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Objective: Conventional cytological diagnosis including duct-washing cytology (DWC) is sometimes performed using ductal epithelial cells collected during mammary ductoscopy; it is useful for detection of early-stage breast cancer such as ductal carcinoma in situ (DCIS). However, conventional cytological diagnosis focuses exclusively on cellular morphology; false negatives and false positives may be caused by inadequate specimen preparation (triggering cell degeneration) or poor examiner diagnostic skills. Molecular diagnosis using RNA biomarkers is expected to compensate for the weaknesses of cytological diagnosis. We previously employed microarray analysis to identify highly expressed genes in DCIS, suggesting that they may be useful for DCIS diagnosis. Here, we explored whether DWC samples yielded RNA of sufficient quantity and quality for RNA biomarker-based diagnosis., Results: We extracted RNAs from 37 DWC samples. RNA from 12 samples exhibited RNA integrities of  ≥ 6, indicative of moderate-to-high quality. We then showed that cocaine and amphetamine regulated transcript prepropeptide (CARTPT) and breast cancer-associated transcript 54 (BRCAT54) mRNA-previously shown by microarray analysis to be highly expressed in DCIS-were detectable in these samples. Therefore, DWC samples may be useful for molecular diagnosis involving RNA biomarkers., (© 2022. The Author(s).)

Objective: The incidence of ductal carcinoma in situ (DCIS) is increasing due to more widespread mammographic screening. DCIS, the earliest form of breast cancer, is non-invasive at the time of detection. If DCIS tissues are left undetected or untreated, it can spread to the surrounding breast tissue. Thus, surgical resection is the standard treatment. Understanding the mechanism underlying the non-invasive property of DCIS could lead to more appropriate medical treatments, including nonsurgical options., Data Description: We conducted a microarray-based genome-wide transcriptome analysis using DCIS specimens obtained by puncture from surgical specimens immediately after surgery., (© 2021. The Author(s).)

Background: Pathological nipple discharge (PND) is a relatively common symptom of breast cancer affecting the nipple. Mammary ductscopy (MD) allows direct visualization of the ductal lumen and collection of a cytological specimen using duct-washing cytology (DWC). Herein, we clarified the diagnostic efficacy of DWC for the detection of breast cancers with PND, compared with fine-needle aspiration cytology (FNAC)., Methods: We retrospectively examined 48 patients with PND who underwent DWC by MD (ductosccopy group; histologically determined by intraductal biopsy [IDB] or surgical specimen). The results of sensitivity and specificity of DWC were compared with that of FNAC (conventional group; histologically determined by core needle biopsy). Clinicopathological factors were compared between the ductoscopy and the conventional groups., Results: Of eight histologically malignant cases in the ductoscopy group, one case was cytologically judged as malignant and three as indeterminate. Sensitivity and specificity of DWC were 50.0% and 82.5%, respectively. Malignant cases were mostly solid papillary carcinomas (SPCs), and benign cases were intraductal papillomas (IDPs). In the conventional group, sensitivity and specificity of FNAC were 88.0% and 38.2%, respectively, and malignant cases were mainly invasive carcinomas of no special type. Tumors in the ductocsopy group had more favorable prognostic features than those in the conventional group., Conclusion: DWC has limited diagnostic value due to the high incidence of SPC, whose cytological features are indistinguishable from IDP. As DWC alone may be unreliable, comprehensive examination with IDB and MD findings is recommended., (© 2020 Wiley Periodicals LLC.)

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.

Background: The definition of complete resection of ductal carcinoma in situ (DCIS) is difficult to standardize because of the high variety of surgical breast conserving procedures, specimen handling, and pathological examinations. Using strictly controlled criteria in a single institute, the present study aimed to determine the ipsilateral breast cancer rate when radiotherapy is omitted following complete resection of DCIS., Methods: We retrospectively examined 363 consecutive DCIS patients who underwent breast-conserving surgery, and of these, 125 (34.4%) had complete resection according to the criteria. We finally included 103 patients who omitted radiotherapy. Ipsilateral and contralateral breast cancer events were assessed., Results: The median follow-up period was 118 months. The incidences of ipsilateral and contralateral breast cancer and ipsilateral invasive breast cancer at 10 years were 10.8%, 9.1%, and 3.6%, respectively. No patient died of breast cancer., Conclusion: If complete resection of DCIS can be ensured, the annual incidence of ipsilateral breast cancer, even without irradiation, can be limited to approximately 1%, which equals the incidence of contralateral breast cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To establish an optimal surveillance schedule after surgery for breast cancer, patients included in an institutional database were retrospectively investigated with respect to the first metastatic site and timing of recurrence., Patients and Methods: We investigated 11,676 pT1-4pN0-2M0 breast cancer patients treated from 1985 to 2009 and followed up until June 2014. Our surveillance protocol included physician visits and examinations with bone scans, liver echography, chest roentgenography and laboratory tests. We evaluated the liver, bones, lungs and pleura as surveillance covering sites (SCS) in addition to parameters such as time points exceeding 80 % with respect to the accumulated percentage of patients of recurrence and the number of surveillance per one recurrence (NSR), calculated by dividing the number of patients at risk of recurrence at the start of a particular time frame by the number of patients of recurrence at SCS within that period., Results: There were a total of 1,962 recurrent patients, including 601 patients with locoregional recurrence, nine patients with recurrence in the opposite breast, 1,349 patients with recurrence at distant sites and three unknown patients. The number of patients with the bones, lungs, liver and pleura as the first site of recurrence was 447, 324, 144 and 69, respectively, and 72.9 % of the distant metastatic lesions belonged to SCS. The five-year overall survival rate after recurrence among the patients with single recurrent site was longer than that observed among the patients with multiple sites of recurrence (43.3 vs 25.3 %; p < 0.0001). In addition, more than 80 % of the patients of liver metastasis were detected within 5 years after surgery, while 80 % of the patients of pleura metastasis were detected within 10 years. The NSR was below 200 for the 10-year period, as was the NSR of the patients with lymph node metastasis and a positive hormone receptor status. In contrast, the NSR of the patients with a negative hormone receptor status was above 200 after 5 years., Conclusions: In this study, the prognosis of the patients with a single site of recurrence was superior to that of the patients with multiple sites. Curable patients with distant metastases included those with single metastatic sites. The optimal surveillance schedule should be established taking into consideration that the incidence of metastasis differs among metastatic sites during follow-up.

Purpose: In order to evaluate the diagnostic and therapeutic potential of mammary ductoscopy and watchful follow-up for treating bloody nipple discharge, we investigated the incidence of cancer evolving from the location related to the affected duct and the disappearance of nipple discharge., Patients and Methods: Between April 1998 and March 2008, we assessed 709 lesions among 624 patients without a diagnosis of malignancy at the time of 6 months after mammary ductoscopy. The median follow-up time was 5.5 years. We reviewed the subjects' charts retrospectively and investigated the dates on which discharge-related cancer was diagnosed and the disappearance of discharge was noted after the initial examination with mammary ductoscopy., Results: The incidence of cancer evolving from the location related to the pathological duct was 11 % (78/709). Nipple discharge disappeared in 480 (85.1 %) of the 564 followed up lesions, with the exception of 78 breast cancers and 67 resected benign lesions. The rate of disappearance for nipple discharge in the cases of intraductal papilloma at the first examination was 82.5 %. In cases in which no obvious lesions were observed on mammary ductoscopy, there was a 90 % probability that the nipple discharge would disappear, and the rate of evolving breast cancer in the cases of atypical papillary lesions at the first examination was significantly higher than that observed in the cases of intraductal papilloma, at 50 and 8.9 %, respectively., Conclusions: Information revealed by mammary ductoscopy is useful for differentiating patients who should be subjected to intensive examinations and those who should expect disappearance of their discharge. Mammary ductoscopy and watchful follow-up can substitute microdochectomy in patients with bloody nipple discharge.

