Yuko Kitagawa

Clinical patterns of metastasis.

In human solid cancer, lymph node status is the most important indicator for clinical outcome. Recent developments in the sentinel lymph node concept and technology have resulted in a more precise way of examining micrometastasis in the sentinel lymph node and the role of lymphovascular system in the facilitation of cancer metastasis.Different patens of metastasis are described with respect to different types of solid cancer. Expect perhaps for papillary carcinoma and sarcoma, the overwhelming evidence is that solid cancer progresses in an orderly progression from the primary site to the regional lymph node or the sentinel lymph node in the majority of cases with subsequent dissemination to the systemic sites. The basic mechanisms of cancer metastasis through the lymphovascular system form the basis of rational therapy against cancer. Beyond the clinical patterns of metastasis, it is imperative to understand the biology of metastasis and to characterize patterns of metastasis perhaps due to heterogeneous clones based on their molecular signatures.

Minimally invasive surgery for gastric cancer--toward a confluence of two major streams: a review.

The minimalization of therapeutic invasiveness in order to preserve quality of life (QOL) is a major topic in the management of early gastric cancer. After laparoscopic surgery for gastric cancer was introduced by Kitano et al. in 1991, an enthusiasm to develop laparoscopic procedures has grown steadily. In the initial phase, early gastric cancer limited to the mucosal layer with no risk of lymph node metastasis was treated by laparoscopic wedge resection or intragastric mucosal resection. Since technical and instrumental advances in endoscopic treatment were achieved by gastroenterologists, these cases can be managed by intraluminal endoscopic approaches. The attention of surgeons then shifted to more radical procedures such as laparoscopic gastrectomy with lymph node dissection, which is comparable to open surgery and can be indicated even in advanced cancer. Although this paradigm shift has already been realized in the field of colorectal surgery, we must pay attention to the particular biological nature of gastric cancer in terms of the potential of peritoneal dissemination. While early-phase recovery after surgery has been improved by laparoscopic surgery, preservation of late-phase QOL by function-preserving surgery is also essential in this regard; therefore, the sentinel node (SN) concept has been a much-discussed topic in gastric cancer surgery to approach this aspect. Recently, the validity of the SN concept has been demonstrated by a number of single institutional studies, and prospective multicenter trials are currently ongoing. Theoretically, various types of function-preserving surgery could be applied in cases of early gastric cancer with negative SNs as less invasive surgery to improve long-term QOL. Although we still have to solve several remaining issues in the treatment of gastric cancers, a confluence of these two major streams, laparoscopic surgery and sentinel node navigation surgery, would enable us to apply a novel individualized minimally invasive approach, both in terms of degree of incisional access and extent of function preservation.

Sentinel Node Mapping for Colorectal Cancer With Radioactive Tracer

AbstractPURPOSE: The aim of this study was to test the feasibility and accuracy of radioactivity-guided mapping of the first lymph nodes found in draining the primary tumor site for colorectal cancer. nMETHODS: We enrolled 56 consecutive patients with preoperative diagnosis of curatively resectable colorectal cancer. Endoscopic injection of technetium Tc 99m–labeled tin colloid (15 MBq) was performed preoperatively, and radioactive sentinel nodes were identified intraoperatively with a gamma probe. Standard radical resection with lymph node dissection was performed in all patients, and all resected nodes were evaluated by routine histopathologic examination. nRESULTS: Radioactivity-guided methods were used to detect sentinel nodes in 51 (91 percent) of 56 patients. The number of lymph nodes resected was 23.9 ± 15.2 per case. The number of sentinel nodes was 3.5 ± 2.1 (range, 0–8) per case. In 18 of 22 patients with lymph node metastasis, the sentinel node was positive. The incidence of metastasis in the sentinel node (22 percent) was significantly higher than that in nonsentinel nodes (3 percent, P < 0.01). Diagnostic accuracy according to sentinel node status was 92 percent (47/51). Four false-negative cases in this study were advanced cases with T3 primary tumors. The detection rate and diagnostic accuracy for patients with T1 or T2 primary tumors (29 cases) were 100 percent each. nCONCLUSION: Intraoperative radioactivity-guided sentinel node mapping was accurate for patients with colorectal cancer with T1 or T2 tumors. The results suggest that sentinel node mapping and intraoperative biopsy may be a sensitive and specific diagnostic method for detecting metastasis in regional lymph nodes in patients with colorectal cancer.

