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The prognosis of esophageal cancer with distant metastasis is dismal. We report a 70-year-old man with esophageal cancer and multiple lung and lymph node metastases. Complete response was achieved following definitive chemoradiotherapy. Twenty-four months after the initial chemoradiotherapy, local recurrence was detected but there was no evidence of distant metastasis. Therefore, the patient underwent salvage esophagectomy. The surgery was well tolerated without any postoperative complications. The patient is still alive 48 months after the salvage surgery. Our experience suggests that salvage esophagectomy is an important component of multimodal therapy for the recurrence of esophageal cancer.

Background: Neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) is beneficial in the setting of a complete pathological response. Rad51 expression affects both chemo- and radiosensitivity in many cancers; however, its role in ESCC is unclear., Methods: Rad51 expression was investigated by immunohistochemical staining with resected specimens in 89 ESCC patients who underwent surgery without preoperative therapy. The association with Rad51 and clinicopathological factors was assessed. The expression of Rad51 was also investigated in pretreatment biopsy specimens in 39 ESCC patients who underwent surgery after NACRT and compared with the pathological response to NACRT., Results: Lymph node metastasis was more frequently observed in Rad51-positive cases than negative cases (58.5 vs. 30.6%, P = 0.0168) in patients treated with surgery alone. Disease-specific survival was decreased in Rad51-positive cases compared to Rad51-negative cases (5 year survival: 79.6 vs. 59.3%, P = 0.0324). In NACRT patients, completed pathological responses were more frequently observed in Rad51-negative cases than in Rad51-positive cases (68.8 vs. 46.5%, P = 0.0171)., Conclusions: Rad51 expression in ESCC was associated with lymph node metastasis and poor survival. Additionally, Rad51 expression in pretreatment biopsy specimens was a predictive factor for the response to NACRT.

Background: The purpose of this study was to clarify the effect of preoperative chemoradiotherapy (CRT) for esophageal cancer on the postoperative course, and to determine the clinical significance of salvage esophagectomy after definitive CRT., Methods: Based on their preoperative treatment, 477 patients with esophageal cancer were classified into three groups: 253 patients who received surgery alone (Group I), 197 who received planned CRT (30-45 Gy, Group II), and 27 who received a salvage esophagectomy (radiation ≥60 Gy, Group III)., Results: Postoperative complications developed in 25, 40, and 59% of the patients in Groups I, II, and III, respectively, with pulmonary complications developing in 10, 15, and 30%, and anastomotic leakage developing in 13, 23, and 37%, respectively. Mortality rates were 2.4, 2.0, and 7.4%, respectively. Multivariate analysis revealed preoperative therapy to be an independent factor associated with postoperative risks: the odds ratios (ORs) of Groups II and III compared to Group I were 1.8 and 4.0 for pulmonary complications, while they were 1.9 and 2.8, respectively, for anastomotic leakage. No critical complications developed in the 14 patients who received salvage surgery performed with strict surgical indications after 2005. The survival of Group III was not significantly different from that of Groups I and II. Most patients who received an R1/R2 resection after definitive CRT died within 2 years after salvage surgery., Conclusions: Preoperative CRT is associated with postoperative complications especially in patients with R2 resection, while long-term survival can be achieved after R0 resections. Salvage surgery should be considered for carefully selected patients in whom R0 resection can be achieved.

Background: The clinical significance of neoadjuvant chemoradiotherapy (NACRT) for potentially resectable esophageal squamous cell carcinoma (ESCC) is unclear., Patients and Methods: Patients with clinical stage II-III ESCC were classified into an NACRT group (n=76) and surgery alone group (n=92). The prognosis and the incidence of postoperative complications were retrospectively investigated. The pathological response to NACRT and patient prognosis were also analyzed., Results: The 5-year survival rate was 47.7% in the surgery alone group and 56.5% in the NACRT group (p=0.4831). The 5-year survival rates of patients in whom NACRT was markedly effective was clearly better than that of the other patients (ineffective/slightly effective: 36.9%, moderately effective: 53.8%, markedly effective: 100%). The incidence of postoperative complications was 31.5% in the surgery alone group and 40.8% in the NACRT group (p=0.2121)., Conclusion: A pathological complete response to NACRT is critical for improving the survival of patients with clinical stageII-III ESCC.

