Surgical trauma-induced adrenal insufficiency is associated with postoperative inflammatory responses.

The hypothalamic-pituitary-adrenal axis is an essential component for the maintenance of homeostasis following trauma. Major surgical trauma often induces overwhelming inflammatory responses leading to sepsis and organ dysfunction. This study was designed to evaluate the adrenal responses both before and after various degrees of surgical trauma and to determine the incidence of postoperative relative adrenal insufficiency resulting in the marked inflammatory response often associated with postoperative complications. Fifty-one surgical patients were divided into groups who underwent major, moderate, and minor surgeries. Before the operation and during resting conditions, a short corticotropin (ACTH) stimulation test was performed in each patient. The postoperative concentrations of serum cortisol, interleukin (IL)-6, IL-10, C-reactive protein (CRP), and plasma ACTH were measured. Fifty of 51 patients were identified as responders to ACTH. The postoperative cortisol levels were the same as those obtained by ACTH stimulation in highly and moderately stressful surgeries. The increases in postoperative IL-6 and CRP levels were greatest with major surgery, intermediate with moderate surgery, and least with minor surgery. Furthermore, plasma ACTH levels increased after major and moderate surgeries; however, there was no significant differences in postoperative serum IL-10 levels. Systemic inflammatory response syndrome (SIRS) was found in 11 of 17 patients (64.7%) who underwent major surgery and in 4 of 16 patients (25%) who underwent moderate surgery (p=0.037). The duration of SIRS was significantly longer in patients undergoing major surgery (62+/-20 hrs) than in patients undergoing moderate surgery (21+/-3 hrs, p=0.038). Postoperative complications were more frequent in patients undergoing major surgery (41.2%) than in patients undergoing moderate surgery (6.3%, p=0.039). Furthermore, there were significant differences in the length of the postoperative stay among the three groups (p<0.01). One nonresponder had serious postoperative inflammatory complications. These results suggest that a short ACTH stimulation test performed preoperatively is a helpful method for determining the maximal cortisol response to surgical trauma and to identify high-risk individuals and that a relative postoperative adrenal insufficiency may be closely related to the decreased cortisol secretion following major surgical trauma.

Argon plasma coagulation for the treatment of superficial esophageal carcinoma.

AIMS: Recently, endoscopic mucosal resection (EMR) has become the first choice of treatment for superficial esophageal cancer without metastasis. However, EMR is not safe for all patients. Argon plasma coagulation (APC) is a noncontact electrocoagulation technique that creates tissue damage. The risk of bleeding may be lower with APC than with EMR. Therefore, we selected APC for the treatment of patients with superficial esophageal cancer who could not undergo EMR. The aim of the present study was to describe these cases and analyze the results of this treatment. PATIENTS AND METHODS: Ten patients with superficial esophageal cancer underwent APC at our institution from February 2001 through January 2002. None of the patients could undergo EMR because of complications. Ablation was performed using an APC probe (ERBE APC probe; ERBE Elektromedizin, Tübingen, Germany), a high-frequency electrosurgical generator (ERBE ICC200), and an argon delivery unit (ERBE APC 300). All patients had uneventful recoveries. RESULTS: No incidents of bleeding from the ablated lesion or infection occurred. Oral intake was resumed on the day after treatment. The mean duration of the procedure was 20 minutes (range, 10 to 40 minutes). Disease recurred in two patients. Two patients died of laryngeal cancer and liver failure, respectively. CONCLUSION: APC is a safe and easy to perform procedure, but the effect of therapy is inferior to that of EMR in terms of the complete resection of the lesion. In conclusion, APC should be limited to cases of superficial esophageal cancer without metastasis in which EMR has been deemed difficult.

[Three advanced gastric cancer patients successfully treated by combination therapy of paclitaxel and cisplatin].

