Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Everolimus, a mammalian target of rapamycin inhibitor used as an antineoplastic drug, is associated with a remarkably high incidence of interstitial lung disease (ILD). The clinical and pathological characteristics of ILD caused by everolimus have not been thoroughly investigated; therefore, we aimed to elucidate the features of everolimus-associated ILD. METHODS: We retrospectively reviewed the medical records of patients who received everolimus for cancer treatment at our hospital. Patient backgrounds were compared between the ILD and non-ILD groups. Chest computed tomography (CT), changes in biomarkers, and lung histopathological features were analyzed for ILD cases. RESULTS: Sixty-six patients were reviewed, and ILD developed in 19. There were no differences in patient demographics between the ILD and non-ILD groups. The severity of ILD was grade 1 (G1) in 9 and grade 2 (G2) in 10 cases. Chest CT showed organizing pneumonia (OP) or a hypersensitive pneumonia pattern. The levels of lactate dehydrogenase, C-reactive protein, Krebs von den lungen-6, and surfactant protein-D (SP-D) at the onset of ILD were significantly higher than those at baseline. Analysis of G1 and G2 ILD subgroups showed a higher SP-D levels in the G2 subgroup. Five patients underwent lung biopsies; all specimens demonstrated alveolitis with lymphocytic infiltration and granulomatous lesions, and some had OP findings. CONCLUSIONS: Everolimus-associated ILD is mild and has a favorable prognosis. Patients with symptomatic ILD were more likely to have higher SP-D levels than those with asymptomatic ILD. Granulomatous lesions are an important pathological feature of everolimus-associated ILD.

DOI： 10.1272/jnms.JNMS.2024_91-211

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INTRODUCTION: Solid papillary carcinoma (SPC) accounts for approximately 1% of all breast cancer cases and occurs primarily in postmenopausal women. We report a rare SPC with invasion in the male breast. CASE PRESENTATION: A 73-year-old Japanese man presented with bloody nipple discharge and a palpable left breast mass. Mammography revealed a well-defined high-concentration mass. Ultrasonography scans demonstrated an intracystic 10 mm mass under the left nipple without enlarged axillary lymph nodes. A core needle biopsy revealed a ductal carcinoma with nuclear grade 1, which excluded an invasive carcinoma. Magnetic resonance imaging exhibited a 7 mm intense early enhancement in the left breast. A left mastectomy and sentinel lymph node biopsy were performed. The patient was diagnosed with pathological stage IA (T1b N0 M0) breast carcinoma, an invasive pure SPC type without neuroendocrine markers. The patient was treated with oral tamoxifen and survived without any recurrence for 12 months. CONCLUSION: Invasive SPC of the male breast may occur as a palpable mass or nipple discharge in older men and has a good prognosis.

DOI： 10.1159/000536034

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PURPOSE: This study aimed to evaluate the clinical usefulness of a deep learning-based computer-aided detection (CADe) system for breast ultrasound. METHODS: The set of 88 training images was expanded to 14,000 positive images and 50,000 negative images. The CADe system was trained to detect lesions in real- time using deep learning with an improved model of YOLOv3-tiny. Eighteen readers evaluated 52 test image sets with and without CADe. Jackknife alternative free-response receiver operating characteristic analysis was used to estimate the effectiveness of this system in improving lesion detection. RESULT: The area under the curve (AUC) for image sets was 0.7726 with CADe and 0.6304 without CADe, with a 0.1422 difference, indicating that with CADe was significantly higher than that without CADe (p < 0.0001). The sensitivity per case was higher with CADe (95.4%) than without CADe (83.7%). The specificity of suspected breast cancer cases with CADe (86.6%) was higher than that without CADe (65.7%). The number of false positives per case (FPC) was lower with CADe (0.22) than without CADe (0.43). CONCLUSION: The use of a deep learning-based CADe system for breast ultrasound by readers significantly improved their reading ability. This system is expected to contribute to highly accurate breast cancer screening and diagnosis.

DOI： 10.1007/s10396-023-01332-9

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Authorship：Corresponding author   Language：Japanese  

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BACKGROUND: Among younger patients, one of the important concerns is whether they can give birth safely. Although previous studies have investigated this topic, many aspects remain unclear owing to potential biases. We aimed to evaluate the prognostic effect of subsequent childbirth after the diagnosis using propensity score matching. METHODS: A single-center retrospective cohort study was conducted. This study included patients aged ≤ 45 years, diagnosed with breast cancer between 2005 and 2014. Patients with and without subsequent childbirth were assigned to the childbirth and non-childbirth cohorts, respectively. Relapse-free survival (RFS) and overall survival (OS) of the childbirth cohort were compared with those of the non-childbirth cohort. The covariates in the propensity score model included age, tumor size, node status, number of preceding childbirths before the diagnosis, estrogen receptor, and human epidermal growth factor receptor 2 status. RESULTS: 104 patients with childbirth and 2250 without childbirth were assigned to the respective cohorts. At a median follow-up of 82 months, the childbirth cohort showed a significantly longer RFS than the non-childbirth cohort (HR = 0.469 [0.221-0.992]; p = 0.047). There was no significant difference in the OS (HR = 0.208 [0.029-1.494]; p = 0.119). After matching, subsequent childbirth was not significantly associated with RFS (HR = 0.436 [0.163-1.164], p = 0.098) and OS (HR = 0.372 [0.033-4.134], p = 0.402). CONCLUSIONS: Subsequent childbirth was not associated with an increased risk of relapse and mortality. It is important to make younger patients aware of these novel findings and aid them in their decision-making.

DOI： 10.1007/s12282-022-01429-y

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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.

DOI： 10.1200/JCO.22.00577

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Language：Japanese   Publisher：(株)篠原出版新社  

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Language：Japanese   Publisher：(一社)日本外科学会  

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BACKGROUND: Radiation-induced sarcoma (RIS) has a 10-year incidence of 0.2-0.27% and a poor prognosis, although the radiation should need for breast-conserving surgery. In particular, radiation-induced fibrosarcoma has been rarer, and its incidence is 2.6-3.7% of RIS. CASE PRESENTATION: A 43-year-old woman with pT1N1M0 breast cancer underwent breast-conserving surgery, chemotherapy, radiation therapy 8 years ago, and continued hormonal therapy. She complained of a hard unprotruded mass palpated in her right upper outer quadrant of breast. Although we suspected local recurrence, core needle biopsy revealed atypical spindled tumor cells without mammary or epithelial markers. A diagnosis of fibrosarcoma was made via tumorectomy. She underwent additional enlarged surgery. CONCLUSIONS: We report a rare case of fibrosarcoma in breast after breast-conserving surgery and radiation therapy. Fibrosarcoma after radiation therapy for breast cancer has been reported in 30 cases, including the present case. The dead and alive cases were not significantly different in terms of age, primary breast cancer, radiation dose, and following months. Patients with breast masses after radiation therapy should be suspected local recurrence and RIS.

DOI： 10.1186/s40792-023-01629-4

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A 52-year-old female with stage Ⅳ, bilateral, HER2-positive, breast cancer as well as bilateral axillary lymph node(LN) metastasis and bilateral pulmonary metastasis was administered trastuzumab plus pertuzumab plus docetaxel as a standard chemotherapy. After this treatment the right breast cancer, right axillary LN metastasis, and bilateral pulmonary metastases contracted, while the left breast cancer and left axillary LN metastasis expanded. Trastuzumab emtansine was then administered, and the left axillary LN metastasis contracted, however, the left breast cancer expanded, resulting in marked breast engorgement. When trastuzumab deruxtecan(T-DXd)was administered, the left breast cancer contracted for the first time during the overall treatment process, and the signs of breast inflammation disappeared. Other lesions showed no recrudescence. T-DXd was administered seven times, and, at the stage of maximum contraction during the treatment period, a total left mastectomy and left axillary LN dissection were performed. Pathological examination then confirmed that tumor cells were no longer present in the left breast and left axillary LN. In this case T-DXd was highly effective for the local treatment of intractable, HER2-positive, breast cancer.

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00296&link_issn=&doc_id=20230324430010&doc_link_id=%2Fab8gtkrc%2F2023%2F005003%2F011%2F0327-0331%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2023%2F005003%2F011%2F0327-0331%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Our case involved a 66-year-old woman who noticed progressive asymmetric involuntary movement, difficulty speaking, and difficulty swallowing. The patient fractured her femur due to a lower extremity involuntary movement while walking. During the course of her treatment for the fracture, her neurological symptoms worsened. Approximately 2 months after becoming aware of her symptoms, she visited our clinic for evaluation of difficulty with unassisted walking and weight loss due to dysphagia. To identify the cause of her neurological symptoms, hematological examination, brain magnetic resonance imaging, single-photon emission computed tomography for cerebral blood flow, electroencephalography, and a somatosensory evoked potential test were conducted. Although the cause of her neurological symptoms could not be determined, computed tomography revealed the presence of breast cancer, which led us to suspect paraneoplastic neurological syndrome (PNS). After breast cancer treatment, her neurological symptoms improved simultaneously. Therefore, the patient was retrospectively diagnosed with PNS. We report a case of PNS whose neurological symptoms followed a subacute course and were relieved after breast cancer treatment.

DOI： 10.1272/jnms.JNMS.2023_90-608

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Language：Japanese   Publisher：金原出版(株)  

＜文献概要＞皮膚悪性腫瘍と他臓器悪性腫瘍の合併はときにみられるが,ともに進行癌の場合は治療に難渋する。症例は72歳,女性。幼少期に受傷した右上肢の熱傷瘢痕から有棘細胞癌が出現し,また所属外リンパ節転移を有するStage IVの右乳癌も重複していた。右上肢からの出血量が多く輸血を要したため,有棘細胞癌の手術を優先した。1cmマージンで切除し,植皮で再建したが,同部位に局所再発がみられ再切除した。乳癌は内分泌療法を施行し,腫瘍・リンパ節の著明な縮小がみられたため,乳房切除,右腋窩リンパ節郭清術を施行した。現在,有棘細胞癌,乳癌ともに完全奏効の状態である。重複癌をきたした場合,予後規定因子やQOL(生活の質)などを踏まえたうえで治療の優先順位を決定することが重要となる。

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This exploratory study compared doses of ferucarbotran, a superparamagnetic iron oxide nanoparticle, in sentinel lymph nodes (SLNs) and quantified the SLN iron load by dose and localization. Eighteen females aged ≥20 years scheduled for an SLN biopsy with node-negative breast cancer were divided into two equal groups and administered either 1 mL or 0.5 mL ferucarbotran. Iron content was evaluated with a handheld magnetometer and quantification device. The average iron content was 42.8 µg (range, 1.3-95.0; 0.15% of the injected dose) and 21.9 µg (1.1-71.0; 0.16%) in the 1-mL and 0.5-mL groups, respectively (p = 0.131). The iron content of the closest SLN compared to the second SLN was 53.0 vs. 10.0 µg (19% of the injected dose) and 34.8 vs. 4.1 µg (11.1%) for the 1-mL and 0.5-mL groups, respectively (p = 0.001 for both). The magnetic field was high in both groups (average 7.30 µT and 6.00 µT in the 1-mL and 0.5-mL groups, respectively) but was not statistically significant (p = 0.918). The magnetic field and iron content were correlated (overall SLNs, p = 0.02; 1-mL, p = 0.014; 0.5-mL, p = 0.010). A 0.5-mL dose was sufficient for SLN identification. Primary and secondary SLNs could be differentiated based on iron content. Handheld magnetometers could be used to assess the SLN iron content.

DOI： 10.3390/cancers14061409

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BACKGROUND/AIM: Carboxyl terminus of Hsc70-interacting protein (CHIP) is a ubiquitin ligase that induces ubiquitination and degradation of its target proteins including oncoproteins. We reported that its down-regulation is associated with tumor progression and metastasis of breast cancer. However, the mechanism through which CHIP gene affects cancer cells is unclear. MATERIALS AND METHODS: We extracted RNA from 45 primary breast cancer samples and compared CHIP mRNA expression profiles, promoter DNA methylation status, and clinicopathological information. RESULTS: CHIP mRNA expression was significantly correlated with the tumor progression status. In several samples, a pinpoint CpG methylation in the CHIP gene promoter region was significantly correlated with CHIP mRNA expression. When this specific CpG was methylated in estrogen receptor (ER)-positive cases, a significant difference in 5-year recurrence was not found compared with ER-negative cases. CONCLUSION: CpG methylation contributes to the long-term prognosis of ER-positive breast cancer.

DOI： 10.21873/anticanres.15534

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Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and its effectiveness in treating TNBCs are not fully understood. We analyzed the effects of decitabine on nine TNBC cell lines and examined genes associated with its cytotoxic effects. According to the effect of decitabine, we classified the cell lines into cell death (D)-type, growth inhibition (G)-type, and resistant (R)-type. In D-type cells, decitabine induced the expression of apoptotic regulators and, among them, NOXA was functionally involved in decitabine-induced apoptosis. In G-type cells, induction of the cyclin-dependent kinase inhibitor, p21, and cell cycle arrest were observed. Furthermore, decitabine enhanced the cytotoxic effect of cisplatin mediated by NOXA in D-type and G-type cells. In contrast, the sensitivity to cisplatin was high in R-type cells, and no enhancing effect by decitabine was observed. These results indicate that decitabine enhances the proapoptotic effect of cisplatin on TNBC cell lines that are less sensitive to cisplatin, indicating the potential for combination therapy in TNBC.

DOI： 10.3390/cancers14010248

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Authorship：Lead author   Language：Japanese  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J00421&link_issn=&doc_id=20211214080003&doc_link_id=10.11477%2Fmf.1543208579&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1543208579&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

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Safe and noninvasive methods for breast cancer screening with improved accuracy are urgently needed. Volatile organic compounds (VOCs) in biological samples such as breath and blood have been investigated as noninvasive novel markers of cancer. We investigated volatile organic compounds in urine to assess their potential for the detection of breast cancer. One hundred and ten women with biopsy-proven breast cancer and 177 healthy volunteers were enrolled. The subjects were divided into two groups: a training set and an external validation set. Urine samples were collected and analyzed by gas chromatography and mass spectrometry. A predictive model was constructed by multivariate analysis, and the sensitivity and specificity of the model were confirmed using both a training set and an external set with reproducibility tests. The training set included 60 breast cancer patients (age 34-88 years, mean 60.3) and 60 healthy controls (age 34-81 years, mean 58.7). The external validation set included 50 breast cancer patients (age 35-85 years, mean 58.8) and 117 healthy controls (age 18-84 years, mean 51.2). One hundred and ninety-one compounds detected in at least 80% of the samples from the training set were used for further analysis. The predictive model that best-detected breast cancer at various clinical stages was constructed using a combination of two of the compounds, 2-propanol and 2-butanone. The sensitivity and specificity in the training set were 93.3% and 83.3%, respectively. Triplicated reproducibility tests were performed by randomly choosing ten samples from each group, and the results showed a matching rate of 100% for the breast cancer patient group and 90% for the healthy control group. Our prediction model using two VOCs is a useful complement to the current diagnostic tools. Further studies inclusive of benign tumors and non-breast malignancies are warranted.

DOI： 10.1038/s41598-021-99396-5

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: A retrospective study of the real-world use of neoadjuvant endocrine therapy (NET) is important for standardizing the role of NET in breast cancer care. METHODS: In a consecutive series of women with operable breast cancer who received NET for ≥28 days, associations of NET objectives, NET outcomes, adjuvant chemotherapy use after NET, and survival with clinicopathological factors were examined. RESULTS: NET objectives were reduction in surgical extent in 49 patients, avoidance of surgery in 31, and treatment until scheduled surgery in 8. The mean duration of NET was 349.5 (range, 34-1,923), 869.8 (range, 36-4,859), and 55.8 (range, 39-113) days, respectively, in these cohorts (success rate: 79.6%, 64.5%, and 100%, respectively), and the differences were significant. Among patients in the former two cohorts, progression-free survival was significantly better in patients with stage 0 or I disease, ductal carcinoma in situ or invasive ductal carcinoma, ≥71% estrogen receptor (ER) positivity, and the surgical extent reduction cohort than the other counterparts. Postoperative chemotherapy use was significantly associated with lymph node metastasis, a high Ki67 labeling index, lymphovascular invasion, and a high preoperative endocrine prognostic index at the time of surgery after NET. Better recurrence-free survival after surgery was significantly associated with high ER expression after NET or high progesterone receptor expression before or after NET. CONCLUSIONS: NET can help reduce surgical extent or avoid surgery in women with early breast cancer, ductal carcinoma, or high ER expression. NET may also aid in decisions related to postoperative systemic therapy to improve survival.

File： JNMS-20-1213.R1_Proof_hi.pdf

DOI： 10.1272/jnms.JNMS.2021_88-603

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BACKGROUND: Neoadjuvant chemotherapy (NAC) is standard therapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer (HER2 + ve BC). There are concerns about the accurate imaging modalities to measure residual tumor during or after NAC. Up to now no standard imaging method for monitoring the efficacy of NAC has been established, and few reports showed ultrasonographic change. We aimed to assess the echogenicity in ultrasonography (US) as the predictive marker of pathological complete response (pCR) for not only TNBC, but also HER2 + ve BC. Furthermore, we also investigated the change in depth (D) and width (W) of the tumor as the predictive value of pCR. METHODS: We retrospectively reviewed a consecutive 59 patients with TNBC and 41 patients with HER2 + ve BC who received NAC. In all of 100 patients, echogenicity, D and W of the tumor were measured before (pre-NAC) and after NAC (post-NAC). The tumor echogenicity was measured at representative region of interest (ROI), and calculated as the relative comparative assessment with fat echogenicity (ROI ratio). RESULTS: pCR was significantly associated with higher post-NAC ROI ratio in TNBC (p = 0.010), while there was no association in HER2 + ve BC (p = 0.885). pCR was significantly associated with smaller sizes of post-NAC D and W in TNBC (p = 0.001, 0.003), while no trend was observed in HER2 + ve BC (p = 0.259, 0.435). The area under the curve (AUC) for post-NAC ROI ratio and D were 0.701, 0.755, respectively. Combined with them, AUC became higher up to 0.762. CONCLUSION: TNBC and HER2 + ve BC showed different morphologic features of residual disease. Echogenicity and tumor size after NAC were both useful to predict pCR for TNBC, but not HER2 + ve BC. In future, radiological imaging needs to be analyzed in terms of breast cancer subtypes.

DOI： 10.1007/s12282-021-01220-5

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BACKGROUND: Breast cancer is a leading cause of cancer death worldwide. Several studies have demonstrated that dogs can sniff and detect cancer in the breath or urine sample of a patient. This study aims to assess whether the urine sample can be used for breast cancer screening by its fingerprints of volatile organic compounds using a single trained sniffer dog. This is a preliminary study for developing the "electronic nose" for cancer screening. METHODS: A nine-year-old female Labrador Retriever was trained to identify cancer from urine samples of breast cancer patients. Urine samples from patients histologically diagnosed with primary breast cancer, those with non-breast malignant diseases, and healthy volunteers were obtained, and a double-blind test was performed. Total of 40 patients with breast cancer, 142 patients with non-breast malignant diseases, and 18 healthy volunteers were enrolled, and their urine samples were collected. RESULTS: In 40 times out of 40 runs of a double-blind test, the trained dog could correctly identify urine samples of breast cancer patients. Sensitivity and specificity of this breast cancer detection method using dog sniffing were both 100%. CONCLUSIONS: The trained dog in this study could accurately detect breast cancer from urine samples of breast cancer patients. These results indicate the feasibility of a method to detect breast cancer from urine samples using dog sniffing in the diagnosis of breast cancer. Although the methodological standardization is still an issue to be discussed, the current result warrants further study for developing a new breast cancer screening method based on volatile organic compounds in urine samples.

DOI： 10.3390/biology10060517

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Accurate pre-operative localization of nonpalpable lesions plays a pivotal role in guiding breast-conserving surgery (BCS). In this multicenter feasibility study, nonpalpable breast lesions were localized using a handheld magnetic probe (TAKUMI) and a magnetic marker (Guiding-Marker System®). The magnetic marker was preoperatively placed within the target lesion under ultrasound or stereo-guidance. Additionally, a dye was injected subcutaneously to indicate the extent of the tumor excision. Surgeons checked for the marker within the lesion using a magnetic probe. The magnetic probe could detect the guiding marker and accurately localize the target lesion intraoperatively. All patients with breast cancer underwent wide excision with a safety margin of ≥5 mm. The presence of the guiding-marker within the resected specimen was the primary outcome and the pathological margin status and re-excision rate were the secondary outcomes. Eighty-seven patients with nonpalpable lesions who underwent BCS, from January to March of 2019 and from January to July of 2020, were recruited. The magnetic marker was detected in all resected specimens. The surgical margin was positive only in 5/82 (6.1%) patients; these patients underwent re-excision. This feasibility study demonstrated that the magnetic guiding localization system is useful for the detection and excision of nonpalpable breast lesions.

