observed clinicopathological differences in MBC between the Western countries and Japan, further prospective studies are needed to evaluate the most suitable treatment strategies.

A preoperative diagnosis of ductal carcinoma in situ (DCIS) is sometimes upstaged to invasive disease postoperatively. Our objective was to clarify the predictive factors of invasive disease using preoperative imaging and to investigate the positive ratio of sentinel lymph nodes (SLN) and the incidence of invasive disease. The subjects were 402 patients with preoperatively diagnosed ductal carcinoma without stromal invasion who underwent breast surgery with concomitant SLN surgery in January 2007 to December 2016. Of the 306 included patients, all 306 patients underwent preoperative MRI and US assessment. Outcomes were analyzed for significance using univariate and multivariate analyses. Of the 306 patients, 115 (37.6%) had invasive disease and 191 (62.4%) had DCIS only. Of the 115 patients with invasive disease, 5 (4.4%) and 4 (3.5%) had macro- and micrometastases in SLN. On the other hand, of the 191 patients with DCIS, only 1 (0.5%) had a micrometastasis. Predictors of invasive disease in the univariate analysis included having a palpable mass, were varied by biopsy method, having a US hypoechoic mass, MRI enhancement, or MRI large enhanced lesion; the size of the mass enhancement ≥ 1.1 cm or a spread of non-mass enhancement ≥ 3.1 cm (P = 0.003). Predictors of invasive disease in the multivariate analysis included US hypoechoic mass and MRI large enhanced lesion. We need to perform SLN biopsy for preoperatively diagnosed DCIS when patients have predictors of invasive disease, but SLN biopsy will no longer be essential for patients when they have no predictors of invasive disease.

Background To promote precision oncology in clinical practice, the Japanese Society of Medical Oncology, the Japanese Society of Clinical Oncology, and the Japanese Cancer Association, jointly published “Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment” in 2017. Since new information on cancer genomic medicine has emerged since the 1st edition of the guidance was released, including reimbursement for NGS-based multiplex gene panel tests in 2019, the guidance revision was made. Methods A working group was organized with 33 researchers from cancer genomic medicine designated core hospitals and other academic institutions. For an impartial evaluation of the draft version, eight committee members from each society conducted an external evaluation. Public comments were also made on the draft. The finalized Japanese version was published on the websites of the three societies in March 2020. Results The revised edition consists of two parts: an explanation of the cancer genomic profiling test (General Discussion) and clinical questions (CQs) that are of concern in clinical practice. Particularly, patient selection should be based on the expectation that the patient's post-test general condition and organ function will be able to tolerate drug therapy, and the optimal timing of test should be considered in consideration of subsequent treatment plans, not limited to treatment lines. Conclusion We expect that the revised version will be used by healthcare professionals and will also need to be continually reviewed in line with future developments in cancer genome medicine.

Mindfulness-based interventions have been receiving growing attention in cancer care.The purpose of this randomized controlled trial is to examine the effectiveness of mindfulness-based cognitive therapy (MBCT) for psychological distress (anxiety and depression), fear of cancer recurrence (FCR), fatigue, spiritual well-being, and quality of life (QOL) in Japanese ambulatory patients with Stage I-III breast cancer.A total of 74 patients were randomly assigned to either an eight-week MBCT intervention group (n = 38) or a wait-list control group (n = 36). The primary outcome was psychological distress, measured on Hospital Anxiety and Depression Scale. The secondary outcomes were FCR (Concerns About Recurrence Scale-overall anxiety subscale), fatigue (Brief Fatigue Inventory), spiritual well-being (Functional Assessment of Chronic Illness Therapy-Spiritual), QOL (Functional Assessment of Cancer Therapy-General), and mindfulness skills (Five Facet Mindfulness Questionnaire). The participants were assessed at baseline (T0), Week 8 (T1), and Week 12 (T2). The results were analyzed using a intention-to-treat linear mixed model.The participants in the MBCT group experienced significantly better outcomes in their psychological distress (Cohen's d = 1.17; P 0.001), FCR (d = 0.43; P 0.05), fatigue (d = 0.66; P 0.01), spiritual well-being (d = 0.98; P 0.001), and QOL (d = 0.79; P 0.001) compared with the control group. The difference remained significant at T2 (four weeks after completion of the intervention).MBCT was demonstrated to improve well-being that encompasses psychological, physical, and spiritual domains in Japanese patients with nonmetastatic breast cancer. The favorable effect was maintained up to four weeks after the completion of the intervention.

