E-cadherin and alpha-catenin expression in human esophageal cancer.

Intercellular adhesion of the epithelial tissue is mainly regulated by the E-cadherin (E-cad) molecule. alpha-Catenin (alpha-cat) is one of the E-cad-associated cytoplasmic proteins that forms a linkage to the cytoskeleton and regulates E-cad function. To investigate the mechanism of dysfunction in cell-cell adhesion in cancerous tissues, we examined E-cad and alpha-cat expression by immunohistochemical staining on 46 human esophageal cancers using our specific monoclonal antibodies. By grading of E-cad and alpha-cat expression as uniformly positive (+), heterogeneous (+/-), or uniformly negative (-), the 46 tumors could be classified into 9 (20%) E-cad(+)/alpha-cat(+), 15 (33%) E-cad(+/-)/alpha-cat(+/-), 21 (46%) E-cad(+/-)/alpha-cat(-), and 1 (2%) E-cad(-)/alpha-cat(-). Twenty-five (54%) of the 46 tumors showed a similar expression of both molecules, while the other 21 tumors (46%) showed E-cad(+/-)/alpha-cat(-). Thus, although the expression of alpha-cat was significantly correlated with that of E-cad, in some tumors the reduction of alpha-cat was greater. Regarding the clinicopathological features, the reduction of alpha-cat expression, as well as that of E-cad, was significantly associated with tumor dedifferentiation, infiltrative growth, and lymph node metastasis (P < 0.01). Furthermore, the frequency of lymph node metastasis in E-cad(+/-)/alpha-cat(-) tumors was significantly higher (90%) than in E-cad(+)/alpha-cat(+) tumors (22%) (P < 0.01) or in E-cad(+/-)/alpha-cat(+/-) tumors (47%) (P < 0.05). These results suggest that not only E-cad but also alpha-cat are important regulators of intercellular adhesion and that alpha-cat is also involved in invasion and metastasis. In particular, reduction of alpha-cat expression is more correlated with invasive phenotype and lymph node metastasis than E-cad expression in human esophageal cancer.

Laparoscopic management for local recurrence of early gastric cancer after endoscopic mucosal resection.

Endoscopic mucosal resection (EMR) is a widely accepted technique for early gastric cancer because it is minimally invasive; however, incomplete resection with subsequent cancer recurrence in the remnant remains a difficult problem. Generally, the margins of the local recurrence lesions are unclear, and second EMR is difficult to perform because of scar formation after the first EMR. We performed a laparoscopic treatment on six patients with residual lesions after EMR and reviewed the safety and efficacy of this management. Laparoscopic management consisted of two techniques: laparoscopic wedge resection with a lesion-lifting method and laparoscopic-assisted distal gastrectomy with mini-laparotomy. Cancerous lesions were completely resected with sufficient surgical margins circumferentially. Mean operative time was 171 min, mean estimated blood loss was 16.5 g, time to first walking was 1 day, duration of epidural analgesia was 2.2 days, and mean length of hospital stay was 13.5 days. There were no intra- and postoperative complications, no conversion to open surgery, and no recurrence after surgery. No patients died of gastric cancer during a median follow-up of 60.3 months (range, 38-84). Laparoscopic management for residual lesions of early gastric cancer after EMR is a safe, effective, and minimally invasive procedure by which curative resection can be expected.

Potent antitumor effects of intra-arterial injection of fibroblasts genetically engineered to express IL-12 in liver metastasis model of rat: no additional benefit of using retroviral producer cell.