Background: Axillary dissection omission for sentinel lymph node-negative patients has been a practice at Cancer Institute Hospital, Japanese Foundation for Cancer Research since 2003. We examined the long-term results of omission of axillary dissection in sentinel lymph node-negative patients treated at our hospital, as well as their axillary lymph node recurrence characteristics and outcomes., Methods: Our study included 2,578 patients with cTis or T1-T3N0M0 primary breast cancer for whom dissection was omitted because they were sentinel lymph node negative. The median observation period was 75 months., Results: In sentinel lymph node-negative patients for whom dissection was omitted, the rates of axillary lymph node recurrence, distant recurrence, and breast cancer mortality were 0.9, 2, and 1 %, respectively. Eighteen patients underwent additional dissection if axillary lymph node recurrence was observed at the first recurrence. Four triple-negative (TN) patients experienced distant recurrence after additional dissection. All four patients were administered anticancer agents after axillary lymph node recurrence and experienced recurrence within 1 year of additional dissection. The axillary lymph node recurrence rate was 0.8 % for luminal and 4.5 % for TN subtypes., Conclusions: The long-term prognoses of patients for whom dissection was omitted owing to negative sentinel lymph node metastases were similar to those reported previously-low recurrence and mortality rates. The frequency of axillary lymph node recurrence and the post-recurrence outcome differed between luminal and TN cases, with recurrence being more frequent in patients with the TN subtype. TN patients also had poorer prognoses, even after receiving additional dissection and anticancer agents after recurrence.

Background: One-step nucleic acid amplification (OSNA) examines lymph node metastasis in a semiquantitative manner with molecular biology techniques. In this study, we conducted a whole-node analysis of non-sentinel lymph nodes (SLNs) using the OSNA method in SLN metastasis-positive breast cancer patients., Methods: With the OSNA method, we compared the rates of positivity of non-SLN metastasis in cases with both SLN micro- and macrometastases., Results: The rates of non-SLN metastasis positivity in those with SLN micrometastasis and macrometastasis were 44% and 48%, respectively, and this difference was not significant. When the study of non-SLN metastasis positivity was focused only on macrometastases, the rates of non-SLN metastasis positivity in patients with SLN micrometastasis and macrometastasis were 19% and 22%, respectively, and there was no significant difference., Conclusion: Regardless of the copy number of SLN metastases, non-SLN metastases were found in approximately half of the cases., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We classified ipsilateral breast tumor recurrences (IBTRs) based on strict pathological rules. Ninety-six women who were surgically treated for IBTR were included. IBTRs were classified according to their origins and were distinguished based on strict pathological rules: relationship between the IBTR and the primary lumpectomy scar, surgical margin status of the primary cancer, and the presence of in situ lesions of IBTR. The prognosis of these subgroups were compared to that of new primary tumors (NP) in the narrow sense (NPn) that occurred far from the scar. Distant-disease free survival of IBTR that occurred close to the scar with in situ lesions and a negative surgical margin of the primary cancer (NP occurred close to the scar, NPcs) was similar to that of NPn. In contrast, IBTR that occurred close to the scar without in situ lesions (true recurrence (TR) that arose from residual invasive carcinoma foci, TRinv) had significantly poorer prognosis than NPn. IBTR that occurred close to the scar with in situ lesions and a positive surgical margin of the primary cancer (TR arising from a residual in situ lesion, TRis) had more late recurrences than NPcs. Precise pathological examinations indicated four distinct IBTR subtypes with different characteristics., (© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Background: The TNM classification of the Unio Internationalis Contra Cancrum was revised for the seventh edition. The major change concerning breast cancer is a change in the stages for patients with T0 or T1N1miM0. In the present study, the seventh edition of the TNM classification was validated in breast cancer., Methods: The stages of 416 breast cancer patients, treated at our hospital in 1996, were classified according to the TNM classification, sixth and seventh editions, and their prognoses were compared., Results: Case distribution using the sixth edition was stage 0, 56 cases (13.5 %); stage I, 158 cases (38.0 %); stage II, 130 [A, 102; B, 28] cases (31.2 [A, 24.5; B, 6.7] %); and stage III, 72 [A, 31; B, 8; C, 33] cases (17.3 [A, 7.5; B, 1.9; C, 7.9] %). According to the seventh edition, the stages for 20 patients, accounting for 19.6 % of IIA cases according to the sixth edition, decreased from IIA to IB. The 10-year overall survivals were stage 0, 91.1 %; stage I, 88.6 %; stage II, 80.8 %; and stage III, 63.9 % according to the sixth edition; and stage 0, 91.1 %; stage I, 88.8 %; stage II, 79.1 %; and stage III, 63.9 % according to the seventh edition. Although no significant differences were seen among the survival rates for stages 0 to II according to the sixth edition, there was a significant difference between stage I and II according to the seventh edition (p = 0.026)., Conclusion: The latest revision of the TNM classification is appropriate for breast cancer from the perspective of prognosis.

Purpose: The indication for postmastectomy radiotherapy (PMRT) in breast cancer patients with one to three positive lymph nodes has been in discussion. The purpose of this study was to identify patient groups for whom PMRT may be indicated, focusing on varied locoregional recurrence rates depending on lymphatic invasion (ly) status., Methods and Materials: Retrospective analysis of 1,994 node-positive patients who had undergone mastectomy without postoperative radiotherapy between January 1990 and December 2000 at our hospital was performed. Patient groups for whom PMRT should be indicated were assessed using statistical tests based on the relationship between locoregional recurrence rate and ly status., Results: Multivariate analysis showed that the ly status affected the locoregional recurrence rate to as great a degree as the number of positive lymph nodes (p < 0.001). Especially for patients with one to three positive nodes, extensive ly was a more significant factor than stage T3 in the TNM staging system for locoregional recurrence (p < 0.001 vs. p = 0.295)., Conclusion: Among postmastectomy patients with one to three positive lymph nodes, patients with extensive ly seem to require local therapy regimens similar to those used for patients with four or more positive nodes and also seem to require consideration of the use of PMRT., (Copyright © 2012 Elsevier Inc. All rights reserved.)

As we have previously demonstrated that some breast cancer cell lines secrete DJ-1 protein, we examined here whether breast cancer cells secrete DJ-1 protein in vivo. To this end, the levels of DJ-1 protein present in 136 specimens of nipple fluid was examined by enzyme-linked immunosorbent assay (ELISA). The average concentration of DJ-1 protein detected in diluted samples from 47 patients with invasive ductal carcinoma (IDC) was 22.4 ng/mL, while it was 18.6 ng/mL in 26 patients with ductal carcinoma in situ (DCIS). In contrast, the average DJ-1 concentration in samples from 63 women with benign lesions was 2.7 ng/mL, demonstrating that higher DJ-1 protein levels were detected in nipple fluid in the presence of cancer cells than in the presence of benign lesions (P < 0.0001). When a cut-off level of 3.0 ng/mL was applied, the higher level of DJ-1 was shown to be of significant clinical value for predicting the presence of breast cancer (85.9% specificity, 75% sensitivity; P < 0.0001). Multivariate logistic analysis that included established factors such as nipple discharge cytology, ductoscopic cytology, and carcinoembryonic antigen level further showed that the level of DJ-1 protein alone is of significant value for predicting the presence of breast cancer. Immunohistochemistry and in situ hybridization also showed that the low expression of DJ-1 protein, despite high mRNA expression, was significantly correlated with high DJ-1 protein levels in the nipple fluid. These data indicate that breast cancer cells secrete DJ-1 protein in vivo, and that its level is a potential indicator of breast cancer in patients with nipple discharge., (© 2012 Japanese Cancer Association.)

