Akihito Nishio

Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus

OBJECTIVES:Macrophage chemoattractant protein-1 (MCP-1) is a chemokine-inducing infiltration of macrophages, which can play several roles in tumor growth and metastasis. We have attempted to clarify the relationship between MCP-1 expression and macrophage infiltration in esophageal squamous cell carcinoma (SCC).METHODS:Paraffin-embedded sections of tissue samples taken from 56 patients with esophageal SCC after curative surgery were immunohistochemically stained for MCP-1, CC chemokine receptor 2 (CCR-2), and thymidine phosphorylase (TP). Macrophage recruitment in SCC was evaluated by monocytic count based on CD68 immunostaining. Microvessels immunostained for Factor VIII-related antigen were counted in SCC, and microvessel density (MVD) was determined. Ki-67 labeling index was calculated based on Ki-67 immunostaining, and an apoptotic index was calculated based on the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling.RESULTS:MCP-1 was expressed in cancer cells of 31 SCC (55.4%) and in stromal cells mainly identified as macrophages of 16 SCC (28.6%). CCR-2 was expressed in stromal cells of all SCC and in vascular endothelial cells of 15 SCC (26.8%). There was a significant correlation between the expression of MCP-1 in cancer cells and of CCR-2 in stromal cells. TP was expressed in stromal cells in 76.7% of the SCC. Monocytic count, MVD, and Ki-67 LI in SCC with MCP-1 expression in cancer cells were higher than that without, and apoptotic index in SCC with MCP-1 expression in cancer cells were lower than that without. Furthermore, the monocytic count was positively correlated with MVD, while it was inversely correlated with apoptotic index. Clinicopathologically, MCP-1 expression in cancer cells was correlated with venous invasion, distant metastasis, and lymph node metastasis. Monocytic count in SCC with venous invasion, distant metastasis, or lymph node metastasis was higher than that without them. Five-year survival rate in the patients with high monocytic count or MCP-1 expression was worse than that with a low monocytic count or without MCP-1 expression.CONCLUSIONS:These results suggest that MCP-1 expression and macrophage infiltration is associated with angiogenic promotion in esophageal SCC. MCP-1 expression may be interactively associated with macrophage infiltration in esophageal SCC; MCP-1 may play an important role in tumor angiogenesis through production of angiogenic factors, such as TP, by recruited macrophages in esophageal SCC. Furthermore, CCR-2 expression in vascular endothelial cells may participate partially in angiogenesis. Clinicopathologically, esophageal SCC patients with MCP-1 expression have no favorable prognosis.

α-Fetoprotein–producing gastric cancer: histochemical analysis of cell proliferation, apoptosis, and angiogenesis

Objectiveα-Fetoprotein (AFP)-producing gastric cancer has been associated with a poor prognosis. In the present study, the cell proliferation, apoptosis, and angiogenesis of this cancer were studied histochemically to determine its malignant potential.MethodsTissue samples were taken from four patients with AFP-producing gastric cancer and 26 patients with AFP-negative gastric cancer. Cell proliferation was evaluated by Ki-67 immunostaining, and the Ki-67 labeling index (LI) was determined. Apoptosis was studied by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling method, and the apoptotic index was determined. Angiogenesis was evaluated by measuring the microvessel density using factor VIII immunostaining, and immunostainings for vascular endothelial growth factor and thymidine phosphorylase were performed.ResultsThe Ki-67 LI of the AFP-producing gastric cancers was significantly higher than that of the AFP-negative gastric cancers (p < 0.01). The apoptotic index of the AFP-producing gastric cancers was significantly lower than that of the AFP-negative gastric cancers (p < 0.01). The microvessel density of the AFP-producing gastric cancers was significantly higher than that of the AFP-negative gastric cancers (p < 0.01). Vascular endothelial growth factor expression was observed in all four of the AFP-producing gastric cancers, whereas thymidine phosphorylase was not expressed in any of the AFP-producing gastric cancers.ConclusionsThese results suggest that AFP-producing gastric cancers have high malignant potential (high proliferative activity, weak apoptosis, and rich neovascularization) compared with that of AFP-negative gastric cancers. These biological characteristics of AFP-producing gastric cancer reflect the aggressive behavior and the poor prognosis of patients with this type of cancer.