We report 3 gastric cancer patients with peritoneal dissemination who were successfully treated with weekly paclitaxel and cisplatin. The patients were 2 men and 1 woman from 57 to 70 years in age. The histological types were 2 poorly-differentiated adenocarcinomas and 1 moderately-differentiated adenocarcinoma. Intravenous infusion of PTX (80 mg/m(2)) and CDDP (25 mg/m(2)) after short premedication was continued for 3 weeks followed by 1 week rest. Ascites improved only after administration of 1 course in all patients.PTX/CDDP is thought to be an effective chemotherapy showing acceptable toxicity against advanced gastric cancer with ascites.

[Prediction of sensitivity to 5-fluorouracil (5-fu) by metabolic and target enzyme activities in colon cancer].

BACKGROUND: 5-Fluorouracil (5-FU) and its derivatives are widely known as some of the most commonly prescribed anticancer drugs, especially for gastrointestinal cancer. Orotate phosphoribosyl transferase (OPRT), dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are initial key enzymes in the 5-FU metabolic pathway. The activities of these enzymes may have the potential to affect the chemosensitivity of 5-FU. PURPOSE: This study was designed to investigate the effect of OPRT, DPD and TS in sensitivity to 5-FU. METHOD: We measured OPRT, DPD and TS activities in 11 colonic cancer tissues. The Collagen Gel Droplet Embedded Culture Drug Sensitivity Test (CD-DST) was used in an in vitro chemosensitivity assay. In these samples, the correlation between sensitivity to 5-FU and enzyme activities was investigated. RESULTS: There were no correlations among OPRT, TS activities and sensitivity to 5-FU. In contrast, there was a significant inverse correlation (r=-0.738) between DPD activity and 5-FU sensitivity. With regression analysis, the coefficient of determination of the activity of the three enzymes versus the sensitivity to 5-FU was 0.61. CONCLUSION: Though measuring OPRT, DPD, TS activities is valuable for prediction of sensitivity to 5-FU, DPD is considered to be the most important predictive factor of 5-FU sensitivity. To improve its accuracy, the finding of a fourth factor such as P-glycoprotein and multidrug resistance-associated proteins (MRP), to be added to OPRT, DPD and TS, is desired.

Lumican expression in advanced colorectal cancer with nodal metastasis correlates with poor prognosis.

Lumican is a member of a small leucine-rich proteoglycan family, and it is reportedly overexpressed in human breast cancer. The expression of lumican in the extracellular matrix in breast cancer is associated with a high tumor grade, low estrogen receptor levels and young age. Lumican expression has been previously reported in colorectal cancer, but the role of lumican in the tumor is not well understood. In this study, we examined the expression and role of lumican in advanced colorectal cancer. Immunohistochemical staining was performed on 158 patients who underwent curative surgery for advanced colorectal cancer with lymph node metastasis. In the normal colorectal tissues, lumican immunoreactivity was observed in the fibroblasts and neural cells, but not in the colorectal epithelial cells. Lumican was localized in the cytoplasm of the cancer cells and its overexpression was detected in 99 of the 158 (62.7%) colorectal cancer patients. Clinicopathologically, there was no association of lumican expression with age, sex, histological typing, or venous and lymphatic invasion. However, lumican expression tended to correlate with the spread of lymph node metastasis and the depth of tumor invasion (p=0.136 and 0.135, respectively). Furthermore, the survival rate was significantly lower in patients with a high lumican expression level than in those with a low lumican expression level (p=0.048). These results indicate that lumican expression is a potential prognostic factor in patients with advanced colorectal cancer with nodal metastasis.

[Correlation between clinical pathologic factors and enzymatic activity of orotate Phosphoribosyl transferase (OPRT), Dihydropyrimidine dehydrogenase (DPD) and Thymidylate synthase (TS) in colorectal cancer].