Background: Malignant phyllodes tumor of the breast is a rare neoplasm for which clinical findings remain insufficient for determination of optimal management. We examined the clinical behavior of these lesions in an attempt to determine appropriate management. We evaluated long-term outcome and clinical characteristics of malignant phyllodes tumors arising from fibroadenomas of the breast., Methods: A total of 173 patients were given a diagnosis of phyllodes tumor and underwent surgery at the Cancer Institute Hospital in Japan between January 1980 and December 1999. Of these patients, 39 (22.5%) were given a diagnosis of malignant phyllodes tumor; in three of these cases, detailed medical records were lost. Malignant phyllodes tumors were classified into two groups based on history of malignant transformation. Of the 36 malignant cases, 11 (30.6%) were primary and were given a diagnosis of fibroadenoma, experienced recurrence during the follow-up period, and were diagnosed with malignant phyllodes tumor (cases with a history of fibroadenoma). The other group was defined as cases without history of fibroadenoma and in whom lesions initially occurred as malignant phyllodes tumors. Based on differences between the two groups, overall survival curves were plotted using the Kaplan–Meier method, and statistical comparisons were performed using the log-rank test and Peto and Peto’s test., Results: The outcome of cases with history of fibroadenoma was significantly better than that of cases without history of fibroadenoma., Conclusions: Patients with malignant phyllodes tumors but without prior history of malignant transformation who exhibit rapid growth within 6 months require aggressive treatment.

In patients with breast cancer, taxane as well as anthracycline play central roles in systemic chemotherapy. By evaluating the pathological response, we can gauge sensitivity to primary chemotherapy. However, biomarkers that would predict a response to taxane have not yet been established. We conducted a prospective randomized trial to evaluate whether selecting patients using sensitivity testing based on the gene expression of the tumor might enhance the probability of the pathological response. Five genes were identified as biomarkers derived from a microarray of DNA gene profiles from microdisected breast tumors. In the experimental arm (B1), 12 cycles of weekly paclitaxel, 80 mg/m(2) , were preoperatively given when the sensitivity test was positive and therefore judged to be sensitive to paclitaxel. When the test was negative, meaning insensitive to paclitaxel, four cycles of FEC100 were given (arm B2). In the control arm (A), paclitaxel was administered weekly without the use of the sensitivity test. A total of 92 patients were enrolled and 86 patients were analyzed. The pathological response rate (pRR) of each arm was 36.4% in B1 (expected sensitive to paclitaxel), 21.1% in A (control) and 12.5% in B2, respectively. Weekly paclitaxel-treated patients selected by the sensitivity test did not enhance the pRR. The study failed to validate sensitivity testing using five gene expressions for primary chemotherapy with paclitaxel in patients with breast cancer. However, this study suggests that a randomized phase II study is a robust tool for obtaining a rapid conclusion on the usefulness of biomarkers and could be the foundation for further large clinical trials., (© 2010 Japanese Cancer Association.)

Metaplastic carcinoma of the breast is a relatively rare cancer and includes various histologic types. In this cancer, metaplastic elements are heterogeneous and sometimes mixed. We investigated, by histopathologic means, these elements and clinical implications that could indicate the clinical course (including the prognosis). Fifty-three metaplastic breast carcinoma cases and their prognoses were investigated by initially examining the presence or absence of spindle-cell elements, and then the presence or absence of other elements. Spindle cells were classified as high or low grade. The number of spindle-cell-positive cases was 24 (45%) of 53. The 24 spindle-cell (+) cases were subdivided into 12 high-grade (HGsp) (distant metastatic rate per 100 person-years, 13.27) and 12 low-grade (LGsp) (0.00) patients. Spindle-cell (-) cases were subdivided into 22 pure squamous cell carcinomas (5.93) and 7 matrix-producing carcinomas (0.00). There were significant differences among the 4 groups with regard to the disease-free period (P = .0081, log-rank test). The distant metastatic risks in the HGsp and pure squamous cell carcinomas groups were significantly higher than that in the matrix-producing carcinoma + LGsp group (nonmetastatic groups) after controlling for the effects of tumor size and lymph node metastasis (P = .019 and P = .016, respectively, Poisson regression model). The presence of high-grade spindle cells was related to the prognosis, and some histologic subtypes may be important with respect to the prognosis. The presence of high-grade spindle cells in metaplastic breast carcinoma may indicate aggressive behavior., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: The impact of sentinel lymph node biopsy on breast cancer mimicking ductal carcinoma in situ (DCIS) is a matter of debate., Methods: We studied the rate of occurrence of sentinel lymph node metastasis in 255 breast cancer patients with pure DCIS showing no invasive components on routine pathological examination. We compared this to the rate of occurrence in 177 patients with predominant intraductal-component (IDC) breast cancers containing invasive foci equal to or less than 0.5 cm in size., Results: Most of the clinical and pathological baseline characteristics were the same between the two groups. However, peritumoral lymphatic permeation occurred less often in the pure DCIS group than in the IDC-predominant invasive-lesion group (1.2% vs. 6.8%, p = 0.002). One patient (0.39%) with pure DCIS had two sentinel lymph nodes positive for metastasis. This rate was significantly lower than that in patients with IDC-predominant invasive lesions (6.2%; p < 0.001)., Conclusions: Because the rate of sentinel lymph node metastasis in pure DCIS is very low, sentinel lymph node biopsy can safely be omitted.

We retrospectively evaluated whether a surgical strategy benefits patients with operable lung metastasis of breast cancer. Between 1960 and 2000, 90 patients (mean age 55.1; range 32-77) with lung metastasis (79 solitary, 11 multiple) underwent surgery as follows: wedge resection (n = 10), segmental resection (n = 11), lobectomy (n = 68) and pneumonectomy (n = 1). The metastases were completely resected in 89% of them. One patient died due to surgical complications. The overall 5- and 10-year cumulative overall survival rates were 54% and 40%, respectively (median, 6.3 years). Fifteen patients survived without relapse for over 10 years. They were 24% of those who progressed for 10 years or more after lung surgery. The most significant prognostic factor was disease-free interval (DFI) and stage at breast surgery. The 10-year survival rates of those with >==3 and <3 years of DFI were 47% and 26%, respectively (P = 0.014). Survival times were significantly longer for patients with clinical stage I at breast surgery than those with stage II-IV (P = 0.013). Our data, although limited and highly selective, suggest that surgical approach to lung metastasis from breast cancer may prolong survival in certain subgroups of patients to a greater extent than systemic chemotherapy alone. Surgical approach to lung metastasis of breast cancer, if possible, should be a treatment of choice to a great extent.

