Showing papers by "Masakazu Toi published in 2010"

Multi-center study evaluating circulating tumor cells as a surrogate for response to treatment and overall survival in metastatic breast cancer.

Abstract: Background Evaluating circulating tumor cells (CTCs) is one way to predict outcome and monitor treatment in patients with MBC. In this prospective study, we evaluated CTCs in predicting treatment efficacy and overall survival (OS) using the CellSearch™ System (Veridex, LLC, Raritan, NJ).

Clinical significance of the 21‐gene signature (Oncotype DX) in hormone receptor‐positive early stage primary breast cancer in the Japanese population

Abstract: BACKGROUND: The 21-gene signature has been intensively studied and incorporated into major guidelines for treatment decision in early breast caner. However, it remains to be examined whether this system is applicable to Asian populations. METHODS: The authors collected 325 tumor tissues from estrogen receptor (ER)-positive primary breast cancer patients who had undergone surgery and were treated with tamoxifen between 1992 and 1998. The tissues were analyzed for the 21-gene signature, and the patients were classified into groups of low, intermediate, or high risk based on the Recurrence Score. RESULTS: A total of 280 patients were eligible, with adequate reverse transcription polymerase chain reaction profiles for the Recurrence Score. Of those, 200 and 80 patients had lymph node-negative and lymph node-positive disease, respectively. The proportions of lymph node-negative patients categorized as being at low, intermediate, or high risk were 48%, 20%, and 33%, respectively. In lymph node-negative patients, the Kaplan-Meier estimates of the distant recurrence rate at 10 years were 3.3% (95% confidence interval [95% CI], 1.1-10.0%), 0%, and 24.8% (95% CI, 15.7-37.8%) for those in the low-risk, intermediate-risk, and high-risk groups, respectively. The risk of distant recurrence in the low-risk group was significantly lower than that in the high-risk group when the entire Kaplan-Meier plots were compared (P < .001, log-rank test). There was a significant difference for overall survival between the low-risk and the high-risk groups (P = .008, log-rank test). CONCLUSIONS: This is the first report to show that the 21-gene signature has value in providing prognostic information in Asian populations with ER-positive, lymph node-negative breast cancer. Cancer 2010. © 2010 American Cancer Society.

A Novel Method for Sentinel Lymph Node Biopsy by Indocyanine Green Fluorescence Technique in Breast Cancer

Abstract: We investigated the feasibility of sentinel lymph node (SLN) biopsy using indocyanine green (ICG) technique in 411 patients with early breast cancer at three institutes. ICG, a fluorescence source, and blue dye were injected into the subareolar area to enable real-time image-guided surgery and identification of SLN fluorescence after meticulous dissection. The subcutaneous lymphatic channels were precisely detected in all cases. SLN identification rate was 99% (408/411) with a mean of 2.3 nodes identified per patient. Thirty-nine cases (9.5%) had SLNs involved and all of them were ICG positive. Thus, the ICG technique has a high SLN identification rate comparable with that of the radioisotope method.

Increased estrogen sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1(17β-HSD1) following neoadjuvant aromatase inhibitor therapy in breast cancer patients

Abstract: Aromatase inhibitors (AIs) are considered the gold standard for endocrine therapy of estrogen receptor (ER) positive postmenopausal breast cancer patients. The therapy may enhance therapeutic response and stabilize disease but resistance and disease progression inevitably occur in the patients. These are considered at least partly due to an emergence of alternative intratumoral estrogen production pathways. Therefore, in this study we evaluated effects of exemestane (EXE) upon the enzymes involved in intratumoral estrogen production including estrogen sulfatase (STS), 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), and estrogen sulfotransferase (EST) and correlated the findings with therapeutic responses including Ki67 labeling index (Ki67). 116 postmenopausal patients with invasive ductal carcinoma, stage II/IIIa, were enrolled in JFMC34-0601 clinical trials between March, 2006 and January, 2008. EXE of 25 mg/day was administered according to the protocol. Pre- and posttreatment specimens of 49 cases were available for this study. Status of STS, EST, 17β-HSD1, ER, progesterone receptor (PgR), human epidermal growth factor receptor type 2 (Her2), and Ki67 in pre- and post-specimens were evaluated. Specimens examined before the therapy demonstrated following features; ER+ (100%), PgR+ (85.7%), and Her2+ (77.6%). After treatment, the number of Ki67, PgR, and ER positive carcinoma cells demonstrated significant decrement in clinical response (CliR) and pathological response (PaR) groups. Significant increment of 17β-HSD1 and STS immunoreactivity was detected in all groups examined except for STS in PaR. EST showed significant increment in nonresponsive groups. Alterations of Ki67 of carcinoma cells before and after therapy were subclassified into three groups according to its degrees. Significant alterations of intratumoral enzymes, especially 17β-HSD1 and STS, were correlated with Ki67 reduction after neoadjuvant EXE therapy. This is the first study demonstrating significant increment of STS and 17β-HSD1 following AI neoadjuvant therapy of postmenopausal ER positive breast carcinoma patients. This increment may represent the compensatory response of breast carcinoma tissues to estrogen depletion.