Purpose: An esophagectomy followed by reconstruction for esophageal cancer is a highly aggressive operation. The purpose of this study was to justify a two-stage operation for high-risk patients with esophageal cancer., Methods: The clinical results of 27 patients who underwent two-stage operation were compared with 118 patients who underwent a simultaneous resection and reconstruction (control subjects). The reasons for the selection of the two-stage operation were underlying general disease in 13 patients (liver dysfunction, n = 6; pulmonary disease, n = 3; poor performance status, n = 2; diabetes and renal failure, n = 1 each) and high-risk operation in 14 other patients (colon interposition, n = 7; salvage operation after definitive chemoradiotherapy, n = 4; and intraoperative events, n = 3). The patients initially underwent an esophagectomy and a cervical esophagostomy. Reconstruction was usually performed 2-3 weeks later., Results: The patients in the two-stage group were older than the control patients (mean 67.8 vs. 61.6 years old). The morbidity rate of the two-stage operation was 29.6%, which was not statistically different than control patients (32.2%). Postoperative complications in the two-stage operation were anastomotic leakage in 5 patients, and pneumonia and wound infection in 1 patient each. No patient experienced in-hospital death. The survival rates were not statistically different between the two groups., Conclusion: A two-stage operation is a safe operation that prevents the occurrence of critical postoperative complications, and it thus may be considered an important treatment strategy for high-risk patients with esophageal cancer.

Esophageal squamous cell carcinoma is often accompanied by intramural metastases, and it has been reported to carry a poor prognosis. Intramural metastasis from gastric cancer to the esophageal wall, however, has rarely been reported. We herein report a rare case of a 46-year-old man with an elevated esophageal lesion, resembling a 0-IIa-type esophageal cancer, which was discovered 13 months after a total gastrectomy performed for gastric cancer. The esophageal tumor, resected by endoscopic mucosal resection (EMR), was an adenocarcinoma with the same histology as the previously resected primary gastric cancer, and it showed massive lymphatic permeation. Soon after the EMR, other similar lesions emerged on the esophageal wall. We therefore considered the esophageal tumor to be a systemic expansion of the primary gastric cancer, and we administered the anticancer drug, S-1. Esophageal intramural metastases from a gastric cancer imply a systemic expansion of the gastric cancer, and portend a poor prognosis.

Background: Abnormal hypermethylation of the CDKN2A (p14ARF and p16INK4a) gene can lead to repression of gene expression and contribute to carcinogenesis and tumor progression., Materials and Methods: In esophageal squamous cell carcinoma (ESCC), the promoter methylation of the p14ARF and p16INK4a gene was investigated in 38 cases by methylation-specific PCR and the expression of each gene in 18 cases was quantified by real-time quantitative reverse transcription-PCR., Results: Aberrant methylation of p14ARF and of p16INK4a was detected in 23 (61%) and 29 (76%) cases, respectively. No relationship was found between clinicopathological variables and p14ARF or p161NK4a promoter methylation. A statistically significant association between p14ARF methylation status and mRNA expression was found (p=0.0441). Regarding p14ARF, a low expression group showed a significantly higher proportion of cases with deep invasion of tumor, lymph node metastasis, and a high TNM stage of disease (p=0.0474, 0.0474, and 0.0441, respectively), and a significantly poor prognosis (p=0.0402). Regarding p161NK4a, no relationship was found among the methylation status, mRNA expression and clinicopathological variables, including survival., Conclusion: Our results suggest that methylation is the predominant mechanism of inactivation of the p14ARF gene in ESCC. The decrease in p14ARF gene expression associated with invasive and metastatic phenotypes may be significant as an indicator of the malignant potential of human ESCC.

