Quality of life following esophagectomy with three-field lymphadenectomy for carcinoma, focusing on its relationship to vocal cord palsy.

To clarify the quality of life of patients who underwent esophagectomy for carcinoma by right thoracotomy, laparotomy and cervical anastomosis, 116 patients who were cancer free at the time of mailing a questionnaire were analyzed. A significant decrease in vital capacity for 3 years postoperatively, as well as in the percentage of ideal body weight, between 3 and 5 years were observed in 57 patients with three-field lymphadenectomy. Patients' quality of life undergoing three-field dissection was worse than those with less radical lymphadenectomy (59 cases) in terms of the performance status and difficulty in talking at 60 months or more postoperatively. Around 20% of all patients reported severe hoarseness due to permanent recurrent nerve paralysis, resulting in poor quantity of food intake at 24 months or less postoperatively and restricted daily activity and difficulty in talking at 60 months or more after the operation. When a patient suffers from vocal cord insufficiency caused by permanent paralysis of the recurrent nerve, early treatment before discharge from the hospital should be performed to improve the quality of life of such a patient.

Endoscopic resection of early gastric cancer treated by guideline and expanded National Cancer Centre criteria.

BACKGROUND: Criteria for endoscopic resection in patients with early gastric cancer (EGC) have been expanded recently by the National Cancer Centre (NCC). This study compared long-term outcomes in patients with EGC who underwent endoscopic treatment according to guideline criteria with those treated according to expanded criteria. METHODS: Baseline and outcome data from patients undergoing curative endoscopic resection for EGC between January 1999 and December 2005 were collected from electronic medical records. Survival time hazard ratios and 95 per cent confidence intervals were calculated using the Cox proportional hazards model. RESULTS: Of 1485 patients who had a curative resection, 635 (42.8 per cent) underwent resection according to traditional criteria and 625 (42.1 per cent) according to expanded criteria. There was no significant difference in overall survival between the groups. CONCLUSION: Patients who have treatment following the expanded criteria have similar long-term survival and outcomes to those treated according to guideline criteria.

Expression of thrombomodulin in esophageal squamous cell carcinoma and its relationship to lymph node metastasis.

Thrombomodulin (TM) is thrombin receptor that was identified originally on the endothelium and acts as a natural anticoagulant. However, we reported previously that TM was also expressed in the squamous epithelium mainly at the intercellular bridges. In this study, we examined TM expression in the primary lesions of 106 patients with esophageal squamous cell carcinomas and in the lymph node metastatic lesions of 59 patients using immunohistochemical methods. The carcinoma tissues expressed TM mainly at the cell-cell boundaries and in the cytoplasm. When TM expression was compared between the primary and metastatic lesions in the 59 patients who had lymph node metastasis, 41 (69%) showed decreased TM expression, 18 (31%) showed no change, and none (0%) showed an increase in the metastatic lesions. Wilcoxon's signed-rank test indicated that tumor cells that were positive for TM expression were significantly rarer in the metastatic lesions than in the primary tumors (P < 0.0001). This result indicates that the decrease in TM expression is associated with metastasis of the carcinoma cells. This phenomenon is very similar to that of E-cadherin, although the structures of both molecules are quite different. The reduction of TM expression seems to play an important role in the metastatic process of esophageal cancer.

Effect of neoadjuvant chemotherapy for lymph node micrometastasis and tumor cell microinvolvement in the patients with esophageal carcinoma.

Micrometastasis (MM) and tumor cell microinvolvement (TCM) in the lymph node were immunohistochemically evaluated using the cytokeratin (CK) antibody between a surgery group (n=20; 929 lymph nodes) and a chemotherapy group (n=20; 1052 lymph nodes). The incidence of MM+/-TCM in the surgery and chemotherapy groups was 50.0 (10/20) and 55.0% (11/20), respectively. Limiting the analysis to TCM alone revealed that the incidence in the chemotherapy group (10.0%; 2/20) was significantly lower than that in the surgery group (40.0%; 8/20; P=0.032). Preoperative chemotherapy in this regime was not effective, except for some patients with TCM alone.