Int6/eIF3e Silencing Promotes Functional Blood Vessel Outgrowth and Enhances Wound Healing by Upregulating Hypoxia-Induced Factor 2α Expression

Abstract: Background— We previously identified INT6/eIF3e as a novel regulator of hypoxia-inducible factor 2α (HIF2α) activity. Small interfering RNA (siRNA)–Int6 adequately stabilized HIF2α, even under normoxic conditions, and thereby enhanced the expression of several angiogenic factors in vitro, suggesting that siRNA-Int6 may induce angiogenesis in vivo. Methods and Results— We demonstrated a 6- to 8-fold enhanced formation of normal arteries and veins in the subcutaneous regions of adult mice 5 days after a single siRNA-Int6 application. Subcutaneous fibroblasts were identified as the major source of secreted angiogenic factors that led to the formation of functional vessels during Int6 silencing. Fibroblasts transfected ex vivo with siRNA-Int6 induced potent neoangiogenesis when transplanted into a subcutaneous region of nude mice. Application of siRNA-Int6 promoted neoangiogenesis in the area surrounding the injury in wound healing models, including genetically diabetic mice, thereby accelerating the closure ...

Angiogenesis in superficial esophageal squamous cell carcinoma: magnifying endoscopic observation and molecular analysis

Abstract: Observations of esophageal squamous cell carcinoma using magnifying endoscopy have now been carried out extensively and, as a result, it has become clear that the morphology of the microvessels evident at the tumor surface reflects the depth of tumor invasion. In M1 and M2 cancer, the surface microvasculature reveals dilation and elongation of the intrapapillary capillary loops (IPCL). However, at this stage, some immature capillaries resembling IPCL also arise inside the tumor and, therefore, the view of the microvasculature should be described as one showing 'intermixing of modified IPCL and IPCL-like immature capillaries (IPCL-like abnormal capillary)'. As cancer invades into the muscularis mucosa (M3 or deeper), an obviously dilated and irregularly branched tumor-specific vasculature, more accurately described as 'neovasculature', can be observed. From our magnifying endoscopy observations and studies of the molecular profile of early esophageal cancer, we conclude that two major angiogenic steps exist in precancerous and M3 lesions in the early phase of cancer progression. In addition, it is now possible to study cell morphology using an endocytoscope with a much higher magnification (×400-×1000) than magnifying endoscopes currently on the market. The histology revealed in this way may reduce the need for conventional biopsy histology in the future.

Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2 homodimers in a clinic-based cohort of patients with metastatic breast cancer

