Background: The clinical course of patients with recurrent breast carcinoma varies greatly. Better characterization of an individual's clinical course for recurrent patients may aid in their clinical management. However, less attention has been paid to evaluating factors associated with the timing of recurrence in those patients. We investigated the clinicopathological indicators that determined the timing of recurrence by univariate and multivariate analysis.
Methods: We retrospectively examined data on 1428 curatively treated Japanese patients who had been surgically treated for breast cancer between 1983 and 2002. From these, 244 (17.1%) who had clearly died of recurrence were entered into this study.
Results: By univariate analysis, tumor size, estrogen receptor (ER), and progesterone receptor (PgR) were significantly correlated with time to recurrence. Multivariate analysis indicated that the time between operation and recurrence was independently influenced by ER and PR.
Conclusions: Our research shows that ER and PgR are independent factors influencing the timing of recurrence of breast carcinoma after curative resection. The combined analysis of these independent factors facilitates prediction of the time to recurrence for each patient.

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Background: In Japan, postoperative relapse occurs within five years in 9.2 to 16% of patients whose breast cancers have not metastasized to lymph nodes at the time of initial surgery (node-negative, n0). Attempts to find molecular markers able to classify n0 breast cancers in terms of postoperative prognosis have not been successful.
Methods: To identify molecular indicators of prognosis for this type of cancer, we used a cDNA microarray consisting of 25,344 human genes to investigate expression profiles of 12 primary breast cancers from patients whose tumors recurred within five years after surgery (5Y-R) and 12 from patients who survived disease-free for more than five years (5Y-F).
Results: Sets of genes characterizing each group in terms of expression patterns in the tumors were selected by Mann-Whitney and random-permutation tests: these panels included 21 genes expressed highly in 5Y-R tumors than in 5Y-F tumors, and 37 with higher expression in the 5Y-F group than in the 5Y-R group.
Conclusions: We established a scoring system to prediction of postoperative prognosis which was 100% accurate as to the actual clinical outcomes of the 24 cases and therefore might be useful for predicting prognosis of n0 breast cancers in a clinical setting. The prognostic score system clearly separated the two groups without any overlap, and accurately predicted prognosis in 6 additional cases. Moreover, the extensive list of tumor-related genes identified in these experiments provides valuable information about progression of breast cancer and suggests potential target molecules for therapy of n0 breast cancers.

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Background: High-dose chemotherapy with autologous stem cell support may have some therapeutic impact on certain groups of the patients with advanced breast cancer (BRCA). Since stem cell contamination by tumor cells might contribute to relapse, development of a tumor cell purging technique would improve the clinical outcome. The present study was undertaken to evaluate the purging efficacy of autologous mobilized CD34⁺ peripheral stem cells in patients with breast cancer (BRCA) in an advanced stage or relapse.
Methods: CD34⁺ cells were selected from autologous peripheral blood stem cells (PBSC) using a clinical scale of magnetic-activated cell sorting system (CliniMACS), followed by high-dose chemotherapy with transplantation of CD34⁺ selected cells. Amplification of cytokeratin 19 (CK19) and 20 (CK20) gene in leukapheresis products were measured to evaluate the performance of tumor cell elimination.
Results: Seven patients were entered into this study. After leukopheresis, 1 patient was dropped form this study due to poor mobilization. Among 6 patient, a total of 8 CD34⁺ selection was performed. The median purity and recovery rate of the CD34⁺ cells post selection was 85.1% (range 62.5-98.1%) and 74.2% (range 50.2-90.2%), respectively. After isolation of CD34⁺ cells, the elimination rate in the logarithmic transformation of CK19 was 2.77 log, and that of CK20 were 2.43 log and 2.53 log. In 4 patients, high-dose chemotherapy was performed, followed by the transplantation of the isolated CD34⁺ cells. Rapid neutrophil recovery, as well as platelet recovery was seen with a median time to reach 0.5 × 10⁹/l neutrophils of 9 days (range 8-9), and 20 × 10⁹/l platelets of 12 days (range 10-13). There was no treatment related death and no serious adverse events directly associated with the selection procedure or infusion of selected cells.
Conclusions: The present study demonstrated that the CliniMACS system is a highly effective positive selection method and that a high purging efficacy could be obtained without compromising the hematopoietic reconstitution capacity of the graft in BRCA patients undergoing high-dose chemotherapy.