Purpose: Sentinel lymph node biopsy (SNB) has been a standard technique in early breast cancer. However, it is not clear that the SNB procedure can be applied to second breast cancer or recurrence occurring in the previously treated breast. The purpose of this study was to clarify the feasibility of the SNB procedure in breast cancer occurring in the previously treated breast, and to investigate the factors related to altered lymphatic flow., Patients and Methods: Between April 2004 and December 2006, 1490 patients underwent the breast SNB procedure. Among them, 31 patients had a history of previous treatments in the same breast. Recent excision biopsy cases were not included in this group. All patients had previous breast-conserving surgery in the same breast. Sixteen patients had axillary dissection, 3 had SNB, and 12 had no axillary treatment. Ten patients had received radiation therapy to the breast and axilla. Visualization of axillary nodes, internal mammary nodes and contralateral axillary nodes was evaluated and compared with pathological results., Results: Axillary nodes were visualized in 23 patients, internal mammary nodes in 7 patients, and contralateral axillary nodes in 7 patients. The patients with previous axillary dissection exhibited altered lymph node distribution, but did not show involvement of contralateral axillary nodes. Visualization of contralateral axillary nodes occurred in 7 of the 10 patients with previous irradiation to breast irrespective of axillary dissection. Twenty-eight patients underwent SNB, 4 of whom showed cancer-positive nodes. Three patients were cancer-positive in non-ipsilateral axillary nodes (one patient showed positive opposite axillary node and two patients showed positive internal mammary nodes)., Conclusion: Previous axillary dissection or irradiation to the breast greatly influences lymphatic flow. Irradiation to the breast may be a strong factor for the visualization of contralateral axillary nodes. Despite the frequent alteration of lymphatic flow, SNB seems to be feasible in secondary or recurrent breast cancer patients.

Background: The impact of skin invasion in node negative breast cancer is uncertain., Methods: We determined the prognosis in 97 node negative breast cancer patients (case group) who had tumors with skin invasion. Then we compared these patients with 4500 node negative invasive breast cancer patients treated surgically in the same period., Results: Patients with skin invasion tended to be older, had more invasive lobular carcinoma and larger tumor size, and were less likely to have breast conserving surgery than those in the control group. The 5-year disease-free survival rate in the case group was 94.0%. There was no significant difference in the 10-year disease-specific overall survival rates in terms of skin invasion in node negative patients (90.7% in the case group, 92.9% in the control group; p = 0.2032)., Conclusion: Results suggest that skin invasion has no impact on survival in node negative invasive breast cancer patients. The adjuvant regimens which the individual institute applies for node negative breast cancer should be used regardless of skin invasion.

Purpose: To confirm which modality, ultrasonography (US) or mammography (MMG), is useful to detect breast cancer in women aged 30 to 39 years, and to compare the sensitivity and findings of these two modalities for invasive carcinoma and ductal carcinoma in situ (DCIS) in the diagnostic setting., Methods: We retrospectively evaluated the sensitivity and findings of these two modalities in 165 patients aged 30 to 39 years, who underwent surgery at the Cancer Institute Hospital between 2001 and 2003. US or MMG were performed after obtaining information on the other modalities previously used and physical examination. The abnormal findings of US were defined as mass lesions and focal hypoechoic areas due to breast cancer. The abnormal findings of MMG were defined as category 3 to 5 (Japanese Mammography Guidelines) masses, calcifications, and other findings due to cancer., Results: Of 165 patients, 147 patients (89%) mammographically showed dense breasts. Histologically, 146 (88%) were invasive carcinomas and 19 (12%) were DCIS. In all carcinomas, the sensitivity of US (95%) was higher than that of MMG (85%). The sensitivity of US for invasive carcinoma (99%) was higher than that of MMG (85%). On the other hand, the sensitivity of MMG for DCIS (89%) was much higher than that of US (68%)., Conclusions: US is more sensitive to detect breast cancers than MMG in this age range, especially for invasive carcinoma. On the other hand, MMG is useful for detecting DCIS, especially when it manifests with microcalcifications.

Purpose: To investigate the relationship between the tumor size of breast cancer by palpation and the sensitivity of mammography (MMG) and ultrasonography (US), and which modality can detect nonpalpable breast cancer in women aged 30 to 39 years., Methods: We retrospectively evaluated the tumor size by palpation, breast density, and the sensitivity of MMG and US in 165 patients aged 30 to 39 years. Palpation, US, and MMG were performed with prior knowledge of the results of other modalities. The tumor size on palpation were classified into Tnp; nonpalpable, T1p; 2 cm or less, T2p; more than 2 cm, but not more than 5 cm, and T3p; more than 5 cm., Results: Of 165 patients, 147 patients (89%) showed mammographically dense breasts. Of 165 cancers, 14 (8%) were Tnp, 40 (24%) were T1p, 82 (50%) were T2p, and 29 (18%) were T3p. The sensitivity of MMG was 57% (8 of 14) for Tnp, 78% (31 of 40) for T1p, 90% (74 of 82) for T2p, and 97% (28 of 29) for T3p. The sensitivity of US was 43% (6 of 14) for Tnp and 100% for palpable cancers. Of 14 nonpalpable cancers, 4 (29%), 4 (29%), and 2 (14%) could be detected by only MMG, bloody nipple discharge, and US., Conclusions: The sensitivity of MMG depends on the tumor size on palpation in this age range. MMG fails to detect relatively large palpable cancers. On the other hand, US can detect all palpable cancers. However, the sensitivity of US declines for nonpalpable cancers. For the detection of nonpalpable cancers, MMG, US, and nipple discharge are complementary modalities.

Aims: The aim of the present study is to clarify the level of radioactive lymph node should be biopsied after the most radioactive SN is removed., Methods: SNB using radionuclide was performed in our hospital for 1179 primary breast cancers between April 2000 and October 2005; most (1177/1179) were performed successfully. Our criterion for harvesting SNs is to remove tissue until no radioactive site is present. The level of radioactivity and the order of removal of each lymph node were compared with pathologic results., Results: More than 2 (overall average 1.9) radioactive SNs were biopsied in 686 of 1177 breasts. Cancer positive results were recorded for 142 breasts with multiple SNs. In 142 breasts, 64 showed metastasis to the most radioactive node only, 39 showed metastasis other than the most radioactive node only, and 39 showed the most radioactive node and other radioactive nodes. Moreover, if several other criteria were applied, false-positive cases were increased significantly., Conclusions: It is necessary to harvest radioactive lymph nodes other than the most radioactive. Moreover, efforts to remove every radioactive lymph node will minimize false-negative results.

Aims: Methods of administering (99m)Tc-phytate during sentinel node biopsy of early breast cancer patients were compared to improve the sensitivity of the technique., Methods: Two injection methods, intradermal vs. intradermal-plus-deep injection, were compared in 648 early breast cancer patients. Intradermal injection was done in 323 consecutive patients (325 breasts), and intradermal-plus-deep injection was done in 325 consecutive patients (329 breasts). The following items were compared: (1) The number of axillary nodes detected scintigraphically and removed surgically, and the breast number of micrometastasis to axillary nodes; (2) The number of internal mammary nodes detected scintigraphically and removed surgically; and (3) The sensitivity of axillary SNB., Results: The number of axillary nodes scintigraphically detected was 1.63+/-0.80 (mean+/-SD) in patients given intradermal injection, and was 1.82+/-0.94 in patients given intradermal-plus-deep injection. The number of axillary nodes surgically removed was 1.78+/-0.93 in patients given intradermal injection, and was 1.95+/-0.99 in patients given intradermal-plus-deep injection. The visualization of internal mammary nodes was superior with intradermal-plus-deep injection (5/325 for intradermal, and 51/329 for intradermal-plus-deep). The putative sensitivity was 71/72 (98.6%) for the intradermal-plus-deep method and 56/62 (90.3%) for the intradermal method. The frequency of detection of micrometastasis was 24 in 71 true positive (38.8%) for the intradermal-plus-deep method and 13 in 56 true positive (23.2%) for the intradermal method., Conclusions: The SNB procedure with the intradermal-plus-deep injection method detected more axillary and internal mammary nodes, more (not statistically significant) micrometastasis and improved the putative sensitivity more than the SNB procedure with the intradermal injection method.