Background: The p53 and p21 genes are closely related to sensitivity to chemoradiotherapy., Patients and Methods: The expressions of the p53 and p21 genes were immunohistochemically examined in 32 patients with esophageal cancer, who underwent an esophagectomy after hyperthermochemoradiotherapy (HCRT). The significance of the expression of these genes for the effect of HCRT was evaluated., Results: HCRT was markedly effective (grade 3 response: no residual viable cancer cells) in 12 cases (38%). The incidences of the grade 3 were 67% and 20% in the cases with a positive and negative p21 expression, respectively (p=0.0213). A multivariate analysis revealed the p21 expression to be a significant independent factor associated with the histological effects. None of the 10 patients with p53-positive and p21-negative tumors showed a grade 3 response, while 55% showed grade 3 response in other combination groups (p < 0.05)., Conclusion: The combination of p53 and p21 expressions in biopsy findings can thus predict the histological effectiveness of HCRT.

Background: A radical esophagectomy with extensive lymph node dissection is the mainstay treatment for submucosal esophageal cancer, though definitive chemoradiotherapy (CRT) has also been applied. However, the treatment outcomes have not yet been extensively investigated., Patients and Methods: Forty-nine patients with submucocal esophageal squamous cell carcinoma, 24 and 25 of whom had been treated by a radical esophagectomy with extensive lymph node dissection (Surgery group) and definitive CRT using 5-Fluorouracil and CDDP with concurrent radiation of 60 Gy (CRT group), respectively, formed the study cohort., Results: In the Surgery group, the overall and cause-specific 5-year survival rates were 75.4% and 90.0%, respectively. No operative or hospital deaths had occurred. In the CRT group, a complete response (CR) had been achieved in 22 (88%) patients. The 3- and 5-year overall survival rates were 79.3% and 36.9%, respectively, while the cause-specific 3- and 5-year survival rates were 75.2% and 55. 7%, respectively. No treatment-related deaths had occurred., Conclusion: These data suggest that: (i) a radical esophagectomy with extensive lymph node dissection can be a standard treatment offering excellent survival and (ii) a definitive CRT is a reasonable alternative to surgery, especially for patients with complications.

Inactivation of the p53 tumor suppressor gene is one of the most frequent genetic alterations observed in human esophageal carcinomas. In patients with esophageal carcinoma, one of the significant pathological features of the tumor is the presence of multiple lesions within the esophagus. However, the molecular mechanisms involved in the occurrence of multiple lesions have remained elusive. To characterize p53 alterations in multiple esophageal carcinomas and to study their roles in carcinogenesis, we performed p53 immunohistochemical and p53 mutation analyses using laser capture microdissection on surgically resected human esophageal carcinomas from 11 patients: 9 patients with multiple esophageal carcinomas, 1 with an intramural metastasis lesion within the esophagus and 1 with an intraepithelial carcinoma lesion contiguous to the main lesion. In each of the patients with multiple esophageal carcinomas, we examined samples from 1 main lesion and 1 representative concomitant lesion. Molecular analyses of samples from fresh-frozen normal tissues and tumor tissues of the main lesion (whole tumor) were also performed by the same method. p53 protein accumulation was observed in 16 (72.7%) of 22 lesions from the 11 cases. No p53 mutation was found in normal esophageal tissues. In the 9 cases of multiple esophageal carcinomas, point mutations were detected in the whole tumor in 1 (11.1%) case, in the microdissected tumor samples of main lesions in 3 (33.3%) cases and in the microdissected tumor samples of concomitant lesions in 3 (33.3%) cases. For the microdissected tumor samples, there was a 54.5% (12/22) concordance rate between the results of immunostaining and molecular analysis. In the 8 cases of whole tumors in which a p53 mutation was not observed, 2 cases revealed p53 mutation in the microdissected tumor samples of the main lesion. All 6 cases of multiple esophageal carcinomas that showed a p53 mutation in the microdissected tumor sample had a discordant p53 mutational status between the main and concomitant lesions. In contrast, both the intramural metastasis lesion and the intraepithelial carcinoma contiguous to the main lesion showed p53 mutational patterns identical to those of the main lesions. In conclusion, the analysis of microdissected DNA by laser capture microdissection is useful for characterizing the heterogeneity of the p53 gene mutation in multiple carcinoma lesions that cannot be accurately analyzed in whole esophageal tumor DNA. The finding of different p53 gene mutations among multiple esophageal carcinoma lesions suggest further evidence of multicentric or field carcinogenesis of the human esophagus.