DOI： 10.3390/cancers13122923

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BACKGROUND: PIK3CA is associated with tumor progression, and the prevalence of its mutation is high in breast cancer. Liquid biopsy offers convenient, non-invasive, and real-time insight into genetic alternation. In this study, we attempted to detect PIK3CA mutations in breast cancer patients through liquid biopsy. METHODS: We recruited patients with histologically confirmed breast cancer with distant metastases between April 2020 and September 2020. Circulating DNA was extracted from plasma (ctDNA) and exosomes (exoDNA). PIK3CA mutations (exons 9 and 20) were analyzed by droplet digital PCR. RESULTS: Of a total of 52 patients recruited, 16 had PIK3CA mutations in their tumor tissue or blood, which comprised 9 with exon 9 mutations (E542K and E545K) and 8 with exon 20 mutations (H1047L and H1047R). In 8 (15%) of the 52 patients, PIK3CA mutations were detected by liquid biopsies using ctDNA in 5 (9%), exoDNA in 6 (11%), and both ctDNA and exoDNA in 3 (6%). Of the 8 patients with PIK3CA mutations detected by liquid biopsies, 3 had no PIK3CA mutations in the primary tumors. CONCLUSIONS: PIK3CA mutations can be detected using liquid biopsy even in patients with no PIK3CA mutations in their primary tumors; thus, combination analysis using tissue and liquid biopsies can provide clinically useful information for patients with breast cancer.

DOI： 10.1272/jnms.JNMS.2022_89-107

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BACKGROUND: In patients undergoing mastectomy for locally advanced breast cancer (LABC), surgical skin flap reconstruction is sometimes required in order to cover large skin defects. This study assessed the efficacy of local, cutaneous (rhomboid) flap reconstruction after mastectomy by comparing data from patients with LABC requiring local flap reconstruction after mastectomy and those that underwent mastectomy alone. METHODS: Data from 68 patients with LABC who underwent mastectomy were reviewed retrospectively; 14 underwent local (rhomboid) flap reconstruction after mastectomy (local flap group) and 54 underwent direct closure after mastectomy (direct closure group). A pinch test was performed to determine the closure method. Data on the operation, postoperative complications, and postoperative quality of life (QOL) were compared between groups. RESULTS: It was possible to close defects in the local flap group that were significantly larger than those in the direct closure group (p=0.0002). There was no significant difference in postoperative complications between groups. Although operative duration was significantly longer in the local flap group than in the direct closure group (p=0.016), the average difference was only 25 minutes. There was no significant difference in variables related to postoperative QOL. CONCLUSIONS: Rhomboid flap reconstruction was effective for covering large defects after mastectomy in patients with LABC.

DOI： 10.1272/jnms.JNMS.2021_88-204

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To minimize the invasiveness and improve the patient's quality of life, sentinel lymph node (SLN) biopsy with magnetic nanoparticles (MNPs) containing superparamagnetic iron oxide is performed on breast cancer patients. Identifying the first SLN by quantification of the amount of MNPs can help to investigate the cancer metastasis. We developed the device for performing iron quantification during surgery. The compact desktop-size device can be easily introduced into operation rooms, and simple system of the device enables identification of the first SLN. We investigated the optimum nonlinear magnetic responses that are attributed to magnetic relaxations under moderate small ac and dc magnetic fields (1 mT) and found that ac magnetic fields with < 5 kHz are effective in the detection of MNPs. In addition, our clinical trials revealed more iron ( 40μg ) in the first lymph node than in the second lymph node ( 10μg ), clearly indicating intraoperative quantification in the first node.

DOI： 10.1109/TMAG.2020.3010641

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression, which play fundamental roles in cancer development. In this study, we found that homeobox A11 antisense RNA (HOXA11-AS), a highly expressed lncRNA in cell lines derived from prostate cancer bone metastases, promoted the cell invasion and proliferation of PC3 prostate cancer cells. Transcription factor homeobox B13 (HOXB13) was identified as an upstream regulator of HOXA11-AS.HOXA11-AS regulated bone metastasis-associated C-C motif chemokine ligand 2 (CCL2)/C-C chemokine receptor type 2 (CCR2) signaling in both PC3 prostate cancer cells and SaOS2 osteoblastic cells. The HOXB13/HOXA11-AS axis also regulated integrin subunits (ITGAV and ITGB1) specific to prostate cancer bone metastasis. HOXB13, in combination with HOXA11-AS, directly regulated the integrin-binding sialoprotein (IBSP) promoter. Furthermore, conditioned medium containing HOXA11-AS secreted from PC3 cells could induce the expression of CCL2 and IBSP in SaOS2 osteoblastic cells. These results suggest that prostate cancer HOXA11-AS and HOXB13 promote metastasis by regulation of CCL2/CCR2 cytokine and integrin signaling in autocrine and paracrine manners.

DOI： 10.3390/genes12020182

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OBJECTIVES: This study investigated harmonized pretreatment volume-based quantitative FDG-PET/CT parameters in breast cancer patients for prognostic value. RESULTS: During a median overall follow-up period of 5.3 years, 91 patients had recurrence and 40 died. Multivariate analysis of ER-positive/HER2-negative patients showed high maximum standardized uptake value (SUVmax) (p = 0.018), high total lesion glycolysis (TLG) (p = 0.010), and clinical N-classification (p = 0.0027) as independent negative predictors of RFS, while high maximum SUVmax (p = 0.037), advanced clinical T-classification (p = 0.030), and advanced TNM stage (p = 0.0067) were independent negative predictors of OS. For recurrence and death in HER2-positive patients, high total TLG (p = 0.037, p = 0.0048, respectively) and advanced TNM stage (p = 0.048, p = 0.046, respectively) were independent prediction factors. In the triple-negative group, independent factors related to recurrence and death were high maximum SUVmax (p = 0.0014, p = 0.0003, respectively) and advanced TNM stage (p < 0.0001, p < 0.0001, respectively). MATERIALS AND METHODS: Records of 546 stage I-III invasive breast cancer patients, including 344 estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 110 HER2-positive, and 92 triple-negative cases, treated at four institutions were reviewed retrospectively. Harmonized primary tumor and nodal maximum SUVmax, metabolic tumor volume (MTV), and TLG indicated in pretreatment FDG-PET/CT results were analyzed. Evaluations of relationships of clinicopathological factors, volume-based quantitative parameters, recurrence-free survival (RFS), and overall survival (OS) for each subtype were performed with a Cox proportional hazards model and log-rank test. CONCLUSIONS: The results indicated that potential surrogate markers for prognosis in patients with the three main subtypes of operable breast cancer include harmonized pretreatment quantitative volume-based FDG-PET/CT parameters, particularly whole-lesion SUVmax and TLG.

DOI： 10.18632/ONCOTARGET.27851

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BACKGROUND: Aortitis following granulocyte-colony stimulating factor (G-CSF) administration has been reported in 0.3-0.47% of cases. To evaluate the characteristics of G-CSF-associated aortitis, we systematically reviewed the literature. METHODS: We searched PubMed and found 49 cases of G-CSF-associated aortitis and cancer comorbidities and analyzed their characteristics and treatments. RESULTS: Since 2004, cases of G-CSF-associated aortitis have been increasing, particularly in Asia (75.5%). The mean age was 60.1 years; 79.6% of patients were 50 years and older; and most patients were females (91.8%). All patients underwent chemotherapy (taxane, 51.0%). The most frequent symptom was fever, which occurred within 10 days (61.2%) of G-CSF administration, similar to that in febrile neutropenia. The period to remission was within 14 days in 44.9% of cases. Steroids were administered to 59.2% of patients; however, treatment efficacy was not significant. No patients died. CONCLUSIONS: High levels of inflammatory cytokines might induce aortitis; however, further studies are warranted.

DOI： 10.1016/j.ctarc.2021.100454

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In the present study, we aimed to clarify features of carcinomatous cirrhosis from breast cancer presenting as refractory transudate ascites and acute liver failure. In our systematic literature review, we identified 26 studies and 31 cases including our case of this rare condition. Our patient was a 49-year-old woman with a history of ascites and liver failure for the past 4 years and currently being treated for invasive ductal breast cancer. On radiography, she had occult liver metastases that were confirmed using laparoscopic liver biopsy. In the 31 cases, data on the reported year, age, type of primary breast cancer, time from breast cancer diagnosis, presence of ascites and/or varices, liver biopsy, diagnostic modalities, outcomes, and survival were documented and analyzed. All cases were reported during 1984-2020, with a mean patient age of 52.9 years. Eighteen patients (58.1%) were diagnosed with ductal breast cancer. Twenty-two patients (70.9%) had ascites. All patients had gradual progression to liver dysfunction. The following tests were performed: computed tomography (77.4%); ultrasound (58.0%); liver biopsy (100%); postmortem biopsy (35.5%), transjugular liver biopsy (32.3%), and laparoscopic liver biopsy (3.2%). Outcomes were reported for 29 patients, of whom 24 (82.3%) died after 1 day to 16 months. Invasive ductal carcinoma was the most common histological type; however, invasive lobular carcinoma was more frequent (32.3%) than its reported incidence in the breast. Carcinomatous cirrhosis has poor prognosis at relatively rash and is difficult to diagnose with usual modalities. It may be associated with E-cadherin loss or CD44 pronouncement.

DOI： 10.1016/j.ctarc.2021.100388

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BACKGROUND: Neoadjuvant endocrine therapy is not the standard of care for breast cancer primarily because the optimal treatment duration remains unclear. This phase 2 prospective multicenter study analyzed time to progression, time to maximal response, and time to treatment failure of neoadjuvant exemestane. METHODS: Inclusion criteria were women aged ≥ 60 years with Stage II or III breast cancer classified as estrogen receptor-positive / human epidermal growth factor receptor 2-negative. Response was defined as a ≥ 10% (minimum of 3 mm) decrease in tumor size compared with the most recent or smallest value, and progression was defined either a new lesion or a ≥ 10% (minimum of 3 mm) increase in tumor size compared with the most recent or smallest value. Maximal response was defined as the final recorded response. RESULTS: This study included 24 women, most of whom had T2 N0 tumors with high estrogen receptor expression. We initially observed a response in 23 patients (96%); however, 6 patients (25%) later experience progression. Time to progression, time to maximal response, and time to treatment failure ranged from 7 to 22 months (estimated median, 35), 1 to 22 months (estimated median, 10), and 2 to 22 months (estimated median, 22), respectively. Treatment durations varied widely, but the estimated optimal duration of neoadjuvant exemestane therapy was 22 to 35 months in patients seeking to avoid surgery and 10 months in patients wishing to receive breast-conserving surgery. CONCLUSIONS: Neoadjuvant exemestane therapy is an effective strategy in older women with hormone-sensitive breast cancer.

File： SBCCSG10 NET TEXT JNMS revised3.docx

DOI： 10.1272/jnms.JNMS.2021_88-509

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

Drug-induced interstitial lung disease (DILD) has been occasionally reported with various causative drugs. In the context of breast cancer, anthracycline infrequently causes pulmonary adverse events. We report a 67-year-old woman with cT2N0M0 triple-negative breast cancer who received neoadjuvant chemotherapy with anthracycline-combined chemotherapy with pegfilgrastim. She developed fever, cough, and shortness of breath after 21 days of the scheduled fourth cycle of anthracycline. Computed tomography revealed drug-induced interstitial pneumonia. Prednisolone (1 mg/kg) was administrated and gradually decreased. Thereby, interstitial pneumonia quickly improved. Partial resection of the left breast and sentinel lymph node biopsy were performed, and we diagnosed ypT1bN0. The patient received 4 cycles of taxane and hypofractional radiotherapy and survived without any recurrences over the following 37 months. We report a rare case of DILD due to anthracycline-combined chemotherapy. Twenty-five cases of DILD with breast cancer after administration of anthracycline have been reported so far. However, 14 cases occurred during taxane. Most of the cases had remission by steroid treatment. The patients with respiratory symptoms during chemotherapy should be suspicious of not only infection but also DILD.

DOI： 10.1159/000520126

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BACKGROUND: The caudal type homeobox 2 transcription factor (CDX2) is a specific and sensitive marker for intestinal carcinoma, but usually not expressed in breast cancer. In CDX2-positive metastatic cancer of occult primary, the origin is highly suspicious of an enteric carcinoma. CASE PRESENTATION: A 50-year-old woman complained of enlarged lymph nodes (LNs) in the right axilla. Mammography and ultrasonography scans showed no abnormal findings in her breasts. Core needle biopsy (CNB) revealed metastatic adenocarcinoma. Immunohistochemical staining was positive for CDX2 intensely. The primary tumor was suspicious of intestinal adenocarcinoma. A dynamic contrast-enhanced magnetic resonance imaging scan revealed an accentuated lesion which was detected using a second-look ultrasound, and diagnosed invasive ductal carcinoma by CNB. A partial mastectomy of the right breast with level I and II axillary LN dissection was performed. A few cells of primary cancer were expressed CDX2 and estrogen receptor. The final pathological diagnosis was T1bN3aM0 stage IIIC. The fluorescent double staining showed that CDX2 simultaneously expressed on the Ki67 positive cells of metastatic tumors. The adjuvant treatment included chemotherapy and radiation, followed by tamoxifen administration. The patient survived without any recurrences over the following 36 months. CONCLUSIONS: We report a rare case of CDX2-positive metastatic breast cancer in the axillary LNs. As some literatures reported vitamin D pathways induced cancer cell apoptosis and inhibition, these metastatic cells of our case might play the effort of autoregulation of inhibiting progression.

DOI： 10.1016/j.ctarc.2020.100300

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Objective: The prognostic value of harmonized pretreatment volume-based quantitativefluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) parameters in metastatic breast cancer patients was investigated. Subjects and Methods: Records of 65 stage IV breast cancer patients, including 29 estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 23 HER2-positive, and 13 triple-negative cases, from four different institutions were retrospectively reviewed. Harmonized standardized uptake value (SUVmax) of the primary tumor (pSUVmax), highest SUVmax of all malignant lesions (wSUVmax), whole-body metabolic tumor volume (WB MTV), and whole-body total lesion glycolysis (WB TLG) shown by pretreatment 18F-FDG PET/CT imaging were calculated. Cox proportional hazards model and log-rank test results were used to evaluate relationships among clinicopathological factors, volume-based quantitative 18F-FDG PET/CT parameters, progression-free survival, and overall survival (OS). Results: Disease progression occurred in 54 patients and 28 died during a median follow-up period of 52.5 months (range 2.6-133.6 months). Univariate analysis of all cases showed associations of negative ER and progesterone receptor (PR) status (P=0.0025), and high T/N stage (P=0.037/P=0.019), pSUVmax (P=0.049), WB MTV (P=0.021), and WB TLG (P=0.0010) with significantly shorter OS. Multivariate analysis confirmed negative ER and PR status (hazard ratio [HR]: 6.42, 95% confidence interval [CI]: 2.27-19.38; P=0.0054), high T stage (HR: 5.10, 95% CI:1.96-18.61, P=0.0064) and WB TLG (HR: 4.69, 95% CI:1.67-12.79, P=0.049) as independent negative OS predictors. In two groups of ER-positive/HER2-negative and triple-negative, WB TLG had a significant association with death (P= 0.021 and P=0.037, respectively) on univariate analysis. In a HER2-positive group, no independent negative OS predictors were observed. Conclusion: In metastatic breast cancer patients, harmonized pretreatment quantitative volume-based 18F-FDG PET/CT parameters, especially whole-body TLG, are potential surrogate markers for prognosis.

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In the original publication of the article, the author group and acknowledgements were published incorrectly.

DOI： 10.1007/s12282-020-01106-y

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BACKGROUND: We suspected that moving a small neodymium magnet would promote migration of the magnetic tracer to the sentinel lymph node (SLN). Higher monitoring counts on the skin surface before making an incision help us detect SLNs easily and successfully. The present study evaluated the enhancement of the monitoring count on the skin surface in SLN detection based on the magnet movement in a sentinel lymph node biopsy (SNB) using superparamagnetic iron oxide (SPIO) nanoparticles. METHODS: After induction of general anesthesia, superparamagnetic iron oxide nanoparticles were injected sub-dermally into the subareolar area or peritumorally. The neodymium magnet was moved over the skin from the injection site to the axilla to promote migration of the magnetic tracer without massage. A total of 62 patients were enrolled from February 2018 to November 2018: 13 cases were subjected to magnet movement 20 times (Group A), 8 were subjected to 1-min magnet movement (Group B), 26 were given a short (about 5 min) interval from injection to 1-min magnet movement (Group C), and 15 were given a long (about 25 min) interval before 1-min magnet movement using the magnetometer's head (Group D). In all cases, an SNB was conducted using both the radioisotope (RI) and SPIO methods. The monitoring counts on the skin surface were measured by a handheld magnetometer and compared among the four groups. Changes in the monitoring count by the interval and magnet movement were evaluated. RESULTS: The identification rates of the SPIO and RI methods were 100 and 95.2%, respectively. The mean monitoring counts of Group A, B, C, and D were 2.39 μT, 2.73 μT, 3.15 μT, and 3.92 μT, respectively (p < 0.0001; Kruskal-Wallis test). The monitoring counts were higher with longer magnet movement and with the insertion of an interval. Although there were no relationships between the monitoring count on the skin surface and clinicopathologic factors, magnet movement strongly influenced the monitoring count on the skin surface. CONCLUSION: Moving a small neodymium magnet is effective for promoting migration of a magnetic tracer and increasing monitoring counts on the skin surface. TRIAL REGISTRATION: UMIN, UMIN000029475. Registered 9 October 2017.

DOI： 10.1186/s12880-020-00459-2

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The histological classification of breast tumors by the General Rule Committee of the Japanese Breast Cancer Society has been revised in the General Rules for Clinical and Pathological Recording of Breast Cancer (18th edition). In this article, the contents of the General Rules 18th edition are presented, and its revised points are briefly described in comparison with the classification of the General Rules 17th edition. The present classification takes into consideration the classification of breast tumors by the World Health Organization 4th edition, however, some differences remain. These differences will be briefly mentioned.

DOI： 10.1007/s12282-020-01074-3

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Publishing type：Research paper (international conference proceedings)   Publisher：American Association for Cancer Research  

DOI： 10.1158/1538-7445.sabcs19-p1-10-15

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Language：Japanese   Publisher：Japanese Society for Medical and Biological Engineering  

The quantitative detection of the magnetic nanoparticles (MNPs) in sentinel lymph nodes (SLNs) can help to diagnose cancer metastasis for breast cancer patients because the SLN (i.e., 1st SLN) containing the largest amount of the MNPs has the metastasis with the highest probability. In this study, we have optimized the frequency of alternating current (AC) magnetic fields under the application of direct current (DC) magnetic fields to achieve the highly-sensitive detection, and demonstrated the intraoperative detection of the MNPs accumulated into the SLNs to reduce the injection amount. Considering the noise signal and hysteresis loss, AC fields with 2-5 kHz was effective for the detection. The clinical trials with breast cancer patients, for the MNP detection using a developed device, revealed that the MNP amount of 1st SLN was ~40 ug. We will pursue the further detailed magnetic characteristics of the device and the MNPs for biomedical applications.

DOI： 10.11239/jsmbe.annual58.284

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BACKGROUND: We have modified and performed neoadjuvant chemotherapy (NAC) using capecitabine + epirubicin + cyclophosphamide combination therapy ( 'CEX' ) for HER-2 negative breast cancer. In this study, we investigate the outcomes achieved in our institute and report the effectiveness and tolerability of this therapy, retrospectively. METHODS: The patients included in this study had breast cancer that was negative for HER-2 and positive for lymph node metastasis or negative for lymph node metastasis with a tumor diameter of 20 mm or greater without any distant metastasis. Additionally, groups with performance status (PS) 0-1, aged 75 or less, and with an EF > 60% were targeted. Clinical evaluations were made after a total of 4 courses of epirubicin: 80 mg/m2, cyclophosphamide: 500 mg/m2 (administered every 3 weeks) and capecitabine: 1500 mg/m2 (administered for 2 weeks and withdrawn for 1 week). RESULTS: Eighteen patients received treatments between 2009 and 2013. All patients achieved clinical benefits. The clinical response rates (CRR) were 83.3% (15/18) and 50% for clinical complete response (cCR). All patients achieved positive aesthetic outcome with breast-conserving surgery. Those patients had satisfactory outcomes, with pathological complete response (pCR) in 33.3% (triple negative (TN): 6, luminal: 0) and n0 in 68.8% (TN: 8, luminal: 3). All patients with pCR are in a relapse-free survival state and are still under observation. The adverse events were grade 2 or lower for all patients. CONCLUSIONS: This study suggested that 'CEX' therapy as NAC could be an important option for individualized treatment. In particular, it was effective for TN breast cancer.

