Hideaki Mabuchi

Prognostic value of tumor-infiltrating dendritic cells expressing CD83 in human breast carcinomas

DCs are the most potent antigen‐presenting cells that play a major role in initiating the antitumor immune response. Although the clinical significance of TIDCs has been investigated in a variety of human cancers, few studies have focused on the in situ maturation status of DCs. We have analyzed the maturation‐specific significance of TIDCs in the prognosis of patients with breast carcinoma. We evaluated 130 breast carcinomas for the presence of TIDCs using immunohistochemistry with an anti‐CD1a antibody for immature DCs and an anti‐CD83 antibody for mature DCs. Intratumoral expression of immunosuppressive cytokines was also examined. All samples contained CD1a+ TIDCs, and 82 (63.1%) samples contained CD83+ TIDCs. The number of CD83+ TIDCs was inversely correlated with lymph node metastasis and with tissue expression of VEGF and TGF‐β, whereas the number of CD1a+ TIDCs was not. Kaplan‐Meier analysis (log rank statistics) revealed a significant association of increasing number of CD83+ TIDCs with longer relapse‐free (p = 0.002) and overall (p < 0.001) survival. Furthermore, among patients with lymph node metastasis, the survival rate of those with larger numbers of CD83+ TIDCs was significantly better than that of patients with fewer CD83+ TIDCs. Multivariate analysis revealed that CD83+ TIDCs had independent prognostic relevance in breast carcinomas. The infiltration of tumors by mature DCs expressing CD83 may be of great importance in initiating the primary antitumor immune response and is confirmed as an independent, immunologic prognostic parameter for survival in patients with breast cancer.

Proteomics-based approach identifying autoantibody against peroxiredoxin VI as a novel serum marker in esophageal squamous cell carcinoma

Purpose: Detection of novel tumor-related antigens and autoantibodies will aid in diagnosis of early-stage cancer and in development of more effective immunotherapies. The purpose of this study was to identify novel tumor antigens in an esophageal squamous cell carcinoma (ESCC) cell line (TE-2) and related autoantibodies in sera from patients with ESCC using a proteomics-based approach. Experimental Design: TE-2 proteins were separated by two-dimensional PAGE, followed by Western blot analysis in which sera of patients with ESCC, healthy controls, and patients with other cancers were tested for primary antibodies. Positive spots were excised from silver-stained gels and analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS). Results: Sera from patients with ESCC yielded multiple spots, one of which was identified as peroxiredoxin (Prx) VI by MALDI-TOF/TOF MS. Western blot analysis against recombinant Prx VI showed reactivity in sera from 15 of 30 (50%) patients with ESCC and 2 of 30 (6.6%) healthy individuals. Autoantibody against Prx VI was found in sera from 1 of 30 (3.3%) patients with other types of cancer (colon cancer). Conclusion: We have identified for the first time an autoantibody against Prx VI in ESCC patients. The proteomic approach implemented here offers a powerful tool for identifying novel serum markers that may display clinical usefulness against cancer.

Impact of the expression of cyclin-dependent kinase inhibitor p27Kip1 and apoptosis in tumor cells on the overall survival of patients with non–Early stage gastric carcinoma

The expression of p27Kip1 and apoptosis have been implicated in tumor aggressiveness and proved to be prognostic predictors for several human malignancies. In this study, the authors sought to investigate the expression of p27Kip1 and apoptosis and their potential significance in determining the prognosis of patients with non–early stage gastric carcinoma.

Proteomics-based identification of autoantibody against heat shock protein 70 as a diagnostic marker in esophageal squamous cell carcinoma

Detection of novel tumor-related antigens and autoantibodies in cancer patients is expected to facilitate the diagnosis of early-stage malignant tumor and establish effective new immunotherapies. The purpose of this study was to identify novel tumor antigens in an esophageal squamous cell carcinoma (ESCC) cell line (TE-2) and related autoantibodies in sera from patients with ESCC using a proteomics-based approach. TE-2 proteins were separated by two-dimensional polyacrylamide gel electrophoresis, followed by Western blot analysis in which sera from patients with ESCC, healthy controls and patients with other cancers were tested for primary antibodies. Positive spots were excised from silver-stained gels and analyzed by matrix-assisted laser disorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF-MS). Sera from patients with ESCC yielded multiple spots, one of which was identified as heat shock protein 70 (Hsp70) by MALDI-TOF/TOF-MS. Concentrations of serum Hsp70 autoantibody were significantly higher for patients with ESCC (mean, 0.412+/-0.096 mg/ml) than for patients with gastric (0.236+/-0.112 mg/ml, P<0.001) or colon cancer (0.231+/-0.120 mg/ml, P<0.001) or healthy individuals (0.207+/-0.055 mg/ml, P<0.001) by enzyme-linked immunosorbent assay. We have identified an autoantibody against Hsp70 in ESCC patients. The proteomic approach implemented herein offers a powerful tool for identifying novel serum markers that may display clinical utility against cancer.

