長嶋 健

原発性乳癌1,043例を対象としてセンチネルリンパ節生検後の再発予後を解析することにより,センチネルリンパ節に潜在性転移を有する症例の臨床的意義および取り扱いについて検証した.センチネルリンパ節生検で転移を認めず腋窩郭清を省略した症例は875例であったが,術後の再検索で49例(5.6%)に潜在性転移を認め,術後補助療法を施行した後に経過観察を行った.観察期間中央値75ヵ月において潜在性転移群の5年無再発生存率は85.0%,腋窩郭清群では87.9%であった.潜在性転移群のリンパ節再発および遠隔再発は,ともに転移陰性群よりも高率に生じたが(p<0.001),腋窩郭清群との間には有意差はなく,また転移の大きさでも差を認めなかった.術後にセンチネルリンパ節の潜在性転移が判明した場合でも,転移陽性例に準じた補助治療を施行すれば生命予後に対する影響は少なく,腋窩郭清を省略することが可能と考えられた.(著者抄録)

BACKGROUND: Aldehyde dehydrogenase 1 (ALDH1)-positive cells exhibit stem-like or progenitor ability and have been considered a clinically important diagnostic and therapeutic target in patients with breast cancer. In this study, the authors evaluated responsiveness to chemotherapy of ALDH1-positive cells in primary and metastatic lesions and its relation to prognosis for patients with lymph node-positive breast cancer. METHODS: In total, 115 patients who had breast cancer with cytologically confirmed lymph node metastases and who underwent surgery after neoadjuvant chemotherapy (NAC) were evaluated. By using ALDH1 immunohistochemistry in core-needle biopsy specimens of the primary tumor, cytology samples of axillary lymph nodes before NAC, and pathologic samples of each after NAC, the clinical significance of ALDH1-positive cell status was evaluated in primary and metastatic lesions before and after NAC. RESULTS: The presence of ALDH1-positive cancer cells, but not ALDH1-negative cancer cells, in primary and metastatic lesions after NAC was associated with a worse prognosis. In multivariate analysis, only ALDH1-positive cells in metastatic lesions after NAC correlated with overall survival. The responsiveness of ALDH1-positive cells to chemotherapy differed between primary and metastatic lesions, and the findings indicated that ALDH1-positive cells in metastatic lesions after NAC may clinically precede those in the primary lesion. CONCLUSIONS: The responsiveness of ALDH1-positive cells to chemotherapy in primary and metastatic lesions and its prognostic significance were clarified in patients with breast cancer. The authors concluded that ALDH1-positive status may represent a surrogate marker as a new concept in patients with lymph node-positive breast cancer. Cancer 2012. (c) 2011 American Cancer Society.

Breast cancer is the most frequent malignancy in women. However, no useful serum markers with high sensitivity and specificity for the detection of early breast cancer have been identified. The search for biological markers of early breast cancer is of continual interest in experimental and clinical breast cancer research. We recently described a simple and highly reproducible three-step proteome analysis for identifying potential disease-marker candidates among the low-abundance serum proteins. Serum samples from breast ductal carcinoma in situ (DCIS) patients and normal controls were subjected to a three-step serum proteome analysis. The steps were the following: first, immunodepletion of most abundant proteins; second, fractionation using reverse-phase high-performance liquid chromatography; and third, separation using two-dimensional electrophoresis (2-DE). Differences revealed by protein staining were further confirmed by Western blotting, immunohistochemical staining, and enzyme-linked immunosorbent assays (ELISA). Twenty-two upregulated and 26 downregulated spots were detected on the 2-DE gels, and a total of 33 proteins were identified by liquid chromatography and tandem mass spectrometry. Western blotting confirmed that the level of vitronectin was significantly increased in DCIS patients compared with that of normal controls. Immunohistochemical staining of vitronectin in breast cancer tissue revealed high expression in small vessel walls surrounding cancer cells and the extracellular matrix of stroma. Moreover, vitronectin serum concentrations, as measured by ELISA, were significantly increased in patients with DCIS or more advanced breast cancer compared with those of normal controls. Vitronectin could serve as a promising serum marker for the detection of primary breast cancer.