DOI： 10.1272/jnms.JNMS.2020_87-204

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BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is increasingly been used to prevent febrile neutropenia (FN) associated with the administration of chemotherapy for various cancers. The most common adverse effects of G-CSF are bone pain and injection-site reactions and aortitis has rarely been reported. We report herein a rare case of G-CSF associated with aortitis in a woman with advanced breast cancer. CASE PRESENTATION: A 72-year-old woman with estrogen receptor-negative human epidermal growth factor 2-positive breast cancer with distant metastases in the lung was admitted. Her treatment was initiated with docetaxel in combination with trastuzumab and pertuzumab followed by the supportive use of a long-acting G-CSF, pegfilgrastim. After administration of pegfilgrastim on day 5, the patient had an intermittent fever (body temperature up to 39.6 °C) on day 9 which continued irrespective of taking levofloxacin. She visited our outpatient clinic on day 13 with no objective symptoms other than fever. Laboratory tests revealed a high neutrophil count (15,000/μl) and a high C-reactive protein (CRP) level (46.35 mg/dl) without any other abnormalities. There was no response upon administration of antimicrobial agents. An 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed thickening of the wall of the descending thoracic aorta and left pleural effusion. Therefore, thoracic aortitis induced by pegfilgrastim was suspected. On day 19, the fever resolved spontaneously followed by a gradual reduction in the neutrophil count and CRP level. In the follow-up CT, the aortic wall thickness and pleural effusion had disappeared. CONCLUSIONS: G-CSF may cause aortitis due to stimulation of the production of inflammatory cytokines. In case of high continuous fever after administration of pegfilgrastim, aortitis should be suspected unless there are other infectious findings.

DOI： 10.1186/s12885-019-6403-9

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BACKGROUND: Sentinel lymph node biopsy is a standard staging procedure for early axillary lymph node-negative breast cancer. As an alternative to the currently used radioactive tracers for sentinel lymph node (SLN) detection during the surgical procedure, a number of studies have shown promising results using superparamagnetic iron oxide (SPIO) nanoparticles. Here, we developed a new handheld, cordless, and lightweight magnetic probe for SPIO detection. METHODS: Resovist (SPIO nanoparticles) were detected by the newly developed handheld probe, and the SLN detection rate was compared to that of the standard radioisotope (RI) method using radioactive colloids (99m Tc) and a blue dye (indigo carmine). This was a multicenter prospective clinical trial that included 220 patients with breast cancer scheduled for sentinel node biopsy after a clinical diagnosis of negative axillary lymph node from three facilities in Japan. RESULTS: Of the 210 patients analyzed, SLN was detected in 94.8% (199/210 cases, 90% confidence interval [CI]) with our magnetic method and in 98.1% (206/210 cases, 90% CI) with the RI method. The magnetic method exceeded the threshold identification rate of 90%. CONCLUSION: This was the first clinical study to use a novel handheld magnetometer to detect SLN, which we demonstrate to be not inferior to the RI method.

DOI： 10.1002/jso.25747

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Language：Japanese   Publisher：日本医科大学医学会  

症例は52歳女性で、乳房に腫瘤を自覚し、当院を受診、触診にて左乳房中央部領域に長径25mmの円形腫瘍を認めた。針生検による病理診断は浸潤性乳管癌、Nuclear grade 2、Estrogen receptor 0%、Progesterone receptor 0%、HER2スコア0、Ki67陽性率10%、サブタイプはtriple negativeであった。化学療法を行うも病変の縮小は得られず、乳腺部分切除術および腋窩リンパ節郭清を施行した。術後、放射線療法と化学療法を施行したが倦怠感が出現し、血液検査にて血小板数の著明な減少を認め緊急入院となった。骨髄穿刺を施行し、乳癌の骨髄転移と診断された。血小板輸血を施行したが、輸血を中止すると血小板数は数日で2.0×10^4/μL以下に減少し、化学療法を再開することはできなかった。血小板輸血を中止しbest supportive careを選択されてから1週間後、上肢筋力の低下が出現し、頭部CT検査にて脳出血の所見を認めた。翌日に意識レベルが低下し、乳癌術後7ヵ月目に永眠された。

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AIM: Lymphocyte predominant breast cancer (BC) is associated with higher pathological complete response (pCR) rate after neoadjuvant therapy (NAT) and favorable outcome in triple negative breast cancer (TNBC) and HER2+ BC. The predictive and prognostic impact of stromal tumour-infiltrating lymphocytes (TILs) after NAT and the change of TILs before (pre-) and after (post-) NAT are not well studied. We aimed to assess the predictive and prognostic value of pre- and post-NAT TILs, as well as their pharmacodynamics modulation and their change for TNBC and HER2+ BC. MATERIALS AND METHODS: Two-hundred and nine consecutive patients (n = 80 TNBC, n = 129 HER2+ BC) who received NAT between 2001 and 2009 in a single institution were included. We evaluated the association between pre-NAT TILs and pCR, and the association between pre- and post-NAT TILs, as well as their immunodynamics change with relapse-free survival (RFS) for patients with residual disease (RD). RESULTS: Low pre-NAT TILs compared to int/high were significantly associated with lower pCR rate (TNBC: 4.0% vs 43.6%; HER2+ BC: 26.0% vs 51.9%). The median follow-up period was 98 months. In TNBC with RD, low pre-NAT TILs showed significant association with shorter RFS (HR = 3.844 [1.190-12.421], p = 0.024) in multivariate analysis. Low post-NAT TILs showed borderline significant association with shorter RFS (HR = 2.836 [0.951-8.457], p = 0.061). The change in TILs was not associated with RFS. In HER2+ BC, low pre-NAT TILs were not associated with RFS. CONCLUSION: In TN and HER2+ BCs, low pre-NAT TILs tumours had a low likelihood of achieving pCR. In TNBC with RD, both low pre- and post-NAT TILs were associated with shorter RFS. These results suggest that TILs information should be taken into account when additional therapies may be given in the post-neoadjuvant setting.

DOI： 10.1016/j.ejca.2019.05.014

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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).

DOI： 10.1369/0022155419841023

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DOI： 10.1136/esmoopen-2018-000476

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Authorship：Lead author   Language：Japanese   Publisher：日本リンパ学会  

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Background: Neoadjuvant endocrine therapy (NET) can improve surgical outcomes in postmenopausal patients with hormone receptor-positive breast cancer. The Ki67 labelling index after NET has a better prognostic power than that at baseline. However, it remains unknown whether a multigene assay with post-treatment samples could predict the prognosis better than that with pretreatment samples. Methods: The prognostic value of the multigene assay Oncotype DX Recurrence Score (RS) was investigated using pretreatment and post-treatment samples from a multicentre NET trial, JFMC34-0601 (UMIN C000000345), where exemestane was given at 25 mg/day for 24 weeks. Results: Both pretreatment and post-treatment RSs were significantly associated with disease-free survival (DFS) (p=0.005 and 0.002, respectively). The combination of pretreatment and post-treatment RSs was also a predictor of DFS (p=0.002) and superior to preoperative endocrine prognostic index (PEPI). Furthermore, combined RS was the only independent prognostic factor in the multivariate analysis among the three RSs (p=0.04). In addition, combined RS could differentiate early recurrence in the high-risk group from mid/late recurrence in the intermediate-risk group, suggesting possible differential treatment strategies based on the risk categories indicated by the combined RS. Conclusions: The combination of pretreatment and post-treatment RSs could provide pivotal information for predicting DFS and differentiating early recurrence in the high-risk group from mid/late recurrence in the intermediate-risk group in patients with hormone receptor-positive breast cancer. A larger study is required to validate the results.

DOI： 10.1136/esmoopen-2018-000476

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

The newly developed radioisotope-free technique based on magnetic nanoparticle detection using a magnetic probe is a promising method for sentinel lymph node biopsy. In this study, a novel handheld magnetic probe with a permanent magnet and magnetic sensor is developed to detect the sentinel lymph nodes in breast cancer patients. An outstanding feature of the probe is the precise positioning of the sensor at the magnetic null point of the magnet, leading to highly sensitive measurements unaffected by the strong ambient magnetic fields of the magnet. Numerical and experimental results show that the longitudinal detection length is approximately 10 mm, for 140 μg of iron. Clinical tests were performed, for the first time, using magnetic and blue dye tracers-without radioisotopes-in breast cancer patients to demonstrate the performance of the probe. The nodes were identified through transcutaneous and ex-vivo measurements, and the iron accumulation in the nodes was quantitatively revealed. These results show that the handheld magnetic probe is useful in sentinel lymph node biopsy and that magnetic techniques are widely being accepted as future standard methods in medical institutions lacking nuclear medicine facilities.

DOI： 10.1038/s41598-018-19480-1

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BACKGROUND AND OBJECTIVES: Emerging evidence suggests that the presence of atypical mitoses is associated with poor prognosis in some types of cancer, but its clinical significance remains uncertain. Here, we investigated the occurrence of atypical mitoses in breast cancers. METHODS: Mitotic figures, including normal and atypical mitoses, were assessed in resected histological sections from 109 patients with invasive carcinoma of no special type (ICNST). Comparisons with clinicopathological features and biomarkers such as Ki67 and phosphohistone H3 (PHH3) were performed. RESULTS: The total number of mitotic figures, including atypical mitoses, was higher in situ and invasive ductal carcinoma components than in normal ducts. Morphological characteristics of atypical mitoses included multipolar, lagged, ring, asymmetrical mitoses, and anaphase bridge. Patients with higher total mitoses and PHH3, and the presence of atypical mitoses showed reduced overall survival (OS), compared to those with lower total mitoses and PHH3, and without atypical mitoses (P = 0.03, 0.02, and <0.001, respectively). In multivariate analysis, the presence of atypical mitoses alone attained significant correlation with shorter OS (P < 0.001). CONCLUSIONS: Atypical mitoses in routinely resected specimens have a robust prognostic value for ICNST of the breast, but its clinical utility remains to be validated in a multicenter large material.

DOI： 10.1002/jso.25152

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

Purpose: To prevent tissue expander (TE) exposure following mastectomy flap necrosis in immediate breast reconstruction, the TE is usually covered completely or partially with a musculofascial (MF) flap. This study compares the complications of the two coverage methods. Methods: We reviewed, retrospectively, 106 cases of immediate TE-based breast reconstruction. The patients were divided into two groups according to whether complete or partial TE coverage was done. In the complete coverage group, the serratus anterior MF flap was dissected and sutured to the pectoralis major muscle to cover the TE completely. In the partial coverage group, the serratus anterior MF flap was not dissected, and the lateral border of the pectoralis major muscle was sutured to the mastectomy skin flaps. Results: The TEs were covered completely in 60 breasts and partially in 46 breasts. The mastectomy flap necrosis rate was significantly higher in the complete coverage group (p &lt
0.01), but there was no incidence of TE exposure in either groups. The lateral migration rate was significantly higher in the partial coverage group (p = 0.033). There were no significant differences in the cranial migration rate (p = 0.133). Conclusions: The complete coverage method is a better option if there is a high risk of mastectomy flap necrosis
however, surgeons should monitor carefully for cranial migration.

DOI： 10.1007/s00595-018-1645-8

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier GmbH  

Breast carcinoma with osteoclast-like giant cells (OGCs) is a rare tumor
however, their clinicopathological aspects remain unclear. We described the clinicopathological characteristics of 8 patients with breast carcinoma with OGCs. Immuno-phenotypes of the OGCs were comparatively examined with that of foreign body giant cells (FBGCs) in 4 cases of granulomatous reaction (GR) without cancerous elements. In most cancers, tumors displayed cribriform and tubular growth patterns. Three cases showed moderate to high nuclear grade, while all the other tumors had low nuclear grade. Six patients were estrogen receptor (ER) positive, while triple negative phenotype was identified in 2 patients. During the follow-up period, 1 patient had local recurrence of the tumor, and all the patients remained alive. All OGCs and FBGCs expressed CD68, a pan-macrophage marker. OGCs in all the breast cancers showed moderate to high expression of CD163 — a marker of M2-macrophage with pro-tumoral function — whereas its expression in FBGCs was low to moderate (p = 0.04). CD86 — a marker of M1-macrophage with a tumoricidal activity — was positive in the OGCs of 3 breast cancers, and in the FBGCs of 3 GR cases (p = 0.15). The expression of CD163 was significantly higher than that of CD86 in the OGCs of breast cancer (p &lt
0.001), whereas they were comparable in the FBGCs of GR (p = 0.79). In summary, we found that breast carcinoma with OGCs mostly exhibited cribriform and tubular growth pattern, ER positivity, and predominantly possessed the M2-macrophage phenotype. However, the clinical significance of OGCs in breast cancer needs to be elucidated in further studies involving a larger number of cases.

DOI： 10.1016/j.prp.2017.11.002

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Background: Neoadjuvant endocrine therapy (NET) has been demonstrated to improve breast-conserving rate and is a widely accepted treatment option for postmenopausal patients with hormone receptor-positive breast cancer. There are few reports on the association of NET response and long-term outcomes. Objectives: To investigate the prognostic value of clinical response to NET. Methods: Long-term outcomes of NET were examined in 107 patients who participated in the multicentre prospective neoadjuvant exemestane study, JFMC34-0601. Patients were treated with 25 mg/day exemestane for 16 weeks followed by an 8-week extension depending on the treatment response. Results: Clinical response included partial response (PR) in 58 patients, stable disease in 41 patients and progressive disease (PD) in 8 patients. Clinical response was significantly associated with disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) (P<0.0001 for all). Especially, patients with PD showed markedly poor outcomes with median DFS=17.8 months (HR (vs PR): 7.7 (95% CI 1.6 to 33)) and median OS=37.7 months (HR (vs PR): 26.3 (95% CI 2.4 to 655)). Preoperative endocrine prognostic index (PEPI) were associated with DFS and marginally with OS (P=0.022 and 0.066, respectively). PEPI=0 indicated an excellent prognosis with 95% 5-year DFS (95% CI 73 to 99). In the multivariate analysis including T stage, nodal status and Ki67, clinical response was an independent prognostic factor for DFS, DDFS and OS (P=0.032, 0.0007 and 0.020, respectively), whereas PEPI was marginally associated with DFS and OS (P=0.079 and 0.068, respectively). Conclusions: Clinical response to NET showed an independent prognostic value. Patients with PD had markedly poor prognosis, indicating a need of additional therapy. PEPI=0 indicated an excellent prognosis. The integration of clinical response and PEPI would improve decision-making with regard to treatment options for endocrine-responsive breast cancer when these results are validated in a larger clinical trial. Trial registration number: UMIN C000000345.

DOI： 10.1136/esmoopen-2017-000314

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J04260&link_issn=&doc_id=20181129410009&doc_link_id=130007530232&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007530232&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

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PURPOSE: Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen. EXPERIMENTAL DESIGN: We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study. RESULTS: The combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10-6, 1.64 x 10-5, and 9.77 x 10-6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10-12), suggesting the cumulative effect of the three SNPs. CONCLUSION: We identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer.

DOI： 10.1371/journal.pone.0201606

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Metaplastic breast carcinoma (MBC) is a rare type of tumor with heterogenous histological patterns. We investigated the immunohistochemical expression of IMP3, an oncofetal protein, in 31 MBC patients in association with histological subtypes and clinical outcomes. The cohort consisted of spindle cell carcinoma (SPC) (n = 11), squamous cell carcinoma (SCC) (n = 14), matrix-producing carcinoma (MPC) (n = 4), carcinoma with osteocartilaginous elements (COC) (n = 1), and low grade adenosquamous cell carcinoma (ASC) (n = 1). IMP3 expression was identified in 7 cases of SPC (64%) and 6 patients of all the other subtypes (p = 0.051). In comparison between IMP3 high (n = 13) and low (n = 18) groups, a large-sized tumor (&gt;= 4.0 cm) was identified in 9 IMP3 high patients, and 14 IMP3 low patients had a small-sized tumor (p = 0.01). High Ki67 positivity was detected in all of the IMP3 high patients and in 7 of the IMP3 low patients (p = 0.002). During the follow-up period, 9 IMP3 high patients died, whereas 15 of the 18 IMP3 low patients remained alive (p = 0.004). A univariate analysis revealed that IMP3 expression and tumor size were significantly associated with poor clinical outcomes (p = 0.03 and &lt; 0.001, respectively). The IMP3 high group was likely to be associated with reduced overall survival compared to the IMP3 low group (p = 0.06). These findings indicate that IMP3 may contribute to the aggressive behavior of MBC, and that this expression could potentially be a prognostic marker of MBC.

DOI： 10.1016/j.anndiagpath.2017.05.015

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Resection for locally advanced breast cancer (LABC) or malignant phyllodes tumors may cause a large skin defect with bone exposure. Although skin grafts are frequently used to cover such defects, they can result in poor cosmetic outcomes and graft acceptance is dependent upon the condition of the recipient site. To overcome the limitations of skin grafts, various flaps have been developed to cover such defects. The present study used a rhomboid flap for the coverage of skin defects after mastectomy and breast-conservative surgery (BCS). A total of 11 patients with malignant breast cancer underwent reconstructive surgery using the rhomboid flap between September 2011 and December 2013 (mastectomy, 9 patients; BCS, 2 patients). Skin resection size, axillary lymph node dissection, bone exposure, length of surgery, wound complications and whether preoperative/postoperative adjuvant therapy was received were analyzed. The maximum size of skin defect covered with the rhomboid flap in the present study was 20x20 cm. There were no major wound complications and all patients underwent postoperative adjuvant therapy on schedule. During BCS, a portion of the flap was used for augmentation of the breast, in addition to coverage of the skin defect, which resulted in good cosmetic outcomes. The rhomboid flap can be quickly and easily fashioned, and it does not require any special instruments.

DOI： 10.3892/ol.2017.6411

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Hormone therapy is the most effective treatment for patients with estrogen receptor alpha-positive breast cancers. However, although resistance occurs during treatment in some cases and often reflects changed estrogen receptor alpha status, the relationship between changes in estrogen receptor a expression and resistance to therapy are poorly understood. In this study, we identified a mechanism for altered estrogen receptor alpha expression during disease progression and acquired hormone therapy resistance in aromatase inhibitor-resistant breast cancer cell lines. Subsequently, we investigated promoter switching and DNA methylation status of the estrogen receptor alpha promoter, and found marked changes of methylation at a single CpG site (CpG4) in resistant cells. In addition, luciferase reporter assays showed reduced transcriptional activity from this methylated CpG site. This CpG region was also completely conserved among species, suggesting that it acts as a methylation-sensitive Ets-2 transcription factor binding site, as confirmed using chromatin immunoprecipitation assays. In estrogen receptor alpha-positive tumors, CpG4 methylation levels were inversely correlated with estrogen receptor alpha expression status, suggesting that single CpG site plays an important role in the regulation of estrogen receptor alpha transcription.

DOI： 10.1016/j.jsbmb.2017.04.001

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

The BRCA-like phenotype is a feature that some sporadic breast cancers share with those occurring in BRCA1 or BRCA2 mutation carriers. As tumors with the phenotype have defects in the DNA damage response pathway, which may increase sensitivity to drugs such as DNA cross-linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR-/HER2- and 53 HR+/HER2-) patients, who received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR. The methylation and/or loss or uniparental disomy (UPD) of BRCA1 (BRCA1 alterations) and the loss or UPD of BRCA2 (BRCA2 alterations) were detected in 27 (37%) and 21 (29%), respectively, of the 73 tumors. Tumors with BRCA1 or BRCA2 alterations were associated with a higher number of genomic aberrations (P&lt;0.001 and P&lt;0.001) and higher percentage of TP53 alterations (P&lt;0.001 and P&lt;0.001) than those without. Overall survival (OS) rates were similar between patients with or without BRCA1 or BRCA2 alterations. However, when 27 patients with BRCA1-altered tumors were classified into those with or without the loss or UPD of PALB2, PAGR1, RAD51B, FANCM, MLL4, or ERCC1/2 in tumors, patients with additional defects in DNA damage response genes had worse OS (P=0.037, 0.045, 0.038, 0.044, 0.041, or 0.019) than those without. These defects may confer chemoresistance and predict poor outcomes in patients with BRCA1-altered breast cancer.

DOI： 10.1002/gcc.22445

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Language：Japanese   Publisher：乳癌基礎研究会  

症例は63歳女性で、6年前、左乳癌に対し乳頭乳輪温存乳房切除術・乳房再建術、センチネルリンパ節生検(SNB)を行った。腋窩リンパ節転移は認めず、T2N0M0ステージIIA、エストロゲン受容体(ER)陽性、プロゲステロン受容体(PgR)陽性、HER2陰性であった。術後6年、定期受診前に左乳輪に腫瘤を自覚し受診した。触診で8mm大の腫瘤を触知した。超音波で左乳頭直下に8mm大の低エコー腫瘤を認めた。左乳頭皮下の腫瘤に対し針生検を行った。左乳房内再発に対し再発部切除および再SNBを行った。SPECT-CTからラジオアイソトープ(RI)が集積しているセンチネルリンパ節(SN)は腋窩でなく、2個ともに胸筋間にあると判断し、セカンドルック超音波を行い2mm大のリンパ節2個が確認された。手術時に2個とも摘出し1個は転移陽性であった。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, "endoxifen." There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.
Experimental Design: We enrolled 279 patients with hormone receptor-positive and human epidermal growth factor receptor 2-egative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.
Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor-positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association wyith Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).
Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. (C) 2016 AACR.

