Hideaki Tahara

Endoscopic screening of early esophageal cancer with the Lugol dye method in patients with head and neck cancers

The poor prognosis for esophageal cancer could be improved if lesions were detected at an early stage. To detect early esophageal cancer, endoscopic screening of the esophagus with the Lugol dye method was performed in patients with head and neck cancers who were asymptomatic but regarded as being at high risk for synchronous or metachronous esophageal cancer. of 178 patients screened, 9 had esophageal cancer (5.1%). Eight of these patients (89%) were at early stages with no lymph node metastasis. Most of the lesions (9 of 13 lesions) were not detectable by barium studies or ordinary endoscopic study. the epidemiologic statistical analysis of the patients confirmed that they had a significantly high observed and expected number (O/E) ratio (39.7; P < 0.001). These results demonstrate the value of endoscopic screening of the esophagus with the Lugol dye method in patients with head and neck cancers and imply that endoscopic screening with the Lugol dye method may be useful for detecting early esophageal cancer in individuals at risk for other causes.

Immunohistochemical evaluation of E-cadherin adhesion molecule expression in human gastric cancer.

E-cadherin (ECD) is one of subclasses of the cadherin family which plays a major role in the maintenance of intercellular adhesion in epithelial tissues. An immunohistochemical study of ECD expression was performed on gastric adenocarcinoma from 103 patients using our monoclonal antibody for human ECD (HECD-1). ECD was strongly expressed in normal gastric epithelium without exception; however, various staining patterns were observed in cancer tissues. The frequency of tumours with preserved ECD expression (Pre-type) and reduced ECD expression (Rd-type) was 42% and 58% respectively. Tumours with a high frequency of Rd-type expression particularly included: undifferentiated tumours (85%, 46/54), Borrmanns type 4 (90%, 9/10), tumours larger than 2.6 cm in diameter (65%, 53/81), tumours invading beyond the subserosa layer (78%, 46/59), and tumours with infiltrative growth (87%, 41/47). Furthermore, the frequency of Rd-type expression in cases with peritoneal dissemination (82%, 9/11) or lymph node metastasis (73%, 43/59) was significantly higher than that in cases without dissemination or metastasis. These results suggest that ECD might play a key role in the genesis of histological differentiation, and that the reduction of ECD expression may affect the mode of invasion and metastasis of human gastric cancer cells.

Prognostic significance of transforming growth factor-α in human esophageal carcinoma : implication for the autocrine proliferation

Background. The authors recently used immunostaining to demonstrate that patients with epidermal growth factor receptor (EGFR) overexpression have poor survival after surgery. However, the clinical significance of transforming growth factor (TGF)‐α, one of the ligands of EGFR, has not been demonstrated in esophageal carcinoma.

Immunohistologic detection of the epidermal growth factor receptor in human esophageal squamous cell carcinoma

Epidermal growth factor receptor (EGF‐R) expression was studied immunohistologically in 38 patients with esophageal squamous cell carcinoma. The EGF‐R was faintly expressed in basal and parabasal layers of normal esophageal epithelia and in cancer nests of 20 patients; it was strongly expressed in all areas of dysplastic epithelia and in cancer nests of 18 patients. The patients with strongly expressed EGF‐R had lymph node metastases more frequently, and their prognosis was poorer than those with faintly expressed EGF‐R. The EGF‐R expression showed a mosaic pattern in 17 patients and a diffuse pattern in 21 patients. The patients with a mosaic pattern had lymph node metastases more frequently and a worse prognosis than those with a diffuse pattern. Expression of EGF‐R in metastatic lymph nodes was similar to that in strongly expressing areas of primary cancers with a mosaic pattern. Thus EGF‐R expression may be an important indicator for malignancies of esophageal squamous cell carcinomas because primary cancer cells with strongly expressed EGF‐R metastasize to lymph nodes more frequently.

Significance of p53 expression as a prognostic factor in oesophageal squamous cell carcinoma

The tumour suppressor gene product p53 is believed to play an important role in the progression of human malignant tumours through mutation and over-expression. Using a microwave oven heating method, we have detected over-expression of p53 in buffered-formalin fixed, paraffin-embedded sections of oesophageal carcinomas immunohistochemically and examined the relationship between the p53 over-expression and postoperative survival. Employing a monoclonal antibody (pAb1801), nuclear p53 was detected in 56 of 105 (53%) tumour specimens. Homogeneous, heterogeneous, and focal immunostaining patterns were noted. No immunostaining was found in adjacent benign tissues. The results in buffered-formalin fixed sections were similar to those in the frozen sections. The cumulative survival rate of patients with p53 expression was significantly lower than that of the patients without expression (P<0.05), even though there were no significant differences between the clinicopathological features of the two groups. The results indicate that the nuclear accumulation of p53 might be an independent prognostic factor in patients with oesophageal squamous cell carcinomas.

Prognostic value of dna ploidy in squamous cell carcinoma of esophagus. Analyzed with improved flow cytometric measurement

Background. The prognostic value of flow cytometric DNA analysis on paraffin‐embedded tumor samples has been controversial in esophageal cancer. To clarify its true significance, the authors developed an improved method that excludes the possibility of contamination by lymphocytes in tumor sample.