Invasive lobular carcinoma (ILC) has a different treatment response from invasive ductal carcinoma (IDC). We assessed whether perioperative chemotherapy was associated with improved prognosis in patients with ILC. Retrospective data of women who underwent surgery for ILC were extracted from the SEER database. Subjects were divided into non-chemotherapy and chemotherapy groups. Overall, 10 537 patients were included, and 2107 patients were stratified into each group after propensity score matching. Perioperative chemotherapy significantly improved 10-year survival rates for ILC, particularly in patients with large tumor size and lymph node metastases. Perioperative chemotherapy is effective for ILC patients with proper selection.

In several recent studies on metastatic breast cancer (MBC), ligand binding domain mutations of the estrogen receptor, which is coded by the ESR1 gene, were induced by long-term endocrine therapy and resulted in acquired endocrine therapy resistance and poor outcomes. Knowledge of the association between the development of ESR1 mutation and the clinicopathologic features may guide the decision-making process of metastatic breast cancer treatment, including endocrine therapy. The aim of the present study was to evaluate the association between the development of ESR1 mutation and the clinicopathologic characteristics of patients with MBC. To evaluate the association between the development of ESR1 mutation and clinicopathologic features, a cohort of 22 patients with MBC were retrospectively analyzed using next generation sequencing. In 14 of 22 patients, four mutations were detected on the metastatic site, including Tyr537Ser, Glu542Asp, Leu536Arg and Arg548Cys. Univariate analysis demonstrated that the duration of aromatase inhibitor and selective estrogen receptor modulator treatment, as well as the age of treatment initiation for early-stage breast cancer, were significantly associated with the development of ESR1 mutation. ESR1 mutation was identified in all five patients who received selective estrogen receptor modulators in the adjuvant setting followed by aromatase inhibitors in the metastatic setting, as well as in two of the three patients who received no selective estrogen receptor modulators in adjuvant setting followed by aromatase inhibitors in the metastatic setting. In conclusion, the results of the present study suggested that administrating adjuvant selective estrogen receptor modulator followed by aromatase inhibitor for metastasis may increase the frequency of ESR1 mutation.

Objective: This study aimed to evaluate the psychometric properties of the Japanese version of the Cancer Survivors' Unmet Needs (CaSUN-J) scale among cancer survivors in Japan. Methods: The CaSUN-J was developed using standardized translation methodology. Content validity was evaluated by a group of experts, and a pilot test was conducted with a convenience sample of 10 cancer patients. A total of 183 Japanese cancer survivors completed the CaSUN-J. The internal consistency of the scale was examined with Cronbach's α. Construct validity was analyzed using correlations with the physical effects, quality of life (QoL), and age. To assess the factorial validity of the CaSUN-J, confirmatory factor analysis (CFA) was performed. Results: The CaSUN-J indicated good readability and high content validity for use as an assessment tool among Japanese cancer survivors. All Cronbach's α coefficients were above the minimum acceptable criterion of ≥0.70. For construct validity, higher physical effect scores, as well as poorer QoL scores and younger patients, were significantly positively associated with higher levels of needs. CFA indicated that the five-factor structure of the CaSUN-J was a good fit to the data. Conclusions: The CaSUN-J can serve as a valid and reliable tool to evaluate unmet needs among Japanese cancer survivors.