DOI： 10.1158/1078-0432.CCR-16-1779

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Objective: Pleomorphic lobular carcinoma (PLC) is a subtype of breast cancer with unique morphological features, but it remains controversial whether PLC should be considered an independent disease entity. The aim of this study was to illustrate cytopathological characteristics of PLC in comparison with other lobular carcinoma variants.
Methods: We investigated clinicopathological features of PLC (n = 11) compared with those of other variants of invasive lobular carcinoma (ILC, non-PLC) (n = 32). Histological variants of the non-PLC group consisted of classic (n = 25), solid (n = 2), alveolar (n = 1) and a tubulolobular type (n = 4). A review of cytological reports and fine needle aspiration (FNA) smear samples was performed for the PLC (n = 9) and non-PLC (n = 27) groups.
Results: : Patients with PLC were older, and had a higher nuclear grade and a higher incidence of axillary lymph node metastasis and triple negative phenotype than non-PLC patients (P = 0.007, P &lt; 0.001, P = 0.02 and P &lt; 0.001, respectively). Cytological findings in PLC included medium-to large-sized nuclei, prominent nucleoli, a moderate-to-severe degree of pleomorphism, apocrine change and background necrosis, none of which were evident in the smears of the non-PLC group (P &lt; 0.001, P = 0.002, P &lt; 0.001, P &lt; 0.001, and P = 0.03, respectively). Despite these differences, patients with PLC and non-PLC showed similar clinical outcomes in our follow-up period.
Conclusions: Based on our results, a cytological diagnosis of PLC should be proposed if there are moderate-to large-sized nuclei, prominent nucleoli, a moderate-to severe degree of nuclear pleomorphism, apocrine change and necrosis in the background in FNA biopsy samples.

DOI： 10.1111/cyt.12362

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Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：Japanese Society for Medical and Biological Engineering  

The magnetic technique using a magnetic tracer and handheld magnetic probe with permanent magnet can be alternatives to the radioisotope technique as a noninvasive promising method for sentinel lymph node biopsy. To identify one sentinel lymph node, 5 mm spatial resolution of the probe is required because sentinel lymph nodes are often clustered in axillary lymph nodes. The aim of this study is to demonstrate a spatial resolution of the magnetic probe by a sensitivity mapping measurement with high spatial resolutions.The longitudinal sensitivity and lateral resolution of the probe was approximately 8 mm and 4 mm, respectively, for 5 μL of the magnetic tracer (Resovist). The probe discriminated the one phantom from two phantoms separated 4 mm in the lateral direction. These results indicate that the magnetic probe with the permanent magnet has the ability to identify one sentinel lymph node from the node clusters in actual usages.

DOI： 10.11239/jsmbe.55annual.390

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Triple negative breast cancer (TNBC) has an aggressive phenotype and poor prognosis. Neoadjuvant chemotherapy (NAC) is often used to treat TNBC, but some patients are resistant to NAC. We postulated that a subpopulation of TNBC cells expressing IMP3, an oncofetal protein, could be resistant to NAC, contributing to the poor prognosis. We investigated immunohistochemical expression of IMP3 in 42 TNBC patients who underwent NAC in association with clinical outcomes. The patients were divided into IMP3 positive (+) (n=19) and negative (-) (n=23) groups. High Ki67 positivity was detected in 13 patients of the IMP3 + group and 8 cases in the IMP3 - group (p = 0.03). While 9 patients in the IMP3 - group (39%) were responders, the majority of the IMP3 + patients (84.2%) were non-responders (p = 0.01). In a Cox proportional hazard model, IMP3 expression was independently associated with poor NAC response and clinical outcomes (p = 0.03 and 0.046, respectively). The IMP3 + group showed a tendency toward shorter overall survival compared to the IMP3 - group with marginal significance (p = 0.07). These findings suggest that IMP3 + tumor cells contributed to the poor clinical outcomes by exerting a chemoresistance to NAC, and that IMP3 expression has prognostic value as a biomarker for chemosensitivity and overall survival in TNBC. (C) 2017 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2017.07.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

© 2016 The Author(s). Background: Signet ring cells (SRCs) often accompany gastrointestinal carcinoma, referred to as SRC carcinoma; however, breast cancers containing SRCs have not been well characterized, leaving the prognostic significance of SRCs undetermined. We have described clinicopathological characteristics of patients with breast cancer containing SRCs in relation to the expression levels of MUC1, MUC2, MUC4, MUC5AC, and MUC6. Methods: Twenty-two breast cancer cases with variable degrees of SRC population were retrospectively studied. Each case was categorized as high (>31%) or low (<30%) SRC tumor. The SRCs were morphologically classified into the intra-cytoplasmic lumen (ICL) type, or the non-ICL type. The expression levels of MUC1, MUC2, MUC4, MUC5AC and MUC6 were determined immunohistochemically. Depending on its subcellular localization, MUC1 was categorized as the luminal and cytoplasmic (LC) type, or the cytoplasmic with circumferential membranous accentuation (CM) type. These histological findings were compared with other clinicopathological parameters. Results: The series consisted of invasive ductal carcinoma (n=9), invasive lobular carcinoma (n=9), and mucinous carcinoma (n=4) cases. The SRC population accounted for 8-81% of the tumor cells. Eight cases had ICL type SRCs, and the remaining 14 had non-ICL type SRCs. Neither the high (n=12) and low (n=10) percentage of SRCs, nor the SRC types affected the clinicopathological parameters. In the low MUC1 group (n=11), larger tumors, higher nuclear grade, lymph node metastasis, and negativity for estrogen receptor was more frequently identified compared to the high MUC1 group (n=11; p=0.01, p=0.002, p=0.008, and p=0.02, respectively). The CM group (n=7) had more patients with large-sized tumors, lymph node metastasis, lymphovascular invasion, and higher Ki67 indices than the LC group (n=15; p=0.04, p=0.001, p=0.006, and p=0.03, respectively). The expression levels of MUC2, MUC4, MUC5AC, and MUC6 showed no clinicopathological significance. Two patients with low MUC1 expression and CM patterns had tumor recurrence, resulting in death, while all the other patients survived without recurrence. Conclusion: Our results demonstrate that in breast cancers containing SRCs, low MUC1 expression and/or its CM subcellular localization patterns are associated with unfavorable clinicopathological factors. The utility of MUC1 expression as a prognostic marker remains to be verified in future studies.

DOI： 10.1186/s13000-016-0584-1

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Language：Japanese   Publisher：日本臨床外科学会  

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To determine the cytomorphological features of complex type fibroadenoma (CFA), we reviewed fine needle aspiration (FNA) cytology with correlation to its histopathology findings, and compared them with non-complex type fibroadenoma (NCFA).
From excisional biopsy or resected specimens of fibroadenoma (FA) cases treated at our institution from 2004 to 2013, we chose 46 patients who underwent FNA before a diagnosis of FA was established. We histologically re-classified them into two groups: CFA and NCFA. FNA diagnosis was retrospectively re-evaluated from FNA reports. We further re-assessed detailed characteristics of each FNA smears to identify cytomorphological features of CFA.
We found that 15 cases fulfilled the diagnostic criteria of CFA, in which 7 (46.7 %) had an FNA diagnosis of "suspicious for malignancy" or "indeterminate" while only 2 NCFA cases had that of "indeterminate" (p = 0.004). FNA smears from CFA cases showed discohesiveness, enlarged nuclei, prominent nucleoli, and fewer myoepithelial cells more often than NCFA. Although no significant difference was noted in patients' age and tumor size between CFA and NCFA, 5 CFA cases (33.3 %) were accompanied by the presence of carcinoma in the same breast or the contralateral breast while no NCFA cases had carcinoma in the breast.
FNA of CFA can lead to erroneous or indeterminate interpretation, due to proliferative and/or hyperplastic changes of ductal epithelium with or without atypia. It is important to recognize the disease entity and characteristic cytomorphological findings of CFA to reach accurate FNA diagnosis of breast lesions.

DOI： 10.1007/s12282-015-0632-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

The carboxyl terminus of the Hsc70-interacting protein (CHIP) is considered to induce the ubiquitination and degradation of several oncogenic proteins, and play a role in the inhibition of tumor progression and invasion under experimental conditions. However, the impact of CHIP expression on the prognosis of breast cancer patients has not yet been established. In this study, using an immunohistochemical method, 272 patients with invasive breast cancer were assessed for the expression of CHIP (graded scores 0-3) and the statuses of biomarkers, such as estrogen receptor (ER), progesterone receptor (PgR), and HER2. The relationships between the statuses of CHIP and biomarkers as well as clinical features were also evaluated, and that between the expression of CHIP and patient prognosis was analyzed. We revealed that the strong expression of CHIP correlated with positive ER (P&lt;0.001), positive PgR (P&lt;0.001), and negative HER2 (P=0.02). In postmenopausal patients, relapse-free survival (RFS) was significantly better in the high CHIP group than in the low CHIP group (P=0.042). In addition, RFS and cancer-specific survival (CSS) were significantly better in patients with ER-positive/CHIP score 3 tumors than in those with ER-negative/CHIP score 0 tumors (RFS: P=0.038, CSS: P=0.0098). The methylation status of CHIP gene promoter did not always account for the down-regulation of its expression. In conclusion, the overexpression of CHIP is a potent prognostic factor of a good prognosis in ER-positive breast cancer patients in the postmenopausal phase.

DOI： 10.1002/cam4.780

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Although fine needle aspiration (FNA) biopsy is an established tool to assess breast lesions, there has been a trend toward using core needle biopsy (CNB) instead. The aim of this study was to compare the diagnostic accuracy of FNA and CNB in special types of breast cancer.
A retrospective review of diagnostic results of pre-operatively performed FNA or CNB, or a combination of the two, was conducted. The cases include histologically proven invasive ductal carcinoma of no special type (NST n = 159), invasive lobular carcinoma (ILC n = 65), mucinous carcinoma (MUC n = 51), and apocrine carcinoma (APO n = 25).
The absolute diagnostic sensitivity of FNA to detect malignancy in ILC and APO patients was inferior to that of NST patients (p &lt; 0.001 for ILC and APO). Within each cancer type, the sensitivity of CNB was higher than that of FNA in the ILC and APO patients (p &lt; 0.001 and p &lt; 0.05, respectively). As for NST and MUC patients, FNA and CNB had equivalent sensitivity. The sensitivity of FNA alone significantly improved when combined with CNB in NST, ILC and APO patients (p &lt; 0.05, p &lt; 0.001, and p &lt; 0.05, respectively).
Our results suggest that FNA has less diagnostic accuracy than CNB for ILC and APO; thus, the use of CNB should be encouraged when these types of cancer are clinically suspected or when the initial FNA is inconclusive.

DOI： 10.1007/s12282-015-0624-9

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DOI： 10.1111/cyt.12298

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MEDICAL ASSOC NIPPON MEDICAL SCH  

Although the use of endocrine therapy in combination with intravenous chemotherapy has not been standardized, the combination of fulvestrant and chemotherapy may be promising. A 62-year-old woman came to our hospital's outpatient clinic with extensive ascites. Approximately 10 years earlier, she had undergone mastectomy and sentinel lymph node biopsy. Pathologically invasive lobular carcinoma, with a maximum diameter of 28 mm, had been diagnosed in the left breast. The cancer had a histological grade of 2, was positive for estrogen receptor (95% or more positive cells), and was negative for both progesterone receptor (less than 1% positive cells) and human epidermal growth factor receptor 2. For 5 years the patient underwent adjuvant endocrine therapy with tamoxifen and then with anastrozole. Four years 2 months after adjuvant endocrine therapy had been completed, she felt abdominal distention, and her symptoms gradually worsened. A series of intensive examinations indicated that the invasive lobular carcinoma had metastasized to the peritoneum, pleura, uterus, and bone. Aromatase inhibitor was administered as a first-line therapy for the metastatic disease and was accompanied by denosumab injected every 28 days. For 2 months after the start of treatment with anastrozole, the ascites did not decrease and tumor markers increased. Because anastrozole had not been effective, fulvestrant (500 mg) and low-dose capecitabine (500 mg) were administered for the first 21 days of a 28-day cycle; this regimen had been shown by a phase 2 trial to be effective and tolerable in patients with metastatic breast cancer. The patient felt an improvement in abdominal distention, and the tumor markers decreased 2 weeks after the start of this combination therapy. By 10 months after the start of the combined therapy the ascites had decreased and pleural effusion had completely disappeared. The uterine wall became thinner, and the endometrial cavity became smaller. Tumor markers continued decreasing. No adverse events were observed. The combination of fulvestrant and low-dose capecitabine is promising because of its efficacy and tolerability for the treatment of patients with estrogen receptor positive, human epidermal growth factor receptor 2-negative metastatic breast cancer.

DOI： 10.1272/jnms.83.81

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Neoadjuvant chemotherapy (NAC) is a standard regimen in treatment of breast cancer patients, but some are resistant to NAC. We hypothesized that breast cancer cells overexpressing epithelial cell adhesion molecule (EpCAM) could be resistant to NAC, contributing to a poor prognosis. Seventy patients with breast cancer were treated with NAC. Core needle biopsy (CNB) specimens and resected tumors before and after NAC, respectively, were examined for expression of EpCAM. In resected tumors, high EpCAM expression correlated with lymphovascular invasion status and nuclear grade (P = 0.01 and 0.008, respectively), and was associated with poor pathological and clinical responses (P &lt; 0.001). High tumoral EpCAM expression in resected tumor was independently related to a poor pathological response. Patients with high EpCAM expression before and after NAC (high-to-high group) showed worse pathological and clinical responses (P = 0.008 and &lt;0.001, respectively) than the patients with high and low EpCAM expression before and after NAC, respectively (high-to-low group). The overall survival rate of the high-to-high group appeared shorter compared with the high-to low-group (P = 0.049). Our findings imply that higher levels of EpCAM in breast cancer may be associated with poor response to NAC via a potential chemoresistant effect.

DOI： 10.1111/pin.12404

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Language：Japanese   Publisher：(一社)日本乳腺甲状腺超音波医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Neoadjuvant endocrine therapy (NAE) has been employed to improve surgical outcomes for hormone receptor-positive breast cancers in postmenopausal women. Endocrine responsiveness is estimated by expressions of hormone receptors, but its heterogeneity has been recognized. Autophagy is an evolutionally conserved process associated with cell survival and cell death and has been implicated in cancer treatment.
Methods: In order to examine the possible association between autophagy and response to endocrine therapy, we evaluated the status of autophagy-associated markers, beclin 1 and LC3, and apoptosis-associated markers, TUNEL and M30, in pre- and post-treatment specimens from 71 patients in a multicenter prospective study of neoadjuvant exemestane (JFMC34-0601).
Results: Immunoreactivity of the autophagy-associated markers, beclin 1 and LC3, in carcinoma cells increased in 14 % and 52 % of the patients, respectively, following the exemestane treatment. These increases were statistically significant (beclin 1, p = 0.016, N = 49; LC3, p &lt; 0.0001, N = 33). The status of M30 immunoreactivity decreased (p = 0.008, N = 47) and TUNEL remained unchanged (N = 53). In addition, tumors with pre-treatment stromal beclin 1 immunoreactivity revealed poor clinical and pathological responses compared with those without stromal beclin 1 immunoreactivity (25 % vs 67 % for clinical response, p = 0.011, N = 51; 0 % vs 41 % for pathological response, p = 0.0081, N = 49). Tumors with positive pre-treatment stromal beclin 1 had a higher baseline Ki-67 labeling index (both hot spot and overall average) than those without (p = 0.042 and 0.0075, respectively, N = 53). Results of logistic regression analyses revealed that stromal beclin 1 was a predictor for clinical and pathological responses while ER, PR, Ki-67, and stromal LC3 expressions were not.
Conclusions: Results of our present study demonstrated that beclin 1 and LC3 immunoreactivity increased in carcinoma cells following exemestane treatment and that the status of pre-treatment stromal beclin 1 is associated with higher carcinoma cell proliferation and poor clinical and pathological responses to NAE.

DOI： 10.1186/s12885-016-2270-9

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Language：Japanese   Publisher：日本外科感染症学会  

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Other Link： https://search.jamas.or.jp/link/ui/2016294955

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

To assess the joint symptoms and the impact on patients' health-related quality of life (HRQOL) due to 5 years of anastrozole from the baseline data in the N-SAS BC 05 trial, a randomized clinical trial was designed to assess the efficacy of 5 additional years of anastrozole among women with breast cancer.
Joint symptoms and HRQOL were evaluated using an original questionnaire for joint symptoms, the Short Form 36-item Health Survey (SF-36), the EuroQol EQ-5D-3L, and a subscale of the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES).
Baseline joint symptom and HRQOL data were collected from 330 patients between November 2007 and March 2010. Joint pain and joint stiffness were reported by 61.6 and 59.1 % of patients, respectively, although these symptoms did not affect the activities of daily living in 96.0 and 97.9 % of patients, respectively. Joint pain was reported in the knee by 61.0 % of patients and in the hand by 36.0 % of patients. Joint stiffness mainly affected the hand (67.9 %), especially the proximal interphalangeal joint, and typically occurred upon waking up or in the morning. Most SF-36 domains had good average scores, although slight decreases in physical functioning and role-physical were observed (compared to the national standard scores). The mean EQ-5D utility score was 0.86, and the total FACT-ES subscale score was 62.2/76.
After 5 years of anastrozole, many of the patients reported joint pain and stiffness in mainly the hand and knee with mild symptoms and good HRQOL.

DOI： 10.1007/s00520-015-2830-6

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Signet ring cell (SRC) carcinoma is a unique subtype of adenocarcinoma; however, the clinicopathological profiles of SRCs in breast carcinoma are yet to be determined. Here, we investigated cyto-histological findings of 11 breast carcinoma cases with SRCs comprising more than 20% of the tumor cells; invasive ductal carcinoma (IDC) (n=4), invasive lobular carcinoma (ILC) (n=4), pleomorphic lobular carcinoma (PLC) (n=1), and mucinous carcinoma (MC) (n=2). The mean age of the patients was 60.2 +/- 13 years, and the mean tumor size was 2.0 +/- 0.8 cm. Three cases of IDC, 1 PLC, and 1 of MC had grade 2 or 3 nuclear atypia, whereas 1 case of IDC, 4 of ILC, and 1 of MC had grade 1 nuclear atypia. Axillary lymph nodes were positive for metastatic carcinoma in 1 patient with IDC and 1 with ILC. In fine needle aspiration smears, intracytoplasmic lumen (ICL) type SRCs were found to be major constituents of SRCs in ILC and PLC, while non-ICL type SRCs were predominant in IDC. MC tumors had SRCs of both ICL and non-ICL types. During our follow-up period ranging from 97 to 3650 (mean 1458 +/- 1055) days, all the patients were alive without recurrence of the tumor. Our results indicate that the nature of SRCs may vary with the histological subtype of breast cancer, but its presence may not indicate poor prognosis. A large study with more cases of breast cancer with SRCs for a longer period may be needed to determine the clinical significance of SRCs.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

© Kurozumi et al. Background: Neoadjuvant chemotherapy (NAC) with taxanes followed by fluorouracil, epirubicin, and cyclophosphamide (FEC), and concurrent trastuzumab is a potent regimen for HER2 over-expressing breast cancer. A high pathological complete response (pCR) rate has been achieved using this regimen; however, the predictive factors and prognostic effects of pCR currently remain unclear. In the present study, we determined whether pCR was related to histological grade (HG) and several biological factors including p27Kip1. We also assessed the prognosis of the pCR and non-pCR groups, and expected differences between those positive and negative for lymph node metastasis after chemotherapy. Methods: A total of 129 Japanese women with HER2-positive invasive breast cancer received either paclitaxel or docetaxel followed by FEC, with the concomitant administration of trastuzumab. The statuses of HG, ER, PgR, Ki67, and p27Kip1 were evaluated to determine their relationship with pCR. Relapse-free survival (RFS) and overall survival (OS) were also analyzed for their relationship with pCR and pathological nodal involvement. Results: pCR was obtained in 84 out of 129 patients and the pCR rate was 65.1 %. The pCR rates related to 5 factors were as follows: HG (grade 3, 70.0 % vs. grades 1-2, 36.8 %), ER (negative, 78.6 % vs. positive, 40.0 %), PgR (negative, 75.3 % vs. positive, 38.9 %), Ki67 (high, 72.0 % vs. low, 47.2 %), and p27Kip1 (low, 71.0 % vs. high, 50.0 %). RFS was significantly better in the pCR group than in the non-pCR group (p = 0.018). Patients with remaining nodal disease in the pCR group had worse OS (p = 0.0002). Conclusions: High-HG, low-ER, low-PgR, high-Ki67, and low-p27Kip1 were identified as predictive factors of pCR in NAC with trastuzumab, while pCR and negative nodes were predictive of better survivals.

DOI： 10.1186/s12885-015-1641-y

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Various studies have indicated a worldwide increase in the number of immediate breast reconstruction surgeries. However, breast reconstruction should not delay or prevent postoperative cancer therapeutics such as adjuvant chemotherapy and radiotherapy. In response to these developments, our team researched the impact of immediate breast reconstruction on postoperative adjuvant chemotherapy.
From April 2006 to March 2011, 116 patients at Saitama Cancer Center underwent postoperative adjuvant chemotherapy following mastectomy with or without immediate breast reconstruction. Fifty patients received postoperative adjuvant chemotherapy following mastectomy with immediate breast reconstruction (IBR group), and 66 patients received the same treatment but without immediate breast reconstruction (non-IBR group). The outcomes were studied retrospectively by chart review. Patients' average age, body mass index, postoperative complication rate, and days to adjuvant chemotherapy were calculated.
Mean age and body mass index of patients were 47.0 +/- A 9.0 years, 22.2 +/- A 3.0 kg/m(2) and 55.5 +/- A 10.1 years, 23.0 +/- A 3.6 kg/m(2) in IBR group and non-IBR group, respectively. Postoperative complication rate was 10.0 % in IBR group and 6.1 % in non-IBR group. Days to adjuvant chemotherapy was 61.0 +/- A 10.5 days in IBR group and 58.0 +/- A 12.3 days in non-IBR group.
Although complication rate and days to adjuvant chemotherapy were slightly increased in IBR group, the delay was not critical to the initiation of adjuvant chemotherapy in these patient groups.