Sentinel lymph node mapping with GI cancer

Precise evaluation of lymph node status is one of the most important factors in determining clinical outcome in treating gastro-intestinal (GI) cancer. Sentinel lymph node (SLN) mapping clearly has become highly feasible and accurate in staging GI cancer. The lunchtime symposium focused on the present status of SLN mapping for GI cancer. Dr. Kitigawa proposed a new strategy using sentinel node biopsy for esophageal cancer patients with clinically early stage disease. Dr. Uenosono reported on whether the SLN concept is applicable for gastric cancer through his analysis of more than 180 patients with cT1-2, N0 tumors. The detection rate was 95%, the false negative rate of lymph node metastasis including micro-metastasis was 4%, and accuracy was 99% in gastric cancer patients with cT1N0. Dr. Bilchik recommended the best technique for identifying SLNs in colorectal cancer: a combination of radiotracer and blue dye method, emphasizing that this technique will become increasingly popular because of the SLN concept, with improvement in staging accuracy. He stressed that this novel procedure offers the potential for significant upstaging of GI cancer. Dr. Saha emphasized that SLN mapping for colorectal cancer is highly successful and accurate in predicting the presence or absence of nodal disease with a relatively low incidence of skip metastases. It provided the “right nodes” to the pathologists for detailed analysis for appropriate staging and treatment with adjuvant chemotherapy. Although more evidence from large-scale multicenter clinical trials is required, SLN mapping may be very useful for individualizing multi-modal treatment for esophageal cancer and might be widely acceptable even for GI cancer.

Sentinel Lymph Node Mapping in Esophageal and Gastric Cancer

In recent years, the sentinel lymph node (SLN) concept has been widely investigated in a variety of solid tumors including gastrointestinal (GI) cancer. This chapter reviews the rationale and refined technical aspects for SLN mapping in upper GI cancer for the intraoperative accurate diagnosis of nodal status to perform individualized minimally invasive surgical approaches. We have described the technical details of the procedure as we have performed it in over 350 consecutive patients with esophageal and gastric cancer and introduced pitfalls and issues remaining. The technical details and clinical applications of SLN mapping differfor patients with esophageal cancer and gastric cancer. Radio-guided method with lymphoscintigraphy using radioisotope-labeled colloid (RI) is essential for SLN mapping for esophageal cancer. Selective lymphadenectomy and SLN-targeted chemoradiotherapy would be feasible and beneficial for the patients with esophageal cancer. For gastric cancer, combined method with dye and RI is recommended for stable and accurate sampling of SLN in the laparoscopic setting. Laparoscopic local resection for superficial gastric cancer with negative SN status would be a reasonable and less-invasive novel procedure based on the SLN concept. We can utilize this procedure not only for an accurate staging but also as a great tool to change the patient care of upper GI cancer by individualized minimally invasive treatments.

Comparative Effectiveness of Neoadjuvant Therapy for HER2–Positive Breast Cancer: A Network Meta-Analysis

BACKGROUNDnThe growing number of antihuman epidermal growth factor receptor-2 (HER2) agents suggests the need for defining the optimal choice of neoadjuvant therapy for HER2-positive breast cancer. This study aims to assess the efficacy and safety of neoadjuvant therapy for HER2-positive breast cancer.nnnMETHODSnRandomized trials that compared different anti-HER2 regimens in the neoadjuvant setting were included. The odds ratio (OR) for pathological complete response (pCR), treatment completion, and safety was utilized for pooling effect sizes. Network meta-analysis using a Bayesian statistical model was performed to combine the direct and indirect evidence of neoadjuvant therapy for HER2-positive breast cancer. All statistical tests were two-sided.nnnRESULTSnA database search identified 1047 articles, with 10 studies meeting the eligibility criteria. A total of 2247 patients in seven different treatment arms were assessed. Anti-HER2 agents evaluated included trastuzumab (tzmb), lapatinib (lpnb), and pertuzumab (pzmb). Network meta-analysis showed no statistically significant difference between dual targeting treatment arms; however, lpnb reduced treatment completion due to adverse events. Patients in dual targeting arms had statistically significantly more pCR than those in other treatment arms (chemotherapy [CT] + tzmb + pzmb vs CT + tzmb, OR = 2.29, 95% credibility interval = 1.02 to 5.02, P = .02). The surface under the cumulative ranking probability curve indicated that CT + tzmb + pzmb had the highest probability of being the best treatment arm in terms of pCR.nnnCONCLUSIONSnThis study indicates that combining two anti-HER2 agents with CT is the most effective treatment modality in the neoadjuvant setting for HER2-positive breast cancer.

HOXB9 Expression Promoting Tumor Cell Proliferation and Angiogenesis Is Associated with Clinical Outcomes in Breast Cancer Patients

BackgroundStudies have suggested that HOXB9 expression in breast cancer cells promotes cellular invasiveness, metastatic ability, and tumor neovascularization in the surrounding tissue in in vitro and in vivo assays. These findings imply that HOXB9 overexpression may alter tumor-specific cell fates and the tumor stromal microenvironment, contributing to breast cancer progression. The objective of this study was to analyze whether these results could be applied to clinical practice.MethodsA total of 141 consecutive, invasive ductal carcinoma patients who underwent surgical treatment were examined. Immunohistochemical staining was performed to evaluate the expression of HOXB9, Ki-67, CD31, and CD34, and the association of tumor proliferation and angiogenesis with HOXB9 expression was analyzed.ResultsOf the 141 tumor specimens immunostained for HOXB9, 69 (48.9%) stained positive. Larger primary tumor size, hormone receptor negativity, HER2 positivity, higher nuclear grade, and number of pathologic nodal metastases were significant variables associated with HOXB9 expression. Notably, 12 (92.3%) of 13 triple-negative breast cancer cases showed HOXB9 expression. Disease-free survival and overall survival were significantly different between the HOXB9-positive and HOXB9-negative groups (hazard ratio 20.714, Pxa0=xa00.001; and hazard ratio 9.206, Pxa0=xa00.003, respectively). Multivariate analysis indicated that HOXB9 expression was the only independent prognostic factor for disease-free survival (hazard ratio 15.532, Pxa0=xa00.009). HOXB9-positive tumors showed a significant increase in the number of vasculature and the Ki-67 ratio compared with HOXB9-negative tumors.ConclusionsHOXB9 expression, which promotes tumor proliferation and angiogenesis, is a significant prognostic factor in breast cancer.

