Hydralazine-induced liver injury

Summary A 68-year-old man developed hepatic injury with no hypersensitivity reaction after three years of hydralazine therapy. The liver injury histologically showed centrilobular zonal necrosis. Clinical, biochemical, and histological recovery followed discontinuation of the drug. Challenge tests and serial liver biopsies revealed that this liver injury was induced by hydralazine.     

Specific Detection of Metastasized Human Tumor Cells in Embryonic Chicks by the Polymerase Chain Reaction

We have established a highly sensitive method for specific detection of metastasized human tumor cells in embryonic chicks using the polymerase chain reaction (PCR). The cells (HT-1080 or KMST-6) were inoculated into the chorioallantoic membrane vein of the chick embryo and DNA of each embryonic organ was extracted. Then, a human β-globin-related sequence (576 bp) in the DNA from the embryonic liver and lung was specifically amplified and detected by gel electrophoresis and by a specific oligonucleotide probe. The amplified fragments from the liver DNA samples increased gradually from 2 h to 7 days after HT-1080 inoculation. On the other hand, with inoculation of non-tumorigenic human embryonal fibroblast KMST-6 cells, the DNA from the embryonic liver 7 days after inoculation did not show the PCR-amplified product. This detection technique can contribute significantly to the precise detection of microscopic metastasis.     

Risk factors for early death due to recurrence after liver resection for hepatocellular carcinoma: results of a multicenter study

BACKGROUND AND OBJECTIVES: Recurrence after partial liver resection for hepatocellular carcinoma (HCC) is a major cause of death from this disease. To identify risk factors for early death from recurrence after liver resection for HCC. METHODS: All 547 patients in this study had greater than 1 year of follow-up after complete resection of HCC (1980-1999) at one of the four hepatobiliary centers in Japan, France, and the United States. Patients who died of recurrence < or =1 year post-resection and all of those alive at least 1 year were compared. Survival and clinicopathological factors associated with death from recurrence within 1 year of resection were analyzed. RESULTS: Overall postoperative mortality rate was 5%. In the first postoperative year, 123 (22%) patients died. Of these, 53 (43%) died of recurrence, 30 (24%) of postoperative complications, and 40 (33%) of liver failure/hemorrhage. On multivariate analysis, tumor size greater than 5 cm (P < 0.02; odds ratio, 3.0), multiple tumors (P < 0.01; odds ratio, 3.3), and greater than 5 mitoses per 10 high-power fields (P < 0.03; odds ratio, 3) were associated with increased risk of early death due to recurrence. CONCLUSIONS: These findings enable identification of patients with HCC who are at high risk for early death due to recurrence following potentially curative resection who might be candidates for adjuvant therapy trials.     

Expression and localization of MUC1, MUC2, MUC5AC and small intestinal mucin antigen in pancreatic tumors

Alterations in the expression of mucin family members play an important role as well as alterations in oncogenes and onco-suppressor genes in carcinogenesis and progression of pancreatic cancer. We analyzed the expression and localization of MUC1, MUC2, MUC5AC and small intestinal mucin antigen (SIMA) in pancreatic tumors. MUC1 expression was observed in almost all samples, whereas MUC2 expression was not. MUC5AC expression was observed in 73.9% of the cancerous regions, 48.7% of the dysplastic regions and 72.0% of the hyperplastic regions but not in the normal pancreatic duct. SIMA expression was observed in 45.7% of cancerous regions, 17.9% of the dysplastic regions and 8.0% of the hyperplastic regions. Furthermore, stromal expression of MUC1, MUC5AC and SIMA was observed in 37.0%, 60.9% and 26.1% of the cancerous regions, respectively. Stromal expression of these mucins was not observed in the hyperplastic regions and normal pancreatic duct and was observed in only two dysplastic regions. The survival of pancreatic cancer patients with stromal expression of MUC1 or SIMA was worse than that of other patients (P=0.04). In conclusion, the localization of mucin expression, especially stromal expression of MUC1 or SIMA, might be a prognostic factor for patients with pancreatic cancer.     