DOI： 10.1007/s12282-013-0480-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

The Cell Cycle Profiling - Risk Score (C2P-RS) based on CDK1 and CDK2 specific activities was significantly associated with relapse in breast cancers. We evaluated the prognostic value of the C2P-RS classification using a Japanese cohort including node-negative, hormone receptor-positive breast cancers treated with adjuvant endocrine therapy alone as systemic therapy. Of 266 patients, 22 (8.3%) relapsed within 5 years after surgery. The distribution of each C2P-RS group was 71.8% in the low group, 12.0% in the intermediate group, and 16.2% in the high group. The 5-year relapse-free survival rate in the low C2P-RS group (97.3%) was significantly higher than that in the intermediate C2P-RS group (84.3%) or the high C2P-RS group (74.4%) (P &lt; 0.001). The univariate analysis demonstrated that age, tumor size, histologic grade, and HER2 had no significant correlations with relapse but the C2P-RS classification (P &lt;0.001) and Ki-67 (P = 0.009) were significantly associated with relapse. Multivariate analysis showed only that the C2P-RS classification was a significant independent prognostic indicator. The C2P-RS classification might be a significant predictor of earlier recurrence in node-negative, hormone receptor-positive breast cancers treated with endocrine therapy. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2014.08.042

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Language：Japanese   Publisher：日本臨床外科学会  

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We describe a 39-year-old woman with metastatic breast cancer who had grade 4 epistaxis induced by bevacizumab. The patient visited our outpatient clinic with complaints of a lump in her right breast, fatigue, dyspnea, abdominal distention, appetite loss, and weight loss of 10 kg over 1 year. Liver dysfunction was detected, with elevated levels of aspartate aminotransferase (271 IU/L), alanine aminotransferase (100 IU/L), alkaline phosphatase (4,205 IU/L), total bilirubin (2.7 mg/dL), and direct bilirubin (2.1 mg/dL). A secondary liver tumor that occupied most of the liver volume was found, and bone metastasis, ascites, and pleural effusion were also discovered. The Eastern Cooperative Oncology Group performance status was 2. A core needle biopsy of the right breast tumor revealed invasive ductal carcinoma of the breast (nuclear grade 1) that was positive for estrogen receptor and progesterone receptor and negative for human epidermal growth factor receptor 2 overexpression and had a high Ki-67 score. We chose combination chemotherapy with paclitaxel (80 mg/m(2) on days 1, 8, and 15) and bevacizumab (10 mg/kg on days 1 and 15) for 28 days (1 cycle). After completion of the first cycle of chemotherapy, the ascites and pleural effusion decreased, and the metastatic liver tumor shrank. The performance status improved from 2 to 1. On day 3 of the third cycle of chemotherapy, however, she began having persistent epistaxis. On day 6, she lost consciousness and was transported to the emergency room of our hospital. The hemoglobin level was 5.6 g/dL. Blood transfusion and endoscopic hemostasis were immediately started. Bevacizumab was discontinued, and paclitaxel alone was continued; after this change, epistaxis did not recur.

DOI： 10.1272/jnms.81.333

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Background: Breast-cancer incidence and mortality have been increasing in Japan. Japanese-specific clinical validity and utility data for the 21-gene assay (Oncotype DX® Breast Cancer Assay; Genomic Health, Inc., Redwood City, USA) are now available. The objective of this study was to evaluate the cost-effectiveness of the 21-gene assay for the guidance of adjuvant chemotherapy decisions in estrogen-receptor-positive, lymph-node-negative, early-stage breast cancer patients, from the Japanese societal perspective.Methods: The recurrence risk group distribution by the 21-gene assay result and the assay's influence on adjuvant chemotherapy recommendations were obtained from a study of 104 patients. A state-transition cohort (Markov) model tracked time from surgery until distant recurrence and from distant recurrence to death. Adjuvant chemotherapy benefit by 21-gene assay risk group was based on published clinical validation studies. Direct and indirect medical costs were obtained from the referral centers. Utilities associated with progression and chemotherapy-related adverse events were extracted from literature. Sensitivity analyses assessed the key drivers and robustness of the primary outcomes.Results: The 21-gene assay identified 48% of patients as low-risk, 36% as intermediate-risk, and 16% as high-risk. Total acute chemotherapy-related costs decreased by \154,066 due to less adjuvant chemotherapy usage. In the high-risk group, adjuvant chemotherapy use increased 18%, leading to survival benefits. Chemotherapy use overall decreased by 19%. Monitoring costs increased by \3,744 but recurrence costs declined by \46,113 per patient. Use of the 21-gene assay increased quality-adjusted-life-years (QALYs) by 0.241 per patient on average; the net cost per QALY gained was \636,752 ($6,368).Conclusions: The 21-gene assay for women with estrogen-receptor-positive, lymph-node-negative, early-stage breast cancer is projected to be cost-effective in Japan. © 2014 Yamauchi et al.; licensee BioMed Central Ltd.

DOI： 10.1186/1472-6963-14-372

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

The aim of this study was to investigate the association between the results of the Recurrence Score (RS) assay and the clinical response to neoadjuvant endocrine therapy in postmenopausal women with breast cancer.
Core biopsy samples at baseline and post-treatment surgical samples were obtained from 80 and 77 of 116 patients, respectively, enrolled in the multicenter prospective study of neoadjuvant exemestane therapy (JFMC34-0601). The 21-gene assay was performed after appropriate manual microdissection. The estrogen receptor (ER), progesterone receptor, HER2 and Ki-67 were assayed by immunohistochemistry at a central laboratory. Clinical response was assessed based on the RECIST (Response Evaluation Criteria In Solid Tumors) guideline.
Sixty-four core biopsy samples and 52 resection samples met the RS quality requirements. The clinical response rate in those patients with a low RS result (low RS group; 19/32, 59.4 %) was significantly higher than that in those patients with a high RS result (high RS group; 3/15, 20.0 %) (P = 0.015) and similar to that in patients with an intermediate RS result (intermediate RS group; 10/17, 58.8 %). The rates of breast-conserving surgery (BCS) were 90.6 % (29/32) in the low RS group, 76.5 % (13/17) in the intermediate RS group and 46.7 % (7/15) in the high RS group. The odds ratio for BCS adjusted for continuous baseline Ki-67 was 0.114 [95 % confidence interval (CI) 0.014-0.721; P = 0.028] between the high and low RS groups. RS values in pre-treatment samples were highly correlated with those in post-treatment samples (Spearman correlation coefficient 0.745, 95 % CI 0.592-0.846).
Our results demonstrate the predictive value of the RS for clinical response to neoadjuvant exemestane therapy in postmenopausal women with ER-positive breast cancer.

DOI： 10.1007/s10147-013-0614-x

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MEDICAL ASSOC NIPPON MEDICAL SCH  

A 64-year-old woman noticed a lump of the right breast and consulted our outpatient clinic. She had undergone multiple excisional biopsies of fibroadenomas in both breasts and mastectomy for invasive ductal carcinoma (IDC) of the left breast After completing 5 years of treatment with adjuvant tamoxifen, she had undergone screening with annual physical examinations and occasional computed tomography. She was declared recurrence-free 13 years after breast cancer surgery, although lumps were detected in the right breast, probably due to fibroadenomas. Mammography, ultrasonography, and magnetic resonance imaging revealed that the lump was irregularly shaped, 2 cm in diameter, and adjacent to a fibroadenoma with macrocalcification. Two axillary lymph nodes were enlarged and suggestive of metastasis. A core needle biopsy revealed IDC of the right breast She underwent a right partial mastectomy with axillary lymph node dissection. The IDC was 2 cm in diameter, of nuclear grade 2, and adjacent to a 0.7-cm fibroadenoma with a macrocalcification. The margins of the IDC close to the fibroadenoma were clearly demarcated by the fibrous capsule of the fibroadenoma. Four axillary lymph nodes were positive for metastasis. In the present case the presence of fibroadenoma might have interfered with the early detection of the contralateral IDC. The history of multiple excisions of fibroadenomas and mastectomy for breast cancer suggests an increased risk of contralateral breast cancer for the patient's entire life; therefore, regular annual follow-up, such as physical examinations and mammography, is recommended.

DOI： 10.1272/jnms.81.168

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BACKGROUND: In this study we investigated if the 21-gene assay result affects adjuvant decision-making in Japanese women with ER+ invasive EBC. PATIENTS AND METHODS: A total of 124 consecutive eligible patients with ER+, HER2-negative EBC and 0 to 3 positive lymph nodes were enrolled. Treatment recommendations, physicians' confidence and patients' decisional conflict before and after knowledge of the Recurrence Score results of the 21-gene assay were recorded. RESULTS: One-hundred four patients (84%) had N0 disease, including micrometastases, and 20 (16%) had N+ disease. Overall, recommendations changed in 33% (95% CI, 24%-43%) of N0 and 65% (95% CI, 41%-85%) of N+ patients. In 27 of 48 (56%) of N0 and 13 of 15 (87%) of N+ patients an initial recommendation for chemohormonal therapy was revised to only hormonal therapy after assay results, and in 7 of 56 (13%) of N0 and 0 of 5 N+ patients from only hormonal to combined chemohormonal therapy. Decisions appeared to follow the Recurrence Score results for low and high values. For patients with intermediate Recurrence Score values, overall recommendations for chemohormonal treatment tended to decrease after assay results. Physicians' confidence increased in 106 of 124 (85.5%; 95% CI, 78%-91%) cases. Patients' decisional conflict significantly improved as indicated by changes in the total score and the 5 defined subscores (P = .014 for Informed Subscore; P < .001 for all others). CONCLUSION: Results from this prospective study in a Japanese population confirm an effect of the 21-gene assay results on adjuvant treatment decision-making, consistent with reported experiences from the United States and Europe.

DOI： 10.1016/j.clbc.2013.10.017

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Tamoxifen is recommended as adjuvant endocrine therapy for patients with minimum-risk breast cancer. It is primarily effective at prevention of contralateral and ipsilateral breast cancer recurrence after breast-conserving surgery. The incidence of contralateral breast cancer and the absolute benefit of endocrine therapy among patients with unilateral minimum-risk breast cancer in Japan, where the incidence of breast cancer is low, are unknown.
We retrospectively studied the incidence of contralateral breast cancer, and the efficacy of endocrine therapy, in a cohort of 2074 Japanese women with unilateral breast cancer whose primary tumor was pTis (n = 1905) or pT1mic (n = 169) (unknown for endocrine therapy, n = 4; unknown for radiotherapy, n = 2). We also assessed the efficacy of endocrine therapy and radiotherapy for prevention of ipsilateral and contralateral breast cancer recurrence in 1205 patients who underwent breast-conserving surgery (unknown for endocrine therapy, n = 2; unknown for radiotherapy, n = 2).
The incidence of contralateral breast cancer per 1000 person-years was 5.1 (95 % confidence interval (CI), 3.7-7.1) among patients without endocrine therapy (n = 1364) and 3.6 (95 % CI 2.1-6.1) among those with endocrine therapy (n = 706). The incidence of ipsilateral breast cancer recurrence after breast-conserving surgery per 1000 person-years was 9.2 (95 % CI 6.5-13) among patients without endocrine therapy (n = 753) and 4.2 (95 % CI 2.2-8.1) among those with endocrine therapy (n = 450). The incidence of ipsilateral breast cancer recurrence after breast-conserving surgery per 1000 person-years was 9.9 (95 % CI 6.3-15.6) among patients without radiotherapy (n = 380) and 5.9 (95 % CI 3.9-9.0) among those with radiotherapy (n = 823).
The incidence of contralateral breast cancer among minimum-risk breast cancer patients in Japan, where the incidence of breast cancer is low, was similar to that in Western countries. Endocrine therapy is indicated for this population.

DOI： 10.1007/s12282-012-0396-4

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Background Because of its superior efficacy to tamoxifen, anastrozole has been widely used in Japan as an adjuvant treatment for postmenopausal, hormone-responsive breast cancer patients. However, anastrozole may affect bone in Japanese patients similar to its effects in Western patients. The aim of this study is to evaluate the rate of bone fracture and bone mineral density (BMD) during anastrozole treatment in Japanese patients.
Patients and methods In this study, 350 postmenopausal women with hormone-responsive, stage I to IIIA breast cancer were enrolled and scheduled to receive adjuvant anastrozole treatment for up to 5 years. Patients underwent clinical examination for bone fractures and annual measurement of BMD during treatment.
Results After a median follow-up of 33.0 months, bone fractures occurred in 1.8 %. Annual fracture rates were 0.3 and 1.2 % during the first and second year, respectively. The overall median BMD significantly decreased, measuring 87.5, 84.3, and 83.5 % at baseline and after 1 and 2 years, respectively. Musculoskeletal disorders were the most common (26.1 %), and hot flashes were the second most common adverse event (7.9 %). Severe adverse events occurred in 5.5 % of all the cases.
Conclusions In this interim analysis, the bone fracture rate was lower than that in the Western population despite a significant reduction of BMD after 2 years of treatment with anastrozole. Adjuvant anastrozole treatment was well tolerated in Japanese postmenopausal women with breast cancer. Long-term follow-up data is necessary to elucidate the racial disparities of the safety profile of anastrozole.

DOI： 10.1007/s10147-012-0512-7

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Aromatase inhibitors (AIs) exert antiproliferative effects by reducing local estrogen production from androgens in postmenopausal women with hormone-responsive breast cancer. Previous reports have shown that androgen metabolites generated by the aromatase-independent enzymes, 5 alpha-androstane-3 beta, 17 beta-diol (3 beta-diol), androst-5-ene-3 beta, and 17 beta-diol (A-diol), also activate estrogen receptor (ER) alpha. Estradiol (E2) can also reportedly be generated from estrone sulfate (E1S) pooled in the plasma. Estrogenic steroid-producing aromatase-independent pathways have thus been proposed as a mechanism of AI resistance. However, it is unclear whether these pathways are functional in clinical breast cancer. To investigate this issue, we assessed the transcriptional activities of ER in 45 ER-positive human breast cancers using the adenovirus estrogen-response element-green fluorescent protein assay and mRNA expression levels of the ER target gene, progesterone receptor, as indicators of ex vivo and in vivo ER activity, respectively. We also determined mRNA expression levels of 5 alpha-reductase type 1 (SRD5A1) and 3 beta-hydroxysteroid dehydrogenase type 1 (3 beta-HSD type 1; HSD3B1), which produce 3 beta-diol from androgens, and of steroid sulfatase (STS) and 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD type 1; HSD17B1), which produce E2 or A-diol from E1S or dehydroepiandrosterone sulfate. SRD5A1 and HSD3B1 expression levels were positively correlated with ex vivo and in vivo ER activities. STS and HSD17B1 expression levels were positively correlated with in vivo ER activity alone. Elevated expression levels of these steroid-metabolizing enzymes in association with high in vivo ER activity were particularly notable in postmenopausal patients. Analysis of the expression levels of steroid-metabolizing enzymes revealed positive correlations between SRD5A1 and HSD3B1, and STS and HSD17B1. These findings suggest that the SRD5A1-HSD3B1 as well as the STS-HSD17B pathways, could contributes to ER activation, especially postmenopause. These pathways might function as an alternative estrogenic steroid-producing, aromatase-independent pathways.

DOI： 10.1007/s10549-013-2788-3

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DOI： 10.1272/manms.10.120

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Kluwer Academic Publishers  

Estrogen and various growth factors affecting tumor behavior are present in the breast cancer microenvironment, but their comprehensive effects and signal crosstalks are different in each case. However, there is no system to evaluate the factors, detected in individual breast cancer cases, that regulate ER activity and tumor progression. In this study, we analyzed the effects of individual breast cancer extracts by our original system using an estrogen-signal reporter cell line, MCF-7-E10, which we previously established. MCF-7-E10 cell line is stably transfected by an estrogen response element (ERE)-green fluorescent protein (GFP) gene
it expresses GFP when estrogen receptors (ERs) are activated by estrogen or growth factor signal-mediated ER phosphorylation. Using this cell line, we analyzed the comprehensive effects of factors derived from breast cancer tissues on ER activity and growth of MCF-7-E10 cells for each case. We also analyzed relationships between these activities and clinicopathologic characteristics of patients who provided cancer specimens. The breast cancer extracts, which reflect the combined activities of growth factors present in individual cases, stimulated MCF-7-E10 cell growth in an estrogen-independent manner, and specifically stimulated growth of other breast cancer cell lines, regardless of ER expression. High growth-promoting activities were seen in tumor regions of specimens with tumors &gt
10 mm in size, HER2 intrinsic subtype, and scirrhous and solid-tubular carcinoma histological subtypes. Anti-human hepatocyte growth factor (HGF) antibody and an inhibitor for insulin-like growth factor-1 (IGF-1) receptor inhibited MCF-7-E10 cell growth by the breast cancer extracts, indicating that signal pathways via HGF or IGF-1 receptor significantly affect breast cancer. These data suggest that growth factors other than estrogen in the tumor extract significantly affect breast cancer aggressiveness in an estrogen-independent manner, and could be useful therapeutic targets. © 2013 The Author(s).

DOI： 10.1007/s12307-013-0139-x

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DOI： 10.1272/jnms.81.192

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

It is still controversial whether axillary lymph node (ALN) dissection (ALND) can be omitted after negative sentinel lymph node (SLN) biopsy (SLNB) in breast cancer (BC) patients with clinically positive ALNs at presentation treated with neoadjuvant chemotherapy (NAC). The study aim was to analyze whether SLNB could be useful in these patients.
In a retrospective study, eligible patients were women with invasive BC with clinically positive ALNs at presentation, treated with NAC then a total or partial mastectomy, with an intraoperative histological examination of SLNs and non-SLNs suspicious for metastasis followed by ALND. Non-SLNs suspicious for metastasis were defined as hard or large nodes located in the same level of the axilla where clinically positive ALNs had been initially identified. The results of SLNB and clinicopathological characteristics were analyzed for correlation with pathological ALN status.
In a consecutive series of 105 women with 107 BC cases, 81 (75.7 %) had at least 1 SLN, and the remaining 26 (24.3 %) had at least 1 non-SLN suspicious for metastasis. The intraoperative (or final) histological examination of these nodes revealed that the false-negative (FN) rate and accuracy were 8.2 (or 6.3) % and 95.1 (or 96.3) %, respectively. Estrogen receptor status at presentation, pathological tumor response, lymphovascular invasion after NAC, and NAC regimen were correlated with pathological ALN status.
The histological examination of SLNs and that of non-SLNs suspicious for metastasis are useful for predicting pathological ALN status in BC patients with clinically positive ALNs at presentation who are treated with NAC.

DOI： 10.1007/s10147-012-0418-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Aromatase inhibitors (AIs) have been reported to exert their antiproliferative effects in postmenopausal women with hormone receptor-positive breast cancer not only by reducing estrogen production but also by unmasking the inhibitory effects of androgens such as testosterone (TS) and dihydrotestosterone (DHT). However, the role of androgens in AI-resistance mechanisms is not sufficiently understood. 5 alpha-Androstane-3 beta,17 beta-diol (3 beta-diol) generated from DHT by 3 beta-hydroxysteroid dehydrogenase type 1 (HSD3B1) shows androgenic and substantial estrogenic activities, representing a potential mechanism of AI resistance. Estrogen response element (ERE)-green fluorescent protein (GFP)-transfected MCF-7 breast cancer cells (E10 cells) were cultured for 3 months under steroid-depleted, TS-supplemented conditions. Among the surviving cells, two stable variants showing androgen metabolite-dependent ER activity were selected by monitoring GFP expression. We investigated the process of adaptation to androgen-abundant conditions and the role of androgens in AI-resistance mechanisms in these variant cell lines. The variant cell lines showed increased growth and induction of estrogen-responsive genes rather than androgen-responsive genes after stimulation with androgens or 3 beta-diol. Further analysis suggested that increased expression of HSD3B1 and reduced expression of androgen receptor (AR) promoted adaptation to androgen-abundant conditions, as indicated by the increased conversion of DHT into 3 beta-diol by HSD3B1 and AR signal reduction. Furthermore, in parental E10 cells, ectopic expression of HSD3B1 or inhibition of AR resulted in adaptation to androgen-abundant conditions. Coculture with stromal cells to mimic local estrogen production from androgens reduced cell sensitivity to AIs compared with parental E10 cells. These results suggest that increased expression of HSD3B1 and reduced expression of AR might reduce the sensitivity to AIs as demonstrated by enhanced androgen metabolite-induced ER activation and growth mechanisms. Androgen metabolite-dependent growth of breast cancer cells may therefore play a role in AI-resistance.