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Background: Twenty cases of invasive ductal carcinoma of the breast with a pure or partial glycogen-rich clear cell carcinoma (GRCC) component are reported. GRCC of the breast is composed almost entirely of polygonal cells with clear cytoplasm. These contain large amounts of partly water-soluble glycogen.
Methods: The cases were analyzed using various parameters, including age at presentation, tumor size, tumor grade, axillary lymph node and Her2/neu status.
Results: Between 1990 and 2004, 723 patients with primary breast carcinomas were treated and clinicopathologic analysis was performed. 20 cases were identified as GRCC among the 723 cases. The patients' age at presentation ranged from 33 to 68 years (mean, 52 years). Tumor size ranged from 1 to 6.5 cm (mean, 2.6 cm); 35% (7 of 20) of cases that underwent axillary dissection had positive lymph nodes. Among 15 of 20 cases who were followed for 1-72 months, 5 cases died from their breast carcinoma within 5 years following the diagnosis.
Conclusion: Our series included more small size carcinomas than did previous series. Lymph node status does not appear to be markedly different from that of the usual invasive ductal carcinomas. Her2/neu expression was similar to that found in common breast carcinomas.

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Background: The clinical significance of bilateral breast cancer is unclear and its influence on prognosis is controversial. We assessed the impact of synchronous and metachronous bilateral breast cancer on the prognosis compared with unilateral breast cancer.
Methods: Between January 1, 1960 and December 31, 2001, 1,214 women were treated for primary operable breast cancers. Thirteen (1.1%) had synchronous bilateral breast cancer; 33 (2.7%) had a metachronous contralateral breast cancer. We compared age at operation, menopausal status, clinical stage, tumor size and histology, lymph node status, hormone receptor status, and use of adjuvant chemotherapy or hormone therapy, and we analyzed the impact of these factors on recurrence and survival in the 46 patients with bilateral breast cancer and the 1,168 patients with unilateral breast cancer.
Results: The 5- and 10-year disease-free survival rates, respectively, were 65% and 65% in metachronous cases, 85.7% and 64.3% in synchronous cases, and 77.9% and 72.1% in unilateral cases. There was no significant difference in overall survival among the three groups. On multivariate analysis, metachronous bilaterality, tumor size, lymph node status and adjuvant hormone therapy were each independent risk factors for recurrence, whereas bilaterality of breast cancer did not influence overall survival.
Conclusions: Our data suggest that metachronous bilateral breast cancer is associated with shorter disease-free survival than synchronous bilateral or unilateral breast cancer, although overall survival does not differ among the 3 groups. Patients with metachronous bilateral breast cancer should be followed particularly closely in order to detect recurrence early and maximize quality of life.

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Background: Although sentinel lymph node biopsy (SLNB) is highly accurate in predicting axillary nodal status in patients with breast cancer, it has been shown that the procedure is associated with a few false negative results. The risk of leaving metastatic nodes behind in the axillary basin when SLNB is negative should be estimated for an individual patient if SLNB is performed to avoid conventional axillary lymph node dissection (ALND).
Methods: A retrospective analysis of 512 women with T1-3N0M0 breast cancer was conducted to derive a prevalence of nodal metastasis by T category as a pre-test (i.e., before SLNB) probability and to examine potential confounders on the relationship between T category and axillary nodal involvement. Probability of nodal metastasis when SLNB was negative was estimated by means of Bayes' theorem which incorporated the pre-test probability and sensitivity and specificity of SLNB.
Results: Axillary nodal metastasis was observed in 6.1% of T1a-b, 25.1% of T1c, 28.7% of T2, 35.0% of T3 tumors. Point estimates for the probability of nodal involvement when SLNB was negative ranged from 0.3-1.3% for T1a-b, 1.6-6.3% for T1c, 2.0-7.5% for T2, and 2.6-9.7% for T3 tumors with representative sensitivities of 80%, 85%, 90% and 95%, respectively. The risk may be higher when the tumor involves the upper outer quadrant of the breast, while it may be lower for an underweight woman.
Conclusions: The probability of axillary lymph node metastasis when SLNB is negative can be estimated using a Bayesian approach. Presenting the probability to the patient may guide the decision of surgery without conventional ALND.