Metastasis-associated protein MTA1 and histone deacetylase form a protein complex with histone deacetylase activity that plays an important role in histone deacetylation, alteration of chromatin structure and transcriptional control. The precise role of the MTA1 protein in the malignant progression of human cancers remains unknown, however, especially its overexpression and relationship with histone acetylation/deacetylation in experimental and clinical tumors. The expression levels of MTA1 protein and the acetylation levels of histone H4 were examined in 70 cases of surgically resected esophageal squamous cell carcinomas, using immunohistochemistry. The intensities of immunostaining of MTA1 protein and acetylated histone H4 in carcinoma tissues (Ca) were compared to normal epithelium (N) contained in the same section. Thirty of 70 cases (42.9%) displayed overexpression of MTA1 protein (N < Ca). Cancers overexpressing MTA1 protein invaded deeper into the esophageal wall (p < 0.005) and showed significantly higher degrees of lymph node metastasis (p < 0.01), higher pathological stage, more lymphatic involvement and poorer prognosis (p < 0.05) than the remaining cases. The acetylation levels of histone H4 inversely correlated to the depth of cancer invasion and pathological stage (p < 0.05), and the patients with higher level of histone H4 acetylation had a better prognosis (p < 0.05). Furthermore, immunostaining patterns of MTA1 and acetylated histone H4 were inversely correlated (p < 0.001), demonstrating the relationship of deacetylation of histone H4 in MTA1-overexpressing carcinomas. In conclusion, the data suggest that the overexpression of MTA1 protein and acetylation level of histone H4 protein, both of which are closely related, might be useful predictors of malignant potential of esophageal squamous cell carcinomas. Thus, strategies involving inhibition of MTA1 function as well as inhibition of histone deacetylation could be novel approaches for the treatment of esophageal squamous cell carcinomas., (Copyright 2004 Wiley-Liss, Inc.)

Vascular endothelial growth factor C (VEGF-C), a member of VEGF gene family, is considered to induce both lymph node metastasis and lymphatic involvement in various cancers related to lymphangiogenesis. We examined the relationship between VEGF-C expression and clinicopathological features in 112 Japanese patients with esophageal squamous cell carcinoma (ESCC) who underwent esophagectomy and reconstruction without preoperative treatment. VEGF-C expression was examined using immunohistochemical staining and RT-PCR in surgically resected tissues. Regarding VEGF-C there were positive findings in 44 (39.3%) cases. VEGF-C expression in ESCC significantly correlated with the depth of tumor (p=0.0131), lymph node metastasis (p=0.0211), lymphatic involvement (p<0.0001) and pathological stage (p=0.0164). The prognosis for the VEGF-C positive group was poorer than that for the VEGF-C negative group (p=0.038). Multivariate analysis indicated that VEGF-C expression in ESCC is an independent factor only in cases of lymphatic involvement. VEGF-C expression in ESCC may play a great key role in lymphatic spread and this may be a consideration in terms of deciding the most appropriate treatment.

Solitary splenic metastasis from esophageal cancer is so rare that such an occurrence in our Japanese patient should be reported. In a 58-year-old Japanese man we detected a solitary splenic tumor by abdominal computed tomography done 6 months after he had undergone an esophagectomy. Transarterial embolization of the splenic artery was without effect. A splenectomy was then done and histological examination of the resected specimen revealed squamous cell carcinoma derived from the esophageal carcinoma.

Background: The preoperative immunological condition of patients with malignant tumors should be considered in determining the prognosis., Methods: A lymphoblastic transformation test in which lymphocytes were stimulated with phytohemagglutinin (PHA) was performed for 155 patients with esophageal squamous cell carcinoma (SCC)., Results: Multivariate analysis demonstrated that a lower preoperative PHA response (p = 0.028), as well as the depth of the tumor (p = 0.011), lymph node metastasis (p = 0.0003), lymphatic permeation (p = 0.002), and the incidence of postoperative complication (p = 0.016) were independent factors associated with a poor prognosis for patients with SCC of the esophagus., Conclusions: A suppressed PHA response is an additional significant prognosticator for SCC of the esophagus.