DOI： 10.1007/s10549-013-2595-x

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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BACKGROUND: Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated. METHODS: Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/-). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups. RESULTS AND DISCUSSION: The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab. CONCLUSIONS: We recommend FISH analysis as a primary HER2 testing because patients with IHC 2+/3+ and nonamplified HER2 had poor outcome. We also support concurrent use of trastuzumab, lapatinib, and cytotoxic and anti-hormonal agents for patients having HR+ tumors with alterations of the PI3K and ER pathway genes.

DOI： 10.1186/1471-2407-13-241

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Language：English   Publisher：SPANDIDOS PUBL LTD  

DOI： 10.3892/ol.2013.1141

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

BACKGROUND: The increasing costs associated with large-scale adjuvant trials mean that the prognostic value of biologic markers is increasingly important. The expression of nuclear antigen Ki-67, a marker of cell proliferation, has been correlated with treatment efficacy and is being investigated for its value as a predictive marker of therapeutic response. In the current study, the authors explored correlations between Ki-67 expression and tumor response, estrogen receptor (ER) status, progesterone receptor (PgR) status, and histopathologic response from the STAGE study (S_tudy of T_amoxifen or A_rimidex, combined with G_oserelin acetate to compare E_fficacy and safety). METHODS: In a phase 3, double-blind, randomized trial (National Clinical Trials identifier NCT00605267), premenopausal women with ER-positive, early stage breast cancer received either anastrozole plus goserelin or tamoxifen plus goserelin for 24 weeks before surgery. The Ki-67 index, hormone receptor (ER and PgR) status, and histopathologic responses were determined from histopathologic samples that were obtained from core-needle biopsies at baseline and at surgery. Tumor response was determined by using magnetic resonance imaging or computed tomography. RESULTS: In total, 197 patients were randomized to receive either anastrozole plus goserelin (n = 98) or tamoxifen plus goserelin (n = 99). The best overall tumor response was better for the anastrozole group compared with the tamoxifen group both among patients who had a baseline Ki-67 index 20% and among those who had a baseline Ki-67 index &lt;20%. There was no apparent correlation between baseline ER status and the Ki-67 index in either group. Positive PgR status was reduced from baseline to week 24 in the anastrozole group. CONCLUSIONS: In premenopausal women with ER-positive breast cancer, anastrozole produced a greater best overall tumor response compared with tamoxifen regardless of the baseline Ki-67 index. Cancer 2013. (c) 2012 American Cancer Society.

DOI： 10.1002/cncr.27818

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

It is speculated that estrogens play important roles in the male breast carcinoma (MBC) as well as the female breast carcinoma (FBC). However, estrogen concentrations or molecular features of estrogen actions have not been reported in MBC, and biological significance of estrogens remains largely unclear in MBC. Therefore, we examined intratumoral estrogen concentrations, estrogen receptor (ER) alpha/ER beta status, and expression profiles of estrogen-induced genes in MBC tissues, and compared these with FBC. 17 beta-Estradiol concentration in MBC (n = 4) was significantly (14-fold) higher than that in non-neoplastic male breast (n = 3) and tended to be higher than that in FBC (n = 7). Results of microarray analysis clearly demonstrated that expression profiles of the two gene lists, which were previously reported as estrogen-induced genes in MCF-7 breast carcinoma cell line, were markedly different between MBC and FBC. In the immunohistochemistry, MBC tissues were frequently positive for aromatase (63 %) and 17 beta-hydroxysteroid dehydrogenase type 1 (67 %), but not for steroid sulfatase (6.7 %). A great majority (77 %) of MBC showed positive for both ER alpha and ER beta, and its frequency was significantly higher than FBC cases. These results suggest that estradiol is locally produced in MBC tissue by aromatase. Different expression profiles of the estrogen-induced genes may associate with different estrogen functions in MBC from FBC, which may be partly due to their ER alpha/ER beta status.

DOI： 10.1007/s12672-012-0126-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

In the present study, clinical tumor response following neoadjuvant chemotherapy (NAC) was diagnosed by magnetic resonance imaging (MRI) and clinicopathological factors, including molecular subtypes at baseline, were analyzed for correlations with pathological tumor responses. In addition, clinicopathological factors were analyzed for a correlation with the MRI capacity to predict pathological complete response (pCR). Clinical tumor response evaluated by MRI following NAC was determined as a clinical CR (cCR) or a residual tumor. cCR was confirmed if no gadolinium enhancement or an enhancement equal to or less than that of glandular tissue was observed in any phase of the MRI. Pathological tumor responses following NAC were classified into grades 0 (no change) to 3 (no residual invasive cancer) according to criteria of the Japanese Breast Cancer Society. pCR was defined as grade 3 in the present study. Of 264 cases of invasive breast cancer in 260 patients (4 synchronous bilateral breast cancer cases), 59 (22%) were diagnosed by MRI following NAC as cCR and 98 (37%) were pathologically diagnosed as pCR. In terms of predicting pCR by MRI, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were 44, 90, 73, 73 and 73%, respectively. Tumor size, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, molecular subtype and histological type were significantly correlated with pathological tumor responses. pCR rates increased in the following order: luminal/HER2-negative (14%), luminal/HER2-positive (32%), triple-negative (46%) and non-luminal/HER2-positive (73%) tumors. Sensitivity and specificity were the highest (60 and 100%, respectively) in triple-negative tumors. PPV decreased in the following order: triple-negative (100%), non-luminal/HER2-positive (92%), luminal/HER2-positive (46%) and luminal/HER2-negative (33%) tumors. In conclusion, MRI evaluation is useful for predicting pCR following NAC, particularly for triple-negative tumors.

DOI： 10.3892/ol.2012.1004

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DOI： 10.3892/mco.2012.4

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Paclitaxel therapy often causes musculoskeletal pain, and some clinical studies have indicated that this pain is due to nerve injury, rather than muscle or joint lesion. We report four clinical cases in which controlled-release oxycodone improved pain intensity in breast cancer patients with severe musculoskeletal pain caused by nab-paclitaxel therapy. In each case, oxycodone was well-tolerated and the symptoms of peripheral neuropathy were quite mild, indicating that oxycodone exhibited a preventive or therapeutic effect on peripheral neuropathy. Therefore, oxycodone may have favorable efficacy and tolerability against cancer therapy-related pain with a neuropathic element in breast cancer patients.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

To predict the efficacy of hormonal therapy at the individual-level, immunohistochemical methods are used to analyze expression of classical molecular biomarkers such as estrogen receptor (ER), progesterone receptor (PgR), and HER2. However, the current diagnostic standard is not perfect for the individualization of diverse cases. Therefore, establishment of more accurate diagnostics is required. Previously, we established a novel method that enables analysis of ER transcriptional activation potential in clinical specimens using an adenovirus estrogen response element-green fluorescence protein (ERE-GFP) assay system. Using this assay, we assessed the ERE transcriptional activity of 62 primary breast cancer samples. In 40% of samples, we observed that ER protein expression was not consistent with ERE activity. Comparison of ERE activity with clinicopathological information revealed that ERE activity was significantly correlated with the ER target gene, PgR, rather than ER in terms of both protein and mRNA expression. Moreover, subgrouping of Luminal A-type breast cancer samples according to ERE activity revealed that ER alpha mRNA expression correlated with ER target gene mRNA expression in the high-, but not the low-, ERE-activity group. On the other hand, the low- ERE-activity group showed significantly higher mRNA expression of the malignancy biomarker Ki67 in association with disease recurrence in 5% of patients. Thus, these data suggest that ER expression does not always correlate with ER transcriptional activity. Therefore, in addition to ER protein expression, determination of ERE activity as an ER functional marker will be helpful for analysis of a variety of diverse breast cancer cases and the subsequent course of treatment.

DOI： 10.1002/cam4.41

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Carcinoma-associated fibroblasts (CAFs) are associated with tumor progression and metastasis, and are able to activate estrogen receptor (ER) in breast cancer. We established a stable transformant of a human breast cancer cell line to detect CAF-specific ER-activating ability, and found that this CAF ability varied among tumors. Some studies have reported a high frequency of alterations among tumor suppressor genes in stromal cells, but do not generally agree as to the frequency. Moreover, the activation mechanism of CAF-induced estrogen signals, including the effects of these gene aberrations, is not fully understood. We investigated the relevance of tumor suppressor gene aberrations and ER-activating ability in CAFs derived from 20 breast cancer patients. Although CAF-specific ER-activating abilities varied among individual cases, all CAFs maintained wild-type alleles for 753 and PTEN. Also, copy number aberrations in these genes were not observed in any CAFs. Our results suggest that the ER-activating ability of the CAFs is regulated independently of aberrations in these genes: and that other mechanisms of tumorstromal interaction may affect activation of estrogen signals in breast cancer. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2012.10.035

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Health-related quality of life (HRQOL), symptoms of depression, and adverse events (AEs) were compared between Japanese postmenopausal patients with hormone-sensitive breast cancer (BC) who received adjuvant tamoxifen, exemestane, or anastrozole in an open-labeled, randomized, multicenter trial designated as the National Surgical Adjuvant Study of Breast Cancer (N-SAS BC) 04 substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. During the first year of treatment, HRQOL and symptoms of depression were analyzed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and its Endocrine Symptom Subscale (ES), and the Center for Epidemiologic Studies Depression Scale (CES-D), respectively. In addition, predefined AEs were analyzed. A total of 166 eligible patients were randomly assigned to receive adjuvant tamoxifen, exemestane, or anastrozole. FACT-B scores increased after treatment began and remained significantly higher in the tamoxifen group than in the exemestane group or anastrozole group during the first year (P = 0.045). FACT-B scores were similar in the exemestane group and anastrozole group. ES scores and CES-D scores were similar in all treatment groups. Arthralgia and fatigue were less frequent, but vaginal discharge was more frequent in the tamoxifen group than in the exemestane group or anastrozole group. HRQOL was better in Japanese postmenopausal women treated with tamoxifen than those treated with exemestane or anastrozole. HRQOL and AEs were similar with exemestane and anastrozole. Given the results of the TEAM trial, upfront use of tamoxifen followed by an aromatase inhibitor (AI) may be an important option for adjuvant endocrine therapy in Japanese postmenopausal women.

DOI： 10.1007/s10549-011-1943-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background Aromatase inhibitors have shown increased efficacy compared with tamoxifen in postmenopausal early breast cancer. We aimed to assess the efficacy and safety of anastrozole versus tamoxifen in premenopausal women receiving goserelin for early breast cancer in the neoadjuvant setting.
Methods In this phase 3, randomised, double-blind, parallel-group, multicentre study, we enrolled premenopausal women with oestrogen receptor (ER)-positive, HER2-negative, operable breast cancer with WHO performance status of 2 or lower. Patients were randomly assigned (1: 1) to receive goserelin 3 . 6 mg/month plus either anastrozole 1 mg per day and tamoxifen placebo or tamoxifen 20 mg per day and anastrozole placebo for 24 weeks before surgery. Patients were randomised sequentially, stratified by centre, with randomisation codes. All study personnel were masked to study treatment. The primary endpoint was best overall tumour response (complete response or partial response), assessed by callipers, during the 24-week neoadjuvant treatment period for the intention-to-treat population. The primary endpoint was analysed for non-inferiority (with non-inferiority defined as the lower limit of the 95% CI for the difference in overall response rates between groups being 10% or less); in the event of non-inferiority, we assessed the superiority of the anastrozole group versus the tamoxifen group. We included all patients who received study medication at least once in the safety analysis set. We report the primary analysis; treatment will also continue in the adjuvant setting for 5 years. This trial is registered with ClinicalTrials.gov,number NCT00605267.
Findings Between Oct 2, 2007, and May 29, 2009, 204 patients were enrolled. 197 patients were randomly assigned to anastrozole (n=98) or tamoxifen (n=99), and 185 patients completed the 24-week neoadjuvant treatment period and had breast surgery (95 in the anastrazole group, 90 in the tamoxifen group). More patients in the anastrozole group had a complete or partial response than did those in the tamoxifen group during 24 weeks of neoadjuvant treatment (anastrozole 70 . 4% [69 of 98 patients] vs tamoxifen 50 . 5% [50 of 99 patients]; estimated difference between groups 19 . 9%, 95% CI 6 . 5-33 . 3; p=0 . 004). Two patients in the anastrozole group had treatment-related grade 3 adverse events (arthralgia and syncope) and so did one patient in the tamoxifen group (depression). One serious adverse event was reported in the anastrozole group (benign neoplasm, not related to treatment), compared with none in the tamoxifen group.
Interpretation Given its favourable risk-benefit profile, the combination of anastrozole plus goserelin could represent an alternative neoadjuvant treatment option for premenopausal women with early-stage breast cancer.

DOI： 10.1016/S1470-2045(11)70373-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

Background: Some studies have shown that high body mass index (BMI) is associated with inferior outcome after adjuvant therapy with anastrozole in breast cancer patients. We aimed to investigate predictive effect of BMI on clinical response to neoadjuvant therapy with exemestane in postmenopausal patients with primary breast cancer.
Patients and methods: The study group consisted of 109 patients from the JFMC 34-0601 neoadjuvant endocrine therapy trial. Patients were categorized into three groups according to BMI: low (BMI &lt; 22 kg/m(2)), intermediate (22 &lt;= BMI &lt; 25 kg/m(2)) and high (BMI &gt;= 25 kg/m(2)). Statistical analyses were performed to explore the predictive effect of BMI on clinical response.
Results: Higher BM1 correlated with positive progesterone receptor status (p &lt; 0.01) and low Ki-67 index (p = 0.03). Objective response rates (ORR) were 21.7% in low BMI, 56.0% in intermediate BM1 and 60.6% in high BM1, respectively (p = 0.01). In a multivariate analysis, low BMI was an independent negative predictor of clinical response.
Conclusion: Low BMI was associated with a decreased ORR to neoadjuvant endocrine therapy with exemestane. Our results may suggest that the predictive effect of BMI varies according to the type of aromatase inhibitor and objective outcome. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.breast.2011.07.015

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Publishing type：Research paper (scientific journal)   Publisher：OMICS Publishing Group  

DOI： 10.4172/2167-0420.1000e105

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aromatase inhibitor shows efficacy for hormone receptor positive postmenopausal breast cancer. We evaluated the activity of 24 weeks of aromatase inhibition with exemestane for primary breast cancer in a neoadjuvant setting. Patients with stage II/IIIA invasive breast cancer with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive status were eligible. Primary end-points were objective response rate (ORR) and safety. A steroidal aromatase inhibitor exemestane of 25 mg/day was administered for 16 weeks with an 8-week extension. Secondary endpoints were rates of breast-conserving surgery (BCS), and change of Ki67 index and ER/PgR expression in central laboratory analyses. Between March 2006 and December 2007, 116 patients were enrolled. Among those, 102 patients completed 24 weeks of administration. The ORR was 47% (55/116) at Week 16 and 51% (59/116) at Week 24, respectively. No serious toxicity was seen. ORR was associated with ER Allred scores but not with PgR scores. The significant reduction in Ki67 index was confirmed. No progression was experienced in tumors with less than 15% Ki67 index. Pathological response was observed in 28 (30%) of 94 evaluated cases. No statistical correlation between pre-treatment Ki67 index and pathological response was detected; however, a trend of correlation was found between the post-treatment preoperative endocrine prognostic index (PEPI), a prognostic score and the pathological response. At diagnosis, 59 patients (51%) would have required mastectomy but 40 patients were converted to BCS, showing an increase in the rate of BCS (77%). The 24-week aromatase inhibition provided preferable clinical benefits with significant reduction in Ki67 index. More precise mechanisms of the response need to be investigated. (Cancer Sci 2011; 102: 858-865)

DOI： 10.1111/j.1349-7006.2011.01867.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Aromatase inhibitors (AIs) were more effective than tamoxifen as a neoadjuvant endocrine therapy (NAE) for postmenopausal women with estrogen receptor (ER)-positive breast cancer. Neoadjuvant AIs were shown to reduce tumor volume and to allow the performance of breast-conserving surgery (BCS) in cases that would normally require mastectomy. Predictive markers of neoadjuvant AIs may be ER-rich, progesterone receptor (PgR)-rich and human epidermal growth factor receptor 2 (HER2)-negative tumors. However, the ability of HER2 expression to predict a response to neoadjuvant AIs is controversial. Pathological tumor size, nodal status, Ki67 level, and ER score are predictive for the survival of postmenopausal women with breast cancer who have been treated with NAE. These factors could be useful in order to select patients who do not require chemotherapy. Indeed, neoadjuvant AIs are a potential treatment option for postmenopausal women with ER-rich breast cancer who prefer BCS despite having large tumors suitable for mastectomy.

DOI： 10.1007/s12282-010-0239-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

This study compared the efficacy and safety of a 3-monthly 10.8-mg depot goserelin (Zoladex(TM)) injection with the current 3.6 mg monthly dose in pre-menopausal Japanese women with estrogen receptor-positive (ER+) early breast cancer. This was a multicenter, open-label, randomized study. Primary endpoint was a non-inferiority analysis (10.8/3.6 mg) of the area under the concentration-time curve (AUC) of estradiol (E(2)) over the first 24 weeks. Secondary endpoints included E(2) and follicle-stimulating hormone (FSH) concentrations, menstruation, and safety and tolerability. In total, 170 patients were randomized to receive goserelin 10.8 mg every 3 months (n = 86) or 3.6 mg every month (n = 84). Mean AUCs for E(2) were similar between treatment groups (18.32 and 18.95 pg/ml center dot week for goserelin 10.8 and 3.6 mg, respectively). AUC ratio was 0.974 (95% confidence interval, 0.80, 1.19), indicating non-inferiority for goserelin 10.8 mg. Serum E(2) and FSH remained suppressed throughout the study and no patient experienced menses after week 16. No clinically important differences in safety and tolerability were observed between the two groups. In terms of E(2) suppression, 3-monthly goserelin 10.8 mg was non-inferior to monthly goserelin 3.6 mg in pre-menopausal women with ER+ breast cancer.

DOI： 10.1007/s10549-010-1332-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Although triple-negative breast cancer (TNBC) is associated with a poor prognosis, recent reports have indicated that a higher proportion of TNBC patients shows a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) than is the case for non-TNBC patients. The aim of this study was to identify markers that predict pCR to NAG in TNBC patients, and to clarify prognostic factors that affect the outcome of TNBC patients with residual disease (RD) after NAG. Among 44 TNBC patients who received anthracycline- and taxane-based combination NAC, we analyzed the relationship between pathological response and clinicopathological characteristics, including immunohistochemical parameters (cytokeratin 5/6, epidermal growth factor receptor, Ki-67, p53, breast cancer susceptibility protein 1 and topoisomerase Ha). We also assessed the prognostic impact on patients with RD by analyzing the correlation between disease-free survival (DFS) and clinicopathological parameters. Sixteen patients (36%) achieved a pCR and log-rank test showed that these patients had a significantly more favorable outcome than patients with RD (DFS, P=0.00184; overall survival, P=0.0080). Among the clinicopathological parameters examined, none was correlated with pathological response, with the exception of p53. Patients with immunohistochemical overexpression of p53 more frequently achieved a pCR than those without p53 overexpression (P=0.0484). In the patients with RD, the Cox proportional hazards model showed that the presence of lymphovascular invasion was significantly associated with shorter DFS (hazard ratio, 13.333; 95% CI 1.587-111.111; P=0.0171). p53 overexpression may be a key predictor of a favorable response to NAG. Since patients with RD, particularly those positive for lymphovascular invasion, had an extremely poor outcome, novel therapeutic approaches for these patients are warranted.

DOI： 10.3892/etm.2011.212

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Language：English   Publisher：CHURCHILL LIVINGSTONE  

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Language：Japanese   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

Chemotherapeutic agents, especially paclitaxel, and endocrinotherapeutic agents such as aromatase inhibitors and antiestrogen, can induce seriously painful symptoms in breast cancer patients during adjuvant treatment before and after surgery. We report five clinical cases in which oxycodone was effective against pain induced by anti-cancer agents during adjuvant treatment. Paclitaxel was used as the anti-cancer agent in each of the five patients. Aromatase inhibitors and anti-estrogen were administered to one and three patients, respectively. The daily dose of controlled-release oxycodone ranged from 10 mg to 270 mg, but none of the patients dropped out due to adverse events caused by oxycodone. Pain intensity measured by NRS decreased to less than 3 out of 10, compared to the baseline in every patient except for one. Oxycodone may be effective against anti-cancer agent-induced pain. In addition, appropriate assessment and management of pain may be crucial for breast cancer patients during adjuvant treatment.