Preoperative diagnosis of lymph node metastases in gastric cancer by magnetic resonance imaging with ferumoxtran-10.

BackgroundKnowledge regarding the presence and location of lymph node metastasis in gastric cancer is essential in deciding on the operative approach. Lymph node metastases have been diagnosed with imaging tests such as computed tomography (CT) and ultrasonography (US); however, the accuracy of such diagnoses, based on size and shape criteria, has not been adequate. Ferumoxtran-10 (Combidex; Advanced Magnetics) is a lymphotropic contrast agent for magnetic resonance imaging (MRI) whose efficacy for the detection of metastatic lymph nodes in various cancers has been reported by several investigators; however, its efficacy for this purpose has not been reported for gastric cancer. We investigated the efficacy of ferumoxtran-10-enhanced MRI for the diagnosis of metastases to lymph nodes in gastric cancer.MethodsSeventeen consecutive patients who were diagnosed with a nonearly stage of gastric cancer were enrolled in the study. All the patients were examined by MRI (Signa Horizon 1.5 T; GE Medical; T2*-weighted images) before and 24 h after the intravenous administration of ultrasmall particles of superparamagnetic iron oxide — ferumoxtran-10 (2.6 mg Fe/kg of body weight) — and the presence or absence of metastasis was determined from the enhancement patterns. The imaging results were compared with the corresponding histopathological findings following surgery.ResultsOf 781 lymph nodes dissected during surgery, the imaging results of 194 nodes could be correlated with their histopathological findings. Fifty-nine lymph nodes from 11 patients had histopathological metastases. In nonaffected normal lymph nodes, we observed dark signal intensity on MRI caused by the diffuse uptake of the contrast medium by macrophages resident in the lymph nodes, which phagocytose the iron oxide particles of ferumoxtran-10. The number of phagocytic macrophages was decreased in metastatic lymph nodes, and they showed various patterns of decreased uptake of ferumoxtran-10. Three enhancement patterns were observed in lymph nodes: (A) lymph nodes with overall dark signal intensity due to the diffuse uptake of ferumoxtran-10; (B) lymph nodes with partial high signal intensity due to partial uptake; and (C) no blackening of lymph nodes due to no uptake of ferumoxtran-10. Patterns (B) and (C) were defined as metastatic. The sensitivity, specificity, positive predictive value, negative predictive value, and overall predictive accuracy of postcontrast MRI were 100% (59/59), 92.6% (125/135), 85.5% (59/69), 100% (125/125), and 94.8% (184/194), respectively. These parameters for predictive accuracy were much superior to these parameters previously evaluated by CT or US. Nodes in the retroperitoneal and paraaortic regions were more readily identified and diagnosed on the MR images than those in the perigastric region.ConclusionThe present study confirmed that ferumoxtran-10-enhanced MRI is useful in the diagnosis of metastatic lymph nodes and that the use of this modality will be helpful in treatment decision-making for gastric cancer patients.

Evaluation of lymph node metastases in gastric cancer using magnetic resonance imaging with ultrasmall superparamagnetic iron oxide (USPIO): diagnostic performance in post-contrast images using new diagnostic criteria

