Miki Noguchi

Axillary reverse mapping using a fluorescence imaging system in breast cancer

The axillary reverse mapping (ARM) procedure is based on the hypothesis that the lymphatic drainage from the upper arm is different from that of the breast. However, the oncologic safety of the procedure has not yet been determined.

The changing role of axillary lymph node dissection for breast cancer

Currently, it is standard practice that patients with negative sentinel lymph nodes (SLNs) do not undergo axillary lymph node dissection (ALND), whereas ALND is mandated in those with positive SLNs. However, the Z0011 trial showed that ALND could be safely omitted in selected patients with positive SLNs. This article presents a review and discussion of the current role and practice of ALND in the surgical management of breast cancer. A review of the English-language medical literature was performed using the MEDLINE database and cross-referencing major articles on the subject. It may be concluded that ALND can be avoided not only in patients with negative SLNs but also in those with positive SLNs who undergo breast-conserving therapy with whole-breast irradiation and appropriate systemic therapy. However, the omission of ALND would be indicated only in patients with a low axillary tumor burden. On the other hand, ALND remains a standard method of treating regional disease not only in patients with clinically positive nodes but also in other SLN-positive patients who do not meet the above criteria. Although the role of ALND has been limited to the prevention of axillary recurrence, SLN biopsy with whole-breast irradiation and systemic therapy can replace ALND in patients with a low axillary tumor burden.

Oncoplastic breast conserving surgery: Volume replacement vs. volume displacement

Oncoplastic breast conserving surgery (BCS) has emerged as a third option between conventional BCS and mastectomy. Oncoplastic BCS includes two fundamentally different approaches: volume replacement and volume displacement. The former involves partial mastectomy and immediate reconstruction of the breast with the transposition of autologous tissue from elsewhere, while the latter involves partial mastectomy and using the remaining breast tissue to fill the defect resulting from extirpation of the tumor. There are several benefits associated with oncoplastic BCS. First, it allows partial mastectomy without cosmetic penalties, and can achieve better cosmetic outcomes than total mastectomy with immediate breast reconstruction. Second, it avoids the need for total mastectomy in an increasing number of patients without compromising local control. Third, partial breast reconstruction is less extensive and has fewer complications than conventional procedures. Partial mastectomy and partial breast reconstruction can be carried out either simultaneously as a one-stage procedure, or using a two-stage approach. Although patients prefer a one-stage procedure, it requires intraoperative confirmation of complete tumor excision using frozen-section analysis. Moreover, oncoplastic BCS requires combined skills, knowledge, and understanding of both oncological and plastic surgeries, which may be optimally achieved by an oncoplastic surgeon.

Is axillary reverse mapping feasible in breast cancer patients

In the surgical treatment of breast cancer, axillary lymph node dissection (ALND) can be avoided not only in sentinel lymph node (SLN)-negative patients but also in SLN-positive patients who undergo breast-conserving surgery with whole-breast irradiation and systemic therapy. However, it should be performed not only in clinically node-positive patients but also in other SLN-positive patients who do not meet the Z-0011 criteria. The axillary reverse mapping (ARM) technique has been developing for identifying and preserving lymphatic drainage from the arm during ALND, thereby expected to minimize arm lymphedema. Nevertheless, ARM nodes could be involved not only in clinically node-positive patients but also in clinically node-negative patients. Previously, it was considered that preservation of the ARM lymphatics or lymph nodes is not oncologically safe in patients with axillary lymph node metastases. However, recent studies have demonstrated that the ARM procedure is oncologically feasible in clinically node-negative, SLN-positive patients when ARM nodes do not coincide with SLNs. When ARM nodes do not coincide with SLNs, they are not involved even in SLN-positive patients. On the other hand, ARM lymphatics/nodes within the boundaries of a standard ALND should be resected in SLN-positive patients, when ARM nodes are SLN-ARM nodes. Therefore, surgical treatment of the axilla can be individualized on the basis of the axillary nodal status.