Orotate Phosphoribosyl Transferase (OPRT), Dihydropyrimidine dehydrogenase (DPD) and Thymidylate synthase (TS) are initial key enzymes in the 5-FU metabolic pathway. In this study, we measured the activities of OPRT, DPD and TS. We also investigated the correlation between these 3 enzymatic activities and the clinical pathologic factors (Histological typing, extent of tumor invasion,extent of metastasis to the lymph nodes,stage, lymphatic invasion and venous invasion). We had surveyed 79 cases of colorectal cancers surgically removed. Poorly-differentiated adenocarcinoma showed a tendency to lower OPRT and higher DPD, as compared to moderately or well-differentiated adenocarcinomas. In case with metastasis to lymph nodes, OPRT showed a tendency to lower activities, but a significant difference was not noticed. TS showed no relation to any of these pathologic factors. In each application of 5-FU, measuring the activities of these three enzymes is important for estimation of the antitumoral effect. With poorly-differentiated adenocarcinoma, it is estimated that many cases would show high DPD and if the enzyme activities can not be measured, so administration of TS-1, which includes DPD inhibitor, may be considered.

Helicobacter pylori infection increases the risk of colorectal adenoma and adenocarcinoma, especially in women.

BACKGROUND: Recent reports suggest that Helicobacter pylori infection can potentially increase the risk of colorectal cancer. The purpose of this study was to assess the association between H. pylori infection and the risk of colorectal adenoma and adenocarcinoma, and to evaluate any differences on the basis of sex. METHODS: The subjects were 669 (40- to 80-year-old) patients who underwent both barium enema examination and total colonoscopy, and who were evaluated for H. pylori infection by (13)C-urea breath test, urease test, or histological diagnosis of biopsied gastric specimens. There were 142 H. pylori-negative and 527-positive patients. The odds ratios (ORs) for H. pylori-positive patients with colorectal adenoma and adenocarcinoma, and for tumor patients with either adenoma or adenocarcinoma were calculated. RESULTS: Among the H. pylori-negative patients, there were 52 patients without tumor, 63 with adenoma, 27 with adenocarcinoma, and 90 with tumor. Among the H. pylori-positive patients, there were 136, 264, 127, and 391 patients respectively. Pooling all subjects, those infected with H. pylori had a significantly increased OR for adenoma, adenocarcinoma, or tumor, compared to H. pylori-free patients (OR, 1.60, 1.80, and 1.66, respectively). For female H. pylori-positive subjects, the risk of having adenocarcinoma or tumor was significantly higher than that for their H. pylori-free counterparts, while for male H. pylori-positive and -negative subjects, there was no such significant difference. CONCLUSIONS: The results therefore suggest that, in patients aged 40-80 years, H. pylori infection increased the risk of colorectal adenoma and adenocarcinoma, with significantly higher risks for female patients.

[Argon plasma coagulation in Barrett's esophagus].

Argon plasma coagulation (APC) is noncontact electrocoagulation technique that creates tissue damage. Recently, it has been reported that Barrett's esophagus and Barrett's adenocarcinoma in situ could be successfully managed by APC. The aims of this treatment are to prevent the developing of adenocarcinoma and to promote the restitution of normal squamous epithelium. Combined antireflux surgery or proton pump inhibitor therapy are indispensable to this treatment. Shorter length of Barrett's epithelium and normalization in pH with PPI treatment were the independent predictors of sustained long-term restitution of squamous epithelium. In patient with Barrett's esophagus, APC offers an effective, minimally invasive alternative to other treatments previously performed.

A study of histopathological assessment criteria for assessing malignancy of gastrointestinal stromal tumor, from a clinical standpoint.