Cyclin A is a protein kinase to act a pivotal role in the mitotic phase of the cell cycle. The purpose of the current study was to elucidate the biological significance of immunohistochemical expression of cyclin A in superficial squamous cell carcinoma (SCC) of the esophagus. Immunohistochemical staining of cyclin A was performed for 45 samples of esophageal superficial SCCs. Clinicopathological features were compared between SCCs with and without cyclin A expression. Twenty-five superficial SCCs (55.6%) had positive expression of cyclin A and the other 20 (44.4%) did not. No significant difference regarding clinicopathological characteristics between esophageal SCCs with and without cyclin A expression. Infiltration of lymphocytes with germinal center cells was observed beneath 17 (68.0%) out of 25 superficial SCCs with cyclin A expression and 15 (75.0%) out of 20 superficial SCCs without cyclin A expression. Although 16 (94.1%) out of 17 superficial SCCs with cyclin A expression were associated with cyclin A expression in germinal center cells in infiltrated lymphoid follicles beneath the tumors, only 2 (13.3%) out of 15 superficial SCCs without cyclin A expression coexisted with cyclin A expression in lymphoid follicles beneath the tumors (P<0.0001). Cyclin A expression in the germinal center cells of the lymphoid follicles beneath the superficial SCCs of the esophagus might be an immunological signal toward the proliferation and progression of the tumors.

Matrix metalloproteinase 7 (MMP-7) may play a key role in the progression of various human malignant tumors. Nuclear beta-catenin enhances the activating expression of MMP-7 genes by binding with the T-cell factor/lymphoid enhancer factor family of transcription factors. We immunohistochemically examined the expression of MMP-7 and beta-catenin to better understand the significance of these factors in the progression of esophageal squamous cell carcinoma. The entire coding region of beta-catenin exon 3 was also analyzed by direct sequencing in all cases. We found that MMP-7 was expressed in 7 (20.6%) of 34 esophageal squamous cell carcinomas. There was a significant relationship between MMP-7 expression and tumor invasion into adjacent structures (P < 0.05). Aberrant nuclear expression of beta-catenin was found in 12 of 34 (35.3%) esophageal cancers and correlated with MMP-7 expression, the statistical difference being (P < 0.05). None of the 34 esophageal cancers examined carried mutations in beta-catenin exon 3. MMP-7 expression correlates with penetrating tumor progression in esophageal cancer. Nuclear translocation of beta-catenin, without mutations in beta-catenin exon 3, is associated with MMP-7 expression.

Hyperthermia has been proved to be intensely cytotoxic to malignant cells when combined with anticancer agents and irradiation. We have applied hyperthermo-chemo-radio-therapy (HCR) using a radiofrequency system with an endotract electrode to the patients with advanced esophageal cancer. In this study, 132 patients with advanced esophageal cancer with invasion to the neighboring structures, who underwent non-curative operation, were analysed. The markedly effective cases was observed in 12.2% in HCR group, while in 2.5% in chemoradiotherapy (CR) group, microscopically. The survival rate of the HCR group was significantly better than that of the CR group (p < 0.05). Pre- and post-operative leukocytopenia caused by preoperative treatment was not found to be a risk factor of postoperative complication. It is important to continue to clarify the factors influencing the effectiveness of preoperative HCR in the future. We hope that HCR will play an even more important role in treatment of esophageal cancer.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme involved in the degradation of 5-FU. DPD activity in peripheral blood mononuclear cells of 30 esophageal cancer patients treated with 5-FU and low-dose CDDP with irradiation was determined at the beginning of each cytostatic cycle, the objective being to determine if DPD activity is related to the occurrence of side-effects and responses to therapy. The DPD activity showed interpatient variability (mean: 325.5 pmol/min/mg protein). 5-FU-related side-effects tended to be registered more frequently in patients with low DPD activity. In particular, nausea occurred in 30.8% of patients in the high DPD activity group but, in 70.6% in those with low DPD activity (p < 0.05). The relationship between the histological response to therapy and DPD activity was nil. We propose that determination of DPD activity prior to initiation of 5-FU-based chemotherapy for patients with esophageal cancer could aid in identifying those at risk for toxicity.