To improve the utility of mammary ductoscopy, we investigated the correlation between endoscopic findings and histologic findings using intraductal biopsy specimens. Seventy-one intraductal biopsy specimens obtained from 63 patients between October 2001 and March 2004 were analyzed retrospectively. All specimens were obtained from monotonous intraductal lesions immediately after observation by mammary ductoscopy and were composed of a pure histologic subtype. With regard to endoscopic findings, color was classified as yellow, red, white, or colorless, and morphology was classified as spherical, lobular, mulberry, or amorphous. The histologic subtype was classified as papillotubular, papillary, degenerated, papillary cancer, solid-type ductal carcinoma in situ (DCIS), or cribriform cancer. The relationship between histologic diagnosis, color, and morphology was investigated. Intraductal biopsy specimens included 25 specimens of carcinoma and 46 specimens of papilloma. There was no significant correlation between color and diagnosis. Fourteen of 25 carcinoma specimens were amorphous, and amorphous morphology was significantly suggestive of malignancy (p < 0.001). Further, cribriform cancer was associated with amorphous morphology and yellow color. Morphology may be a useful endoscopically delineated parameter for differentiating intraductal lesions.

When breast-conserving therapy was introduced at the Cancer Institute Hospital (CIH) in Tokyo in 1986, we instituted our own strategy as follows: 1) every effort is to be made for complete tumor resection while avoiding deformity of the breast, and 2) radiotherapy (RT) is applied only to the patients with positive surgical margins. This is, in turn, to clarify the group of patients in whom postoperative RT can be safely spared. Among 9670 patients operated on for primary breast cancer during the 16.5 year period from 1986 to 2002 at CIH, there were 2449 patients who underwent breast-conserving surgery (BCS). During the 6.5 years mean follow-up period, ipsilateral intrabreast tumor recurrence (IBTR) developed in 99 of the 2449 patients, with an overall rate of 4.0% and an annual rate of 0.62%. These 2449 patients were categorized into four subgroups according to either negative or positive margins and with or without radiotherapy. The IBTR rates and the number of patients in each subgroup were 5.5% in 1351 margin(-)RT(-) patients, 1.0% in 307 margin(-)RT(+) patients, 2.4% in 680 margin(+)RT(+) patients, and 4.5% in 111 margin(+)RT(-) patients. These results either with or without RT seem to be quite comparable to or even better than the results of BCS with RT reported from Western countries, where less emphasis seems to be placed on completeness of the local tumor resection with BCS, while RT is administered to basically all patients following BCS. IBTR was categorized into true recurrence (TR) and second primary lesion (SP) according to the margin status at the time of BCS, the former being lesions developed in patients with positive margins and the latter being those in patients with negative margins. It was demonstrated that in patients with positive margins, TR was much more common than SP, whereas in patients with negative margins, these incidences were just the opposite (i.e., TR was 60% less common than SP) and postoperative RT was effective in preventing both TR and SP, the effect on the latter being much more striking. With RT, the incidence of developing TR in patients who had positive margins was reduced to almost equal to that in margin(-) patients treated with no RT. Our method of IBTR categorization is based on biological consideration and detailed histopathologic examination, and appears to be the only biologically reasonable means so far that has been proposed for distinction between these two biologically different entities. TR and SP can be further reduced to exceptionally low levels in patients who received RT despite negative margins, though it would not seem reasonable to administer RT to all of these patients because the actual number of patients who would benefit is comparatively small. From these observations, it seems that our imaging, pathologic examination, and surgical approaches for patients who are candidates for BCS have been highly valid, and our criteria for sparing postoperative RT as well as categorization of IBTR into TR and SP are quite appropriate. Although our results with BCS seem to deserve wide recognition, they are not from randomized clinical trials, so the findings must be confirmed by a study in order to investigate whether the results at CIH can be applied generally at other institutions.

Background: Few reports have addressed the feasibility and safety of classic Cyclophosphamide, Methotrexate, and Fluorouracil (CMF) therapy in Japanese female breast cancer patients., Methods: Twenty-four Japanese patients who received classic CMF, identical to the originally described treatment regimen were studied in terms of treatment dose, treatment delay, and toxicity., Results: Classic CMF was not discontinued in any of the cases. The median delay in treatment was 14 days, and the mean administered dose of cyclophosphamide was 98.2% of the planned dose. None of the patients suffered severe side-effects such as febrile neutropenia; however, in 22 patients in whom the effect of CMF on hair loss could be assessed, 7 (31.8%) had to wear hats or wigs., Conclusions: Classic CMF is a feasible and safe regimen in Japanese breast cancer patients. In Japan, this regimen is still available for some specific groups of early breast cancer patients.

A patient with intraductal papilloma who had abnormal bloody discharge from Montgomery's areolar tubercle underwent mammary ductography, mammary ductoscopy from the tubercle, and microdochectomy.A 43-year-old woman who was being followed-up for left breast cancer noticed bloody discharge from Montgomery's areolar tubercle of the right breast. Because the discharge continued for 2 months, further examinations were conducted. Mammary ductoscopy of Montgomery's areolar tubercle showed a normal internal duct structure. The presence of yellowish superficial lesions suggested intraductal inflammation or superficial hyperplasia of the duct epithelium. Lavage cytology revealed benign papillary lesions. Since the discharge continued and we could not completely exclude malignancy, microdochectomy was performed. Histologically a lactiferous duct was connected to Montgomery's areolar tubercle and an intraductal papilloma was seen in part and considered to have caused the bloody discharge. Bloody discharge from Montgomery's areola tubercles is extremely rare, the present case was our first experience with ductoscopy of Montgomery's areolar tubercle out of 641 cases of mammary ductoscopy performed on patients with bloody nipple discharge from 1998 to 2004. In our case, Montgomery's areolar tubercles were connected to a lactiferous duct. Although there are a few breast carcinomas that cause bloody discharge and eruption of areola, areolar preservation should be performed with the knowledge that disease may also involve the areola through the lactiferous ducts.

Aims: To study the significance of lymphatic drainage disruption due to a surgical scar in sentinel node mapping (SNM) in breast cancer patients., Methods: We reviewed patients with stage I breast cancer who had undergone SNM and had an old surgical scar in the ipsilateral breast., Results: Of 534 breast cancer patients who had undergone SNM, five patients had an old scar in the ipsilateral breast. Inter-pectoral nodes, internal nodes, intramammary nodes, and contralateral axillary nodes were identified as sentinel nodes in three cases. In the remaining two cases, no sentinel lymph nodes were identified., Conclusions: An old surgical scar in the breast may cause lymphatic drainage disruption, resulting in abnormal radioactive colloid uptake during SNM.