BACKGROUND: As no established histopathological criteria exist for assessing the malignant potential of gastrointestinal stromal tumor (GIST), recurrence or metastasis is occasionally observed in lesions diagnosed histopathologically as benign. The present study aimed to clarify the histopathological criteria for assessing the malignancy of GIST, from a clinical standpoint. METHODS: The subjects were 22 patients with GIST expressing CD117 (c-kit) and/or CD34, who were followed up for more than 2 years. Clinically, GIST malignancy was diagnosed if any of the following criteria were met: peripheral invasive growth, lymph node metastasis, metastasis to another organ, peritoneal dissemination, recurrence, or death. GIST was also categorized as either benign or malignant by a new histological malignancy classification system, based on the determination of significant factors indicating malignancy in the clinical classification system above. RESULTS: Significant factors for malignancy identified in the clinical malignancy classification were: tumor hemorrhage/necrosis (present vs absent; P = 0.0053), tumor size (<5 cm vs > or =5 cm; P = 0.0022), and Ki-67 labeling index (<3% vs > or =3%; P = 0.0002). A new histological malignancy classification, based on a combination of these three factors, was developed. A significant correlation existed between the clinical system and the new histological malignancy classification system (P = 0.0008). The recurrence-free survival rate was 100% in the histologically benign cases and 37.5% in the histologically malignant cases (P = 0.0012). CONCLUSIONS: The new histological malignancy classification for GIST was demonstrated to be useful from a clinical standpoint.

Correlation of hypoxia inducible factor-1alpha with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer.

Hypoxia inducible factor (HIF)-1alpha is a transcription factor that regulates the transcription of genes associated with cell proliferation and vascular development. In various cancer tissues, HIF-1alpha is associated with clinicopathological factors, such as the tumor size, histological grade, and lymph node status. Although HIF-1alpha plays a critical role in tumor growth by inducing vascular endothelial growth factor (VEGF), it is unclarified whether HIF-1alpha affects lymphatic metastasis. The purpose of this study is to clarify the correlation of HIF-1alpha protein expression with lymph node metastasis in esophageal squamous cell carcinoma (ESCC). The expressions of HIF-1alpha and VEGF-C, which is one of the main lymphangiogenic factors, were examined in five ESCC cell lines and 48 surgical specimens of ESCC. HIF-1alpha and VEGF-C mRNAs were expressed in all the five ESCC cell lines as determined by RT-PCR analysis. Immunohistochemically, 34 of the 48 patients (70.8%) were positive for HIF-1alpha and 29 patients (60.4%) were positive for VEGF-C. Clinicopathologically, HIF-1alpha expression correlated with lymphatic invasion and VEGF-C expression (P = 0.003 and P = 0.01, respectively). Furthermore, HIF-1alpha expression tended to correlate with lymph node metastasis (P = 0.09). These findings suggest that HIF-1alpha plays a role in lymphatic invasion and lymph node metastasis through the induction of VEGF-C in ESCC.

High efficacy of imatinib for recurrent gastrointestinal stromal tumor in the jejunum: a case report.

Gastrointestinal stromal tumor is a mesenchymal tumor of the digestive tract. Although there used to be no effective therapy for the tumor, there have been many recent reports on the efficacy of imatinib. We report on a 53-year-old female patient with a primary tumor of the jejunum who underwent 3 operations. As the tumor could not be removed at the 3rd operation, she was given imatinib orally. Results showed significant reduction ratios of the tumor area (83.0%) and volume (92.2%) at 18 months after starting imatinib administration. Also, the mean reduction ratios of the tumor area and volume per month (%/M) after starting imatinib treatment showed remarkable results, especially during the initial 3 weeks: 53.9%/M and 49.5%/M, respectively. Whether imatinib is the first choice of treatment for GIST or not, and what is the appropriate dose and period should be resolved.

Detection of lymph node micrometastasis in esophageal carcinoma.