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In this study, we conducted an immunohistochemical analysis of primary breast tumors and metachronous brain metastases to compare the differences in the expression of biological markers between the two. Carcinoma tissues from primary breast tumors and metachronous brain metastases collected from 21 patients were examined immunohistochemically for the expression status of the estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor (HER)-2, Ki-67, bcl-2 and p53, and the results were compared. In addition, the relationships between the expression of these factors and prognosis were evaluated. There were no significant differences in the frequencies of ER-, PgR-, HER-2-, bcl-2- or p53-positivity between the primary breast tumors and metachronous brain metastases. While the Ki-67 labeling index (LI) was high in both the primary breast tumors and brain metastases, it was significantly higher in the brain metastases than in the corresponding primary breast tumors (P=0.003). With regard to the prognosis, breast cancer patients who showed ER-positivity in the primary tumors showed significantly longer survival after primary diagnosis (P=0.0076). Furthermore, breast cancer patients who exhibited ER-positivity, bcl-2-positivity or p53-negativity in the primary tumors showed significantly longer intervals from primary diagnosis to the detection of the brain metastases. Of all the markers, only the Ki-67 LI was significantly higher in the brain metastases than in the primary breast tumors. We confirmed that the tumor characteristics were worse in the metachronous brain metastases.

DOI： 10.3892/etm_00000088

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Ipsilateral breast tumor relapse (IBTR) after breast-conserving treatment (BCT) may represent two distinct types of lesion, including a true recurrence (TR) or a new primary tumor (NPT). The aim of this study was to ascertain the difference between TRs and NPTs and to show the clinical significance of classifying IBTR into these two types of recurrence. Patients (n = 2,075) with unilateral invasive breast cancer who underwent BCT between 1987 and 2005 at Saitama Cancer Center were analyzed. IBTR was classified into TR and NPT, which was based on all clinical and pathological features of both a primary tumor and IBTR that can be evaluated. IBTR-free survival and the risk factors were analyzed in order to compare the findings for TR and NPT. In addition, the salvage surgical methods for IBTR and overall survival after IBTR were analyzed. Sixty patients with IBTR were classified into 52 with TR and eight with NPT. IBTR-free survival was significantly shorter in the patients with TR than those with NPT. Young age, tumor size, a positive surgical margin, and omission of radiation therapy (RT) were significant risk factors for TR. Omission of RT was the only significant risk factor for NPT. In 27 patients who underwent a repeat lumpectomy for TR, four had a second IBTR. The overall survival after IBTR was worse in patients with TR than NPT. TR and NPT show quite different clinical features. Classifying IBTR into TR or NPT can therefore help to select the most appropriate treatment for IBTR.

DOI： 10.1111/j.1524-4741.2009.00884.x

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Background It is currently unclear which patients with breast cancer with sentinel lymph node (SLN) metastases do not need axillary lymph node dissection (ALND).
Patients and methods A cohort of 1,132 women who had unilateral invasive breast cancer with clinically negative nodes or nodes suspicious for metastasis, were intraoperatively diagnosed as having negative SLNs, and did not undergo an immediate ALND. Our intraoperative histological investigation uses H&E staining of a frozen section from a maximum cut surface of each SLN. Of these 1,132 women, 132 (11.7%) were postoperatively diagnosed as having positive SLNs, which classifies them as having an intraoperative, false-negative SLN biopsy (SLNB). Patient and tumor characteristics, treatment methods, and the prognoses of these patients were investigated and compared with the remaining 1,000 patients who were negative for SLNB.
Results Of the 132 patients with intraoperative, false-negative SLNB, none underwent a further ALND. With a median follow-up period of 58.1 months, none of these patients exhibited recurrence in the axillary nodes. Their recurrence-free survival rates were not statistically different from those of patients with negative SLNB.
Conclusions ALND can be avoided in most patients with breast cancer with intraoperative, false-negative SLNB.

DOI： 10.1007/s12282-009-0154-4

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Language：Japanese   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

A recent foreign clinical trial showed that the combination of docetaxel plus cyclophosphamide (TC) is associated with a superior disease-free survival compared with doxorubicin plus cyclophosphamide as adjuvant chemotherapy for breast cancer. To assess the tolerability and safety of TC in a Japanese patient population, we conducted a multicenter, open-labeled clinical trial. Eligible patients were women who had axillary lymph node-negative breast cancer with surgical excision of the primary tumor. Patients were treated with 4 courses of TC (75 and 600 mg/m2, respectively), administered intravenously every 3 weeks. The primary endpoint was feasibility, which was defined as the proportion of patients who completed 4 courses of the chemotherapy. From October 2006 to November 2007, 39 patients were enrolled and 32 were evaluable. Seven patients were excluded because of the inadequate treatment schedule. Feasibility was 96.9% (31/32). One patient did not complete treatment because of the hypersensitivity. The mean administered dose was 73.2 mg/m2 for docetaxel and 588.3 mg/m2 for cyclophosphamide, respectively. The mean relative dose intensity was 96.1% and 95.7%, respectively. The grade 3/4 toxicity including leukopenia, neutropenia, and febrile neutropenia was manageable. From these results, we consider that TC might become a standard non-anthracycline adjuvant regimen for operable breast cancer.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Background: Expression analysis of estrogen response genes (ERGs) may help to predict the effectiveness of endocrine therapies in breast cancer patients. We produced a custom-made, 3-dimensional microarray system (3DMS), using previously identified ERGs, and analyzed expression of ERGs on breast cancer tissues. Materials and Methods: aRNA was synthesized from 27 breast cancer tumors. The aRNAs were applied to the infrastructure of a 3DMS with spotted cDNA probes to 36 ERGs. Data were analyzed by cluster analysis. Results: All 2 7 specimens were classified clearly into one of two clusters based on whether the ERGs were up or down regulated. These groups correlated with high expression of ER (P&lt;0.05) and Her2 (P&lt;0.05). In some cases, ERG expressions were low even though the tumor was ER positive. Conclusion: 3DMS may be useful for accurately predicting prognosis and whether endocrine therapies targeting the ER would be effective in an individual breast cancer patient.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

Ipsilateral breast tumor relapse (IBTR) is a potentially a significant problem after breast conserving surgery (BCS). With a median follow-up period of 64.7 months, IBTR occurred as a first relapse in 67 (3.0%) of a total of 2243 patients and distant recurrence occurred in 167 (7.4%). A positive surgical margin and the omission of radiotherapy (RT) were independently associated with IBTR. The five-year cumulative IBTR rates were 5.1% in patients with positive margins and 2.0% in the patients with negative margins. The five-year cumulative IBTR rates were 1.8% in patients with RT and 8.1% in patients without RT. IBTR was independently associated with distant-recurrence-free survival rates as well as age, nodal metastasis, lymphovascular invasion and progesterone receptor status. The five-year distant-recurrence-free survival rates were 81.9% in patients with IBTR and 93.2% in patients without IBTR. In order to prevent IBTR, a negative margin and the administration of RT are therefore considered to be important in patients who undergo BCS. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.breast.2009.06.001

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It remains to be clarified whether a positive sentinel lymph node biopsy (SLNB) can predict the number of metastatic axillary nodes. This study examined a consecutive series of women with unilateral invasive breast cancer who underwent axillary lymph node dissection after an intra-operative positive SLNB. The numbers of positive and negative sentinel lymph nodes (SLNs) were analyzed for a likelihood of pN1a, pN2a, and pN3a diseases as per the UICC TNM classification. Of the 368 study patients, 165 (45%) had one positive SLN and one or more negative SLNs. This result represented the most common combination of positive and negative SLNs. It was also the most predictive indicator (93%) of pN1a disease and the least predictive indicator (7% or 0%) of pN2a or pN3a disease, respectively. The numbers of positive and negative SLNs can predict the number of metastatic axillary nodes in breast cancer patients. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.breast.2009.05.007

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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CHIP is a U-box-type ubiquitin ligase that induces ubiquitylation and degradation of its substrates, which include several oncogenic proteins(1-12). The relationship between CHIP and tumour progression, however, has not been elucidated. Here, we show that CHIP suppresses tumour progression in human breast cancer by inhibiting oncogenic pathways. CHIP levels were negatively correlated with the malignancy of human breast tumour tissues. In a nude mouse xenograft model, tumour growth and metastasis were significantly inhibited by CHIP expression. In contrast, knockdown of CHIP (shCHIP) in breast cancer cells resulted in rapid tumour growth and metastastic phenotypes in mice. In cell-based experiments, anchorage-independent growth and invasiveness of shCHIP cells was significantly elevated due to increased expression of Bcl2, Akt1, Smad and Twist. Proteomic analysis identified the transcriptional co-activator SRC-3 (refs13-19) as a direct target for ubiquitylation and degradation by CHIP. Knocking down SRC-3 in shCHIP cells reduced the expression of Smad and Twist, and suppressed tumour metastasis in vivo. Conversely, SRC-3 co-expression prevented CHIP-induced suppression of metastasis formation. These observations demonstrate that CHIP inhibits anchorage-independent cell growth and metastatic potential by degrading oncogenic proteins including SRC-3.

DOI： 10.1038/ncb1839

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The estrogen pathway plays an important role in the etiology of human endometrial carcinoma (EC). We examined whether estrogen biosynthesis in the tumor microenvironment promotes endometrial cancer. To examine the contribution of stromal cells to estrogen signaling in EC, we used reporter cells stably transfected with the estrogen response element (ERE) fused to the destabilized green fluorescent protein (GFP) gene. In this system, the endometrial cancer stromal cells from several patients activated the ERE of cancer cells to a variable extent. The GFP expression level increased when testosterone, a substrate for aromatase, was added. The effect was variably inhibited by aromatase inhibitors (Als), although the response to Als varied among patients. These results suggest that GFP expression is driven by estrogen synthesized by aromatase in the endometrial cancer stromal cells. In a second experiment, we constructed an adenovirus reporter vector containing the same construct as the reporter cells described above, and visualized endogenous ERE activity in primary culture cancer cells from 15 EC specimens. The GFP expression levels varied among the cases, and in most primary tissues, ERE activities were strongly inhibited by a pure anti-estrogen, fulvestrant. Interestingly, a minority of primary tissues in endometrial cancer showed ERE activity independent of the estrogen-ER pathway. These results suggest that Al may have some therapeutic value in EC; however, the hormonal microenvironment must be assessed prior to initiating therapy.

DOI： 10.1677/ERC-07-0227

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This multicenter phase II trial evaluated the efficacy and tolerability of 4 months of neoadjuvant exemestane in 44 postmenopausal patients with estrogen receptor (ER)-positive and/or progesterone receptor-positive, stage II to IIIB breast cancer measuring &gt;= 3 cm. Pathological response was assessed by a central review board using response criteria proposed by the Japanese Breast Cancer Society. Clinical response [complete or partial response (PR)] was assessed by caliper, mammography, or ultrasound. Rates of breast-conserving surgery (BCS) and adverse events were also evaluated. A pathological response was observed in 13 (43%) of 30 patients who underwent surgery at 4 months. Fourteen patients were excluded from the pathological analysis: eight continued exemestane because of PR or stable disease (SD) at 4 months, three underwent chemotherapy because of progressive disease, and three underwent surgery within 2 months because of adverse events. A clinical response was seen in 27 (66%) of 41 evaluable patients. BCS was performed in 27 (90%) of 30 patients who underwent surgery at 4 months. Of the ten patients eligible for mastectomy at baseline, six chose to continue exemestane treatment without surgery because of a PR or SD at 4 months. Adverse events, most of which were grade 1, occurred in &lt;= 10% of patients. These results suggest that neoadjuvant exemestane treatment is effective and well tolerated in postmenopausal women with ER-positive breast cancer. Further studies are required to determine the optimal duration of neoadjuvant treatment and to identify response criteria that can more accurately predict long-term outcomes.

DOI： 10.1007/s10549-007-9529-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

A recent report indicated that a high prevalence of basal-like breast tumors (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, human epidermal growth factor receptor [HER] 2-negative, and cytokeratin 5/6-positive and/or HER1-positive) could contribute to a poor prognosis in African American women with breast cancer. It has been reported that Japanese women with breast cancer have a significantly better survival rate than other races in the USA. These findings suggest that breast cancers in Japanese women have favorable biological characteristics. To clarify this hypothesis, we conducted a cohort study to investigate the prevalence of intrinsic subtypes and prognosis for each subtype in 793 Japanese patients. This study revealed a very low prevalence (only 8%) of basal-like breast tumors with aggressive biological characteristics in Japanese patients. Survival analysis showed a significantly poorer prognosis in patients with basal-like tumors than in those with luminal A tumors (ER- and/or PR-positive, and HER2-negative) with favorable biological characteristics. These findings support the hypothesis that breast cancers in Japanese women have more favorable biological characteristics and a better prognosis than those in other races. In conclusion, the prevalence of basal-like breast tumors could influence the prognosis of breast cancer patients of different races. The prevalence of intrinsic subtypes should be taken into account when analyzing survival data in a multi-racial/international clinical study. (C) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.breast.2007.07.017

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本癌学会  

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Language：English   Publisher：The Japanese Breast Cancer Society  

Background: A regional nodal recurrence is a major concern after a sentinel lymph node biopsy (SLNB) alone in patients with breast cancer. In this study we investigated patterns and risk factors of regional nodal recurrence after SLNB alone.<BR>Patients and Methods: Between January 1999 and March 2005, a series of 1,704 consecutive breast cancer cases in 1,670 patients (34 bilateral breast cancer cases) with clinically negative nodes or suspicious nodes for metastasis who underwent SLNB at a single institute (Saitama Cancer Center) were studied. All 1,704 cases were classified based upon presence or absence of a metastatic lymph node, treated with or without axillary lymph node dissection (ALND). The site of first recurrence was classified as local, regional node, or distant. The regional node recurrences were subclassified as axillary, interpectoral, infraclavicular, supraclavicular, or parasternal.<BR>Results: After a median follow-up period of 34 months (range, 2-83 months), first recurrence occurred in local sites in 32 (1.9%) cases, regional nodes in 26 (1.5%) cases, and distant sites in 61 (3.6%) cases. In 1,062 cases with negative nodes treated without ALND and 459 cases with positive nodes treated with ALND, 11 (1.0%) and 15 (3.3%) recurred in regional nodes, respectively, and 4 (0.4%) and 2 (0.6%) recurred in axillary nodes, respectively. Of 822 cases of invasive breast cancer with negative nodes treated with SLNB alone, 10 (1.4%) recurred in regional nodes, and 4 (0.5%) recurred in axillary nodes. In the 10 patients with regional nodal failure, all of the tumors were negative for estrogen receptor (ER) and/or progesterone receptor (PR) and were nuclear grade (NG) 3.<BR>Conclusions: The axillary recurrence rate was low in patients treated with SLNB alone. Omitting ALND is concluded to be safe after adequate SLNB. Risk factors for regional nodal failure after SLNB alone are negative hormone receptor status and high NG.

DOI： 10.2325/jbcs.14.16

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Sentinel lymph node (SLN) biopsy has become a common procedure for breast cancer patients. Many reported feasibility studies have revealed a high identification (95.4 of 2,125 cases) and accuracy rate on histopathological analysis (94 frozen and 97 paraffin). However, about 5 to 8 of cases false-negative are in this examination. Various methods of histopathological examination have been reported by many authors, but the Philadelphia consensus meeting recommended that sections less than 2.0 mm in thickness should be prepared and examined to detect metastasis larger than 2.0 mm. In addition, immunohistochemistry for cytokeratin is considered to be useful to detect isolated tumor cells (ITC) in the representative sections. On the other hand, real-time reverse transcriptase-polymerase chain reaction (RT-PCR) might detect micrometastasis (larger than 0.2 mm) (sensitivity and specificity; 89.5 and 96.7 frozen sections) and expected to be used as a routine method instead of histopathological examination.

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Language：English   Publisher：The Japanese Breast Cancer Society  

We report a case of nipple adenoma incidentally found in a mastectomy specimen, and describe its unique histological appearance and the immunohistochemical distribution of Ki-67 positive tumor cells. A 45-year-old woman with no symptoms or sign related to the nipple had a left mastectomy for invasive breast cancer. A small nipple adenoma, 7 mm in size, was incidentally recognized in the nipple of the resected breast. Histologically, the tumor in the nipple was composed of numerous proliferative ducts with a tubular and florid papillomatous appearance. Many demarcations between squamous cells of the epidermis and tumor cells were recognized in the summit as well as the lateral wall of the nipple. A high Ki-67 labeling index (20.3%) was recognized in the tumor cells in the superficial region, and a low labeling index (0.7%) was seen in the deeper region of the tumor. Based on these proliferative patterns, the symptoms and clinical signs related to the nipple that are often found in patients with nipple adenoma are thought to be associated with the destruction of the epidermis of the nipple by the invasion of benign tumor cells with high proliferative activity.

DOI： 10.2325/jbcs.897

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Sentinel lymph node biopsy (SLNB) is standard care for patients with early-stage breast cancer, and axillary lymph node dissection (ALND) is considered unnecessary when sentinel lymph nodes (SLNs) are tumor-free. Additional non-SLN metastasis in patients with positive SLNs can be estimated using several risk factors such as primary tumor size, metastatic tumor size in SLNs, lymphatic vessel invasion, and so on. All patients with positive SLNs may be treated with further ALND based on their own risk for non-SLN metastasis. Recent randomized clinical trials have already proved less surgical morbidity and better QOL for SLNB alone compared with ALND. However, trials concerning the efficacy of ALND in positive SLNB patients in preventing local regional recurrence and improving overall survival compared with no ALND, and also, concerning the effectiveness of ALND compared with axillary radiation therapy (RT), have not yielded clear results. The prognostic significance of micrometastasis in SLNs or bone marrow also remains to be determined. So far SLNB is not acceptable for patients with positive nodes in the axilla at initial diagnosis even if their axillary metastases are down-staged to negative by neoadjuvant chemotherapy. Although basically SLNB does not need to be performed for patients with pure ductal carcinoma in situ (DCIS), it is recommended for patients with an initial diagnosis of DCIS which is large, palpable, high grade, or found in younger patients. Because these types of DCIS have higher incidences of accompanying invasive lesions. In addition if patients will undergo mastectomy, SLNB is recommended because of the inability to perform SLNB after mastectomy. SLNB may be acceptable for patients with T3 or T4b tumors, even though SLN identification is lower yet SLN involvement is higher compared with T1 or T2 tumors, and systemic adjuvant therapy is more important for patients with T3 or T4b tumors. SLNB is a bridge to further axillary treatment such as ALND or axillary RT, and which strategy, including no further treatment, is best considered individually based on recurrence risk, treatment responsiveness and use or non-use of systemic therapy.

DOI： 10.2325/jbcs.14.362

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Other Link： http://search.jamas.or.jp/link/ui/2008154591

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

Gynecomastia is a benign proliferative lesion caused by various etiological factors and may result from a relative imbalance between serum estrogen and androgen levels. The histological alterations are similar, and gynecomastia can progress from a florid type to a fibrous type. The Ki-67 labeling index (LI) of gynecomastia specimen was investigated and higher Ki-67 LI was observed in florid and intermediate than in fibrous gynecomastia (P=0.017). A correlation was found between the duration of disease and Ki-67 LI (P=0.041): the shorter the duration the higher the Ki-67 LI. Thus, Ki-67 LI seems a useful tool to examine proliferation activity of gynecomastia and can assist in determination of appropriate treatment of gynecomastia with hormonal therapy.

DOI： 10.1111/j.1440-1827.2006.02025.x

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To investigate the relationship between human leukocyte antigen (HLA) type and bilateral breast cancer, a total of 213 female breast cancer patients were entered into this study. The lymphocyte cytotoxicity test was used for HLA typing. HLA frequency and haplotype antigen frequency were calculated with a microcomputer. A chi-squared test was used for comparing HLA frequency. At the start point of follow-up, 187 patients (87.8%) had unilateral and 26 patients (12.2%) had bilateral breast cancer. After a 10-year follow-up, 183 patients (85.9%) were unilateral and 30 patients (14.1%) were bilateral. Haplotype frequency of A24-Cw7 was significantly higher in bilateral breast cancer patients compared with unilateral breast cancer patients (p &lt; 0.001). After the 10-year follow-up, 4 of 187 patients (2.1%) with unilateral breast cancer developed bilateral breast cancer. Two of 19 patients (110.5%) with haplotype A24-Cw7 developed bilateral breast cancer, whereas only 2 of 168 patients (1.2%) without haplotype A24-Cw7 developed bilateral breast cancer (p &lt; 0.01). The true frequency of developing contralateral breast cancer in patients with haplotype A24-Cw7 was 93 per 100,000 per year. The risk of bilateral breast cancer in patients with haplotype A24 and Cw7 is 12 times higher compared with those without the haplotype. HLA typing is useful for selecting patients who are at high risk of contralateral breast cancer.