Intraepithelial carcinoma concomitant with the main tumor is a conspicuous feature in squamous cell carcinoma (SCC) of the esophagus. The aim of the current study was to clarify the clinicopathologic features of superficial spreading type SCC of the esophagus. Ninety-seven patients with esophageal squamous cell carcinoma, whose main carcinoma is invading the mucosa or submucosa, were investigated in the current study. The clinicopathologic features were compared between 13 cases demonstrating a superficial spreading type carcinoma in which the spreading size of the tumor was 5 cm or more in length and 84 cases with the size less than 5 cm. Although no significant difference was observed regarding lymphatic invasion, venous invasion, intramural metastasis and lymph node metastasis, the survival rate of patients with superficial spreading type carcinoma was much better than that of patients with ordinary superficial carcinoma of the esophagus. Coexistence of superficial spreading type carcinoma may be correlated with a favorable prognosis of patients with superficial esophageal SCC.

Purpose: Cyclin B1 plays an important role as a mitotic cyclin in the G(2)-M phase transition during the cell cycle. The aim of the present study was to elucidate the biological significance of cyclin B1 expression in squamous cell carcinoma (SCC) of the esophagus., Experimental Design: We analyzed immunohistochemically the expression of cyclin B1 in the tumor specimens from 120 patients with SCC of the esophagus that had been treated with surgical treatment without any preoperative therapies., Results: The positivity rate of cyclin B1 expression was 56.7% (68 of 120). One-, 3-, and 5-year survival rates in esophageal SCCs with cyclin B1 expression were 82.8, 61.6, and 50.7%, respectively, and they were significantly lower than those in esophageal SCCs without cyclin B1 expression (97.8, 85.5, and 78.6%, respectively; P = 0.005). Cyclin B1 expression was found to be an independent prognostic indicator in esophageal SCCs in a multivariate analysis. When immunostaining for cyclin B1 was classified as a nuclear dominant pattern and cytoplasmic dominant pattern, 1-, 3-, and 5-year survival rates in esophageal SCCs with nuclear dominant expression of cyclin B1 were 66.7, 47.9, and 28.7%, respectively, and they were significantly lower than those in esophageal SCCs with cytoplasmic dominant expression (92.5, 70.0, and 66.3%, respectively; P = 0.005). A multivariate analysis demonstrated that the nuclear dominant cyclin B1 expression was an independent prognosticator in patients with esophageal SCCs expressing cyclin B1., Conclusions: Our results demonstrate that cyclin B1 expression, especially nuclear dominant expression, can be significant as a prognostic indicator in esophageal SCCs.