BACKGROUND/AIMS: The presence of lymph node metastasis is the most important prognostic factor in esophageal squamous cell carcinoma. Molecular biology techniques have improved the ability to recognize micrometastasis in lymph nodes, bone marrow, and peripheral blood. Previous studies have demonstrated that cytokeratin 19 reverse transcriptasepolymerase chain reaction can detect tumor cells even when lymph nodes appear normal histologically. However, the presence of pseudogenes for cytokeratin 19 have reduced the specificity of reverse transcriptase-polymerase chain reaction, thereby reducing its clinical worth as a sensitive diagnostic technique. METHODOLOGY: We examined the expression of mRNA for cytokeratin 19 using a newly designed set of primers, and compared the results with data from histologic examinations. Samples were obtained from tumors, intact tissues, resected lymph nodes and in 10 patients who underwent esophagectomy via right thoracotomy with lymph node dissection in the neck, mediastinum and abdomen. RESULTS: All tumors, non-cancerous tissues were positive for cytokeratin 19 by reverse transcriptasepolymerase chain reaction. However, 2 of the 6 lymph nodes that appeared normal on histologic examination were positive for cytokeratin 19; sensitivity and specificity were 100% and 67%, respectively. CONCLUSIONS: Reverse transcriptase-polymerase chain reaction using new primers for cytokeratin 19 detected micrometastasis in specimens of lymph nodes from patients with squamous cell carcinoma. This method may increase the accuracy of tumor staging and provide clinicians with valuable information that will help individualize treatment options.

Biological behavior of mucoepidermoid carcinoma of the esophagus.

Mucoepidermoid carcinoma of the esophagus (MEC) is uncommon and has not been fully investigated. The biological behavior and clinical aspects of MEC were studied. The clinical features of eight patients with MEC were compared with 51 cases of squamous cell carcinoma of the esophagus (SCC). Proliferating cell nuclear antigen (PCNA), p53, and carcinoembryonic antigen (CEA) were stained in the resected specimens by immunohistochemistry. Seven out of 8 cases (87.5%) had stage III by TNM classification. Four cases died of widespread metastases and 2 cases died of local recurrence within 2 years after the surgery. Neither chemotherapy and radiotherapy were effective against MEC. Overall median survival periods were 10.8 months for MEC and 32.1 months for SCC (P<0.05). When patients in stage III alone were compared, MEC tended to have a worse prognosis than SCC (P=0.058). Immunohistochemical studies revealed that the positive rates of PCNA and CEA were significantly higher in MEC than in SCC (P<0.05), while there was no significant difference in p53 positive rate. Esophageal MEC had an aggressive biological nature and was resistant to adjuvant therapies. The poor prognosis of esophageal MEC may be caused by high proliferative and metastatic potential.

Intracystic hemorrhage of a simple hepatic cyst.

An unusual case involving hemorrhage of a benign intrahepatic cyst in which the correct diagnosis was made preoperatively is reported. A 60-year-old man presented with acute onset of left upper quadrant abdominal pain. On admission, computed tomography and ultrasonography revealed an 8-cm hepatic cyst in the left lateral segment of the liver. Serum concentrations of CA19-9 (170 mu/mL), DUPAN2 (1600 mu/mL), and SPAN1 (94 mu/mL) were elevated. Twenty-three days after admission, magnetic resonance imaging revealed a hyperintense 13-cm lesion that appeared heterogeneous on T1-weighted sequences and relative hypointensity of the bottom on T2-weighted sequences. Percutaneous transhepatic drainage of the cyst was performed 27 days after admission, and serosanguineous fluid was obtained; abdominal pain resolved. Tumor marker concentrations decreased by 1 week after drainage. Six days after drainage, the drainage fluid became purulent. The infection persisted and a left lateral segmentectomy and cholecystectomy were performed 24 days after the cyst was drained. Pathology confirmed that the cyst was benign. The use of magnetic resonance imaging and tumor markers may allow the differentiation of benign hepatic cyst from malignant lesions and obviate the need for surgery.

The natural history of gastric varices.