Abstract: We have recently described the correlation between quantitative measures of HER2 expression or HER2 homodimers by the HERmark assay and objective response (RR), time-to progression (TTP), and overall survival (OS) in an expanded access cohort of trastuzumab-treated HER2-positive patients with metastatic breast cancer (MBC) who were stringently selected by fluorescence in situ hybridization (FISH). Multivariate analyses suggested a continuum of HER2 expression that correlated with outcome following trastuzumab. Here we investigate the relationship between HER2 expression or HER2 homodimers and OS in a clinic-based population of patients with MBC selected primarily by IHC. HERmark, a proximity-based assay designed to detect and quantitate protein expression and dimerization in formalin-fixed paraffin-embedded (FFPE) tissues, was used to measure HER2 expression and HER2 homodimers in FFPE samples from patients with MBC. Assay results were correlated with OS using univariate Kaplan-Meier, hazard function plots, and multivariate Cox regression analyses. Initial analyses revealed a parabolic relationship between continuous measures of HER2 expression and risk of death, suggesting that the assumption of linearity for the HER2 expression measurements may be inappropriate in subsequent multivariate analyses. Cox regression analyses using the categorized variable of HER2 expression level demonstrated that higher HER2 levels predicted better survival outcomes following trastuzumab treatment in the high HER2-expressing group. These data suggest that the quantitative amount of HER2 expression measured by Hermark may be a new useful marker to identify a more relevant target population for trastuzumab treatment in patients with MBC.

Predictive value of CD24 and CD44 for neoadjuvant chemotherapy response and prognosis in primary breast cancer patients.

Abstract: PURPOSE: We investigated the significance of CD24 and CD44 expression for predicting responses to chemotherapy and prognosis in primary breast cancer patients. PATIENTS AND METHODS: Diagnosis of breast cancer was confirmed by core needle biopsy, and immunohistochemical studies were performed. Preoperatively, patients received anthracycline-containing chemotherapy. Expression of CD44 and CD24 was assessed immunohistochemically and the relationship with chemotherapy response and with prognosis was analyzed. RESULTS: Between 2001 and 2004, 139 women were enrolled in this study. In the correlation analysis, CD24 expression was negatively associated with pathological response to chemotherapy (p = 0.0003). A machine learning technique with an alternating decision tree (ADTree) showed that four logical rules are involved in predicting the response depending on the combination of CD24, HER2, tumor stage, CD44, progesterone receptor, and patient age. In the survival analysis, patients having CD44 (++) showed a significantly favorable prognosis as compared with others (p = 0.0002). A multivariate analysis showed that CD44 expression had an independent prognostic value (p < .0001). CONCLUSION: We found a significant correlation between CD44 expression and prognosis and between CD24 expression and response to chemotherapy. CD24 and CD44 expressions would be useful predictive markers, although further studies are needed.

Down-regulation of heat-shock protein 70 (HSP-70) correlated with responsiveness to neoadjuvant aromatase inhibitor therapy in breast cancer patients.

Abstract: Background: Aromatase inhibitor (AI) has been established as an effective endocrine therapy in estrogen receptor (ER)-positive postmenopausal breast cancer patients. Our recent proteomic analysis demonstrated that ten proteins were significantly altered in their expression levels before and after the therapy in the patients receiving neoadjuvant AI. Among these newly identified proteins, heat-shock protein 70 (HSP-70) was the most significantly correlated with both clinical and pathological responses. Therefore, in this study, we further evaluated the significance of this HSP-70 alteration using immunohistochemistry. Materials and Methods: A total of 32 patients treated with neoadjuvant exemestane or letrozole in whom pre- and posttreatment tumor tissues were available were included. Immunohistochemical evaluation of ER, progesterone receptor (PgR), Her-2, Ki-67 and HSP-70 was performed. Results obtained were compared to both clinical and biological responses of the patients. Results: The majority of the patients responded to treatment (16 patients with partial response, 14 with stable disease and 2 with progressive disease). The means of ER, Ki-67 and HSP-70 were significantly different between treatment responders and non-responders. Decrement of HSP-70 and Ki-67 after AI treatment and pretreatment Ki-67 labeling index of >10% tumor cells were significantly associated with clinical responsiveness to AI treatment (p<0.0001). There was a significant positive correlation between changes of HSP-70 and Ki-67 before and after the therapy. Conclusion: Decrement of HSP-70 in breast carcinoma cells plays important roles in therapeutic mechanisms of AIs through suppressing tumor cell proliferation in breast cancer patients.