BackgroundWe assessed the value of magnetic resonance imaging (MRI), using ultrasmall superparamagnetic iron oxide (USPIO) with new diagnostic criteria, in the evaluation of regional lymph node metastases in gastric cancer.MethodsThirty-one patients with gastric cancer were enrolled. 1000 lymph nodes were dissected during surgery, and of these, 519 nodes (51.9 %) were identified by currently used MRI imaging analysis. We evaluated lymph nodes on USPIO-post-contrast T2*-weighted images using the following two criteria: (1) we diagnosed the nodes on T2*-weighted images according to conventional criteria, where a node having an overall low signal intensity (pattern A) was nonmetastatic, while a node having partial (pattern B) or overall (pattern C) high signal intensity was metastatic; (2) we subdivided pattern B nodes on T1-weighted images using the new criteria, in which a node for which the high-intensity area on T2*-weighted images was not defined as adipose tissue on T1-weighted images (pattern B1) was metastatic, while a node for which the high-intensity area was defined as adipose tissue (pattern B2) was nonmetastatic.Results(1) The results using the conventional criteria were 96.2% sensitivity, 92.5% specificity, 76.3% positive predictive value (PPV), 99.0% negative predictive value (NPV), and 93.3% accuracy. (2) The results using the new criteria were 96.2% sensitivity, 98.3% specificity, 90.1% PPV, 99.0% NPV, and 97.1% accuracy.ConclusionThe assessment of lymph node metastases from USPIO-post-contrast MRI alone using the new criteria was useful in the diagnosis of regional lymph node metastases in gastric cancer.

Proliferating cell nuclear antigen expression in the gallbladder with pancreaticobiliary maljunction

Background and Objective: To clarify the histogenesis of cancer of the gallbladder of the patients with pancreaticobiliary maljunction (PBMJ), the proliferating cell activity of the epithelium of gallbladder was examined.

Laparoscopic approach for early gastric cancer within a paraesophageal hiatal hernia

We present a case of early gastric cancer located in gastric volvulus associated with paraesophageal hiatal hernia. Two lesions of EGC were diagnosed in the distal third of the stomach, most of which had herniated into the left chest through a large hiatal defect in an organoaxial fashion. Routinely, laparoscopic-assisted distal gastrectomy (LADG) is our preferred approach for EGC, and the presence of hiatal hernia in this case did not alter our approach. Laparoscopic repair of hiatal hernia was performed successfully followed by LADG. A review of the literature supports a minimally invasive approach for both procedures and shows it to be safe, effective, and technically feasible. Further, LADG is shown to be oncologically adequate in terms of tumor margins and lymph node dissection, but its relevance to long-term disease-free survival still needs to be studied in well-designed prospective trials.

Clinical Characteristics and Immunohistochemical Examination of Gastric Adenosquamous Carcinoma. Expression of Proliferating Cell Nuclear Antigen(PCNA), Apoptotic Cell, p53, CD44 and Intratumoral Microvessel Density(CD34).

胃腺扁平上皮癌 (以下, 本症) の特徴を検索する目的で, 本症を対象として一般型進行胃癌症例 (以下, 一般型) と比較検討した. まず両者を臨床的に比較し, PCNA, Apoptotic cell, p53, CD44, CD34の発現状態を免疫組織化学的に検討した. 臨床的に本症では肝転移率が高く, Stageの高い症例の多いことが特徴であり, その予後は一般型に比べて有意に不良であった. 本症のPCNA陽性細胞率は一般型に比べて有意に高値であり, Apoptotic Indexは一般型より有意に低率であった. p53, CD44発現陽性率は本症ではいずれも一般型に比べて有意に高率であり, 発現陽性例では両癌成分ともに同等に発現していた. さらに, 腫瘍内血管密度の検索では, 本症は一般型に比べて有意に高値であった. 今回の検討から, 本症は増殖活性が高く, p53などの遺伝子異常が蓄積され, アポトーシス活性が低く, 進展過程で豊富な新生血管が生じて癌細胞が転移しやすい状況を形成している可能性が示唆された.

A Case of Peutz-Jeghers Syndrome Associated with Advanced Jejunal Cancer.

我々は進行空腸癌を合併したPeutz-Jeghers症候群 (以下, P-J症) の1例を経験したので報告する. 症例は43歳, 男性のP-J症患者である. 腸閉塞症にて近医より当院を紹介された. 消化管精査の結果, 胃, 小腸および大腸に多発性のポリープを認め, 腸閉塞症状が反復するため外科的治療を行った. 開腹の結果, 腹膜播種を伴う全周性の空腸癌を認め, 組織学的診断は粘液癌であった. 本例は高度進行癌であったため, どのような経路を経て癌が発生したか推察できなかった. P-J症のポリープの癌化を示唆する報告が増えてきた現在, その癌化の機序は解明されるべき重要な課題であると考えられ, P-J症の診断確定時より癌の合併も念頭においた厳重な経過観察を行う必要があると思われた.