Protooncogene TCL1b functions as an Akt kinase co-activator that exhibits oncogenic potency in vivo.

Protooncogene T-cell leukemia 1 (TCL1), which is implicated in human T-cell prolymphocytic leukemia (T-PLL), interacts with Akt and enhances its kinase activity, functioning as an Akt kinase co-activator. Two major isoforms of TCL1 Protooncogenes (TCL1 and TCL1b) are present adjacent to each other on human chromosome 14q.32. In human T-PLL, both TCL1 and TCL1b are activated by chromosomal translocation. Moreover, TCL1b-transgenic mice have never been created. Therefore, it remains unclear whether TCL1b itself, independent of TCL1, exhibits oncogenicity. In co-immunoprecipitation assays, both ectopic and endogenous TCL1b interacted with Akt. In in vitro Akt kinase assays, TCL1b enhanced Akt kinase activity in dose- and time-dependent manners. Bioinformatics approaches utilizing multiregression analysis, cluster analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway mapping, Venn diagrams and Gene Ontology (GO) demonstrated that TCL1b showed highly homologous gene-induction signatures similar to Myr-Akt or TCL1. TCL1b exhibited oncogenicity in in vitro colony-transformation assay. Further, two independent lines of β-actin promoter-driven TCL1b-transgenic mice developed angiosarcoma on the intestinal tract. Angiosarcoma is a rare form of cancer in humans with poor prognosis. Using immunohistochemistry, 11 out of 13 human angiosarcoma samples were positively stained with both anti-TCL1b and anti-phospho-Akt antibodies. Consistently, in various cancer tissues, 69 out of 146 samples were positively stained with anti-TCL1b, out of which 46 were positively stained with anti-phospho-Akt antibodies. Moreover, TCL1b structure-based inhibitor ‘TCL1b-Akt-in’ inhibited Akt kinase activity in in vitro kinase assays and PDGF (platelet-derived growth factor)-induced Akt kinase activities—in turn, ‘TCL1b-Akt-in’ inhibited cellular proliferation of sarcoma. The current study disclosed TCL1b bears oncogenicity and hence serves as a novel therapeutic target for human neoplastic diseases.

Local therapy and survival in breast cancer with distant metastases.

This review article presents an evaluation of the effects of local therapy on survival of breast cancer patients with distant metastases along with a discussion of their relevance. Primary and recurrent breast cancers with distant metastases are systemic diseases with poor prognosis. However, several retrospective studies have demonstrated that surgical removal of the primary breast tumor has a favorable impact on the prognosis of stage IV breast cancer patients. Similarly, it has been reported that surgical resection of metastatic lesions in the lung as well as the liver yields unexpectedly promising results. The interaction of local treatment and systemic therapy may be important, because surgery and radiotherapy are only local treatments. However, it remains uncertain whether these encouraging findings are due to the surgical procedure itself or preoperative patient selection. Only a randomized prospective study can definitively show whether local treatment can prevent death from stage IV disease or recurrent breast cancer with distant metastases. Until data from prospective studies are available, clinicians must weigh retrospective experiences and clinical judgment in deciding whether to offer surgery or radiotherapy to these patients. J. Surg. Oncol. 2012; 105:104–110.

An autocrine/paracrine circuit of growth differentiation factor (GDF) 15 has a role for maintenance of breast cancer stem-like cells