Interleukin-12 (IL-12) mediates significant antitumor effects in animal models but associated with dose-dependent toxicity in human. To achieve local expression of IL-12 at the tumor site without systemic toxicity, we performed intra-arterial administration of fibroblasts genetically engineered to produce IL-12 protein with or without retrovirus (CRIP- IL-12 or 3T3-IL-12) in liver metastasis model. Rat breast cancer cells ( MADB - 106) were injected into the portal vein of syngeneic Fisher rats on day 0, and fibroblasts were injected into the hepatic artery on day 7. On day 21, liver weight and number of liver tumors were examined. As controls, CRIP cells expressing retrovirus carrying lacZ marker gene (CRIP-lacZ) or saline (Hanks balanced salt solution, HBSS) were injected. Administration of CRIP-IL-12 significantly reduced tumor metastasis in liver measured by number of foci (CRIP- IL-12: 45.2 +/- 36.7, CRIP-lacZ: >250, HBSS: >250, P<.05) and by liver weight (CRIP-IL-12: 13.0+/-2.5 g, CRIP-lacZ: 30.4+/-8.5 g, HBSS: 26.0+/-7.6 g, P<.05). 3T3-IL-12, which produced only IL-12 protein but not IL-12 retrovirus, also had significant antitumor effects equivalent to CRIP-IL-12. Intra-arterial injection of IL-12--producing fibroblasts into the liver may be an effective therapy for liver tumors reducing systemic toxicity, and could be developed for clinical application.

P53 expression in esophageal dysplasia - a possible biomarker for carcinogenesis of esophageal squamous-cell carcinoma.

The tumor suppressor gene product p53 has been detected in a high percentage of esophageal squamous cell carcinoma. To evaluate the role of this protein in carcinogenesis, we examined the p53 overexpression both in esophageal dysplasia and in esophageal squamous cell carcinoma in the same patients. Using anti-p53 antibodies pAb1801 and CM-1, we analyzed immunohistochemically 36 dysplastic lesions from 36 patients with esophageal cancer. Nuclear p53 was detected in 14 of 36 dysplasias (39%). From mild to moderate to severe dysplasia, p53 positivity showed tendency to increase in number. Seventeen of the 36 squamous cell carcinomas showed p53 expression (47%). There was a significant concurrent p53 expression in esophageal dysplasia and its related squamous cell carcinoma (p=0.00345). These results indicate that p53 mutation is closely associated with the initiation of this cancer.

Immunohistochemical evaluation of alpha-catenin expression in human gastric cancer.

E-cadherin (E-cad) plays a major role in the maintenance of cell-cell adhesion in epithelial tissues, and impaired E-cad expression correlates with tumour invasion and metastasis. Alpha-catenin (alpha-cat), an undercoat protein of adherens junctions, binds to the cytoplasmic domain of E-cad and is essential for linking E-cad to actin-based cytoskeleton. We investigated E-cad and alpha-cat expression in 60 human gastric cancers immunohistochemically. The 60 gastric cancers were classified into 18 (30%) in which alpha-cat expression was preserved, and 42 (70%) reduced cases. The reduction of alpha-cat expression was significantly related to dedifferentiation, depth of invasion, infiltrative growth and lymph node metastasis. We also examined the co-expression of alpha-cat and E-cad. Seventeen (28%) tumours preserved both molecules [alpha-cat(+)/E-cad(+)] and 33 (55%) tumours reduced both [alpha-cat(-)/E-cad(-)], whereas 9 (15%) tumours exhibited alpha-cat(-)/E-cad(+). The frequency of lymph node metastasis in alpha-cat(-)/E-cad(+) tumour (67%) was significantly higher than that in alpha-cat(+)/E-cad(+) tumours (24%) and was close to that in alpha-cat(-)/E-cad(-) tumours (82%). The frequency of haematogenous liver metastasis in alpha-cat(-)/E-cad(+) tumours (44%) was significantly higher than that in alpha-cat(+)/E-cad(+) tumours (6%) or alpha-cat(-)/E-cad(-) tumours (9%). Thus, in all E-cad(+) tumours, the frequency of lymph node and liver metastasis was higher in alpha-cat(-) tumours than in alpha-cat(+) tumours. alpha-Cat expression is apparently better at predicting tumour invasion and metastasis than E-cad expression.

Excision of a urachal sinus with use of a voice-controlled laparoscope.