Phenotypic characteristics of tumour-infiltrating lymphocytes in human oesophageal cancer tissues defined by quantitative two-colour analysis with flow-cytometry.

Phenotypic subpopulations of tumourinfiltrating lymphocytes (TIL) separated from human oesophageal cancer tissues were defined by quantitative two-colour analysis with flow-cytometry (FACScan), and their characteristics were investigated by comparison with peripheral blood lymphocytes (PBL) and intra-oesophageal lymphocytes from noncancerous tissue (IEL) as the controls. Fifteen patients (13 males and 2 females) with squamous cell carcinoma of the oesophagus were entered into the study. Lymphocytes were analyzed by FACScan and the frequencies of the subpopulations were determined using monoclonal antibodies for surface markers. Single colour analysis revealed a predominance of T cells among TIL and a significant reduction of natural killer (NK) cells compared with the controls. Two-colour analysis showed that CD4+Leu8− (helper T cells) and CD8+CD11b− (cytotoxic T cells) were significantly increased among TIL when compared with the controls. This significant increase of both helper and cytotoxic T cells, which are indispensable components of cellular immunity, strongly implies that TIL are performing a role in the expression of antigen-specific cellular immunity against the tumours. This is the first report of a phenotypic study of human oesophageal cancer that clearly indicates the significance of the TIL and suggests their potential for use as a source of adoptive immunotherapy.

Principal lymphocyte subpopulation in local host response to human oesophageal cancer

We investigated what subpopulations of tumour-infiltrating lymphocytes (TIL) play a key role in in vivo function and what determines the degree of local host response represented by lymphocyte infiltration in human oesophageal cancer. We examined the increased subpopulation of TIL in “good responders” (GR) (patients with intensively TIL infiltrated tumours) when compared with “poor responders” (PR) (patients with weakly TIL infiltrated tumours). The frequency of each subpopulation was determined by quantitative flow-cytometric measurement on TIL separated from fresh tumours. Of TIL in GR, the frequency of CD3+ cells increased significantly (P<0.05) but the frequencies of CD16+, Leu7−, and CD16+ Leu7− cells were low and did not increase significantly compared with those in PR. With respect to T-cell subsets of TIL in GR, the frequency of CD8+ cells was significantly higher than that in PR (P<0.01), and CD4+/CD8+ ratio was lower than that in PR (P< 0.025). On two-colour analyses, most of CD8+ cells (cytotoxic/suppressor T-cells: Tc/s) did not co-express CD11b and the frequency of CD8+ CD11b− cells (cytotoxic T-cell: Tc) increased significantly compared with that in PR. Clinicopathological and phenotypic analysis of peripheral blood lymphocytes revealed that there are no major differences in general immunocompetence between GR and PR. These results suggest that Tc/s, especially Tc, might play a key role in local host response. They also suggest that not only the general immune status of the host but also the identification of class I major histocompatibility complex antigens by the host at the tumour site may strongly affect the degree of host response in oesophageal cancer.

The possible involvement of platelet activation in endotoxin-induced renal insufficiency in a rabbit model

The effects of the anticoagulants, heparin and low molecular weight heparin (LMWH), and the antiplatelet agents, prostaglandin E1 (PGE1) and aspirin, on endotoxin-induced renal insufficiency not induced by prerenal factors, were investigated using rabbits to evaluate the clinical usefulness of these drugs and their possible involvement in the activation of hemostasis in renal insufficiency. The intravenous administration of PEG1, at 0.4 μg/kg/min, or aspirin, at 5 mg/kg, significantly restored all the parameters of renal function measured in the present study, namely, effective renal plasma flow, glomerular filtration rate and urine N-acetyl-β-D-glucosaminidase, as well as histological renal ischemic changes. On the other hand, neither heparin nor LMWH, even at a high dose, improved any parameter. As the antiplatelet effect is the common property of PGE1 and aspirin, it is suggested that the activation of platelets may be prerequisite to the occurrence of renal insufficiency induced by endotoxin. The results of this study thus show that PGE1 or aspirin may be applied in clinical use for renal insufficiency complicated by sepsis or endotoxemia.

Comparison of postoperative results following terminal esophagoproximal gastrectomy and esophageal transection for esophageal varices

The results of 44 terminal esophagoproximal gastrectomies (TEPG) and 53 esophageal transections (ET) for esophageal varices, performed during the period between January, 1975 and March, 1989, were retrospectively compared. The results examined prognosis, recurrence of esophageal varices and late postoperative complications. The 5-year survival rates for patients who underwent selective or prophylactic surgery were 85.9% following TEPG and 81.6% following ET. However, the 10-year survival rate for the former group was significantly lower than that for the latter group at 59.3% versus 70.0% (P<0.05) because of the number of deaths due to hemorrhage and liver failure caused by anastomotic ulcers. The respective 5-year recurrence rates of varices for the TEPG and ET groups were 18.4% and 26.4%, respectively, while the 10-year recurrence rate for the former group was again significantly lower than that for the latter group at 27.1% versus 53.7% (P<0.01). As for postoperative late complications, reflux esophagitis and/or anastomotic ulcers were found twice as frequently after TEPG as after ET. Thus, although TEPG was more effective for preventing variceal recurrence it left the potential for an anastomotic ulcer to develop, which was the dominant cause of death more than 5 years after surgery.