First identified as a developmental gene, HOXB9 is also known to be involved in tumor biological processes, and its aberrant expression correlates with poor prognosis of various cancers. In this study, we isolated a homeodomain-less, novel HOXB9 variant (HOXB9v) from human breast cancer cell line-derived mRNA. We confirmed that the novel variant was produced from variationless HOXB9 genomic DNA. RT-PCR of mRNA isolated from clinical samples and reanalysis of publicly available RNA-seq data proved that the new transcript is frequently expressed in human breast cancer. Exogenous HOXB9v expression significantly enhanced the proliferation of breast cancer cells, and gene ontology analysis indicated that apoptotic signaling was suppressed in these cells. Considering that HOXB9v lacks key domains of homeobox proteins, its behavior could be completely different from that of the previously described variationless HOXB9. Because none of the previous studies on HOXB9 have considered the presence of HOXB9v, further research analyzing the two transcripts individually is warranted to re-evaluate the true role of HOXB9 in cancer.

In the medical field, surgical videos can be used to introduce surgical skills. Medical students and residents watch the videos to study the surgical skills and increase learning speed by compensating for the lack of experience in surgical rooms due to limited opportunity to join in surgery. To record egocentric surgical videos by a wearable camera is a solution to record surgical skills of a surgeon in detail. However, most egocentric surgical videos are of quite long duration. For example, in the case of tumor removal in breast surgery, a video recording time often reaches 2[Formula: see text]h. With that length, it is time consuming to see important scenes in the video, particularly because many surgical videos include nonessential scenes such as sterilization and preparation of tools. For extracting specific scenes from a long video, we can apply scene estimation by machine learning. Furthermore, it is important to know where the surgeon is looking to observe the area of the incision in detail. In particular, it is vital to be able to zoom in on key elements, allowing viewers to see the incision area and the fine details of the necessary surgical skills. In this study, we aimed to highlight incision scenes from egocentric surgical videos in the spatiotemporal domain by utilizing two neural networks for the temporal and spatial highlights. For the temporal highlights, we designed a neural network that estimates the incision scenes by learning gaze speed, hand movements, number of hands, and background movements in egocentric surgical videos. For the spatial highlights, in order to estimate the important area to zoom in, we designed a neural network that learns the surgeon’s gaze on natural features of surgical scenes to form a probability map as a representation of the estimated gaze area. The estimated gaze area was also used to calculate the appropriate zoom-in position and zoom-in ratio. To control the highlighted parameters in accord with user preferences, we also made a user interface that allows for the selection of playback speed gain and zoom ratio gain. For the evaluation, we verified the performance of the networks by a quantitative assessment and conducted a user study with medical doctors by showing an actual surgical video to obtain a qualitative assessment on the proposed system.

This study examined the relationship between symptom burdens and work-related outcomes, including work participation and overall work impairment (OWI) among breast cancer survivors (BCS) receiving adjuvant endocrine therapy (AET).This was a cross-sectional study with 140 BCS of working age receiving AET. Data were collected using self-report questionnaires that included an assessment of symptoms and their employment status, and OWI. Data were analyzed using descriptive statistics and multiple logistic regression analysis.A total of 111 (79%) survivors reported being employed at the time of the survey. Symptom burdens were not associated with unemployment. Of the 110 working BCS receiving AET, symptom burdens were significantly related to a higher degree of OWI (OR ​= ​2.14, 95% CI, 1.58-2.89,Participating BCS receiving AET continued to work while experiencing symptoms, with survivors who experienced high symptom burdens being negatively affected in their work life. Healthcare providers need to assess and manage symptoms and their impact on work, with the help of employers, to improve the quality of work life of BCS receiving AET.