Background: The use of neoadjuvant chemotherapy for breast cancer is effective as postoperative adjuvant therapy, permits more lumpectomies, and can be used to study breast cancer biology. Although pathological response is the strongest prognostic factor, response rates vary according to various parameters, such as dissociation between breast and axillary node responses. Purpose: To clarify the correlation of response rates between breast tumors and metastasized lymph nodes and to identify the clinical significance; response rates measured on imaging were evaluated among breast cancer patients with axillary lymph node involvement. Material and Methods: Subjects consisted of 98 patients diagnosed with node-positive breast cancer who received chemotherapy before surgery. The response to the therapy was evaluated by changes in the largest dimensions of the breast mass and of regional lymph nodes measured on a multidetector row helical CT before and after chemotherapy. The percent reduction was calculated as a response rate. The correlation between response rate and patient outcome was analyzed retrospectively. Results: Breast tumor response rates correlated statistically well with those of lymph nodes (p &lt; 0.001). Disease-free cases had a greater tumor and/or nodal response rates than recurrence cases (p = 0.021, p &lt; 0.001, respectively), regardless of tumor size, histological grade and HER2 amplification. Cancer-associated death was observed more frequently in cases with lower response rates compared to surviving cases (p = 0.007, p = 0.021, respectively). The prognostic difference was found most strongly in nodal response rates (p = 0.001). Conclusion: The present series evaluated the therapeutic effect of NAC on breast tumors and metastasized lymph nodes, and a significant correlation with patient outcome was observed. Evaluating the response rate measured by imaging could be used as a surrogate marker for prognosis before assessment of the pathological response which is ordinarily obtained after surgery.

Background Primary chemotherapy (PCT) for breast cancer is effective as postoperative adjuvant therapy, which permits more lumpectomies and can be used to study breast cancer biology. Many reports indicate that the presence or absence of residual cancer after PCT has been proposed as a critical prognostic factor for prolonged disease-free and overall survival. However, pathological complete response (pCR) has not been obtained for all cases, and the majority of the patients indicate partial response to PCT. Methods The subjects consisted of 41 breast cancer patients failing to achieve a pCR to PCT. Enhanced MRI using a 1.5-T system was carried on just before chemotherapy induction and before surgery. The correlation between tumor reduction rate derived from MRI and occurrence of early events in breast cancer patients was analyzed retrospectively. Results In the median, 40 (23-48) months&apos; follow-up, 14 recurrences and 7 deaths were observed. Disease-free cases had a greater tumor reduction rate than recurred cases (p = 0.0035). If the average of 56% was chosen as the cutoff value, the significant difference was found between the groups with high and low tumor reduction rates (p = 0.0036) with a hazard ratio 2.62. Moreover, cancer-associated deaths were often observed in the cases with the lower tumor reduction rate compared with alive patients (p = 0.0003). Conclusions The evaluation of tumor reduction rates on MRI was considered to be useful for predicting early outcome among breast cancer patients who cannot achieve pCR after PCT.

There is growing evidence that tumor-associated macrophages (TAMs) promote tumor growth and dissemination. Many individual reports have focused on the protumor function of molecules linked to the recruitment of macrophages, but little is known about which factor has the strongest impact on recruitment of macrophages in breast cancer. To elucidate this question, we performed RT-PCR using species-specific primers and evaluated tumoral and stromal mRNA expression of macrophage chemoattractants separately in human breast tumor xenografts. The correlation between the tumoral or stromal chemoattractant mRNA expression including monocyte chemoattractant protein-1 (MCP-1) (CCL2), MIP-1 alpha (CCL3), RANTES (CCL5), colony-stimulating factor 1, tumor necrosis factor alpha, platelet-derived growth factor (PDGF)-BB and macrophage infiltration were compared. There was significant positive correlation between stromal MCP-1 expression and macrophage number (r = 0.63), and negative correlation between tumoral RANTES expression and macrophage number (r = -0.75). However, no significant correlation was found for the other tumoral and stromal factors. The interaction between the tumor cells and macrophages was also investigated. Tumor cell-macrophage interactions augmented macrophage-derived MCP-1 mRNA expression and macrophage chemotactic activity in vitro. Treatment of immunodeficient mice bearing human breast cancer cells with a neutralizing antibody to MCP-1 resulted in significant decrease of macrophage infiltration, angio-genetic activity and tumor growth. Furthermore, immunohistochemical analysis of human breast cancer tissue showed stromal MCP-1 had a significant correlation with relapse free survival (p = 0.029), but tumoral MCP-1 did not (p = 0.105). These findings indicate that stromal MCP-1 produced as a result of tumor-stromal interactions may be important for the progression of human breast cancer and macrophages may play an important role in this tumor-stroma interaction. (C) 2009 UICC