Coexpression of vascular endothelial growth Factor and p53 protein in squamous cell carcinoma of the esophagus

OBJECTIVE:p53 plays a role in tumor angiogenesis, and vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. The aim of the present study was to clarify how expression of p53 protein participates in angiogenesis, and whether the coexpression of VEGF and p53 protein has a significance for angiogenesis and the clinicopathological features in esophageal squamous cell carcinoma (SCC).METHODS:Tissues samples were taken from 60 patients with esophageal SCC after surgery. The expression of VEGF and p53 protein in these SCC was examined immunohistochemically. Microvessel density (MVD) was determined by counting microvessels in tumor sections stained for Factor VIII-related antigen. Ki-67 labeling index (LI) was calculated, based on Ki-67 antigen immunostaining, as a proliferative marker. Apoptotic index (AI) was calculated, based on the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling, to evaluate apoptosis.RESULTS:VEGF expression was observed in 58.3%, and p53 protein expression was observed in 61.7% of the 60 patients. VEGF and p53 protein were significantly coexpressed in 26 (43.4%). Histological venous invasion (p < 0.01) and distant metastasis (p < 0.05) were significantly correlated with p53 protein expression. The two parameters were more frequently observed in the SCC with VEGF/p53 coexpression than in those without the coexpression. The MVD and Ki-67 LI were significantly higher (p < 0.01 and p < 0.001), and the AI was significantly lower (p < 0.001) in the SCC with p53 protein expression than in the SCC without it. The MVD and Ki-67 LI were higher, and the AI was lower in the SCC with VEGF/p53 coexpression than in those without the coexpression. The 5-yr survival rate in patients with the coexpression was poorer than in the other patients.CONCLUSION:These results suggest that mutant p53 expression is associated with angiogenesis and distant metastasis in esophageal SCC, and that the coexpression of p53 and VEGF may play an important role in angiogenesis, and have important clinical significance.

Laparoscopic resection of a retroperitoneal schwannoma.

Although laparoscopic surgery for retroperitoneal diseases has been widely performed, there are few reports of laparoscopic resection for retroperitoneal tumors. We present the case of a 5-cm retroperitoneal tumor compressing the right common iliac vein and inferior vena cava that was successfully resected using a laparoscopic technique. Dissection between the tumor and the large vessels was performed safely using a harmonic scalpel and an ultrasonic surgical aspirator. Histopathology of the resected tumor showed a benign schwannoma. Laparoscopic surgical techniques should be considered for treatment of selected retroperitoneal tumors.

Ulcer in the gastric tube for esophageal replacement: A comparison of 12 esophageal cancer patients with or without postoperative radiotherapy

Background and Aims: Ulcer in the gastric tube for esophageal replacement, which was caused by peptic factors or postoperative radiotherapy (Rx), are occasionally reported. The aim of this study was to clarify the clinicopathologic features of the ulcers in the gastric tube.

Expression of membrane-type 1 matrix metalloproteinase in coronary vessels of allotransplanted primate hearts.

BACKGROUND The mechanisms of intimal thickening in cardiac allograft vasculopathy (CAV) remain controversial after heart transplantation. Matrix metalloproteinase-2 (MMP-2) plays a crucial role in degrading extracellular matrix (ECM) during neointimal formation. Recently, it has been revealed that MMP-2 is activated by membrane-type 1 matrix metalloproteinase (MT1-MMP). This process involves tissue inhibitor of MMP-2 (TIMP-2), forming an MT1-MMP/TIMP-2/pro-MMP-2 complex. In this study, we hypothesize that these components contribute to the pathogenesis of CAV. METHODS Heterotopic cardiac allografting was performed in randomly paired Japanese monkeys with an immunosuppressive regimen of intravenous administration of antihuman CD18 monoclonal antibody. The donor hearts were harvested at Days 22, 28, 40, 41, and 95 posttransplantation. We examined expression of MMP-2, MT1-MMP, and TIMP-2 of graft vessels using immunohistochemistry and protein level by western blot analysis. RESULTS Pathologically, various degrees of neointimal formation were observed. In the allografts harvested at Days 22, 28, 40, and 41, MT1-MMP was expressed in the endothelial cells and smooth muscle cells (SMCs) in media of some arteries without histological change, accompanied by expression of MMP-2 and TIMP-2. In the severely thickened neointima of the allograft harvested at Day 95, MMP-2 and faint MT1-MMP were expressed in SMCs of severely thickened neointima and media; TIMP-2 expression was seen only in noncollagenous tissue of severely thickened neointima. MMP-2 protein was more intensely expressed in the allograft harvested at Day 95 than in the allograft harvest at Day 41, while TIMP-2 protein level was almost same in the 2 samples. CONCLUSION We observed the simultaneous expression of MMP-2, MT1-MMP, and TIMP-2. Thus, ECM degradation triggered by MT1-MMP/TIMP-2/pro-MMP-2 complex could be a novel mechanism of CAV.