Apoptosis and cell proliferation in esophageal sqamous cell carcinoma treated by chemotherapy.

The p53 gene is associated with G1 arrest during the cell cycle and with apoptosis. To evaluate the preoperative chemotherapeutic effect in esophageal squamous cell carcinoma, we retrospectively investigated the apoptotic index (AI) and Ki-67 labeling index (Ki-67LI) in relation to the expression of p53. Thirty patients with esophageal carcinoma who had received chemotherapy prior to surgery were examined using the terminal deoxynucleotidyl-transferase-mediated in-situ end-labeling (TUNEL) method for evaluating AI and immunohistochemical staining with anti Ki-67 and anti p53 antibody for evaluating Ki-67LI and p53 expression, respectively. The histological response rate of chemotherapy was 20.0%. A significant correlation between p53-negative expression and response to chemotherapy was found (P<0. 01). The AIs and Ki-67LIs in p53-negative tumors with ineffective responses to chemotherapy were significantly higher than those in p53-positive tumors with ineffective responses (P<0.05). The AIs and Ki-67LIs were significantly lower in p53-negative tumors with effective responses to chemotherapy than those in p53-negative tumors with ineffective responses (P<0.05 and P<0.01, respectively). Furthermore, significant correlations were found between AIs and Ki-67LIs in p53 negative tumors (r=0.60, P<0.05). In esophageal carcinoma, p53-negative tumors with highly proliferative cells might be susceptible to apoptosis induced by chemotherapy.

Expression of desmoglein-I cell-adhesion molecule in primary tumors and metastatic lymph-nodes of esophageal cancer.

The expression of desmoglein I (DGI) in both primary turners and metastatic lymph node of esophageal carcinoma was studied immunohistochemically in 102 patients using an anti-DGI monoclonal antibody. Normal squamous epithelial cells strongly expressed DGI at their cell-cell boundaries. DGI expression in the tumors was divided into DGI (++), DGI (+), DGI (-) according to the staining intensity. DGI (+) or DG (-) tumors had lymph node metastases more frequently than DGI (++) tumors (p<0.01). DGI expression was the same or of less intensity, than in the primary tumor in 128 (85%) out of 151 metastatic lymph nodes. These results indicate that reduction or loss of DGI expression may promote lymph node metastases.

Response of patients with cirrhosis who have undergone partial hepatectomy to treatment aimed at achieving supranormal oxygen delivery and consumption.

BACKGROUND: This study was undertaken to evaluate the response to therapy aimed at achieving supranormal cardiac and oxygen transport variables (cardiac index > than 4.5 L/min/m2, oxygen delivery > 600 ml/min/m2, and oxygen consumption > 170 ml/min/m2) in patients with cirrhosis who have undergone partial hepatectomy and to assess the relationship between those parameters and outcome. METHODS: Thirty-four consecutive patients underwent elective hepatectomy for hepatocellular carcinoma. The postoperative outcomes and hemodynamic and oxygen transport values in 16 patients (group S) who maintained supranormal values were compared with those in 18 patients (group N) treated to maintain normal hemodynamic values. Patients in group S received volume expansion and then, if necessary, dobutamine (3 to 15 micrograms/kg/min) to increase cardiac index, oxygen delivery, and oxygen comsumption simultaneously during the first 12 hours. RESULTS: The hemodynamic targets were reached by 56% of patients in group S during the first 12 hours and 31% during the next 12 hours. Postoperative blood lactate levels at 12 and 24 hours were lower in group S than in group N, and total bilirubin concentrations, hepatic venous oxygen saturation, and arterial ketone body ratio, useful markers of postoperative liver function, also showed more favorable changes in group S than in group N. Postoperative morbidity and mortality rates were not significantly different in the two groups, but the incidence of hyperbilirubinemia and liver failure was much lower in group S than in group N. CONCLUSIONS: These results suggest that fluid therapy aimed at achieving a supranormal pattern by 12 hours after hepatectomy improved the systemic oxygen demand-supply dynamics and hepatic hemodynamics, decreasing the incidence of postoperative hyperbilirubinemia and liver failure in patients with liver cirrhosis.