Background. Neoadjuvant chemotherapy (NAC) has been widely accepted for advanced breast cancer patients, and pathological complete remission (pCR) was revealed to be an important prognostic factor. The pCR status of cytologically proven axillary metastases (ALN-pCR) offers a more powerful prognostic predictor than pCR of the main tumor. This study evaluated the clinical significance of residual micrometastases and discusses screening methods after NAC in patients with cytologically proven axillary metastases. Methods. Eighty patients with a diagnosis of cytologically proven axillary metastases received NAC. All dissected lymph nodes were evaluated using multislice sectioning and cytokeratin immunohistochemistry, and categorized into four groups: no metastases (ALN-pCR), and with metastases &lt;= 0.2 mm (ALN-itc), &gt;0.2 mm but &lt;= 2 mm (ALN-mic), and &gt;2 mm (ALN-mac). Disease-free survival (DFS) and overall survival ( OS) were calculated by Kaplan-Meier method based on the status of residual metastases. Results. DFS in patients with ALN-pCR and ALN-itc was significantly longer than that with ALN-mic (P = 0.007, P = 0.045, respectively). OS with ALN-pCR was significantly longer than that with ALN-mic (P = 0.004). There was no significant difference in DFS or OS between ALN-mac and ALN-mic. These data showed the clinical significance of microresidual metastases &gt;0.2 mm after NAC in patients with cytologically proven axillary metastases. Conclusions. Using multislice sectioning, screening for ALN-mic after NAC was clinically important, and that for ALN-itc was not clinically essential.

It has been revealed that sentinel lymph nodes (SLNs) from patients with node-negative breast cancer involve RT-PCR detected micrometastases and isolated tumour cells. However, the prognostic significance of the pathologically undetectable micrometastases is still controversial. in this study, we evaluated Foxp3 positive regulatory T cells (Treg) in SLNs as host-side immune marker that has the potential to detect these micrometastases. In the analyses of training set (n = 30), elevated Treg was strongly associated with the pathologically undetectable micrometastases. In the analyses of validation set (n = 129) in patients with node-negative, relapse-free survival in patients with elevated Treg was significantly shorter than those with lower Treg (p = 0.005). Furthermore, in multivariate analyses, elevated Treg was correlated with relapse-free survival (p = 0.012). Our data indicate that Treg may increase in the microenvironment of SLNs along with pathologically undetectable micrometastases and is a prognostic predictor in patients with node-negative breast cancer. (C) 2009 Elsevier Ltd. All rights reserved.

We report a rare case of breast cancer with cartilaginous and/or osseous metaplasia. A 59-year-old woman had a large lump in her left breast, which had enlarged gradually over a period of 2 years. Mammography, ultrasonography and aspiration cytology suggested phyllodes tumor with carcinoma. She underwent wide excision and sentinel lymph node biopsy. Because of the existence metastatic tumor cells in the sentinel lymph node on frozen section, sequential axillary lymph node dissection was conducted consequently. Histologically, the tumor consisted of invasive ductal carcinoma and spindle-cell carcinoma, including cartilaginous metaplasia. Adjuvant chemotherapy and whole-breast irradiation were performed. However, she died of multiple metastases to the liver 2 years after surgery. Breast cancer with cartilaginous and/or osseous metaplasia belongs to a special type of invasive carcinoma, and the incidence is very low. We here present our case and a review of the literature.

Radiofrequency ablation (RFA) has recently been used to treat small breast cancer. However, there are no data on the long-term morphological features after the procedure. The present study attempts to clarify the characteristics of and changes in the ablated lesion. A total of 17 breast cancer patients underwent RFA using a single needle featuring an internally cooled electrode; this was followed by whole-breast irradiation and adjuvant systemic therapy. Magnetic resonance imaging (MRI) using a 1.5-T system was performed before and 1, 3, 6, and 12 months after ablation, and the morphological characteristics and the size of the ablated lesion were evaluated. Mammography was also performed for a comparison with the MRI measurement. MRI displayed no residual enhancement of the tumor after RFA; there was an altered signal intensity with peripheral enhancement, however, and the area decreased in size gradually at a rate of 3.3% per month. Mammography showed a ring surrounding a roundish area whose size was equal to that seen with MRI. Our current series demonstrated the morphological characteristics on breast imaging after RFA plus radiation therapy. The size of the ablated area decreased over time. These findings are valuable for clinical follow-up of breast cancer patients undergoing RFA.

症例は60代女性．左乳房腫瘤の急速な増大を自覚し来院した．左乳房CE領域に直上の皮膚が菲薄化し赤紫色を呈する約10cmの腫瘤を認めた．MMGでは左乳房の大部分を占める，高濃度，境界明瞭な腫瘤像を認めた．USでは境界明瞭平滑な球形のcystic lesionを認め，内部に乳頭状に隆起する2つのisoechoic lesionを認めた．造影CT，造影MRIでは，周囲との境界が明瞭な約10cmの嚢胞と内腔に突出する結節像を認めたが悪性を疑わせる造影効果を認めなかった．穿刺吸引細胞診を2回行ったが明らかな悪性所見を認めず，嚢胞内乳頭腫の疑いにて腫瘤摘出術を施行した．病理診断は被膜組織内への浸潤を伴うIntracystic solid-papillary carcinomaであった．放射線治療を追加し，内分泌療法にて経過観察中である．嚢胞内乳頭腫との鑑別が困難であった巨大嚢胞内乳癌を経験したので，文献的考察を加えて報告した．