The role of radiotherapy for thymic carcinoma

OBJECTIVE: The aim of this study is to evaluate retrospectively the role of radiotherapy for thymic carcinoma. METHODS: Between 1973 and 1998, 14 patients with thymic carcinoma were treated at Gunma Prefectural Cancer Center. Two patients who had hematogenous metastasis were excluded from this study, therefore 12 patients were analyzed. The Masaoka staging system was used; four patients were diagnosed with stage III disease and eight patients with stage IV disease. The pathological subtype according to the World Health Organization histological criteria for thymic tumors was squamous cell carcinoma (low-grade histology) in six cases and undifferentiated carcinoma (high-grade histology) in six. Ten patients underwent thoracotomy, and two patients underwent excisional biopsy without thoracotomy. Ten patients (83%) received radiotherapy as a curative intent, and the median dose was 60 Gy. Systemic chemotherapy was administered to four patients (33%), and the majority (75%) of the regimens contained cisplatin. RESULTS: The 3-year overall survival rate was 25%. Histological subtype (low-grade versus high-grade), surgical resection (complete versus incomplete), radiotherapy and chemotherapy were evaluated as prognostic factors in a univariate analysis. Low-grade histology and complete resection were good prognostic factors, although these were not statistically significant. Patients who received radiotherapy had a better outcome than those who did not. The major sites of recurrence were the pleura and pericardium. Recurrence within the radiation field was observed in one of seven patients in whom failure patterns could be evaluated. CONCLUSION: Complete resection is mandatory if possible. Radiotherapy plays an important role in treating thymic carcinoma in terms of reducing local recurrence and prolonging survival time. Establishment of an innovative treatment protocol that includes chemotherapy is necessary to control intrathoracic relapse and distant metastasis.     

Epidermal growth factor receptor regulates aberrant expression of insulin-like growth factor-binding protein 3

Epidermal growth factor receptor (EGFR) is frequently overexpressed in esophageal carcinoma and its precursor lesions. To gain insights into how EGFR overexpression affects cellular functions in primary human esophageal cells, we performed gene expression profiling and identified insulin-like growth factor-binding protein (IGFBP)-3 as the most up-regulated gene. IGFBP-3 regulates cell proliferation through both insulin-like growth factor-dependent and independent mechanisms. We found that IGFBP-3 mRNA and protein expression was increased in EGFR-overexpressing primary and immortalized human esophageal cells. IGFBP-3 was also up-regulated in EGFR-overexpressing cells in organotypic culture and in EGFR transgenic mice. Furthermore, IGFBP-3 mRNA was overexpressed in 80% of primary esophageal squamous cell carcinomas and 60% of primary esophageal adenocarcinomas. Concomitant up-regulation of EGFR and IGFBP-3 was observed in 60% of primary esophageal squamous cell carcinomas. Immunohistochemistry revealed cytoplasmic localization of IGFBP-3 in the preponderance of preneoplastic and neoplastic esophageal lesions. IGFBP-3 was also overexpressed in esophageal cancer cell lines at both mRNA (60%) and protein (40%) levels. IGFBP-3 secreted by cancer cells was capable of binding to insulin-like growth factor I. Functionally, epidermal growth factor appeared to regulate IGFBP-3 expression in esophageal cancer cell lines. Finally, suppression of IGFBP-3 by small interfering RNA augmented cell proliferation, suggesting that IGFBP-3 may inhibit tumor cell proliferation as a negative feedback mechanism. In aggregate, we have identified for the first time that IGFBP-3 is an aberrantly regulated gene through the EGFR signaling pathway and it may modulate EGFR effects during carcinogenesis.     