DOI： 10.1111/j.1075-122X.2006.00335.x

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We do not yet know the results from multicenter randomized trials comparing survival after sentinel lymph node biopsy (SLNB) alone and axillary lymph node dissection (ALND). Therefore, in this study, the prognostic significance of the type of axillary surgery is analyzed in combination with other known prognostic factors in patients with breast cancer. In a series of 1325 consecutive patients with unilateral breast cancer who underwent SLNB between January 1999 and June 2004 at a single institution, 884 underwent SLNB alone following an intraoperative negative histologic investigation and 441 underwent ALND. Disease-free survival (DFS) and overall survival (OS) were analyzed to correlate with clinicopathologic features and treatment methods using both univariate and multivariate analyses Cox proportional hazard regression models. With a median follow-up period of 31 months, 29 (3.3%) and 37 (8.4%) patients relapsed after SLNB alone and ALND, respectively. Tumor size (Tis, T1-2 versus T3-4), histologic nodal involvement (negative versus positive), nuclear grade (NG) (1, 2 versus 3), lymphatic vessel invasion (LVI) (absent, weak versus intense), estrogen receptor (ER) status (positive versus negative), type of axillary surgery (SLNB alone versus ALND), type of breast surgery (partial versus total mastectomy), and radiation therapy (yes versus no) significantly correlated with DFS by univariate analysis, demonstrating better DFS in the former category than the latter for each variable. The multivariate analysis revealed that NG, LVI, ER status, and radiation therapy significantly correlated with DFS, and ER and histologic nodal involvement correlated with OS. As the type of axillary surgery had no impact on the prognosis of patients with breast cancer, a SLNB alone is safe as determined by a negative histologic investigation.

DOI： 10.1111/j.1075-122X.2006.00329.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

We investigated the regulatory effect of tamoxifen (TAM) on fibronectin (FN) expression in estrogen-dependent MCF-7 breast carcinoma cells both in vitro and in vivo. In vitro, MCF-7 cells were cultured with 17 beta-estradiol (E-2) and/or TAM. In the animal experiment in vivo, MCF-7 tumors were grown in ovariectomized athymic mice by implanting a sustained release E-2 pellet. The E-2 pellets were removed after 3 weeks of E-2 treatment. Animals were then divided into four groups: 1) an E-2 (0.72 mg/pellet) pellet [E-2(+)]; 2) an E-2 and a TAM (5 mg/pellet) pellet [E-2(+)TAM]; 3) no treatment [E-2(-)] and 4) a TAM pellet [E2(-)TAM]. Following each treatment for 4 weeks, all animals were sacrificed and tumors were removed. Specimens, cells (in vitro) or tumors (in vivo), were homogenized and assayed for FN by Western blots. In the in vitro experiment, FN expression in MCF-7 cells decreased by incubating with 10(-9) M E-2, and increased with 10(-6) M TAM. The effect of TAM increasing FN expression was inhibited by incubation accompanied with 10(-9) M E-2 or 1 mu g/ml transforming growth factor-beta (TGF-beta) neutralizing antibody. In the in vivo animal experiment FN expression in the tumors of E-2(+) mice was lower than that of E-2(-) mice. However, TAM increased FN expression in the tumors regardless of E, pellet. These results suggest that TAM increases FN expression of MCF-7 breast carcinoma cells and that these regulatory effects of TAM on FN expression are partly mediated by TAM-induced TGF-beta.

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Purpose. Several radioactive agents are used Cor sentinel lymph node biopsy (SLNB) in breast cancer, but We are Still unsure which of these is best. We retrospectively compared the effectiveness of two radioactive agents, Tc-99m-phytate and Tc-99m-human serum albumin (HSA), when used in combination with blue dye.
Methods. A consecutive series of 533 clinically node-negative patients with a collective 539 breast carcinomas were divided into two groups for treatment with SLNB. The HSA-group consisted of 264 patients (with a collective 266 breast cancers) and the P-group consisted of 269 patients (with a collective 273) breast cancers) treated with Tc-99m-HSA and Tc-99m-phytate, respectively, in combination with blue dye. We analyzed the identification and radioactivity of SLNs in the two groups.
Results. The identification rate of SLN was significantly higher in the P-group than in the HSA-group. The same results were produced by analysis using the radioactive agent alone, but not by using the blue dye alone. Most importantly, the highest radioactivity of SLNs per case was more than five times higher in the P-group than in the HSA-group, and this difference was significant.
Conclusion. Our historical analysis of the two radioactive agents used in different periods could not exclude the influence of the improved skill of the Surgeons. However, because the specific accumulation of phytate in SLNs was greater than that of HSA, phytate might result in a higher SLN identification rate. Thus, Tc-99m-phytate is better than Tc-99m-HSA as a radioactive agent for SLNB in breast cancer.

DOI： 10.1007/s00595-005-3128-y

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DOI： 10.2325/jbcs.13.179

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In postmenopausal breast cancers, locally produced estrogen by adipose stromal cells causes the progression of tumor growth. Although aromatase, a key enzyme of estrogen synthesis, is highly expressed in the adipose stromal cells, and aromatase inhibitors show greater efficacy in postmenopausal breast cancers, the mechanism of increasing aromatase activity in the stromal cells remains unclear. To analyze the estrogen signals and to detect the estrogen receptor (ER)-activating ability of adipose stromal cells for individual human breast cancers, we developed a new reporter cell system. To visualize the activation of ER, we first established a stable transformant, named E10, of human breast cancer MCF-7 cells by transfection with the estrogen-responsive element-green fluorescent protein gene. E10 cells specifically express GFP when ER is activated by estrogen or by coculture with adipose stromal ells isolated from breast tumor tissues in the presence of testosterone, a substrate for aromatase. Treatment of adipose stromal cells with dexamethasone, a stimulator of aromatase gene expression, resulted in an increase in the expression of GFP in E10 cells in the coculture. Using this system, we characterized the adipose stromal cells of 67 human breast cancers and found that GFP expression levels vary among the cases, suggesting that the ability of adipose stromal cells to activate Ells is unique for individual breast cancers. High induction levels of GFP were observed more frequently in postmenopausal cases than in premenopausal cases, whereas they did not significantly correlate with the ER expression status. Aromatase inhibitors inhibited the induction of GFP expression in the coculture, but the sensitivities to the drugs varied among the individual cases. Aromatase gene expression levels in adipose stromal cells did not always correlate with their ability to induce GFP. These results suggest that this system to detect total ER activation based on the interaction with adipose stromal cells is a useful tool for analyzing local estrogen signals and for tumor-stromal interactions.

DOI： 10.1158/0008-5472.CAN-04-3236

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We investigated dihydropyrimidine dehydrogenase (DPD) activity and its expression in breast cancer cases, and evaluated the pro gnostic significance of DPD expression in invasive breast cancer. A total of 49 paired of breast cancer tissues and the adjacent normal breast tissues were evaluated in this study. DPD expression of 191 patients with invasive breast cancer was also evaluated immunohistochemically. DPD activity in breast cancer ranged from 13.4-360.0 pmol/mg/min (mean, 162.9 pmol/mg/min). DPD activity in breast cancer tissues was significantly (p&lt;0.001) higher than in adjacent normal breast tissue. DPD activity was significantly higher in DPD expression-positive tumors than DPD expression-negative tumors. The level of DPD activity was correlated with DPD expression. Patients with DPD expression-positive tumors had a significantly (p&lt;0.05) poorer prognosis in disease-free survival compared to those with DPD-negative tumors. When evaluated in patients treated with 5-FU or 5-FU derivatives, DPD expression was a significantly (p&lt;0.05) poorer prognostic factor in disease-free and overall survival. Using a Cox proportional hazards model, nodal status, ER status, and DPD expression were independent prognostic factors for both disease-free and overall survival. In conclusion, DPD expression may function as a marker of DPD activity and may be a prognostic indicator for patients with breast cancer.

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This study aimed to determine the prognostic significance of histological scoring system based on heterogeneity of invasive ductal carcinoma, for node-negative breast cancer patients. We studied 108 patients of node-negative invasive ductal carcinoma with invasive tumor &gt;5 mm. Histological score of each patient was evaluated based on histological subtype of invasive ductal carcinoma and pattern of. its heterogeneity. Score of each subtype was defined as follows; papillotubular carcinoma: score 1, solid-tubular carcinoma: score 2 and scirrhous carcinoma: score 3. The existence of histological heterogeneity was examined, and corresponding score was doubled in a pure case and scores of two dominant subtypes were summed in a composite case. Overall survival curves defined by sores were drawn by Kaplan-Meier method and the difference in survival rate was evaluated by log-rank test. The most significant difference of overall survival was recognized between low score group (scores 2, 3 and 4) and high score group (scores 5 and 6) (p &lt; 0.001). In addition, multivariate analysis confirmed that only histological score was an independent prognostic factor. These results suggested that assessment of histological heterogeneity of invasive ductal carcinoma could serve as independent potent prognostic factor for node-negative invasive ductal carcinoma of the breast, and this method might be useful to decide indication of postoperative adjuvant chemotherapy.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Background. Although TNP-470, a synthetic analog of fumagillin, may inhibit vascular intimal hyperplasia, the effects of TNP-470 on smooth muscle cell (SMC) proliferation have not been demonstrated in vivo. The aim of this study was to confirm the effect of TNP-470 on vascular SMC proliferation using a rat carotid artery balloon injury model.
Materials and methods. Rats were treated with vehicle or with TNP-470 at low dosage (10 mg/kg), medium dosage (20 mg/kg), or high dosage (40 mg/kg). The animals received subcutaneous injections of materials three times a week from the day following balloon injury. All rats were sacrificed at 2 weeks after injury. The ratio of intimal-to-medial cross-sectional areas (I/M ratio) and the PCNA labeling index was calculated for each group. The DNA synthesis of cultured SMCs was also evaluated using [H-3]thymidine incorporation assays. Smooth muscle cells were stimulated with basic fibroblast growth factor and TNP-470 (0.01-100 ng/ml) were added.
Results. The inhibition of intimal hyperplasia increased in a dose-dependent manner. TNP-470 also decreased PCNA expression in the neointima and inhibited DNA synthesis of cultured SMCs.
Conclusion. TNP-470 may be useful in the prevention of vascular intimal hyperplasia. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/S0022-4804(03)00119-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Drug resistance to tamoxifen (Tam) is a significant clinical problem but the mechanism through which this occurs remains elusive. We have developed a number of xenograft models of Tam-stimulated growth that model breast cancer progression using estrogen receptor positive MCF-7 or T47D breast cancer cells. When estrogen-stimulated T47D:E2 tumors are treated long term with Tam, Tam-stimulated tumors develop (T47D:Tam) that are stimulated by both estrogen and Tam. When HER-2/neu status is determined, it is clear that the T47D:Tam tumors express significantly higher levels of HER-2/neu protein by immunohistochemistry and mRNA as measured by real-time RT-PCR. The T47D:Tam tumors also express higher levels of estrogen receptor and progesterone receptor protein than their estrogen-stimulated T47D:E2 counterparts. We compared out results to the MCF-7 model of Tam-stimulated growth. The MCF-7:Tam ST (estrogen- and Tam-stimulated) and MCF-7:Tam LT (estrogen- inhibited, Tam-stimulated) were bilaterally transplanted to account for any mouse to mouse variation and characteristic growth patterns were observed. TUNEL staining was performed on MCF-7:Tam LT treated with either estrogen or Tam and it was concluded that estrogen- inhibited tumor growth was a result of increased apoptosis. Three phases of tumor progression are described that involve increases in HER-2/neu expression, de-regulation of estrogen receptor expression and increases in apoptosis which in concert determine the phenotype of drug resistance to Tam. (C) 2003 Published by Elsevier Science Ltd.

DOI： 10.1016/s0960-0760(02)00251-0

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Background: Sentinel lymph node biopsy (SLNB) is an important treatment option for breast cancer patients, as it can accurately predict axiUary status. Our previous study using dye with or without radioisotope showed the accuracy and sensitivity of SLNB to be 97% and 94%, respectively. Based on these results, axillary lymph node dissection (ALND) was eliminated starting in January, 1999 in patients with intraoperatively negative SLNB at our institution. The present study shows the results and outcomes of SLNB as a sole procedure for patients with invasive breast cancer. Patients and Methods: Three-hundred-fifty-four patients and 358 cases of invasive breast cancer (4 bilateral breast carcinoma) treated with SLNB alone after an intraoperative negative SLNB were studied prospectively from January 1999 to December 2001. Results: The number of the identified SLNs per case ranged from 1 to 8 (mean, 2.5). Of a total of 358 cases, 297 (83%) were treated with hormone therapy and/or chemotherapy, and 281 (78%) were treated with radiotherapy to the conserved breast (50 Gy +- 10 Gy boost), the axilla (50 Gy), or the both sites. After a median follow-up of 21 (range 6-42) months, no patient developed an axillary relapse. Four cases initially recurred in distant organs and one case in the conserved breast. Conclusions: Our results indicate that an intraoperative negative SLNB without further ALND may be a safe procedure when strict SLNB is performed. To better assess the safety, however, may require longer follow-up.

DOI： 10.1007/BF02967615

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

This study evaluated the results of breast-conserving therapy experienced in one institute. A total of 217 breasts in 215 patients with clinical stages I and II breast cancer undergoing breast-conserving therapy between August 1991 and December 1999 were included. The actuarial 5-year local recurrence-free survival, disease-free survival and overall survival rates were 97.4%, 88.5% and 92.5%, respectively. Microscopic margins were negative in 176 (81.1%) of the total breasts and positive in 41 (18.9%). There were no differences in the age at operation, tumor size, clinical stage, lymph node status, estrogen receptor status, or distance from tumor to nipple between patients with positive surgical margins and with negative surgical margins. During the follow-up period, local recurrence Occurred in seven patients. Local recurrence was significantly less frequent in patients with surgical margin-negative tumors than those with surgical margin-positive tumors, and also in ER-positive tumors than ER-negative or ER-unknown tumors. There was no difference in overall survival between patients with and without breast-recurrence. Using multivariate analysis, the surgical margin was determined to be an independent predictive factor for local recurrence in the conserved breast. Nodal status and ER status were independent prognostic factors, but local recurrence did not have an independent negative impact on survival. We conclude that microscopic surgical margin is the most important factor associated with local recurrence in the conserved breast among patients treated with breast-conserving surgery and radiation therapy of 50 Gy. Local recurrence however, has no adverse effect on survival of patients.

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Background: Breast-conserving therapy has been widely utilized as a treatment option for women with early breast cancer. However, no randomized study comparing modified radical mastectomy and breast-conserving therapy has been conducted in Japan. Methods: Two hundred and twenty-eight Japanese women with early breast cancer enrolled in the Gunma Breast Conserving Therapy Study between 1991 and 1994 were examined to determine whether there is any difference in disease-free survival or overall survival between radical mastectomy and breastconserving therapy. After informed consent was obtained, a total of 119 patients underwent breast-conserving therapy and 109 underwent mastectomy. Results: Mastectomy was a more frequently utilized treatment than breast-conserving therapy in patients with clinical stage II lesions, older age, larger tumor size or shorter distance between tumor and nipple. The mean follow-up period for all patients was 81 months (median 86 months). There was no significant difference in overall survival or disease-free survival between breast-conserving therapy and mastectomy even after adjusting for the clinical stage of the disease. A multivariate analysis of tumor size, lymph node status, estrogen receptor status and operation method using the Cox proportion hazard model confirmed that only lymph node status was an independent prognostic factor. Conclusion: Breast-conserving therapy is comparable to modified radical mastectomy in overall survival and disease-free survival.

DOI： 10.1007/BF02967581

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

It is important to determine which factors are predictive for the prognosis of patients treated with breast conserving surgery (BCS) and radiation therapy (RT) in order to make a decision as to the adjuvant treatment. Although estrogen receptor (ER) is known to be a predictive marker for antiestrogens in breast cancer, the prognostic effect of hormone receptors has not been fully analyzed in Japanese breast cancer patients treated with BCS and RT. A total of 153 breast cancer patients having up to three positive nodes in the axilla as identified histologically and treated with both BCS and RT with or without systemic therapy were enrolled in this study. All tumors were measured for ER and progesterone receptor (PR) using ligand-binding assay (LBA). ER was inversely related to patients' age, however, PR was not related to any clinical features. When ER was classified into negative, weakly positive and strongly positive categories, with cut-off levels of zero and 50 fmol/mg protein, the relapse-free survival (RFS) was significantly better in patients with tumors having strongly positive ER than in patients with tumors having negative ER. Multivariate analysis revealed that ER as well as nodal status, was an independent predictive factor for RFS, however, PR was not. As a result, we believe that ER measured by LBA is valuable for predicting prognosis of early-stage breast cancer patients treated with BCS and RT.

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/sj.bjc.6600040

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Other Link： http://www.nature.com/articles/6600040.pdf

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Background: The effects of antiestrogens on angiogenesis in breast cancer are not fully defined. In this study we investigated the in vitro effects of antiestrogens at different concentrations on vascular endothelial growth factor (VEGF) production in estrogen receptor (ER)-positive breast cancer cells. Method: The dose-dependent effects of 17β-estradiol (E2), 4-hydroxytamoxifen (40HT), and 10182,780 were analyzed both with reference to growth rates and VEGF protein production using enzyme-linked immunosorbent assay (ELISA) in MCF-7 cells. Results: E2 stimulated both the growth rates and VEGF production of MCF-7 cells in the same manner. Although 40HT stimulated the growth rates as an agonistic effect in an estrogen-free media at levels ranging from 1 nM to 1 μM, it did not stimulate VEGF expression at the same levels except for at 1 μM. Although 40HT had a weak agonistic effect on VEGF production at 1 μM in an estrogen-free media, it significantly inhibited Erftimulated VEGF production at the same level. A cytotoxic effect was observed with 10 μM 40HT that paradoxically caused a prominent increase in VEGF production. ICI182,780 had no significant effects on the growth rates or VEGF production in this cell line. Conclusions: These results support the hypothesis that tamoxifen could inhibit angiogenesis induced by estrogens in ER-positive breast cancer cells.

DOI： 10.1007/BF02967545

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

The purpose of this study was to compare the results of 133 cases (131 patients) of subcutaneous mastectomy with axillary dissection between 1983 and 1999 and 910 cases of radical mastectomy during the same period. The median followup period of the subcutaneous mastectomy group and the radical mastectomy group were 66 months and 81 months, respectively. The age at operation was significantly (p &lt; 0.01) younger in the subcutaneous mastectomy group than in the radical mastectomy group and the clinical stage was significantly (p &lt; 0.01) earlier. Lymph node metastasis was significantly (p &lt; 0.01) higher in the radical mastectomy than in the subcutaneous mastectomy group. There was no difference in ER status between the two groups. There was local recurrence in 5 (3.8%) members of the subcutaneous mastectomy group and in 12 (1.3%) members of the radical mastectomy group, There was no difference in disease-free survival and overall survival between the two groups. Divided into two subgroups by lymph node status, there was no difference in disease-free survival and overall survival between the two groups. Local recurrence occurred more frequently (p &lt; 0.05) in the subcutaneous mastectomy group, however, than in the radical mastectomy group when no lymph node metastasis was found. Multivariate analysis using the Cox hazard model showed that operation method and lymph node status were independent prognostic factors for local recurrence, whereas, lymph node status and ER status were independent prognostic factors of disease-free survival. In conclusion, subcutaneous mastectomy presents a risk factor for local recurrence, but the survival rate of the subcutaneous mastectomy group is as favourable as the radical mastectomy group.

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Objective: To assess recurrence of breast cancer following local excision alone for ductal carcinoma in situ. Methods: Eighteen patients who received complete resection for noninvasive ductal carcinoma between 1982 and 1997 were investigated in this study. The mean age of the patients was 45 (29-78) years old. The initial presentation was a clinically palpable tumor in 4 patients, nipple discharge in 6, and microcalcification on mammograms in 8. Patients with palpable tumor underwent wide excision with at least a 2-cm free margin. Patients whose mammograms showed microcalcification underwent lumpectomy, and those who showed nipple discharge underwent duct-lobular segmentectomy. Five patients who underwent lymph node dissection up to level I or II had no lymph node metastasis. The mean follow-up period was 86 months. Results: Local recurrence in the conserved breast was seen in five (27.8%) of 18 patients. The actuarial five-year event-free survival was 76.2%. The histological type of the recurrent tumor was ductal carcinoma in situ in three patients and invasive carcinoma in two. There was no difference in age at initial operation or histological subtype between patients with and without recurrent disease, but patients presenting with nipple discharge initially had a significantly shorter ipsilateral disease-free interval than those presenting with tumor or microcalcification on mammograms. All patients with local recurrence in the conserved breast were treated with breast-conserving surgery or subcutaneous mastectomy. Conclusion: Local recurrence frequently occurs in patients presenting with nipple discharge treated by duct- Iobular segmentectomy for noninvasive ductal carcinoma. Either wide excision with a larger free margin or adjuvant radiation therapy following duct-lobular segmentectomy should be considered for these patients.

DOI： 10.1007/BF02967478

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG  

We report herein the case of a 40-year-old man with grade II invasive ductal carcinoma of the breast (pT1, pN0, M0: stage I) in whom a recurrence developed shortly after completion of a 2-year course of tamoxifen and 5-fluorouracil therapy following a mastectomy. Although the metastatic tumor was estrogen receptor-positive, hormone therapy combined with chemotherapy had no significant effect on tumor growth, and the patient died from disseminated tumors 2 years 6 months after completion of the adjuvant therapy. It is noteworthy that the circulating estradiol level increased from 18.0 to 892.3 pg/ml during the period of tumor progression and dissemination. We interpret these findings as an indication of high aromatase activity in the metastatic tumors. We suggest that extending tamoxifen treatment to 5 years or longer be recommended for the standard adjuvant hormone therapy of male breast cancer to prevent the early recurrence of hormone-responsive disease.

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DOI： 10.3804/jjabcs.10.29

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