[Show abstract][Hide abstract] ABSTRACT: 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).
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.
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.
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.
The American Journal of Gastroenterology 10/2004; 99(9):1667-74. DOI:10.1111/j.1572-0241.2004.30733.x · 10.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thymidine phosphorylase (TP), which has been shown to be identical to platelet-derived endothelial cell growth factor, is expressed in tumor-associated macrophages (TAMs) as well as cancer cells. The aim of this study was to clarify the differences or relationships of TP expression in TAMs and cancer cells in esophageal squamous cell carcinoma (SCC). Tissues samples were taken from 56 patients with esophageal SCC after curative surgery. The expression of TP in TAMs or SCC cells was examined using a monoclonal antibody to TP (clone 654-1). Microvessels in SCC that stained positively for Factor VIII-related antigen were counted (microvessel density, MVD). Macrophages in SCC that stained positively for CD68 antigen were counted (monocytic count). Ki-67 antigen was immunostained with MIB-1, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling was performed, and Ki-67 labeling index (LI) and apoptotic index were calculated. The expression of TP in stromal cells and cancer cells was observed in 43 (76.8%) and 33 patients (58.9%), respectively. There were significant correlations between TP expression in stromal cells (TAMs) as well as in cancer cells and venous invasion, distant metastasis, or MVD. There was a correlation between TP expression in cancer cells and lymph node metastasis, and there were correlations between TP expression in TAMs and monocytic count or Ki-67 LI; however, there was no correlation between TP expression in TAMs and lymph node metastasis. On the other hand, in SCCs with TP expression in both TAMs and cancer cells, higher frequencies of venous invasion and distant metastasis, higher MVD and lower apoptotic index were observed than in other SCCs. The 5-year survival rate in patients with TP expression in both TAMs and cancer cells was poorer than that in patients with TP expression in neither TAMs and cancer cell. In conclusion, these results suggest that co-expression of TP in TAMs and cancer cells is strongly associated with angiogenic promotion and distant metastasis. However, other effects of TP, such as promotion of tumor growth and lymph node metastasis, may be different depending on whether these are expressed in TAMs or cancer cells in esophageal SCCs. Patients with coexpression of TP in TAMs and cancer cells may be associated with a poor prognosis.
Diseases of the Esophagus 02/2002; 15(1):67-73. DOI:10.1046/j.1442-2050.2002.00223.x · 1.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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).
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.
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.
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.
The American Journal of Gastroenterology 07/2001; 96(6):1733-40. DOI:10.1111/j.1572-0241.2001.03866.x · 10.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
In 62 patients with a reconstructed gastric tube, after esophagectomy for esophageal cancer, esophagogastroduodenoscopy was performed. Ulcers of the gastric tube were detected in 12 patients: six with postoperative Rx and six without Rx. The 12 patients with gastric tube ulcers (GU-group) were reviewed and compared to the remaining 50 patients without ulcers of the gastric tube (Control-group). Clinicopathologic features of gastric tube ulcers were compared between the patients with and without Rx.
There was no difference in any parameter between the patients of the GU- and Control-groups. Comparing the patients of the GU-group with and without Rx, the ulcers of the gastric tube in the patients without Rx were frequently located in the lower part of the gastric tube (P = 0.067), detected in a later period after surgery (P = 0.055), associated with cervical esophagitis (P = 0.03), and less associated with gastritis (P = 0.03). In three patients of the GU-group without Rx, Helicobacter pylori was detected in the gastric tube. Two of the three patients had a history of peptic ulcers before surgery, and had recurrence of the gastric tube ulcers.
Gastric tube ulcers without postoperative Rx may have different characteristics compared to those induced by Rx.
Journal of Gastroenterology and Hepatology 03/2001; 16(2):137-41. DOI:10.1046/j.1440-1746.2001.02415.x · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
The Journal of Heart and Lung Transplantation 01/2001; 19(12):1193-8. DOI:10.1016/S1053-2498(00)00188-1 · 6.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report a case of branchial cleft-like cysts (intrathyroidal lymphoepithelial cysts) associated with Hashimoto's thyroiditis. Palpation did not detect any nodules. Multiple cystic lesions were detected in the lateral side of the thyroid bilateral lobes by imagings of an I-123 scintigram, Tl-201 scintigram, sonography, and computerized tomography. Sonography displayed multiple cysts with strong echogenic spots in the cystic fluid. Repeated fine needle aspiration biopsies of the cysts consistently revealed only normal lymphocytes. Although these lesions could not be given diagnosis, subtotal thyroidectomy leaving the intact isthmus was performed. Microscopic findings revealed multiple branchial cleft-like cysts lined by flattened epithelial cells. Surrounding the epithelial lining were dense lymphoid follicles with large, reactive germinal centers. The remaining thyroid parenchyma showed Hashimoto's thyroiditis. Multiple branchial cleft-like cysts should be considered when sonographic examination reveals multiple cysts in the lateral side of the bilateral lobes, and fine needle aspiration biopsy displays only normal lymphocytes. To our knowledge, this is the first case of branchial cleft-like cysts associated with Hashimoto's thyroiditis reported in Japan.