Purpose: To classify and assess ipsilateral breast tumor recurrences (IBTR) after breast-conserving therapy., Methods: Between 1986 and 2001, 2,137 patients who had breast cancer underwent breast-conserving surgery with or without radiotherapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. Of these patients, 83 (3.9%) had an IBTR. We classified the IBTR as a new primary cancer (NP) if the primary tumor had completely negative margins at first operation by detailed pathological examination and if the IBTR had an intraductal component. All other IBTRs were judged true local recurrence (TR)., Results: Of the 83 patients, 42 patients were classified as TR (29 had no radiotherapy) and 41 as NP (40 had no radiotherapy). Mean time to disease recurrence was 37 months for TR (52% were within 2 years) versus 55 months for NP (19% were within 2 years) (p=0.031). Six patients (14%) with TR did not receive re-operation, and 67% received salvage mastectomy and 19% re-lumpectomy. All cases of NP were operable, 78% underwent salvage mastectomy and 22% underwent re-lumpectomy. Distant metastases were observed in 33% of patients with TR and 5% of patients with NP, and cause-specific death occurred in 6 cases with TR and in one with NP. The patients with NP had improved 5-year rates of overall survival (NP 91% vs. TR 76%, P=0.0627) and distant disease-free survival (NP 93% vs. TR 61%, P=0.0028). Patients with NP more often developed contralateral breast cancer (NP 37% vs. TR 12%, P=0.018), Conclusions: Patients with NP had better survival rates than those with TR. Distinguishing new primary breast carcinomas from local disease recurrences may have importance in therapeutic decisions and chemoprevention strategies.

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.

Background: Sentinel node (SN) biopsy has been becoming a standard method for early stage breast cancer. Scintigraphic image of SN helps the biopsy procedure. It is reported that the scintigraphic detection rate is not 100%. The value of taking additional projection view in SN detection was assessed in breast cancer patients., Patients and Methods: Consecutive 114 breast cancer patients with upper lateral quadrant tumor were included in this study. After injection of 99mTc-phytate, scintigram was taken at the projection of anterior oblique (AO) 30 degrees view and an additional AO 60 degrees view. Images were evaluated visually., Results: In 7 of 114 patients, an axillary hot node was hidden on the activity at the injected site on AO 30 degrees view, and was visualized on AO 60 degrees view. In 17 of 114 patients, the axillary hot node was seen as a hump from the injected activity, and was separate on AO 60 degrees view. In 90 of 114 patients, the axillary hot node was separately seen on AO 30 degrees view., Conclusion: Multi-directional views are helpful to depict the axillary sentinel nodes that are concealed behind the injected radioactivity.

Aim: Large multicenter, randomized trials have revealed the advantages of using tamoxifen for 5 years vs 2 years in breast cancer patients. The aim of this report is to confirm the optimal duration of tamoxifen administration in a study of Japanese breast cancer patients., Methods: Japanese post-menopausal estrogen receptor-positive breast cancer patients treated with mastectomy were randomly assigned to either a 5-year or 2-year course of tamoxifen. The primary endpoint was disease-free survival, with secondary endpoints of overall survival and a reduction in the development of metachronous contra-lateral breast cancer., Results: A total of 256 breast cancer patients were randomized to a 5-year or 2-year tamoxifen administration group. After a median follow-up time of 81 months, there were no significant differences seen in terms of disease-free or overall survival (p=0.65 and 0.56, respectively). Furthermore, the impact of the 5-year use of tamoxifen on the development of contra-lateral breast cancer did not reach statistical significance (p=0.0511). However, 5-year tamoxifen use was closely associated with gynaecological complications (p=0.0081)., Conclusion: We could not show a beneficial effect of using tamoxifen for 5 years over 2 years in Japanese estrogen receptor-positive patients. This is likely due to the small number of patients enrolled in our study; however, racial disparity may influence this result. A reevaluation is necessary to study the advantages of the 5-year use of tamoxifen in the Japanese racial subgroup.

Background: Radioguided sentinel node biopsy (SNB) of breast cancer patients has become a standard method for detecting early stage breast cancer. However, no standard radiopharmaceutical exists., Methods: 99mTc rhenium colloid or 99mTc phytate SNB was used to aid detection in breast cancer patients. For each radiopharmaceutical, 100 patients were examined. The following points were compared: (1) scintigraphic detection rate of axillary sentinel nodes (detectability and number when detectable) and internal mammary sentinel nodes; (2) the number of nodes detected scintigraphically and the number detected during surgery; (3) sensitivity, specificity, accuracy, negative predictive value, and positive predictive value for axillary sentinel nodes., Results: Axillary sentinel nodes of patients were biopsied using either 99mTc rhenium or 99mTc phytate. The number of axillary nodes surgically removed from patients given 99mTc rhenium was 2.28+/-1.08 (mean+/-SD), and the number of axillary nodes surgically removed from patients given 99mTc phytate was 1.68+/-0.82. Some patients given 99mTc rhenium showed a spill-over of radioactivity from sentinel nodes. Concordance of scintigraphically detected nodes and surgical removed nodes was superior for 99mTc phytate compared to that with 99mTc rhenium, with a statistically significant difference. The sensitivity and negative predictive value was superior with 99mTc phytate compared to that with 99mTc rhenium, even though no statistical difference was detectable. However, visualization of internal mammary nodes was superior with 99mTc rhenium., Conclusion: In breast cancer patients, 99mTc phytate is a better choice for the detection of axillary SNB than 99mTc rhenium colloid. However, 99mTc rhenium colloid is a better choice for the detection of internal mammary nodes.

Purpose: To establish the novel prognostic markers for breast cancer, gene expression profile was examined genome-wide., Methods: We used cDNA microarray consisting of 18,432 human genes to compare genome-wide expression profiles of eight primary breast cancers, four from patients who died of breast cancer within 5 years after surgery (5D group) and four who survived disease-free for more than 5 years (5S group)., Results: We identified 21 genes whose expression was greater in tumors from the 5D group than in 5S tumors, and 23 with higher expression in the 5S group than in the 5D group. We established a Prognostic Index (PI) for prediction of postoperative prognosis, based on the aberrant expression profiles of ten of those genes. Among 20 additional cases chosen blindly, ten presented with high prognostic scores (>7, good) according to the PI; the remaining ten cases revealed scores <7 (poor). The PI predicted the actual 5-year clinical outcomes of these 20 cases with 100% accuracy., Conclusion: Our PI system is reliable in clinical settings for predicting postoperative risk for breast cancer. The extensive list of genes provides valuable information about progression of breast cancer and suggests potential target molecules for treating this disease.

Background: Breast cancer has emerged as one of the most frequent malignancies among Japanese women; however, the long-term survival of Japanese breast cancer patients is uncertain., Methods: We analyzed the chronological changes in the clinical and pathological characteristics, treatment procedures and the long-term prognosis of 15 416 Japanese women with 16 217 primary breast cancers treated in the Cancer Institute Hospital in Tokyo between 1946 and 2001., Results: Our analysis revealed a chronological increase in the mean patient age, postmenopausal patients and non-invasive carcinomas. Operative procedures became less extensive, with approximately 45% of breast cancer patients in 2000-2001 receiving breast-conserving treatment. Radiotherapy to the regional lymph nodes decreased, while postoperative chemotherapy and hormonal treatments have become more frequent. The survival rate has improved steadily during the past 5 decades. The 10-year crude overall survival rate improved from 61% before 1960 to 83% in the 1990s., Conclusions: The survival rate of Japanese women with breast cancer has dramatically improved during the past 5 decades.