A 34-year-old man with an umbilical urachal sinus underwent a voice-controlled robot-assisted laparoscopic excision. In the operational procedure, three trocars were inserted into the peritoneal cavity. Exploration with a laparoscope revealed a cystic lesion at the middle part of the lower abdomen that extended about 4 cm in the major axis just from the umbilicus. The caudal stump of the urachus was ligated with an absorbable clip and divided. The cephalic side of the lesion was ligated just at the umbilicus with an Endo-Loop and divided. The lesion was then peeled from the peritoneum and taken from the peritoneal cavity. The robot allowed a safer and more secure movement of the scope. The postoperative course was uneventful, the surgical wound scars were very small, and the cosmetic results were satisfactory. There was no recurrence and no transformation of the navel. Our experience was encouraging enough to suggest that voice-controlled robot-assisted laparoscopic excision in patients with urachal disease is a beneficial therapeutic option that is easy, safe, and minimally invasive, with excellent cosmetic results.

Hand-assisted laparoscopic splenectomy for a huge splenic cyst: operative technique and case report.

We report the case of a huge splenic cyst that was successfully treated by hand-assisted laparoscopic splenectomy. A 17-year-old girl with a chief complaint of left-sided abdominal pain was admitted to our department for investigation of a splenic tumor. Ultrasonography, computed tomography, and magnetic resonance imaging revealed a huge cystic lesion in the spleen measuring approximately 10 cm in diameter. Hand-assisted laparoscopic splenectomy was safely performed to diagnose and treat the splenic tumor. The histologic diagnosis was an epithelial cyst of the spleen with no atypical cells in the cyst wall. Hand-assisted laparoscopic splenectomy may be a good method of managing a huge splenic cyst that becomes symptomatic and potentially life-threatening through enlargement, rupture, and secondary infection.

[Postoperative brain metastasis from esophageal carcinomas: report of 4 cases].

Out of 83 cases received resection of primary esophageal lesion, 4 patients were affected by metastatic brain tumor which was reported to rarely occur. All 4 patients had symptoms of central nervous system. Three of them were diagnosed by CT and the other one at autopsy. All of the primary esophageal tumors were advanced and of histological stage III or IV. They located in the middle or lower thoracic esophagus. Brain tumor of one case was removed and this case was of progression free at the last presentation. The other 3 cases were not received resection of metastatic brain tumors and died. All of 3 were autopsied and two of them had no metastasis in the lung. Therefore, it was considered that these hematogenic metastases were not through lung filtrations but through other routes, which Batson O. V. experimentally proved and designated as vertebral vein system in 1940. It is concluded that aggressive surgical intervention to metastatic brain tumors was beneficial with regard to prognosis for cases without other metastatic lesions.

[Malignant pericardial effusion after esophageal cancer surgery successfully treated by intrapericardial instillation of CDDP].

The patient is a 63-year-old male with pericardial effusion who fell into cardiac tamponade one year and eight months following radical operation for esophageal cancer (stage IV). Because the cytological diagnosis for the punctured specimen of pericardial effusion indicated class V, we recognized it as pericardial recurrence and instilled CDDP 20 mg and 25 mg into the pericardial cavity. The pericardial effusion disappeared completely. There are many reports of CDDP instillation into the pleural cavity or the peritoneal cavity, but few into the pericardial cavity. For esophageal cancer, this is the first report in Japan. The patient is still alive at present after fourteen months have passed. It is considered that this method is effective for malignant pericardial effusion due to advanced esophageal cancer.

[Significant role of cisplatin and 5-FU combination chemotherapy for first-line intensive treatment for advanced esophageal cancer].