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Background: Sentinel lymph node biopsy using a vital dye is a convenient and safe method to assess lymph node status in breast cancer. However, intensive training is necessary to obtain a satisfactory detection rate and to avoid false-negative results. This paper presents a novel method using indocyanine green fluorescence imaging to detect sentinel lymph nodes.
Methods: Fluorescence images were obtained using a charge coupled device camera with a cut filter as the detector, and light emitting diodes at 760 nm as the light source. When indocyanine green was injected around the areola, subcutaneous lymphatic channels draining from the areola to the axilla were visible by fluorescence within a few minutes. The sentinel lymph node was then dissected by fluorescence navigation.
Results: Sentinel lymph node biopsy using the present method was performed on eighteen patients. Subcutaneous lymphatics were detectable by fluorescence in all patients, and sentinel nodes were successfully identified in 17 of 18 cases (detection rate: 94%). It was possible to detect the lymphatic channels and nodes receiving indocyanine green with higher sensitivity by the fluorescence signal than by the green color.
Conclusion: Sentinel node biopsy guided by indocyanine green fluorescence imaging is a promising technique for further clinical exploration.

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Background: Breast microcalcifications are difficult to depict by ultrasound (US). However, recent advances in US equipment and the refinement of breast imaging techniques have improved the detection and characterization of small breast lesions. The present study attempts to determine whether US examination is able to demonstrate nonpalpable breast lesions associated with mammographically detected microcalcifications without mass density or distortion, and to evaluate the clinical reliability of US-guided procedures, especially in cases of ductal carcinoma in situ (DCIS) of the breast.
Methods: The subjects consisted of 73 patients with breast cancer diagnosed preoperatively as DCIS by stereotactic core needle biopsies, all of whom had microcalcifications without other abnormalities on mammography. The radiological appearance and size of the clustered microcalcifications were evaluated. US examinations were performed preoperatively, and the detection rates were assessed. Sonographically detected lesions underwent US-guided wire localization followed by surgical excision.
Results: The lesions associated with microcalcifications were identified sonographically in 54 of 73 cases (74%), and the pathological examination revealed breast cancer in all of the corresponding specimens. Lesions with linear-branching shape, segmental-linear distribution and category-5 calcifications on mammography had a high level of visibility on US. The US visible cases had a larger size of calcified area on mammography when compared with US invisible cases. Pathologically, the lesions were more frequently seen on US in cases with minimally invasive cancer or with comedo type DCIS.
Conclusions: US examination is an effective method for identifying and localizing breast microcalcifications, and can be used as an alternative to stereotactic localization in selected patients with early breast cancer.

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Two rare cases, each with a solitary brain metastasis from breast cancer with extensive nodal metastases as the first site of distant metastasis, were locally treated with surgery and irradiation. The outcome of the two treated cases indicated an excellent and non-recurrent post-therapeutic survival period of more than 3 and 8 years, respectively. In a 50-year-old woman (Case 1), a solitary brain metastasis was found to have developed after standard radical mastectomy and adjuvant chemotherapy with doxorubicin and tegafur-uracil (UFT) and hormonal therapy with tamoxifen for left breast cancer. The brain metastasis was treated twice surgically followed by radiotherapy. One year and 6 months later, local recurrence of the brain metastasis appeared and was treated surgically again. No other treatment was done thereafter. Since then, no other distant or lymph node metastasis occurred, and to date her outcome has been non-eventful for 8 years and 5 months. In a 63-year-old woman (Case 2), a solitary brain metastasis was found to have developed after standard radical mastectomy and adjuvant chemotherapy with cyclophosphamide, epirubicin and fluorouracil (CEF) for right breast cancer. The brain metastasis was treated locally with surgery and irradiation of 50 Gy. She thereafter received no further treatments. Since then neither distant metastases nor local recurrence have developed, and to date the post-treatment outcome has been uneventful for 37 months. Our findings suggest that patients who developed a solitary brain metastasis as the first site of distant metastasis from breast cancer have a chance of achieving long-term disease-free survival when treated with aggressive local therapy, even in the presence of extensive lymph node metastases at the primary surgery site for breast cancer.