Purpose: To assess the presence of invasion in non-palpable breast cancer with microcalcifications., Material and Methods: We investigated 157 patients with non-palpable breast cancer with microcalcifications, who had undergone stereotactic core biopsy or vacuum-assisted breast biopsy and operation at the Cancer Institute Hospital between 1995 and 2001. We investigated the correlation between the area of calcification (maximum range of microcalcifications measured in mm by direct mammography), morphology of calcification on mammography, histological subtype of intraductal carcinoma (comedo or non-comedo) and frequency of invasion, and lymph node metastasis. The chi-square test was used in the statistical analysis and p values less than 0.05 were considered statistically significant., Results: Invasion was observed in 33 of 157 pts (21%), of whom 23 showed minimal invasion, which is less than 0.5 cm in greatest diameter. The risk of invasion was 13% within 10 mm of the microcalcifications (n =70), 25% from 11 to 30 mm (n =59), and 32% more than 31 mm from the microcalcifications (n =28). The risk of invasion was 16% for punctate-round and amorphous type (n =87) microcalcifications, and 27% for pleomorphic and linear-branching types (n =70)(p =0.092). In addition, invasion was found 10% of the time within 10 mm of punctate-round and amorphous type microcalcifications, and 20% of the time at 11 mm or more. On the other hand, invasion was found 15% of the time within 10 mm of pleomorphic and linear-branching type microcalcifications, and 37% of the time at 11 mm or more. In 72 cases of intraductal carcinoma diagnosed by pathological examination, invasion was found in 10 of 31 (32%) comedo type intraductal carcinomas and in 5 of 41 (12%) non-comedo types (p =0.0379). There were 5 cases (3.2%) with axillary lymph node metastasis, all of which widely extended more than 21 mm from the microcalcifications., Conclusion: The risk of invasion was 10% within 10 mm of punctate-round and amorphous type microcalcifications, and 37% at more than 11 mm of pleomorphic, linear-branching microcalcifications.

Preclinical studies have demonstrated the synergistic anti-tumour activity of combination therapy with the oral cytostatics, 5'-deoxy-5-fluorouridine (5'-DFUR) and cyclophosphamide (CPA), in human breast cancer xenograft models. This study was performed to evaluate the efficacy and safety of this oral combination chemotherapy in the treatment of metastatic breast cancer. In all, 101 patients with metastatic breast cancer were enrolled in the study, and the data for 94 eligible patients of these were evaluated. The patients received twice daily oral combinations of 5'-DFUR (1200 mg/body/day) and CPA (100 mg/body/day) for 2 weeks, followed by a 1-week rest period. After a median of 19 treatment cycles (range 1-66 cycles), 16 patients (17.0%) had a complete response, and 40 patients (42.6%) had partial responses. The response rate was 59.6% (95% CI, 49.0-69.6%). The median time to progression and overall survival times were 11.7 and 40.3 months, respectively. The toxicity was mild and tolerable, and the related grade 3/4 clinical adverse effects consisted of haematological toxicity in 21 patients (22%) and nonhaematological toxicity in five patients (5%). These results suggest that the oral combination chemotherapy of 5'-DFUR and CPA has low toxicity and is a novel, very convenient and effective treatment for metastatic breast cancer.

Sentinel node (SN) biopsy is a promising replacement for standard axillary lymph node dissection for the staging of early breast cancer, and various techniques have been studied to identify SNs with dye or radioactive colloid. This study assesses the effect of the dose of radioactivity and the time before biopsy in order to set standards for the use of 99mTc-rhenium sulphide for the detection of SNs in breast cancer patients. Sixty patients with stage T1-2 N0 M0 breast cancer underwent SN biopsy, which was immediately followed by standard axillary dissection to confirm the SN results. For SN biopsy, 99mTc-rhenium colloid was injected peritumorally. A 1 day (morning injection and afternoon surgery) or 2 day (day before afternoon injection and morning surgery) protocol was applied. A dose-finding study was performed simultaneously using 7.4-37 MBq for the 1 day protocol and 37-74 MBq for the 2 day protocol. A scintigram was taken at 2 h for the 1 day protocol and 16 h for the 2 day protocol. After the injection of blue dye, SN biopsy was performed with a gamma probe, followed by standard axillary node dissection. The radiation exposure received by the surgical team during the operation was monitored. Histopathological comparison between SNs and axillary nodes was performed. Patient characteristics that might affect the radiocolloid uptake by SNs were assessed. SNs were identified in all patients regardless of the dose or administration protocol used. Two patients showed false negative pathological SN results, and the negative predictive value was 96% and the positive predictive value was 100%. In addition, radiation exposure to the surgical team and the amount of radioactive surgical waste were low, especially at lower doses. Two groups of patient characteristics were related to SN uptake. One was the body mass index (BMI) and the other was the age or menopausal status. Patients with a larger BMI tended to take up a smaller amount of 99mTc colloid. Older or post-menopausal patients showed lower SN uptake. 99mTc-rhenium sulphide colloid is an efficient radiopharmaceutical for SN detection. Both 1 day and 2 day protocols have equally good efficacy, and the recommended dose is 7.4 MBq for the 1 day protocol and 37 MBq for the 2 day protocol. Patients with larger BMI and older or post-menopausal patients tend to take up less 99mTc colloid.

Background: The disease status of axillary lymph nodes at diagnosis is the most powerful predictor of prognosis for patients with breast cancer. Axillary lymph node dissection (ALND) has been the standard treatment. Recently, lymphatic mapping and sentinel lymph node biopsy (SNB) have been suggested as alternatives to ALND. However, a clear indication for SNB has not yet been established. The goal of this study was to determine which patients might best benefit from the SNB method., Methods: A retrospective study compared the relationship of age, menopausal status, tumor size group, histology and clinical evaluation of nodes to histological axillary lymph node status in 5892 consecutive Japanese breast cancer patients who underwent ALND. A simulation analysis with reported SNB sensitivity and specificity was carried out., Results: Clinical lymph node evaluation was the most relevant factor to predict axillary nodal status. However, even patients with no clinical nodal involvement (N0) showed only 71% axillary nodal negativity. Tumor group based on tumor size and histology also related to axillary nodal status. The simulation analysis revealed that of patients with negative lymph node probability, more than 66% were good candidates for SNB., Conclusion: The clinically negative node (N0) is the most important indication for SNB. Therefore, the candidates for SNB should be picked from the patients with N0. When no histological information is available, patients whose tumor is 20 mm or smaller are candidates for SNB. When histological information is available, the SNB indication extends to patients whose type of tumor has histologically good prognosis or a low probability of having nodal involvement, regardless of tumor size.

We began performing breast-conserving surgery (BCS) in 1986 to achieve complete resection of breast cancer and omit postoperative radiotherapy (RT) if serial and detailed pathologic examination of the resected specimen within a 5-mm width showed that the of margin was cancer free. At of the end of 1998, 1,233 sides of the breast had been conserved, of which 827 sides were shown to have cancer-free margins. As of the end of 2001, with a mean observation period of 79 months, ipsilateral breast tumor recurrence was recognized on 46 sides (19 recurrences, 27 multiple cancers), for a recurrence rate 5.6% and an annual recurrence rate of 0.85%. This rate is slightly better than those reported by eminent institutions in the USA and Europe which all perform RT, confirming the accuracy and safety of our BCS.