BACKGROUND/AIMS: Recent improvements in the treatment of gastric varices have resulted in better rates of hemostasis and eradication. This prospective study was conducted in order to examine the natural history of gastric varices and whether prophylactic treatment is required. METHODOLOGY: Between January 1991 and December 1996, 52 patients with cirrhosis and no history of prior variceal treatment were enrolled. RESULTS: Bleeding from gastric varices occurred in 4 patients. Hemorrhage was stopped successfully in all of these patients. The cumulative bleeding rates at 1, 3, and 5 years were 3.8%, 9.4%, and 9.4%, respectively. Erosive gastritis or gastric ulcer was not detected in 3 of these 4 patients at the time of entry into the study, although an ulcer or erosion was found at the point of gastric variceal hemorrhage in all four patients at the time of variceal rupture. There were no significant differences in patient characteristics with ruptured versus non-ruptured varices at the time of their study entry. CONCLUSIONS: Factors which could be used to predict bleeding from gastric varices were not identified. Furthermore, the overall incidence of hemorrhage from gastric varices was found to be low. Once gastric variceal hemorrhage did occur, bleeding from these varices was successfully stopped in all cases. Therefore, prophylactic treatment of gastric varices is not recommended.

New techniques: combined endoscopic injection sclerotherapy and ligation for acute bleeding from gastric varices.

BACKGROUND/AIMS: Combined endoscopic injection sclerotherapy and endoscopic variceal ligation was used for the treatment of acute bleeding from gastric varices. METHODOLOGY: Between July 1995 and August 1998, three cirrhotic patients with acute bleeding from gastric varices were treated. Endoscopic variceal ligation of the puncture point and bleeding point was performed simultaneously. RESULTS: Acute bleeding from the gastric varices was successfully stopped in all cases. CONCLUSIONS: Combined endoscopic injection sclerotherapy and endoscopic variceal ligation can be used to stop bleeding and prevent rebleeding from gastric varices.

Endoscopic scleroligation is a superior new technique for preventing recurrence of esophageal varices.

This study compared a new method, endoscopic scleroligation, intravariceal injection sclerotherapy followed by ligation plus extravariceal injection sclerotherapy, with ligation plus extravariceal injection sclerotherapy. Fifty-nine patients with cirrhosis and esophageal varices were treated by endoscopic scleroligation (ESL group, n = 28) or ligation plus extravariceal injection sclerotherapy (EVL + extraEIS group, n = 31). The demographics and clinical characteristics of the two treatment groups were similar, as was the rate of complete eradication with initial treatment. However, the 1- and 3-year cumulative recurrence rates in the ESL group (3.8% and 22.4%) were very significantly lower than those in the EVL + extraEIS group (48.3% and 81.0%) (p < 0.0001). The overall survival rates in the two groups were similar. In conclusion, endoscopic scleroligation is superior to ligation plus extravariceal injection sclerotherapy in preventing variceal recurrence. The efficacy of intravariceal injection sclerotherapy before ligation is believed to arise from the eradication of feeder vessels.

International airport and emergency medical care.

The Nippon Medical School New Tokyo International Airport Clinic (Airport Clinic) was opened in 1992 as Japan's first 24-hour international airport clinic. To date, it has provided medical services to a total of 117,953 patients. Of these, 85,545 (72.5%) were airport employees, 28,662 (24.3%) were passengers, and 3,746 (3.2%) were others. Of the total, non-Japanese patients accounted for 8,485 (7.2%). In the year to March 31, 2001, the Clinic treated an average of 43.9 cases per day. The number of emergency patients was 2,969 or 2.3% of the total, of whom 500 (0.4%) were non-Japanese. There were 47 deaths, with age ranging from 14 to 84 (average age 64.0). The ratio of males to females who died was 28:19. Of the 47 deaths, 18 were non-Japanese. Pulmonary thromboembolism is considered to have played a role in 25 of the deaths. Based on more than 8 years of airport clinical experience, we believe that a first-class international airport should have excellent medical facilities that can provide quality emergency medical services to travelers and disaster victims.