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We encountered a case of inflammatory local recurrence of breast cancer after breast conserving surgery which attained pathological CR after combination therapy with trastuzumab and paclitaxel. The patient was a 49-year-old premenopausal woman whose left breast cancer (T2N0M0) was treated by breast conserving surgery (Bp + Ax). The pathological diagnosis was scirrhous carcinoma, g, ly1, v0, t2, n0, ER (-), PgR (+) and stage IIA. Postoperatively, the residual breast was treated by 50 Gy irradiation followed by hormone therapy (Tamoxifen citrate + LH-RH analog). At 26 months after the surgery, local recurrence developed as inflammatory breast cancer. As the recurrent tumor was confirmed to be HER2-positve (3 + by IHC), combination therapy with trastuzumab and paclitaxel was started. After the 6 courses of pharmacotherapy were completed, she was judged to have clinical CR, and subsequently underwent total breast excision (Bt) and skin grafting. No visible cancer cell was observed in the resected specimens, pathological CR was diagnosed. Postoperatively, the patient is receiving trastuzumab alone every other week, and at present 10 months after the second operation, the patient is in CR status and is visiting the outpatient clinic. No severe side effects (over grade 3) from this therapy have been observed. It is suggested that combination therapy with trastuzumab and paclitaxel for inflammatory local recurrence after breast conserving surgery is a treatment of choice.

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We report a rare case of a huge cavernous hemangioma arising in a male breast.
A 60-year-old man first noticed 1 × 2 cm elastic hard nodule just below his right nipple ten years previously. It enlarged 5 × 5 cm over six years. When he came to our clinic, it was size of child head (510 mm in circumference), was an elastic hard with a rather smooth surface, and firmly fixed to the chest wall. Magnetic resonance imaging (MRI) and multidetectocomputed tomography (MDCT) showed a large mass infiltrating into the chest wall. Fine needle aspiration cytology (FNA) and core needle biopsy (CNB) failed to obtain proper material except for old bloody fluid or necrotic connective tissue, precluding a correct diagnosis preoperatively. Mastectomy with partial resection of the chest wall was subsequently performed. Histologically, it was found to be a cavernous hemangioma without cellular atypia. In such a case, complete excision is recommended to exclude the possibility of an underlying malignant lesion.

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Primary malignant lymphoma of the breast is rare, and Burkitt's lymphoma is especially rare. We report the case of a 44-year-old woman in whom Burkitt's lymphoma involving both breasts was diagnosed. The patient was referred to our hospital because of a diffuse, firm swelling, like a bulky ball, in both breasts. Fine-needle aspiration cytology (FNAC) of both breast masses revealed malignant lymphoma (ML), and diffuse large B-cell lymphoma was diagnosed based on the results of immunohistochemical studies of a core needle biopsy specimen. The gallium scan revealed very hot lesions in both breasts, but there was no evidence of disseminated disease. We instituted initial therapy, with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus intrathecal chemotherapy without performing a chromosome analysis, because the clinical course was very aggressive. A CR was achieved, but after eight cycles of CHOP therapy, the ML relapsed. We then resected the mass in the left breast, and when examination of the surgical specimen revealed relapse of ML and t (8;11)(q24;q32) translocation, Burkitt's lymphoma was diagnosed. High-dose chemotherapy followed by peripheral-blood stem cell transplantation was performed, but the patient died 10 months after her initial presentation at our hospital.

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We report a rare case of gravid macromastia (GM) treated after delivery. A 23-year-old woman with left breast enlargement was referred to our hospital. Laboratory investigations revealed an elevated serum CA19-9 level of 200.3 U/ml. Gravid macromastia was diagnosed by clinical examination (US, MRI) and 11G mammotome biopsy. Tumorectomy of the left breast and mammoplasty were performed. The mass had proliferated to the exclusion of normal gland. Histological examination revealed abundant proliferation of stromal loose connective tissue and interposed fat cells surrounding normal and lactating lobules. The epithelial cells were positive for CA19-9 on immunohistochemical staining. Serum CA19-9 decreased to normal levels 3 months after operation. GM is exceedingly rare and occurs in less than 0.001-0.003% of all pregnant women. Once established, the condition is likely to continue to successive pregnancies. This benign tumor is sometimes difficult to distinguish from malignant tumors since it shows few histological characteristics and grows rapidly. Attention is necessary to diagnose tumors of the breast during pregnancy.

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We report a case of lasting fever and cough with pulmonary infiltrates progressing 4 months after adjuvant radiotherapy following surgery for breast cancer. Chest radiography and computed tomography demonstrated alveolar opacities outside the irradiated pulmonary area. Laboratory data revealed neutrophilia and increased levels of C-reactive protein. Bronchoalveolar lavage fluid displayed increased lymphocyte counts, and transbronchial lung biopsy revealed histological patterns compatible with cryptogenic organizing pneumonia (COP). Corticosteroid therapy resulted in marked clinical improvement. From the histological and clinical findings, this case was judged to be a case of COP induced after radiotherapy for breast cancer, similar to those reported recently.

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