Does hoarseness of voice from recurrent nerve paralysis after esophagectomy for carcinoma influence patient quality of life?

BACKGROUND: Recurrent laryngeal nerve injury caused by esophageal cancer surgery is worrisome but often temporary; it is unclear when and how the paralysis is resolved. Hoarseness of voice from vocal cord paralysis (VCP) can have detrimental effects on postoperative patients. The aims of this study were to clarify the progress of nerve paralysis related to difficulty in talking after surgery and to assess whether hoarseness influences patient quality of life. STUDY DESIGN: Between 1985 and 1996, 141 esophageal cancer patients undergoing a resection by the Akiyama procedure were cancer free 1 year after surgery. Among them, 51 patients with VCP on discharge from the hospital were retrospectively reviewed. Their VCPs, body weights, and pulmonary functions were examined yearly. They were given a questionnaire relating to the difficulty in talking 1 year after surgery. RESULTS: VCP on discharge spontaneously healed within 1 year of surgery in 21 patients (41.2%), with the mean duration of difficulty in talking 5.7 months. The remaining 30 patients had persistent VCP 1 year after surgery; 4 VCPs spontaneously healed approximately 2 years after surgery. Eleven of the 30 patients with persistent VCP, who complained of severe hoarseness at 1 year postoperatively from inability to close the glottis during exertion, showed debilitation in performance status, abilities to go up stairs, and swallowing. In the group of patients with severe hoarseness, the percentage of ideal body weight (90.6%+/-11.0%) preoperatively and pulmonary functions at 3 years postoperatively were deteriorated, resulting in 3 patients with repeated aspiration pneumonia. CONCLUSIONS: The inability to compensate for aspiration, presenting as severe hoarseness, may be dependent on the preoperative nutritional state of patients along with degree of vocal cord atrophy and a decrease in pulmonary support. Persistent nerve paralysis deteriorates quality of life until it is adequately treated.

Expression of p53 and p21 is useful for the prediction of preoperative chemotherapeutic effects in esophageal carcinoma.

The p53 and p21 genes are associated with G1 arrest during the cell cycle and with apoptosis, both of which have a close relationship with the effect of chemotherapy. In this study, we investigated the correlation between p53 and p21 expression in biopsy specimens and the histological effect of chemotherapy in esophageal carcinoma. A total of 30 patients with esophageal squamous cell carcinoma received preoperative chemotherapy, then underwent esophagectomy with lymph node dissection. The response rate of primary lesion and metastatic nodes was 20.0% and 25.9%, respectively. The positive rate of p53 and p21 expression was 56.7% and 36.7%, respectively. Preoperative chemotherapy against primary lesions was ineffective in all the patients who expressed p53, but not p21. In contrast, chemotherapy was effective against metastatic lymph nodes which were p53 negative but p21 positive. These findings suggest that p21 positive expression in the absence of p53 is associated with favorable effects of preoperative chemotherapy in patients with esophageal carcinoma. Therefore, the expression of these genes should be examined in biopsy specimens to predict the chemotherapeutic outcomes in patients with esophageal carcinoma.

Fat emulsion administration in the early postoperative period in patients undergoing esophagectomy for carcinoma depresses arachidonic acid metabolism in neutrophils.

The aim of this study was to evaluate the effect of fat emulsion administration on neutrophil arachidonic acid and leukotriene B4 (LTB4) generation in surgically stressed patients. Total parenteral nutrition was administered to 17 patients for 2 wk after esophagectomy for carcinoma. Eight patients received fat with glucose (fat group, 30% of total calories) and 9 patients received glucose (glucose group) as a non-protein calorie source from the day of the operation to the seventh postoperative day (POD), and they gradually were converted to enteral nutrition during the second postoperative week. The arachidonic acid in the fat group decreased in the serum from POD 4 to 14. and in neutrophils from 12 h after the beginning of surgery to POD 14, compared to preoperative levels. LTB4 production by A23187-stimulated neutrophils was highest 6 h after the beginning of surgery, when neutrophil arachidonic acid concentration was decreasing, and then fell below the preoperative value from POD 4 to 14 in both groups. LTB4 production on POD 14 was lower in the fat group than in the glucose group. Biosynthesis of arachidonic acid from linoleic acid is inhibited in surgically stressed patients receiving fat emulsion, resulting in the diminished synthesis of LTB4 by neutrophils. The decrease in LTB4 may diminish chemotactic and chemokinetic signals to other leukocytes.