Background: Chemoradiotherapy (CR) and hyperthermochemoradiotherapy (HCR) have been performed on numerous patients with esophageal cancer. These neoadjuvant therapies for esophageal cancer are done widely. The purpose of this study is to demonstrate the recent advances in surgical and oncological treatment., Methods: From 1967 to 2000, 847 patients who underwent an esophagectomy were classified into 4 groups according to the date of operation. Group 1 consisted of 110 patients who underwent an esophagectomy in the first 10-year period (1967-1976), group 2 consisted of 194 patients who had operations from 1977 to 1986, group 3 comprised 400 patients who had operations from 1987 to 1996, and group 4 comprised 143 patients who had operations from 1997 to 2000. From 1967 to 2000, 322 patients with neoadjuvant therapy and esophagectomy were classified into 6 groups according to the kinds of anticancer drugs that were administered. Group A received regimen A, using BLM (5 mg iv) 6 times as the chemotherapeutic drug in the early period (1965-1990); group B received regimen B, using cis-diaminedichloroplatinum (CDDP) (40 mg/m2) 3 times as the chemotherapeutic drug in the second period (1990-1997); and group C received regimen C, using CDDP (40 mg/m2) and 5FU (250 mg/m2) daily in the most recent period (1997-2000). The HCR group was also divided into the following 3 groups: Group D, who received regimen A and hyperthermia 6 times in the early period; group E, who received regimen B and hyperthermia 6 times in the next period; and group F, who received regimen C and hyperthermia 6 times in the most recent period. The local response and the long-term results were investigated., Results: A complete removal of the primary tumor was achieved in 29%, 39%, 62%, and 68% of the patients in groups 1, 2, 3, and 4, respectively. The 30-day operative mortality rates were 11%, 4%, 1%, and 0% in groups 1, 2, 3, and 4, respectively. The 5-year survival rates for all patients in groups 1, 2, and 3 were 16.7%, 19.2%, and 44.4%, respectively. The cases in which CR or HCR was evaluated to be effective numbered 44 (48.4%) in group A, 22 (73.3%) in group B, 8 (66.7%) in group C, 79 (63.7%) in group D, 36 (73.5%) in group E, and 12 (75.0%) in group F. Our clinical results thus showed CDDP to have a greater effect than BLM, while HCR was shown to have a greater effect than CR., Conclusions: Preoperative therapy, especially using CDDP and hyperthermia, has improved thanks to recent advances in the treatment of esophageal cancer.

Squamous epithelial dysplasia is frequently encountered in the cancerous esophagus. However, its biological and clinical significance have not yet been fully elucidated. Investigations in squamous cell dysplasia of the esophagus have been performed to date in our department. We consider dysplasia to be the earliest malignancy of the esophagus based on such biologic features as the histopathologic findings, the proliferative activity, and the altered expression of cancer-associated genes. It is essential to detect and treat these early lesions endoscopically. Hopefully the findings of further studies of dysplasia can help to elucidate the mechanism of carcinogenesis in esophageal squamous cell carcinoma.

Background: The unique pathologic features of esophageal tumors in patients with esophageal cancer includes the presence of multiple occurrence within the esophagus. The aim of this study is to clarify the molecular mechanism of carcinogenesis of multiple esophageal squamous cell carcinomas in the Japanese., Methods: We studied the relationship between the incidence of patients with multiple carcinomas and the coexistence of dysplasia lesions with p53 protein accumulation, alcohol consumption, and cigarette smoking. Among 76 cancer lesions and 60 cases of dysplasia, p53 accumulation was studied by means of immunohistochemical analysis., Results: The incidence of patients with multiple carcinomas in the high-risk group was 33%, and the incidence of patients with a coexistence of dysplasia in the high-risk group was 67%. The incidence of patients with multiple carcinomas or the coexistence of dysplasia in the high-risk group was much higher than that of the middle-risk and low-risk groups (P <.0001 and P =.04, respectively). The average number of abnormal epitheliums, such as cancer and dysplasia, in the high-risk group was 3.2 +/- 2.1. The average number of abnormal epitheliums was much higher than that of the other groups (P =.02). For carcinoma lesions, the incidence of lesions with a positive p53 protein accumulation in the high-risk group was 91%. Regarding dysplasia lesions, the incidence of lesions with a positive p53 protein accumulation in the high-risk group was 80%. The incidence of both cancer and dysplasia lesions with a positive p53 protein accumulation in the high-risk group was higher than that of the other groups., Conclusions: The pattern of p53 accumulation in dysplasia in the high-risk group was closely similar to that in cancer of the high-risk group. These findings support the concept of field carcinogenesis of the esophagus.

Background: In order to acquire an improved prognosis, preoperative hyperthermia combined with chemotherapy and radiotherapy (HCR) has been performed in our department for patients with esophageal carcinoma., Methods: The experimental and clinical investigations that have been continuously performed in our department were introduced with regard to the therapeutic effect brought by HCR for carcinoma, chiefly for esophageal carcinoma., Results: A series of our investigations have demonstrated the excellent anticancer effect of HCR for esophageal carcinoma., Conclusions: Preoperative HCR has contributed to improvements in the prognosis of patients with esophageal carcinoma and is expected to make marked progress in the future with further development of anticancer agents and improvements in the hyperthermia devices.