Germline mutations and copy number changes in DNA damage repair (DDR) genes such as BRCA2 are associated with aggressive forms of prostate cancer (PCa). Although the prevalence of BRCA2 variants in PCa is increasing in Japan, the genomic and biological implications in Japanese patients are unclear. An 81‐year‐old male presented with prostatic adenocarcinoma with neuroendocrine differentiation accompanied by metastatic lung nodule and brain metastases. Platinum‐based doublet chemotherapy combined with etoposide resulted in partial and complete remissions of brain and lung metastases, respectively. Next‐generation sequencing of biopsy and peripheral blood samples demonstrated a somatic BRCA2 mutation at c.7008‐2A>C and a germline mutation at p.E2877*. The patient's son had been diagnosed with breast cancer 2.5 years ago and was found to have the same germline BRCA2 mutation. BRCA2 mutation increases the risks of aggressive PCa and other cancer types in Japanese males. These forms may be highly responsive to platinum‐based chemotherapy.

DNA methylation is a typical epigenetic phenomenon. Numerous methods for detecting global DNA methylation levels have been developed, among which LC-MS/MS has emerged as an excellent method from the viewpoint of sensitivity, reproducibility, and cost. However, LC-MS/MS methods have limitations due to a lack of the stability and the standardization required for a laboratory assay. The present study aimed to establish a robust assay that guarantees highly accurate measurements of global DNA methylation levels. There are at least three facets of the developed method. The first is discovery of the solvent conditions to minimize sodium adducts. The second is improvement of separation of nucleosides by LC using the columns that had not been used in previous similar studies. The third is success in reduction of the uncertainty of the measurement results, which was achieved by the calibration using the ratio of mdC but not the absolute amount in the presence of internal standards. These facets represent the advantage over methods reported previously. Our developed method enables quantification of DNA methylation with a short time length (8 min) for one analysis as well as with the high reproducibility of measurements that is represented by the inter-day CV% being less than 5%. In addition, data obtained from measuring global DNA methylation levels in cultured cell lines, with or without pharmacological demethylation, support its use for biomedical research. This assay is expected to allow us to conduct initial screening of epigenetic alterations or aberration in a variety of cells.

Current immunohistochemistry methods for diagnosing abnormal cells, such as cancer cells, require multiple steps and can be relatively slow compared with intraoperative frozen hematoxylin and eosin staining, and are therefore rarely used for intraoperative examination. Thus, there is a need for novel rapid detection methods. We previously demonstrated that functionalized fluorescent ferrite beads (FF beads) magnetically promoted rapid immunoreactions. The aim of this study was to improve the magnetically promoted rapid immunoreaction method using antibody-coated FF beads and a magnet subjected to a magnetic field. Using frozen sections of xenograft samples of A431 human epidermoid cancer cells that express high levels of epidermal growth factor receptor (EGFR) and anti-EGFR antibody-coated FF beads, we reduced the magnetically promoted immunohistochemistry procedure to a 1-min reaction and 1-min wash. We also determined the optimum magnetic force for the antibody reaction (from 7.79 × 10−15 N to 3.35 × 10−15 N) and washing (4.78 × 10−16 N), which are important steps in this technique. Furthermore, we stained paraffin-embedded tissue arrays and frozen sections of metastatic breast cancer lymph nodes with anti-pan-cytokeratin antibody-coated FF beads to validate the utility of this system in clinical specimens. Under optimal conditions, this ultra-rapid immunostaining method may provide an ancillary method for pathological diagnosis during surgery. (J Histochem Cytochem 58:XXX–XXX, 2010)

This paper presents CoSummary, an adaptive video fast-forwarding technique for browsing surgical videos recorded by wearable cameras. Current wearable technologies allow us to record complex surgical skills, however, an efficient browsing technique for these videos is not well established. In order to assist browsing surgical videos, our study focuses on adaptively changing playback speeds through the learning and detecting collaborative scenes based on surgeon hand placement and gaze information. Our evaluation shows that the proposed method is able to highlight important collaborative scenes and skip less important scenes during surgical procedures. We have also performed a subjective study with surgeons in order to have professional feedback. The results confirmed the effectiveness of the proposed method in comparison to uniform video fast-forwarding.