Cancer stem cells are thought to be responsible for tumor growth, recurrence, and resistance to conventional cancer therapy. However, it is still unclear how they are maintained in tumor tissues. Here, we show that the growth differentiation factor 15 (GDF15), a member of the TGFβ family, may maintain cancer stem-like cells in breast cancer tissues by inducing its own expression in an autocrine/paracrine manner. We found that GDF15, but not TGFβ, increased tumor sphere formation in several breast cancer cell lines and patient-derived primary breast cancer cells. As expected, TGFβ strongly stimulated the phosphorylation of Smad2. GDF15 also stimulated the phosphorylation of Smad2, but the GDF15-induced tumor sphere forming efficiency was not significantly affected by treatment with SB431542, an inhibitor of the TGFβ signaling. Although TGFβ transiently activated ERK1/2, GDF15 induced prolonged activation of ERK1/2. Treatment with U0126, an inhibitor of the MEK-ERK1/2 signaling, greatly inhibited the GDF15-induced tumor sphere formation. Moreover, cytokine array experiments revealed that GDF15, but not TGFβ, is able to induce its own expression; furthermore, it appears to form an autocrine/paracrine circuit to continuously produce GDF15. In addition, we found heterogeneous expression levels of GDF15 among cancer cells and in human breast cancer tissues using immunohistochemistry. This may reflect a heterogeneous cancer cell population, including cancer stem-like cells and other cancer cells. Our findings suggest that GDF15 induces tumor sphere formation through GDF15-ERK1/2-GDF15 circuits, leading to maintenance of GDF15high cancer stem-like cells. Targeting GDF15 to break these circuits should contribute to the eradication of tumors.

Feasibility study of axillary reverse mapping for patients with clinically node-negative breast cancer

BACKGROUND The axillary reverse mapping (ARM) procedure was developed to identify and preserve arm lymphatic drainage during axillary lymph node dissection (ALND), thereby theoretically reducing the incidence of arm lymphedema. However, the oncological safety of this procedure has not yet been determined. METHODS Two hundred ninety-two patients with clinically negative nodes (cN0) underwent both sentinel lymph node (SLN) biopsy and ARM. SLN was identified by dye and gamma probe methods, and ARM nodes were identified using a fluorescence imaging system. If SLN was histologically positive, ALND was performed with removal of ARM nodes. Otherwise, identified ARM nodes were preserved unless they coincided with SLN. Postoperatively, SLN as well as ARM nodes were histologically examined with H&E staining. RESULTS SLN was identified in 286 of 292 patients, and ARM nodes were identified in 90 patients. In 54 patients with positive SLN, SLN was the same as the ARM node in 19 patients (the concordance type), whereas it was not an ARM node in the remaining 35 patients (the separate type). Non-SLN and ARM node was not involved in 51 of 54 patients with positive SLN, while it was involved in 3 patients of the concordance type. CONCLUSIONS When ARM nodes were involved in patients with cN0, these were most often the SLN-ARM nodes. Therefore, it may be concluded that ARM nodes that do not coincide with SLNs might be preserved during ALND in SLN-positive patients.

Nipple- or Skin-Sparing Mastectomy by the “Moving Window” Operation and Immediate Breast Reconstruction

Skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM) by the “Moving Window” operation and immediate breast reconstruction (IBR) with tissue expander have been developed to minimize the skin incision and improve the cosmetic outcome of the reconstructed breast for patients with breast cancer. The authors describe SSM or NSM via a small periareolar incision with axillary incision using wound retractors without disposable endoscopic instruments. After the entire breast tissue was removed, immediate breast reconstruction (IBR) using a tissue expander was performed through the axillary incision. Although the follow-up period in this study was short, the moving window operation appears to be useful to minimize skin incision, reduce blood loss, and improve cosmetic outcome of SSM or NSM with IBR without compromising local control.

A novel oncoplastic technique for breast cancer localized in the lower pole of the breast

1 Breast Center, Kanazawa Medical University Hospital, Uchinada-Daigaku, Ishikawa, Japan 2Department of Breast and Endocrine Surgery, Kanazawa Medical University Hospital, Uchinada-Daigaku, Ishikawa, Japan 3Department of Surgical Oncology, Kanazawa Medical University Hospital, UchinadaDaigaku, Ishikawa, Japan 4Department of Plastic Surgery, Kanazawa Medical University Hospital, UchinadaDaigaku, Ishikawa, Japan