Quality of guideline development assessed by the evaluation committee of the japan society of clinical oncology

Abstract: The Japan Society of Clinical Oncology started implementing clinical practice guidelines for cancer in 2001 It created a Guideline Committee and has published cancer-related information in collaboration with individual subspecialty cancer societies The society then established an Evaluation Committee to assess the quality of guidelines The quality of development and general characteristics of guidelines were reviewed using the AGREE instrument The six standardized domain scores and 23-item crude scores were described, and items with a low median score or a wide inter-quartile range were explored Kappa statistics for inter-rater reproducibility were also described Domains in which the median score was >50 points in 18 guidelines developed between March 2005 and May 2009 included “scope and purpose,” “rigor of development,” and “clarity and presentation” Domains with a median score < 50 points were “stakeholder involvement,” “applicability,” and “editorial independence” Scores in all domains except “stakeholder involvement” were higher during the second half of the period than during the first half of the period, although P values were 010–093 Crude scores remained low for items 5, 7, 19, 20, 22, and 23, and the inter-quartile ranges of items 2, 6, 10, and 22 were wide Kappa statistics ranged from –002 to 064, and they were especially low for items 3, 5, 7, 18, and 23 Guideline quality has tended to improve during the 10 years since the society started this activity However, issues remain to be improved through continuous revisions

HER-2/neu cytoplasmic staining is correlated with neuroendocrine differentiation in breast carcinoma.

Abstract: HER2 oncoprotein plays an essential role in breast cancer growth and differentiation. Determination of HER2 status contributes not only to predicting survival but also to selecting the patients for anti-HER2 therapy. HER2 protein expressed in human cancer cells often contains variant forms as well as the full-length wild-type form. In the present study, we investigated the subcellular localization of HER2 protein in 1053 primary breast cancer tissues. HER2 protein was stained by various immunohistochemical methods and studied by immunoelectron microscopy to confirm the intracellular localization. Thirty-four of 1053 specimens showed cytoplasmic staining of the intracellular domain of HER2 protein by the HercepTest and CB-11. In contrast, no immunoreactivity to the antibodies against the extracellular domain was observed. None of the 34 specimens showed amplification of the HER2 protein by fluorescence in situ hybridization. Subsequently, we studied the association of the cytoplasmic expression of HER2 with neuroendocrine differentiation. Interestingly, all 34 specimens had some positive signals of neuroendocrine markers such as synaptophysin, chromogranin A, neuron-specific enolase, and CD56. Although the result is preliminary, it warrants further study on the role of the cytoplasmic variant form of HER2 in breast cancer growth, particularly in the aspect of neuroendocrine differentiation.

Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan.

Abstract: Background To compare the cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and the anthracycline-containing regimen cyclophosphamide, epirubicin, and fluorouracil (CEF) to evaluate the efficacy and safety of the latter.

[Molecular targeted therapy for breast cancer treatment, challenge to cure].

Abstract: Clinical outcome of breast cancer patients has been improved by development of molecular target agents such as trastuzumab and lapatinib. However, it is still difficult to "cure" all the patients. In order to improve the results, understanding the mechanisms of action and resistance is crucial. Detection of accurate predictive markers of response to these therapies are also required. Various new drugs and their combinations are being challenged in the (pre)clinical trial along this strategy. In this review, we summarize the current findings in target therapy for breast cancer patients.

A multicenter, randomized phase II study of neoadjuvant chemotherapy including trastuzumab with cyclophosphamide with docetaxel in patients with operable HER2-positive breast cancer (JBCRG-10 study).

Abstract: TPS105 Background: Japan Breast Cancer Research Group (JBCRG) is collaborating with Breast International Group (BIG) to develop new evidence for breast cancer treatments in Japan. Combination regimens of anthracyclines and taxanes have been widely used as preoperative systemic therapy (PST) in patients with operable breast cancer. However, we have several clinical questions related to PST: (1) additional effect of cyclophosphamide (CPA) to standard regimen (anthracycline and taxane) to identify preferred regimen for PST, (2) preferable order of anthracycline and taxane, (3) relation between the order of anthracycline and taxane and cardiac toxicity and (4) effect and safety of anthracycline-free regimen. To answer to these questions, we conduct this JBCRG 10 study. Methods: One hundred eighty HER2-positive breast cancer patients (T1C-3, N0-1, M0) are planned to be enrolled. Patients will receive the following treatment: (1)FEC-TCH group, 4 cycles of 5-fluorouracil (5-FU; 500 mg/m2, q3w) + epirubicin (EPI;...