RERESECTION FOR LOCAL RECURRENCE OF RECTAL CANCER

Local recurrence is one of the major reasons that rectal cancer surgery is unsuccessful. The aim of this study was to investigate the surgical characteristics of patients undergoing reresection for local recurrence of rectal cancer. A total of nine patients were enrolled in this study, six of whom underwent total pelvic exenteration, one, posterior exenteration, one, abdominoperineal resection with sacral resection, and one, lymph node dissection alone. The mean operative time was 8h 15min, and the mean operative blood loss was 2 325 ml. Although major postoperative complications occurred in four patients (44%), there were no postoperative or hospital deaths. Lateral lymph node metastasis was detected in all four patients whose lateral lymph nodes were dissected or extirpated at the reresection. Two patients survived for more than 5 years without rerecurrence, and the cumulative 5-year survival rate was 26%. The para-aortic lymph nodes were the most common site of first rerecurrence. The results of this study indicate that patients who undergo reresection for local recurrence of rectal cancer are at high risk of developing lateral or para-aortic nodal metastasis. Nevertheless, reresection may be a therapeutic option for the local recurrence of rectal cancer.

Hepatic resection of giant cavernous hemangioma of the liver.

Surgical treatment of giant hemangioma of the liver is still controversial. The aim of this study is to examine the efficacy of hepatic resection for giant hemangioma of the liver. Twenty patients with giant cavernous hemangioma of the liver were treated by hepatic resection. The mean diameter of the hemangiomas was 13.9 cm (range, 6.5-30 cm). The surgical outcome was reviewed retrospectively. Major hepatectomy was performed in 14 patients and minor hepatectomy in 6 patients. Complications occurred in 7 of the 20 patients treated by hepatic resection. At a mean follow-up of 79 months (range, 12-173 months), 18 patients were symptom free whereas 2 patients had died--one died of pneumonia at 2 years and the other died of gastric cancer 6 years after surgery. Mean intraoperative hemorrhage and blood transfusion in all patients was 4,343 mL (range, 270-24,000 mL) and 1,860 mL (range, 0-8,800 mL) respectively. In the seven patients with preoperative high levels of fibrin degradation products (FDP), mean intraoperative hemorrhage and blood transfusion were markedly higher (9,371 mL and 3,714 mL respectively) than in the 13 patients without abnormal FDP (1,603 mL and 900 mL respectively). Preoperative hematologic status returned to normal after operation in all patients. Hepatic resection is a useful treatment for giant cavernous hemangioma of the liver. More careful management to reduce intraoperative hemorrhage is recommended to increase the safety of surgery, particularly in patients with preoperative abnormal FDP.

Three elderly patients with lower esophageal cancer successfully treated by transhiatal esophagectomy assisted by mediastinoscopy.

Mediastinoscopy-assisted transhiatal esophagectomy recently has been applied in patients with intrathoracic esophageal cancer. Elderly patients with esophageal cancer experience several types of complications and often cannot undergo standard transthoracic esophagectomy. In this study, three elderly patients with preoperative complications underwent mediastinoscopy-assisted transhiatal esophagectomy for esophageal cancer located in the lower part of the esophagus. Patient 1 was an 80-year-old man with alcoholic liver cirrhosis. Patient 2 was a 78-year-old man with bronchial asthma. Patient 3 was an 81-year-old-man with diabetes mellitus and an atherosclerotic obstruction of the lower extremities. In these patients, mediastinoscopy-assisted transhiatal esophagectomy concomitant with reconstruction by means of a gastric tube was performed. Lymph node dissections of the middle and lower mediastinum and of the abdomen, including the regions surrounding the left gastric and celiac arteries, were performed. Postoperative complications developed only in patient 1; minor leakage of the esophagogastrostomy and high bilirubinemia were observed. Metastasis was detected in the lymph nodes surrounding the celiac artery in patient 1 and surrounding the left gastric artery in patients 2 and 3. Patient 2 died of pneumonia 18 months later, but the other patients have been well, without recurrence of the cancer after surgery. In conclusion, mediastinoscopy-assisted transhiatal esophagectomy has some benefits for elderly esophageal cancer patients who experience preoperative complications.