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis of esophageal basaloid squamous carcinoma (BSC) was studied immunohistochemically and compared with that of squamous cell carcinoma (SCC). In tissues taken from six patients with esophageal BSC and 35 with esophageal SCC, angiogenesis was evaluated by measuring microvessel density (MVD), defined as the microvessel count determined using factor VIII-related antigen immunostaining, and by measuring immunoreactivity of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (dThdPase). Three of the six patients with BSC had distant metastases. There was no difference of MVD between BSC and SCC (22.0 +/- 4.6 vs. 27.6 +/- 9.4). VEGF expression tended to be more frequently observed in BSC than in SCC (100% vs. 60.0%; p = 0.066). Strong expression of VEGF was detected in three BSC with distant metastases; however, there was no difference in the rate of strong VEGF expression between BSC and SCC. The MVD in the cases of BSC with strong VEGF expression, i.e. in the cases with distant metastases, was higher than that in the cases of BSC with weak VEGF expression (p=0.049). There was no difference in dThdPase expression of the cancer cells between BSC and SCC (50.0% vs. 54.3%), whereas the infiltrating stromal cells of all the BSC expressed dThdPase. Strong dThdPase expression in the cancer cells or in the infiltrating stromal cells was observed in two and three BSC, respectively. However, there were no differences in the rate of cancer cells or stromal cells with strong dThdPase expression between BSC and SCC. In one BSC with high MVD and distant metastases, VEGF and dThdPase were both strongly expressed. The vascularity of esophageal BSC was not different from that of SCC. VEGF may participate in angiogenesis of esophageal BSC and may influence the rate of metastasis in esophageal BSC patients. dThdPase may play a partial rule in angiogenesis and metastasis in some cases of BSC.
Diseases of the Esophagus 02/2000; 13(2):142-7. DOI:10.1046/j.1442-2050.2000.00102.x · 1.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
Key Wordsreoperation–local recurrence–rectal cancer–lateral lymph node
Surgery Today 10/1999; 29(10):999-1003. DOI:10.1007/s005950050635 · 1.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Alpha-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.
Tissue 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.
The 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.
These 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.
The American Journal of Gastroenterology 06/1999; 94(6):1658-63. DOI:10.1111/j.1572-0241.1999.01158.x · 10.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. The aim of this study was to clarify the significance of VEGF expression in esophageal squamous cell carcinoma (SCC).
Tissues samples were taken from 52 patients with esophageal SCC after surgery. VEGF expression in these SCCs was examined immunohistochemically. Microvessels in the tumor stained for Factor VIII-related antigen were counted. Ki-67 antigen as a proliferative marker was immunostained with MIB-1, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling was performed for the evaluation of apoptosis. Ki-67 labeling index (LI) and apoptotic index were then calculated.
VEGF expression was observed in 30 of the patients (57.7%). The microvessel count was significantly higher (p = 0.007), and the apoptotic index was significantly lower (p < 0.0001) in the SCC with VEGF expression than in the SCC without it, but no significant difference was observed in the Ki-67 LI between these groups. There was an inverse correlation between the microvessel count and the apoptotic index (p = 0.007). In the clinicopathologic factors, histologic venous invasion of cancer cells (p = 0.039) and lymph node metastasis (p = 0.049) were significantly correlated with VEGF expression. The survival rate after curative surgery was better in the patients without VEGF expression (p < 0.05), and distant organ metastasis after surgery was frequently observed in the patients with VEGF expression (p = 0.023).
These results suggest that VEGF expression is associated with angiogenesis in esophageal SCC, and may be a prognostic factor in patients with esophageal SCC. Furthermore, apoptosis may be influenced by angiogenesis in esophageal SCC.
[Show abstract][Hide abstract] ABSTRACT: We report on a patient with small cell carcinoma of the esophagus treated with effective combination chemotherapy followed by surgical resection. A 69 year-old male had an ulcerated tumor in the middle part of the esophagus, which was microscopically diagnosed as small cell carcinoma of the esophagus. After combination chemotherapy, endoscopy showed that the esophageal tumor had changed into a shallow ulcer. No cancer cell was found in the biopsy specimen of the ulcer. A subtotal esophagectomy with regional lymph node dissection was performed. Histological examination showed that a few cancer cells remained in a microvessel of the submucosal layer in the removed esophagus and no cancerous lesion was found in regional lymph nodes. The patient was well and was able to remain at home. However, he eventually died 21 months after first detection of the carcinoma due to progression of multiple lung and mediastinal lymph node metastases. After complete or partial remission is achieved by the combination chemotherapy, surgical resection may be recommended as the second therapy that occasionally produces long-term remission and possibly long-term survival for patients with small cell carcinoma of the esophagus, such as the present case.
[Show abstract][Hide abstract] ABSTRACT: The levels of cell proliferation, apoptosis and angiogenesis were compared histochemically in gastric cancer and its hepatic metastases.
Tissue samples were taken from 7 patients with gastric cancer associated with synchronous and/or metachronous hepatic metastases. In the 7 gastric cancers and in 4 synchronous and 4 metachronous hepatic metastases, Ki-67 immunostaining was performed to measure the labeling index (Ki-67 LI). Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling was performed to measure the apoptotic index, and immunostaining for factor VIII-related antigen was performed to measure the microvessel density.
The Ki-67 LI was higher in the gastric cancer and the metachronous hepatic metastasis than in the synchronous hepatic metastasis (primary lesions vs. synchronous foci vs. metachronous foci: 47.1% vs. 39.3% vs. 48.0%; P < 0.05). The apoptotic index was lower in the gastric cancer and the metachronous hepatic metastasis than in the synchronous hepatic metastasis (3.50% vs. 5.01% vs. 2.64%; P < 0.05). The microvessel density was higher in the gastric cancer and the metachronous hepatic metastasis than in the synchronous hepatic metastasis (36.0 vs. 22.2 vs. 34.2; P < 0.05).
The present results suggest that tumor growth as indicated by cell proliferation, apoptosis and angiogenesis is less vigorous in synchronous hepatic metastasis than in primary lesion and/or metachronous hepatic metastasis.