N-acetyl cysteine inhibits cell cycle progression in pancreatic carcinoma cells.

The antioxidant N-acetyl cysteine (NAC) is a precursor of intracellular glutathione (GSH) and is also a well known as one of the chemopreventive agents which act through a variety of cellular mechanisms. We examined the effects of NAC on cell cycle progression in the pancreatic carcinoma cell lines, SW1990 and JHP1. Cells were incubated with or without NAC. Cell cycle distribution was analyzed by flow cytometry and immunoblotting. NAC suppressed cell proliferation in a concentration-dependent manner, whereas NAC increased intracellular glutathione content significantly in a dose-dependent manner. The percentage of cells in the G1 phase after treatment with NAC was significantly higher than the percentage seen for control cells. Cyclin D1 expression of carcinoma cells treated with NAC decreased remarkably compared with cells without NAC treatment. Thus, the antiproliferative effect of NAC by prolongation of the G1 phase in human pancreatic carcinoma cells shows its possible utility as an antitumor agent.

Positive impact on surgical treatment for asymptomatic patients with esophageal carcinoma.

BACKGROUND/AIMS: The prognosis of patients with esophageal carcinoma remains unsatisfactory. The purpose of this study was to clarify the clinicopathologic characteristics of asymptomatic patients. METHODOLOGY: We retrospectively compared 78 cases of asymptomatic esophageal carcinoma (AEC) with 341 cases of symptomatic esophageal carcinoma (SEC). RESULTS: In 47 of 78 patients with AEC, the tumors were discovered by mass screening and in 31 patents by follow-up examination for other disease. Nearly 70% of the patients with AEC had a carcinoma in situ (Tis) or T1 tumor, whereas nearly 70% of the patients with SEC had T3 or T4 tumors. The incidences of lymph node metastasis, lymphatic invasion and vascular invasion were significantly lower in patients with AEC than in those with SEC. The 5-year survival rate in AEC and SEC were 59.3% and 22.9%, respectively. With regard to the cause of death, 26.8% (11/41) of patients with AEC and 59.9% (166/277) of patients with SEC died of esophageal carcinoma. CONCLUSIONS: In order to improve the prognosis of esophageal carcinoma, an effort should be made to detect early esophageal carcinoma among patients at risk for tumors when they are still asymptomatic.

Analysis of macroscopic appearance and p53 expression in superficial esophageal carcinoma.

BACKGROUND/AIMS: The purpose of the present study was to investigate the relationship between macroscopic appearance of superficial esophageal carcinoma, with particular attention to the horizontal and vertical extent of tumor growth, clinicopathologic findings and p53 expression. METHODOLOGY: Eighty-seven patients with superficial esophageal carcinoma were divided into three groups: 1) group A, patients with protruding or distinct depressed lesions (n = 28); 2) group B, patients with superficial and flat lesions > or = 5 cm in length (n = 45); and, group C, patients with superficial and flat lesions (5 cm in length (n = 14). Tumors were examined immunohistochemically for p53 expression. RESULTS: The incidence of submucosal invasion, lymph node metastasis and lymphatic invasion was significantly higher in group A than in groups B and C. The rate of p53 expression was significantly lower in group B than in the other two groups. The prognosis in groups B and C was better than that in group A. CONCLUSIONS: Vertical extent was more strongly associated with tumor depth, lymph node metastasis and prognosis than was horizontal extent, although p53 overexpression was related to both the vertical and horizontal extent of tumors. Analysis of the macroscopic appearance of superficial esophageal carcinoma is useful in choosing treatment strategies.

Does preoperative chemotherapy cause adverse effects on the perioperative course of patients undergoing esophagectomy for carcinoma?