Neoadjuvant use of 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by docetaxel (T) with concurrent COX-2 inhibitor in women with stage II/III breast cancer: A subanalysis of cardiac function.

Abstract: e11073 Background: Anthracycline and taxane have been widely used and studied in neoadjuvant setting for treatment of locally advanced breast cancer. Although addition of COX-2 inhibitors might enh...

Abstract P1-11-18: Neoadjuvant Use of 5-Fluorouracil/Epirubicin/Cyclophosphamide (FEC) Followed by Docetaxel (T) with Concurrent COX-2 Inhibitor in Women with Stage II/III Breast Cancer: A Sub-Analysis of Cardiac Function

Abstract: BACKGROUND: Anthracycline and taxane have been widely used and studied in neoadjuvant setting for treatment of locally advanced breast cancer. Although addition of COX-2 inhibitors might enhance the anticancer effect of chemotherapy, many studies were halted with the concern of possible cardiotoxicity. This sub-study is to evaluate the change in cardiac function of patients during treatment with pre-operative FEC-T with concurrent celecoxib until and after surgery. METHODS: A group of 47 patients, age ranged from 33 to 58 years (mean age 46±6 years), who received four cycles of 3-weekly FEC followed by four cycles of 3-weekly T with concurrent oral celecoxib before surgery (F: 500mg/m 2 ; E: 100mg/m 2 ; C: 500mg/m 2 ; T: 100mg/m 2 ; Celecoxib: 200mg bid), were studied. Echocardiography was performed at baseline, after 4 cycles of FEC and after 4 cycles of T before surgery, and 6 months, 12 months and 18 months after surgery to evaluate changes in left ventricular ejection fraction (LVEF) across time-points. Paired sample statistics was conducted. RESULTS: Patients tolerated well with this regimen. Neither life-threatening toxicity nor clinical symptom of cardiac toxicity was observed. Of 47 evaluable cases, LVEF was assessed in 47 patients pre-operatively and in 32 patients post-operatively. During concurrent celecoxib treatment, the mean LVEF increased from 68.5%±6.6% at baseline to 72.3%±3.6% after FEC and to 73.0%±4.1% after T. When compared to baseline, the changes were statistically significant after FEC (p=0.002 ) and after T (P CONLCUSIONS: Neoadjuvant FEC-T with concurrent celecoxib is well-tolerated. The short-term treatment increased LVEF during the course of neoadjuvant chemotherapy and remains good LVEF after surgery. This is an interesting finding which warrants further investigation of the possible protective effect on cardiac function. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-18.

Alternation of estrogen receptor and progesterone receptor expression in primary breast cancer patients treated with neoadjuvant chemotherapy.