In Japan, 41% of surgeries for breast cancer were breast conserving treatment (BCT) in 2000. The indications for BCT in the guidelines of the Japanese Breast Cancer Society (1999) are as follows: (1) tumor size is 3 cm or less, (2) image diagnosis indicates no sign of extensive intraductal spread, (3) cases with multiple tumor are excluded, (4) radiation therapy is possible, (5) the patient wants to receive BCT. The pathological negative margin is favorable in BCT; however, we estimate based on our study that only about 30% of all breast cancers can be completely resected by partial mastectomy. To extend the indications for BCT, the roles of postoperative radiotherapy, endocrine therapy and preoperative chemotherapy will be important. Patients with ipsilateral breast tumor recurrence (IBTR) have increased risk of distant metastases, and the presence of IBTR is an important predictive factor for distant metastases. When we discuss the indications and limits of BCT, we have to take the rate of IBTR into careful consideration.

Background: To diagnose intraductal lesions endoscopically the Japanese Association of Mammary Ductoscopy classified the endoscopical appearance of lesions into three types. We investigated the correlation between endoscopic classification and histological diagnosis., Methods: From April 1998 to February 2001, we enrolled 129 female patients who were diagnosed histologically and whose intraductal lesions were detected by mammary ductoscopy. The endoscopic classification consists of three types. The polypoid type is a localized expansive lesion. This type is divided into two subtypes, the solitary subtype (solitary polypoid lesion) and the multiple subtype (multiple polypoid lesions). The combined type is polypoid lesion(s)coexisting with a superficial type. The superficial type is a superficial spreading lesion such as a continuous luminal irregularity accompanied by no obvious elevations., Results: There were 65 cases of breast cancer and 64 cases of benign papillary lesions. Fifty-four cases of benign papillary lesions and 7 cases of breast cancer were classified as the polypoid-solitary type. Seven benign cases and 13 cases of cancer were classified as the polypoid-multiple type. Two benign cases and 16 cases of cancer were classified as the combined type. Only one benign case and 29 cases of cancer were classified as the superficial type. There is significant correlation between endoscopical types and the histological diagnosis (p<0.0001)., Conclusions: Endoscopic classification is useful to diagnose intraductal lesions.

Background: We have defined 18 chromosomal regions in which allelic losses were frequent among breast cancers. We examined whether specific allelic losses might correlate with any clinicopathological factors., Methods: We tested DNA from matched normal and tumor tissues for loss of heterozygosity (LOH) at 18 microsatellite loci from a cohort of 504 patients who had undergone surgery for breast cancer., Results: LOH at 3p14.3 correlated with a larger size of tumor (greater than 2 cm). LOH at 1p22, 3p25.1, 3p14.3, or 17q21.1 correlated with loss of estrogen receptors. LOH at as many as eleven regions correlated with loss of progesterone receptor, suggesting that these represent general phenomena associated with progression of cancer. Above all, allelic losses at 11q23-24, 13q12, 17p13.3, or 22q13 significantly correlated with lymph-node metastasis (11q23-24, p= 0.0042; 13q12, p=0.0207; 17p13.3, p=0.0478; 22q13, p=0.0162)., Conclusion: These results suggest that some clinical characteristics of breast cancers are determined by loss of tumor suppressor genes present at specific chromosome regions. Especially, LOH at 11q23-24, 13q12, 17p13.3, and 22q13 is a significant predictor of lymph-node metastasis for patients who have undergone surgery for breast cancer, and may serve as a negative prognostic indicator.

Radiotherapy (RT) is not always necessary for the prevention of ipsilateral breast recurrence in cases where cancer is not detected in the remaining breast tissue after breast conserving surgery. In addition, under these circumstances, the rate of a second primary cancer of the remaining breast is theoretically equal to the rate of contralateral breast cancer. In performing breast conserving treatment (BCT) at our institution we do not treat with RT if a strict serial pathological examination of the specimen (every 5 mm) reveals that the case has been safely resected (negative surgical margins). From 1986 to 1998, 827 patients (157 were ductal carcinoma in situ, and 670 were invasive) underwent BCT without RT at the Cancer Institute Hospital. Ipsilateral breast cancer was observed in 46 cases or 5.6% (0.85% annually) during a median observation period of 67 months. Of these 46 cases, 19 (2.3%) were diagnosed as a recurrence and 27 cases (3.3%) were second primary cancers. This recurrence rate is equivalent to the rate observed in 406 cases of BCT (1.7%) that were treated with RT. Most of these cases had shown positive surgical margins. Furthermore, the rate of occurrence of second cancers is not significantly different from the rate of occurrence of contralateral breast cancers. These results suggest that, by selecting irradiation cases based on careful pathological examinations, BCT can be safely performed.

Sentinel node was detected by 99mTc labeled nanocolloid in five patients with breast cancer. Surgery of breast cancer was done at 16 hours after the administration of 74 MBq of 99mTc labeled nanocolloid. Sentinel node was searched by scintigraphy prior to surgery and by gamma-probe during surgery. Radioactivity of injected site, sentinel nodes, blood contaminated gauze, and other garbage was measured by GM detector. Radiation to medical staffs was monitored by a pocket radiation detector and film batches. Sentinel nodes were successfully detected both by scintigraphy and gamma-detector. More than 70% of radioactivity remained in the administered site at 16 hours. Small amount of radioactivity was detectable in the sentinel node. Almost no radioactivity was detectable in blood-contaminated gauze and other garbage. Radiation dose to the main surgeon was 4 to 6 microSv per surgery by a pocket radiation detector. Radiation dose to the assistant surgeon was 2 microSv per surgery. Radiation dose by labeling or injection was 0 to 1 microSv per procedure. No detectable radiation was measured by film batches. It is concluded that the detection of sentinel node by 99mTc labeled nanocolloid is a safe procedure from the point of radiation safety consideration.

In Japan, day surgery for breast cancer usually means partial mastectomy without axillary dissection for small carcinoma under local anesthesia in the outpatient clinic. If histopathological examination of the specimens by serial section reveals that the cancer is noninvasive and completely resected with negative surgical margins, no additional surgery under general anesthesia is needed, and the patient does not require hospitalization. We call this procedure "probe lumpectomy". From 1991 to 1998, 169 patients underwent probe lumpectomy in our institution, and there were no major complications. Of these 169 patients, 64 did not require hospitalization. Ipsilateral breast cancer was observed in two patients, and these tumors were diagnosed not as recurrence but as second primary cancers. No distant metastases were observed. As sentinel node biopsy, which is not always easy under local anesthesia, becomes more common, the indications for day surgery or short-stay surgery will expand. As breast cancer is a malignant disease, informed consent and careful follow-up are needed if the treatment is completed only in the outpatient clinic.

Background: Ductal carcinomas in situ (DCIS) are sometimes treated too aggressively by surgery. We discuss minimal invasive surgery for DCIS on the basis of our experience at the Cancer Institute Hospital in Tokyo., Methods: We performed surgery for 667 cases of DCIS between 1987 to 1998. This twelve year period we divided into three periods; 1987-1990,1991-1994, and 1995-1998., Results: DCIS comprised 10% of all breast cancers, and tended to increase in incidence over time. The number of minimally invasive procedures such as breast conserving treatment (BCT), surgery without axillary dissection, and day surgery increased in later periods. In BCT for DCIS the surgical margin status is the most important factor, the rate of negative surgical margins was higher in DCIS than invasive cancer, and especially high in cases of mammographically detected nonpalpable cancer, the incidence of which is increasing yearly. The outcome of the 667 cases was very good. No distant metastases were observed, and the incidence of ipsilateral breast cancer(including second primary cancer) in these cases was 5%, Conclusions: Because small cancers, including nonpalpable cases, will be detected more frequently, minimal invasive surgery will become more common for DCIS.