[Background]In adjuvant settings of HER2 positive cancer, trastuzumab has been shown to be effective in combination with anthracycline- based chemotherapy followed by taxane-based chemotherapy. However, the role of anthracyclines for the treatment of breast cancer has remained in controversy,due to the increased risk of cardiotoxicity and secondary carcinogenesis. Recently, additional anthracycline-free treatment regimens have also been reported. In a single-arm multicenter trial of 406 patients treated with paclitaxel plus trastuzumab for Citation Format: Watanuki R, Hayashida T, Yuko K, Kikuchi M, Nakashoji A, Yokoe T, Toyota T, Seki T, Takahashi M, Kitagawa Y. Optimal omission of anthracycline in adjuvant chemotherapy of HER2 positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-11.

Assessing Erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification status in breast and gastric cancer is necessary for deciding the best therapeutic strategy. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are currently used for assessing protein levels and gene copy number (CN), respectively. The use of next-generation sequencing (NGS) to measure ERBB2 CN in breast cancer is approved by the United States Federal Drug Administration as a companion diagnostic. However, a CN of less than 8 is evaluated as “equivocal”, which means that some ERBB2 amplification cases diagnosed as “HER2 negative” might be false-negative cases. We reviewed the results of gene profiling targeting 160 cancer-related genes in breast (N = 90) and non-breast (N = 19) cancer tissue, and compared the ERBB2 CN results with the IHC/FISH scores. We obtained an estimated CN from the measured CN by factoring in the histological proportion of tumor cells and found that an ERBB2-estimated CN of 3.2 or higher was concordant with the combined IHC/FISH outcome in 98.4% (88/90) of breast cancer cases, while this was not always evident among non-breast cancer cases. Therefore, NGS-estimated ERBB2 CN could be considered a diagnostic test for anti-HER2 therapy after the completion of adequate prospective clinical trials.

Cancer chemoprevention is defined as the use of natural, synthetic, or biochemical agents to reverse, suppress, or prevent carcinogenic processes in neoplastic diseases. Although the precise mechanisms that promote breast cancer are not fully understood, several recent clinical trials suggest that chemoprevention is a rational and attractive strategy for selected high-risk populations in a prophylactic setting. Conventionally, endocrine interventions using selective estrogen receptor modulators and aromatase inhibitors have already been applied clinically in high-risk populations. In particular, the chemoprevention approach for BRCA germline mutation carriers is drawing attention as an alternative option to invasive prophylactic mastectomy. Although the evidence from prospective clinical studies was limited, this review aims to provide an up-to-date overview of the biological mechanisms and the efficacy of various chemopreventive agents, including new promising candidates that target BRCA deficiency, and discuss future challenges and prospects for breast cancer chemoprevention.