We evaluated the efficacy of first-line chemotherapy consisting of cisplatin and 5-fluorouracil combination therapy (in the following, FP) in intensive treatment for esophageal cancer. This first-line chemotherapy was administered to 18 patients with squamous cell carcinoma. Three patients had T2 tumor, 10 had T3 and 5 had T4. Lymph node metastasis was detected in 10 patients and not detected in 8 patients. Five patients had distant metastasis. Ten patients showed a partial response and the response rate was 55.6%. Of these 10 patients, 5 were followed with surgery, 3 of whom survived without recurrence of the disease. Five patients were treated by FP, radiation therapy or combination of FP and radiation. Of these 5 patients, 2 showed a complete response. On the other hand, 8 nonresponders died from progressive disease, despite following intensive treatment. These results suggest that first-line chemotherapy by FP, which requires following intensive treatment, improves the overall long-term survival of advanced esophageal cancer patient.

[Usefulness of hepatic arterial infusion chemotherapy for liver metastasis in gastric cancer].

UNLABELLED: We have performed intra-hepatic arterial chemotherapy for 9 patients with liver metastasis arising from gastric cancer. We mainly used 5-FU and CDDP as antineoplastic drugs. RESULTS: The median survival after gastrectomy was 600 days. Of 9 cases, 2 showed CR, 4 PR, 2 NC, 1 PD. The response rate was 67%. The 9 cases were classified into 2 groups. One group, the short-term survival group, concised of 5 patients that had no more than 2 years survival and the other, the long-term survival group, consisted 4 patients that had more than 2 years survival. We compared these 2 groups and found no difference in the primary lesions between the 2 groups. The patients in the long-term survival group had fewer and smaller metastatic lesions in the liver than the patients of the short-term survival group. The patients in the long-term survival group had no unresectable lesions except liver metastasis when gastrectomy was performed. However, 2 patients in the short term survival group had unresectable lymphatic involvement at the time gastrectomy was performed. Of 9 patients, 6 died from the extrahepatic lesion. CONCLUSION: The intra-arterial chemotherapy was effective and useful for liver metastasis arising from gastric cancer. However, the majority of patients died from extrahepatic lesions. We should therefore consider the use of systemic chemotherapy with intra-arterial chemotherapy.

[Evaluation of chemosensitivity testing by CD-DST, and TS and DPD activity in cases of colorectal liver].

We evaluated the usefulness of the following three in vitro assays in cases of resected colorectal liver metastases. Chemosensitivity by collagen gel droplet drug sensitivity test (CD-DST) was very low in all cases, suggesting this method is not predictive for this disease. In contrast, thymidylate synthetase (TS) activity and dihydropyrimidine dehydrogenase (DPD) activity in tumor tissue were high in many patients with recurrent disease. Thus, these enzyme activities are promising for assessment of clinical outcome following hepatic resection of colorectal liver metastases. Further analyses with large numbers of cases are needed to determine the significance of these in vitro studies.

[Malignant islet cell tumor of the pancreas with multiple liver metastases effectively treated by transcatheter arterial embolization with degradable starch microspheres--a case report].

A 57-year-old woman underwent distal pancreatectomy for malignant islet cell tumor of the pancreas in 1991. One year later, multiple liver metastases appeared. Although three transcatheter arterial embolizations (TAE) with spongel and nine ethanol injections were performed over seven years, the tumors were growing gradually. Therefore, TAE with degradable starch microspheres (DSM) was selected. Under angiography, TAE of the left hepatic artery was done using 900 mg of DSM following injection of Farumorubicin (20 mg), Lipiodol (3 ml) and cisplatin (90 mg). The tumors in the embolized hepatic area were remarkably decreased in size, and satisfactory local control was obtained. Thereafter, TAE with DSM was carried out twice, and she is still living with outpatient treatment. Thus, it is suggested that TAE with DSM could be a promising, alternative therapeutic modality for liver metastases from malignant islet cell tumor of the pancreas.

[Evaluation of hepatic resection following hepatic arterial infusion chemotherapy for colorectal liver metastases].

We evaluated the significance of hepatectomy following hepatic arterial infusion (HAI) chemotherapy for colorectal liver metastases. The prognosis of 4 cases with initially resectable tumors was discouraging, indicating no benefit of preoperative HAI for resectable tumors. The 2- and 3-year survival of patients who underwent hepatectomy after downstaging by HAI of originally unresectable metastases were 100% and 67%, respectively, suggesting that hepatectomy combined with HAI is a promising modality for those patients. However, it seems that the control of extrahepatic disease and decision making for the timing for surgical therapy are issues requiring improvement.