The aim of this study was to clarify whether preoperative chemotherapy caused adverse effects on the perioperative course of patients undergoing esophagectomy. A total of 42 esophageal cancer patients were entered into a randomized trial and were analyzed. Twenty-one patients were assigned to immediate surgery (Surgery Group). The other 21 received two 5-day courses of chemotherapy comprising cisplatin (70 mg/m2) on day 1, and fluorouracil (700 mg/m2) and leucovorin (20 mg/m2) on each of days 1 to 5 (chemotherapy group). Hospital mortality comprised of one patient (2.3%) who had undergone an operation in the beginning of this series at 21 days after chemotherapy. Thereafter, the interval between the chemotherapy and operation was prolonged, with the average being 35 +/- 7 days. Preoperatively, both the lymphocyte counts and serum albumin levels were not increased in the chemotherapy group of patients even though their body weights increased. In the chemotherapy group, the operation time and the blood loss were increased and, on the 1st postoperative day, the development of systemic inflammatory response syndrome was high but the level of C-reactive protein was low. The incidence of positive microbial cultures of sputum and/or wound discharge within 8 postoperative days was higher in the chemotherapy group (42.9%) than in the surgery group (4.8%). The host defense damage caused by chemotherapy may be prolonged and may show adverse effects in patients undergoing esophagectomy in the early postoperative period. Minimally, a 4-week interval between the completion of chemotherapy and operation is recommended for preventing surgical mortality related to the preoperative chemotherapy.

The role of neoadjuvant radiochemotherapy using low-dose fraction cisplatin and 5-fluorouracil in patients with carcinoma of the esophagus.

OBJECTIVE: We clarified the role of neoadjuvant radiochemotherapy in patients with carcinoma of the esophagus and compared it to neoadjuvant chemotherapy. METHODS: We retrospectively examined 40 patients diagnosed with advanced thoracic esophageal carcinoma who underwent neoadjuvant therapy followed by esophagectomy between 1993 and 1999. We divided them into 2 groups: radiochemotherapy (17) and chemotherapy (23). Radiochemotherapy patients underwent 40 Gy radiation and low-dose fraction cisplatin (7 mg/body/day, 5 days a week x 4 weeks) and 5-fluorouracil (350 mg/body/day x 28 days). Chemotherapy patients received high-dose fraction cisplatin/5-fluorouracil involving 2 courses of cisplatin (70 mg/m2/day on day 1) and 5-fluorouracil (700 mg/m2/day on days 1-5). RESULTS: Complete pathological response was 17.6% in the radiochemotherapy group and 0% in the chemotherapy group respectively. No hospital mortality occurred in the radiochemotherapy group, and 1 of the 23 chemotherapy patients died in the hospital due to postoperative complications. The incidence of residual tumors was significantly higher in the chemotherapy group (34.8%) than in the radiochemotherapy group (0%). Actuarial survival in the radiochemotherapy group at 1 year was 80.2% and at 3 years 53.5%. Actuarial survival in the chemotherapy group at 1 year was 56.5% and at 3 years 30.4%. CONCLUSIONS: Histological effectiveness was greater in patients treated with preoperative radiochemotherapy than those treated with preoperative chemotherapy. The combination of radiation and low-dose fraction CDDP/5-FU thus is first choice in neoadjuvant radiochemotherapy for the advanced esophageal carcinoma.

[Postoperative changes in acute phase protein in patients with esophageal cancer].

Thirty-three patients with esophageal cancer were studied to assess the relationship between nutritional state and the acute phase protein responses. Blood samples taken preoperatively and days 1, 4, 7 and 14 after operation were analyzed for C-reactive protein, fibrinogen, alpha 1-antitrypsin, alpha 1-acid glycoprotein and haptoglobin. Significant Spearman's coefficients were found between percent of ideal body weight (IBW) and alpha 1-acid glycoprotein (r = -0.42), between prealbumin and alpha 1-anti-trypsin (r = -0.55), and between retinol-binding protein and alpha 1-antitrypsin (r = -0.51). Postoperatively, the levels of C-reactive protein, fibrinogen, alpha 1-anti-trypsin and alpha 1-acid glycoprotein were significantly lower in the poorly nourished group than in the other groups. The changes of acute phase proteins in the immediate postoperative period were affected by the preoperative nutritional state, and were less marked in the poorly nourished patients. Between two groups of patients in whom lymph node dissection was carried out in 2 or 3 areas, no significant differences were observed in the acute phase protein responses postoperatively. The measurement of acute phase proteins is very important in assessing the body defense capacity of the patient, but it should be noted that the changes may be affected by several factors including malnutrition.