e12576 Background: From the results of ACOSOG Z0011, IBCSG23-01 and AMAROS trials, axilla surgery in node-positive breast cancer (BC) tends to be less invasive with sentinel node biopsy (SNB) followed by adjuvant therapy and regional node irradiation (RNI). However, optimized axilla treatment including SNB without RNI is still debated. The Japanese Society for Sentinel Node Navigation Surgery conducted a multi-institutional prospective cohort study to compare SNB with SNB followed by axillary lymph node dissection (ALND) in cases with positive-sentinel lymph nodes (SLN)(UMIN No. 000011782, Jpn J Clin Oncol, p.876-9, 2014). Methods: Female BC patients with cT1-3N0-1M0 were eligible. When 1 to 3 positive micrometastases or macrometastases in SLN were confirmed by histological or molecular diagnosis, SNB alone or additional ALND had been decided by physician’s discretion. Primary chemotherapy before or after SNB was acceptable for registration. Lymph node sampling was also allowed in the SNB group. Cases with bilateral BC, isolated tumor cells only in SLN, past history of invasive cancer within 5 years at the registration were ineligible. The primary endpoint was the 5-year recurrence rate of regional node (RN) in the SNB group. The secondary endpoint was overall survival (OS). We planned to collect 240 patients to reject that the 5-year recurrence rate of RN was more than 10% assuming the rate 5%. To compare the SNB group and ALND group, the propensity score matching (PSM) was performed. Matching variables were initial treatment, metastatic size and numbers of SLN, clinical stage, age, body mass index, menopausal status, family history, past history of invasive cancer, breast surgery. Results: Eight-hundred eighty cases had been registered between 2013 and 2016. In the 871 eligible cases, 308 cases were the SNB group. At the median follow-up of 6.3 years, 5-year recurrence rate of RN was 2.7% [95% confidence interval, 1.4% to 5.4%] and 5-year OS was 97.6% [94.9% to 98.8%]. After PSM, 209 cases were matched in the SNB and ALND group. Among them, 343 cases (82%) received operation at initial treatment. Partial and total mastectomy was performed in 225 (54%) and 193 cases (46%), respectively. One-positive SLN was recorded in 366 cases (88%), 2 in 48 (11%) and 3 in 4 (1%). Macrometastases and micrometastases in SLN were diagnosed in 271 (65%) and 147 cases (35%), respectively. Three-hundred seventy-six cases (90%) belonged to luminal-like subtype. RNI was underwent in 42 cases (20%) of the SNB group and 13 cases (6%) of the ALND group. Five-year recurrence rate of RN was 2.1% [0.8% to 5.5%] and 2.0% [0.8% to 5.3%] for the SNB and ALND group, respectively. Conclusions: Our series suggests that RNI is not necessary for regional control in cases with 1 to 3 positive SLN. In conclusion, SNB alone is acceptable in cases with fewer metastatic SLN. Clinical trial information: UMIN No. 000011782.

The homeobox (HOX) family consists of 39 genes whose expressions are tightly controlled and coordinated within the family, during development. We performed a comprehensive analysis of this gene family in cancer settings. Gene correlation analysis was performed using breast cancer data available in The Cancer Genome Atlas (TCGA) and data from the patients admitted to our hospital. We also analyzed the data of normal breast tissue (GSE20437). We next collected gene expression and prognosis data of breast cancer patients (GSE11121, GSE7390, GSE3494, and GSE2990) and performed unsupervised hierarchal clustering by the HOX gene expression pattern and compared prognosis. We additionally performed this analysis to leukemia (available in TCGA) and sarcoma (GSE20196) data. Gene correlation analysis showed that the proximal HOX genes exhibit strong interactions and are expressed together in breast cancer, similar to the expression observed during development. However, in normal breast tissue, less interactions were observed. Breast cancer microarray meta-data classified by the HOX gene expression pattern predicted the prognosis of luminal B breast cancer patients (p = 0.016). Leukemia (p = 0.00016) and sarcoma (p = 0.018) presented similar results. The Wnt signaling pathway, one of the major upstream signals of HOX genes in development, was activated in the poor prognostic group. Interestingly, poor prognostic cancer presented stronger correlation in the gene family compared to favorable prognostic cancer. Comprehensive analysis of the HOX family demonstrated their similar roles in cancer and development, and indicated that the strong interaction of HOX genes might be specific to malignancies, especially in the case of poor prognostic cancer.

Eribulin mesylate (eribulin) is an efficient microtubule inhibitor that is used for metastatic breast cancer. However, breast cancer can develop resistance to eribulin. This resistance mechanism needs to be elucidated. A transposon mutagenesis screen was conducted using a pPB-SB-CMV-puro-SD plasmid and pCMV-PBase transposase. Viability and cytotoxicity were analyzed by MTT assay and flow cytometry, respectively. Real-time PCR and western blot were used for gene expression analysis. In addition, vivo study was also designed to analyze therapy efficiency. TAB2, which is part of the nuclear factor-kappa B (NF-κB) pathway, was identified as a candidate eribulin-resistant gene. TAB2 down-regulation resulted in significantly lower cell viability and higher cytotoxicity of cells treated with eribulin, while TAB2 up-regulation showed opposite results. Similarly, combination of NF-κB inhibitors [Bay-117082 and QNZ (quinazoline derivative)] with eribulin showed significantly lower cell viability and higher drug cytotoxicity than single agent treatment with eribulin in MDA-MB-231 cells. However, QNZ increased NF-κB activity in MCF7 cells by up-regulating TAB2, which reduced the sensitivity to eribulin. Furthermore, combination of Bay-117082 with eribulin induced greater regression of MDA-MB-231 tumors compared to eribulin monotherapy in vivo. These results consistently illustrated that TAB2-NF-κB pathway may increases resistance to eribulin in breast cancer models. Moreover, these results support the use of a combination strategy of eribulin with NF-κB inhibitors, and provide evidence that transposon mutagenesis screens are capable of identifying drug-resistant genes.