Historical review of lymphatic mapping in gastrointestinal malignancies.

The advent of sentinel lymph node mapping (SLNM) has had a profound impact on the surgical management of breast cancer and melanoma over the past decade. However, SLNM in gastrointestinal malignancies is still in its infancy. The role of SLNM in gastrointestinal malignancies is to increase staging accuracy and to reduce the understaging associated with standard surgical and pathological techniques. Numerous authors have described the successful use of SLNM in colon, rectal, gastric, esophageal, and anal canal malignancies, with a high degree of accuracy and upstaging by detailed pathological analysis of the sentinel nodes. Over the past 2 years, research and publications related to gastrointestinal lymphatic mapping have dramatically increased worldwide.

Direct inhibition of the transforming growth factor‐β pathway by protein‐bound polysaccharide through inactivation of Smad2 signaling

Transforming growth factor‐β (TGF‐β) is involved in the regulation of cell proliferation, differentiation, and apoptosis and is associated with epithelial–mesenchymal transition (EMT). Inhibition of the TGF‐β pathway is an attractive strategy for the treatment of cancer. We recently screened for novel TGF‐β inhibitors among commercially available drugs and identified protein‐bound polysaccharide (PSK) as a strong inhibitor of the TGF‐β‐induced reporter activity of 3TP‐lux, a TGF‐β1‐responsive luciferase reporter. Protein‐bound polysaccharide is used as a non‐specific immunostimulant for the treatment of gastric and colorectal cancers in Japan. The anticancer activity of this agent may involve direct regulation of growth factor production and enzyme activity in tumors in addition to its immunomodulatory effect. Although several clinical studies have shown the beneficial therapeutic effects of PSK on various types of tumors, its mechanism of action is not clear. In the present study, Western blot analysis showed that PSK suppressed the phosphorylation and nuclear localization of the Smad2 protein, thereby suggesting that PSK inhibits the Smad and MAPK pathways. Quantitative PCR analysis showed that PSK decreased the expression of several TGF‐β pathway target genes. E‐cadherin and vimentin immunohistochemistry showed that PSK suppressed TGF‐β1‐induced EMT, and FACS analysis showed that PSK inhibited the EMT‐mediated generation of CD44+/CD24− cells. These data provide new insights into the mechanisms mediating the TGF‐β‐inhibiting activity of PSK and suggest that PSK can effectively treat diseases associated with TGF‐β signaling. (Cancer Sci 2012; 103: 317–324)

Loss of p16INK4a expression is associated with vascular endothelial growth factor expression in squamous cell carcinoma of the esophagus.

Vascular endothelial growth factor (VEGF) expression has been suggested to correlate with intratumoral microvessel density, tumor advancement and prognosis in esophageal squamous cell carcinoma (ESCC). Previous studies have showed that disruption of cell cycle regulator p16 is related to oncogenesis and tumor progression in ESCC. We hypothesized that VEGF expression in ESCC is reflected by abnormalities in the p16INK4a gene. To clarify the regulatory role of p16INK4a in VEGF expression in vitro, we transferred the p16INK4a gene into a p16INK4a‐deleted ESCC cell line and observed changes in VEGF expression. Furthermore, we immunohistochemically assessed the expression of the cell cycle regulators (p16, p53 and RB) and VEGF in 90 surgically resected specimens of ESCC. Introduction of p16INK4a cDNA by the p16 expression vector significantly suppressed cell proliferation in the p16INK4a‐deleted cell line TE8 (p < 0.0001). VEGF secretion by TE8 cells transfected with the p16INK4a vector was significantly suppressed as compared to non‐transfected TE8 cells (p < 0.0001) and TE8 cells transfected with a control vector (p = 0.0015). The immunohistochemical studies of ESCC primary tumor specimens showed that loss of p16 expression was significantly correlated with VEGF‐positive expression (p = 0.0004). The cumulative postoperative survival rate in the group with p16‐positive and VEGF‐negative expression was significantly higher than in the other groups. Neither p53 nor RB expression had any impact on outcome. Aberrant p53 expression tended to be associated with VEGF expression, but the trend did not reach statistical significance. Our study demonstrated that VEGF expression was correlated with p16 expression in ESCC. Our results suggest that p16 may have a regulatory role in VEGF expression in ESCC.