Quadruple cancer including Bowen's disease after arsenic injections 40 years earlier: report of a case.

This report describes the successful treatment of quadruple cancer including Bowen's disease in a 71-year-old man who had been given injections of salvarsan, an arsenic compound, for syphilis more than 40 years earlier. Resection of a skin lesion on his chest subsequently confirmed a diagnosis of Bowen's disease, 3 years after which he was operated on for concurrent gastric cancer and sigmoid colon cancer. A fourth cancer was discovered on his left vocal cord 2 weeks after this operation; it was resected 2 years later. A discussion of multiple malignant neoplasms and the possible relationship between arsenic and cancer is presented following this case report.

The usefulness of laparoscopy-assisted distal gastrectomy in comparison with that of open distal gastrectomy for early gastric cancer.

BACKGROUND: The technique of laparoscopy-assisted distal gastrectomy (LADG) was developed for early gastric cancer, but its feasibility and the associated clinical outcome remain unclear. METHODS: We reviewed 24 patients who underwent LADG (LADG group) and 35 patients who underwent traditional open distal gastrectomy (ODG group) for early gastric cancer in our hospital, and compared the clinical data of the two groups. RESULTS: The clinical and pathological backgrounds of the patients in the two groups were similar. The duration of surgery was not significantly different between the two groups, but the blood loss in the LADG group was significantly less than that in the ODG group. The number of removed lymph nodes was not significantly different between the two groups. The times to the first passing of flatus, first walking, and the restarting of oral intake; the length of hospital stay; and the duration of epidural analgesia were significantly shorter in the LADG group. The morbidity rate in the LADG group was lower than that in the ODG group. CONCLUSIONS: LADG is a safe and minimally invasive surgical technique, after which we can expect a faster recovery.

Growth-regulatory mechanism of two human esophageal-cancer cell lines in protein-free conditions.

We investigated the growth-regulatory mechanism of 2 esophageal squamous-cancer cell lines, TE2-NS and TE3-OS cells, both of which can grow stably in protein-free conditions in vitro. Protein-free conditioned media from TE2-NS and TE3-OS cells stimulated the growth of these cells. Exogenous epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), insulin-like growth factor (IGF)-I and -II enhanced cell proliferation by 2.2- to 3.8-fold in protein-free conditions, as compared with an untreated control. Receptor-binding assays showed that both TE2-NS and TE3-OS cells possessed a single class of high-affinity binding sites for IGF-I and 2 classes of binding sites for TGF-alpha, as confirmed on the cell membrane by immunochemistry. These results suggest that EGF, TGF-alpha and IGFs are candidates for the autocrine growth factor in cancer cells. The addition of inhibitory monoclonal antibodies against TGF-alpha and EGFR, but not those against either EGF or IGF-IR, significantly inhibited growth of the cells. Immunocytochemical staining and ELISA of the conditioned media both confirmed the production of TGF-alpha protein, but not EGF protein, in these cell lines. The data for a protein-free culture system strongly suggested that TGF-alpha, but not EGF or IGF, is biologically important as an autocrine growth factor in the growth of these cell lines in vitro.

Dissecting thoracic aorta and fusiform aneurysm of the abdominal aorta.

A 59-year-old woman with dissection of the thoracic aorta and a fusiform aneurysm of the abdominal aorta without evidence of Marfan's syndrome underwent aneurysmorrhaphy with a bifurcated expanded polytetrafluoroethylene graft. Histological specimens of the aneurysmal wall revealed the presence of idiopathic cystic medial necrosis. As typical findings of idiopathic cystic medial necrosis in the aortic wall are very rare except in cases of Marfan's syndrome, the present case is reported and the implications of this condition are discussed.