Purpose It has been suggested that the biologic characteristics of breast cancer may differ among different geographic or ethnic populations. Indeed, triple-negative breast cancer (TNBC), the most lethal breast cancer subgroup, has been reported to occur at a higher incidence in Japan than in the United States. However, most genomic studies of these tumors are from Western countries, and the genomic landscape of TNBC in an Asian population has not been thoroughly investigated. Here, we sought to elucidate the geographic and ethnic diversity of breast cancer by examining actionable driver alterations in TNBC tumors from Japanese patients and comparing them with The Cancer Genome Atlas (TCGA) database, which gathers data primarily from non-Asian patients. Materials and Methods We performed comprehensive genomic profiling, including an analysis of 435 known cancer genes, among Japanese patients with TNBC (n = 53) and compared the results with independent data obtained from TCGA (n = 123). Results Driver alterations were identified in 51 (96%) of 53 Japanese patients. Although the overall alteration spectrum among Japanese patients was similar to that of TCGA, we found significant differences in the frequencies of alterations in MYC and PTK2. We identified three patients (5.7%) with a high tumor mutational burden, although no microsatellite instability was observed in any of the Japanese patients. Importantly, pathway analysis revealed that 66.0% (35 of 53) of Japanese patients, as well as 66.7% (82 of 123) of TCGA cohort, had alterations in at least one actionable gene targetable by US Food and Drug Administration–approved drug. Conclusion Our study identified actionable driver alterations in Japanese patients with TNBC, revealing new opportunities for targeted therapies in Asian patients.

Many driver pathways for cancer cell proliferation have been reported. Driver pathway activation is often evaluated based on a single hotspot mutation such as EGFR L858R. However, because of complex intratumoral networks, the impact of a driver pathway cannot be predicted based on only a single gene mutation. Here, we developed a novel diagnostic system named the “EGFR impact score” which is based on multiplex mRNA expression profiles, which can predict the impact of the EGFR pathway in lung cancer cells and the effect of EGFR-tyrosine kinase inhibitors on malignancy. The EGFR impact score indicated robust predictive power for the prognosis of early-stage lung cancer because this score can evaluate the impact of the EGFR pathway on the tumor and genomic instability. Additionally, the molecular features of the poor prognostic group resembled those of biomarkers associated with immune checkpoint inhibitors. The EGFR impact score is a novel prognostic and therapeutic indicator for lung adenocarcinoma.

Background/aim The present study assessed whether and how tumor cells undergoing hypoxia contribute to disease progression after moving to areas with different oxygen conditions. Materials and methods Human colorectal carcinoma HCT116 cells cultured under mild hypoxia were subjected to in vivo experiments using transfer to immunodeficient murine recipients and to in vitro experiments using pharmacological inhibition of fatty acid β-oxidation (FAO). Results Bone involvement and hepatic metastases were accelerated in transfer models of hypoxically cultured HCT116 cells. Hypoxic HCT116 cells exhibited FAO-dependent glycogen synthesis. FAO-dependent and -independent induction of gene expression also occurred under hypoxia. The distribution of glucose transporter 1 expression compared with heme oxygenase 1 expression in HCT116 cell spheroids seemed consistent with differential dependence of hypoxic expression of these molecules on FAO. Conclusion These results provide insights into the contribution of hypoxia to tumor progression and the relevance of FAO.