[Significance of preservation of tracheal proper sheath at the time of cervical and upper mediastinal lymph node dissection for thoracic esophageal cancer].

Extended lymph node dissection in the neck and upper mediastinum often brings about postoperative pulmonary complications. Since September 1987, we have performed this type of lymph node dissection in 18 patients paying special attention to the preservation of tracheal proper sheath along with left bronchial artery and autonomic nerve branches. We compared their postoperative respiratory and circulatory outcomes with those of 17 patients in whom lymph node dissection was carried out without consideration for these aspects. Tracheal mucosal damage, respiratory functional parameters such as PaO2, AaDO2 and Qs/Qp and actual incidence of pneumonia significantly improved in recent cases undergoing meticulous dissection in the neck and upper mediastinum. However, neither circulatory dynamics nor incidences of recurrent nerve palsy and arrhythmia showed a significant improvement. The postoperative period required for reappearance of cough reflex was shorter in this group of patients, but the difference was not significant. The results indicated that pulmonary disorders occurring frequently after extended lymph node dissection for thoracic esophageal cancer was able to be well controlled by meticulous dissection procedure as mentioned above.

[Clinicopathological studies of the recurrence of esophageal squamous cell cancer--with special reference to the mode of recurrence and operative procedure].

In 93 out of 201 patients (46%) with squamous cell carcinoma of the esophagus who underwent radical resection (excluding death within 30 days after operation), the site of recurrence could be identified by means of X-ray, CT, ultrasonography, and biopsy. Recurrence was found in 55% of 93 cases within 12 months after surgery and in 86% of 93 cases within 24 months. Of 93 patients with recurrences, lymph node recurrences were present in 44 cases, visceral recurrences in 32 cases, both lymph node and visceral recurrences in 11 cases and others in 6 cases. Neck and/or upper mediastinal lymph node recurrences were found in 10 out of 15 patients who had recurrences within 3 months after surgery. Careful examination should be made in the left recurrent nerve chain and extended lymph node resection of upper mediastinal region should be performed under the adequate indication. Esophageal squamous cell cancer has a tendency to recur in the lymph nodes initially, and visceral metastases may occur thereafter. The incidence of visceral recurrence increased remarkably, when neck and/or upper mediastinal lymph nodes were involved at the time of operation. Accordingly, both irradiation and chemotherapy should also be applied for improving the prognosis of esophageal carcinoma.

[A study on the changes in the tracheo-bronchial mucosa after esophagectomy for esophageal cancer; with special reference to the influence of neck and upper mediastinal lymph node dissections].

The tracheo-bronchial mucosa of 27 surgical patients with esophageal cancer was examined by bronchofiberscope postoperatively, and the changes of the mucosa were divided into four grades, i.e., GI: no change or slight redness only (7 cases), GII: Severe redness or erosion (7 cases), GIII: Ulcer formation (11 cases) and GIV: Necrosis of the mucosa (2 cases). All the GI-III changes were reversible. However, GIV change was irreversible. The biopsy specimens were taken from the mucosa of the tracheal bifurcation on the 7th postoperative day, showing squamous metaplasia in 9 of 13 patients. Bilateral modified neck and upper mediastinal lymph node dissections were performed in 18 of 27 patients. The change of the mucosa was judged as GIII or IV in 12 of 18 patients (67%), whereas the change was less significant in the remaining 6 patients. Namely, the degree of mucosal change did not necessarily correspond with the extent of lymph node dissection. The changes of the mucosa were considered to be brought about not only by tracheo-bronchial ischemia but also by injurious effects on the pulmonary parenchyma following aggressive lymph node dissection. The assessment of the degree of the mucosal change might be a useful indicator for postoperative management of esophageal cancer patients.