Abstract: To the Editor: Since the benefits of post-operative adjuvant therapy were established in the Early Breast Cancer Trialist’s Collaborative Group (EBCTCG) overview (1), many clinical trials have been conducted in order to improve the prognosis. In parallel, to increase the application of breast-conserving surgery (BCS), neoadjuvant chemotherapy (NAC) was developed, with a pathological complete response (pCR) used as a surrogate marker for a favorable prognosis. If the patient achieves pCR after NAC, the risk of recurrence is very low. However, therapeutic strategies after NAC have not yet been established. There are some clinical questions regarding whether additional chemotherapy is needed for non-pCR cases after NAC, and whether additional treatment is required for pCR cases. When evaluating the profiles of tumor cells, we often observe that the features of post-operative tissue do not always correspond with those of pre-operative biopsy specimens. In particular, the alteration of hormone receptor (HR) expression after NAC is very important for decision-making regarding postoperative endocrine therapy. However, it remains controversial whether endocrine therapy should be conducted in cases of HR-negative conversion. To further clarify this issue, we evaluated the HR status before and after NAC among operable breast cancer patients, and attempted to validate the alteration of the HR status. Patients enrolled in this study were women with primary invasive breast cancer, confirmed by core needle biopsy (CNB) or incisional biopsy, between January 2000 and February 2006 at the Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital. One hundred and sixty-five cases with operable early breast cancer (cT1-3, cN0-2, and cM0) received NAC. The NAC regimen was FEC (5-fluorouracil: 500 mg ⁄ m, epirubicine: 100 mg ⁄ m, and cyclophosphamide: 500 mg ⁄ m) every 3 weeks for four cycles followed by docetaxel (75 mg ⁄ m) every 3 weeks for four cycles (2). In evaluating the HR status, pre-treatment and surgical specimens were stained with mouse monoclonal antihuman ERa antibody (1D5; DAKO, Glostrup, Denmark) and anti-human PgR antibodies (PgR636, DAKO). Hormone receptor expression was scored by assigning proportion and intensity scores, according to Allred’s procedure (3). Scores of 0–2 were designated as negative, while 3–8 were considered positive. Except for patients with bilateral breast cancer or who achieved a pCR, a total of 107 patients among 165 cases were evaluated for receptor status conversion. The characteristics of these patients were not significantly different. The median age was 51 years (range, 23–71 years). Fifty-nine patients were aged less than 50 years and 48 patients were aged 50 or more. The pretreatment ER ⁄ PgR status in CNB or excisional biopsy was classified into four groups: ER+ ⁄ PgR+, ER+ ⁄ PgR), ER) ⁄ PgR+, and ER) ⁄ PgR), with 63 (58.9%), 24 (22.4%), 2 (1.9%) and 18 (16.8%) cases, respectively. Table 1 shows the conversion of HR after NAC. On preoperative evaluation, there were 89 HR+ cases (83.2%) and 18 HR) cases (16.8%). Negative conversion of HR was seen in five cases (4.7%), and no positive conversions were noted. The HR status in almost all patients was not changed by NAC. In the conversion of the ER and PgR status after NAC, there were 87 pre-treatment ER+ cases, and 83 were unchanged after treatment. In primary ER) cases, positive conversion was observed in only one case. This result indicates that the ER status was also not affected by NAC in most cases (95.4%). However, 19 (17.8%) cases exhibited the negative conversion of the PgR status, and positive conversion from PgR) comprised 6.5% (7 ⁄ 107) (Table 2). PgR+ cases were then divided into two groups: negative conversions were noted in Address correspondence and reprint requests to: Shigehira Saji, MD, PhD, Department of Breast Surgery, Division of Clinical Trials and Research, Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan, or e-mail: shige@cick.jp.

Bio-Optical Devices in Indocyanine Green Fluorescence Guided Sentinel Node Biopsy for Breast Cancer~!2009-10-04~!2009-12-23~!2010-05-26~!

Abstract: Background: The indocyanine green (ICG) fluorescence method is a newly developed technology to facilitate the sentinel node biopsy with the guidance of ICG fluorescence images. However, the surgical technique is still difficult, since the sentinel node cannot be indentified before skin incision and careful dissection of the subcutaneous lymphatic vessels is necessary. In this paper, an axillary pressing technique is introduced. Materials and methods: The subcutaneous lymphatic vessels just under the skin were easily detectable, but the detection of the sentinel nodes deep under the skin was difficult by ordinary observation of the fluorescence images. By pressing the axillary skin against the chest wall, the sentinel node is close to the skin and the fluorescence signal becomes intense enough to be detected. The skin incision was made on the pressure-induced fluorescent spot, and the sentinel node was directly approached with the guidance of fluorescence without dissecting the subcutaneous lymphatic vessels. Results: Pressure-induced fluorescence signal in the axilla was observed in all of 36 cases. Direct approach to the axillary sentinel nodes without tracing the subcutaneous lymphatic vessels was successful in 33 cases. Conclusions: The ICG fluorescence method is reliable and little training is required. The axillary pressing technique is useful to make it more popular.

The Indocyanine Green Fluorescence Navigation May be Useful to Personalize Lymph Nodes Dissection~!2009-10-30~!2009-12-23~!2010-05-26~!

Abstract: The indocyanine green (ICG) fluorescence imaging is a tool to detect sentinel nodes and the associated lymphatic network including para-sentinel nodes. According to recent experiences in breast cancer treatment, a real-time lymphatic mapping with ICG fluorescence may provide a possibility of being able to personalize lymph node dissection. This novel concept needs to be investigated in various types of diseases.