Randomized phase II study comparing mitomycin, cisplatin plus doxifluridine with cisplatin plus doxifluridine in advanced unresectable gastric cancer

Various chemotherapies have been used to treat inoperable gastric cancer. Most combination therapies include cisplatin (CDDP) and fluoropyrimidine (5-FUs), which are thought of as key drugs. In the present study, we randomly compared mitomycin (MMC) and CDDP plus doxifluridine (5'-DFUR), which is an oral 5-FU and an intermediate metabolite of capecitabine (Xeloda), with CDDP plus 5'-DFUR in advanced unresectable gastric cancer. Regimen A was CDDP (70 mg/m2, by 2-hour intravenous drip infusion on day 1), MMC (7 mg/m2, injected intravenously on day 2), and oral 5'-DFUR (1200 mg/m2, on days 4 to 7, 11 to 14, 18 to 21 and 25 to 28; 3 days rest and 4 days administration). Regimen B was identical to regimen A without MMC. RESULTS: The response rate was 25.0% (8/32 patients) in Regimen A, 17.2% (5/29) in Regimen B (p=0.541). The median survival time was 241 days in Regimen A and 179 days in Regimen B (p=0.498). In Regimen A, although no significant difference was observed, end points such as response rate and suvival improved. Thus, we concluded that a randomized controlled phase III study with more subjects should be conducted.     

Analysis of alteration of p75NTR processing and signalling by PS2 mutation and gamma-secretase inhibition

The presenilins (PSs) were identified as causative genes in cases of early-onset familial Alzheimer's disease (AD) and current evidence indicates that PSs are part of the gamma-secretase complex responsible for proteolytic processing of type I membrane proteins. p75NTR, a common neurotrophin receptor, was shown to be subject to gamma-secretase processing. However, it is not clear if the p75NTR downstream signal is altered in response to gamma-secretase cleavage, and further there is a possibility that AD-related PS mutations may affect this cleavage, resulting in pathogenic alterations in signal transduction. In this study, we confirmed that p75NTR downstream signalling is altered by PS2 mutation or gamma-secretase inhibition in SHSY-5Y cells. The activity of the small GTPase RhoA is strongly affected by these treatments. This study demonstrates that gamma-secretase and PS2 play an important role in regulating neurotrophin signal transduction and either mutation of PS2 or inhibition of gamma-secretase disturbs this function.     

Clinical and immunological studies on patients with Graves' disease preoperatively treated with corticosteroids and iodides

The purpose of this study was to evaluate the acute effects of corticosteroid and iodide preoperative therapy in patients with Graves' disease in terms of thyroid function and immunological parameters. The above combination was prescribed for 4 patients who had experienced severe side effects from antithyroid drugs (ATD) in order to reduce the possibility of post-thyroidectomy thyroid storm. Corticosteroids were employed daily for four days, and iodides were given daily for two weeks prior to thyroidectomy. The free T₃ values decreased rapidly to euthyroid levels following the administration of both drugs, although the free T₄ values were still much higher than normal in 3 of the 4 patients at the time of surgery. By comparison, 3 of 8 patients treated with ATD also had thyroid hormone levels above normal. Studies of lymphocyte subsets revealed that the percentage of helper T cells was significantly less in the corticosteroidiodide treatment group than in the control and ATD groups. It is thus possible that postoperative thyroid storm might be prevented through corticosteroid-iodide therapy by virtue of the reduction of free T₃ values to within the normal range by the time of surgery. The acute suppression of helper T cells was another result of this form of therapy observed.     

Traumatic right coronary arterial-right atrial fistula

A healthy 25 year old man presented with a machinery murmur and a history of a penetrating thoracic injury. Hemodynamic and angiographie evaluation demonstrated a fistula from the right coronary artery to the right atrium that was later successfully repaired. This case and similar reported cases indicate that fistula formation is a late complication of penetrating thoracic injuries. The onset of the murmur occurs with enlargement of the fistula and typically is delayed for several weeks to months after the initial injury.