Shi-Ping Luh

Genetic polymorphisms of XRCC1 and risk of the esophageal cancer.

A variety of environmental factors were identified to be associated with the risk of esophageal cancer. The variation in capacity of DNA repair might influence environmental chemical‐associated carcinogenesis. We hypothesized that the polymorphic XRCC1 genes might modify cancer susceptibility of the esophagus. To investigate the effect of XRCC1 genetic polymorphisms on codons 194, 280 and 399, we evaluated data from 105 patients of esophageal squamous cell carcinoma and 264 healthy controls, matching with age (±3 years), gender and ethnicity. The distribution of the 3 genotypes were not significantly different among patients and controls. However, among alcohol drinkers, the XRCC1399 Arg/Arg genotype was more frequently found in patients with esophageal cancer. After adjustment with other environmental confounders, the OR for the genotype of XRCC1399 Arg/Arg was 2.78 (95% CI =1.15–6.67) as compared with the XRCC1399 Arg/Gln and XRCC1399 Gln/Gln genotypes in the alcohol drinkers. Similar trends were observed among cigarette smokers and areca chewers. However, they did not reach a statistical significance. Our findings suggest that the polymorphic XRCC1 genes might modify the risk of alcohol‐associated esophageal cancers.

Genetic polymorphisms of p53 and GSTP1,but not NAT2,are associated with susceptibility to squamous-cell carcinoma of the esophagus.

The interaction of genetic and environmental factors can determine an individuals susceptibility to various cancers. We present a hospital‐based case‐control study, which included 90 patients of esophageal squamous‐cell carcinoma (ESCC) and 254 healthy people in Taiwan, to investigate the effects of genetic polymorphisms of p53, GSTP1 and NAT2 on the risk of ESCC. Polymorphisms of p53, NAT2 and GSTP1 were determined by PCR‐RFLP. The codon 72 p53 Pro allele was more frequently found in ESCC patients [odds ratio (OR) 1.86, 95% confidence interval (CI) 1.04–3.35 for Arg/Pro genotype and OR 2.56, 95% CI 1.29–5.08 for Pro/Pro genotype]. In cigarette smokers, the frequency of GSTP1 Ile/Ile genotype was higher in ESCC patients (OR 2.8, 95% CI 1.4–5.7). Among alcohol drinkers, borderline significance was also found for GSTP1 Ile/Ile genotype (OR 2.0, 95% CI 0.9–4.4). Results were not similar for the NAT2 genetic polymorphism. Using logistic analyses, we found that individuals with p53 Pro/Pro genotype had a significantly higher risk of developing ESCC than those with Arg/Arg genotype (OR 2.3, 95% CI 1.1–5.1), after adjusting for other significant environmental risk factors. This result remained similar (OR 2.2, 95% CI 1.0–4.8 for p53 Pro/Pro vs. Arg/Arg), even after further adjustment for NAT2 and GSTP1 polymorphisms. The codon 72 p53 Pro/Pro genotype in the general population and GSTP1 Ile/Ile in cigarette smokers may predict a higher risk of developing ESCC. Int. J. Cancer 89:458–464, 2000.

Significance of P53 and Rb Protein Expression in Surgically Treated Non-Small Cell Lung Cancers

BACKGROUND Alterations of the P53 or Rb gene are among the most frequently observed genetic changes in primary lung cancer. Nevertheless, there has been no final conclusion on the relationship between P53 or Rb protein expression and clinico-pathological parameters in primary lung cancer. A large-scale study was performed to examine the clinicopathological and prognostic significance of P53 and Rb expressions in 207 surgically resected non-small cell lung cancer (NSCLC) patients. METHODS Tumor specimens were obtained from 207 primary NSCLC surgically resected from January 1990 through December 1994. The avidin-biotin-peroxidase method was used to determine the expression of P53 or Rb of tumor cells using anti-P53 or anti-Rb monoclonal antibodies. The relationships between P53 or Rb protein expression and the clinicopathological parameters were analyzed. RESULTS Expression of P53 or Rb protein was detected in 115 (55.6%) and 136 (65.7%) of the 207 lung tumors, respectively. P53 had significantly higher positive results in patients with regional lymph node metastasis and advanced tumor stage. Rb expression was significantly lower in lung cancers with a macro- or microscopic picture of tumor necrosis. Additionally, an inverse correlation between the expression of Rb and P53 was found. By multiple variate analysis, P53 expression and pathological stage were independent, significant prognostic factors. Further analysis demonstrated P53 expression was an independent prognostic factor in stage 1, but not in other stages. CONCLUSIONS P53 expression is especially useful as a prognostic factor in stage 1 lung cancer.

The effects of inhaled nitric oxide, gabexate mesilate, and retrograde flush in the lung graft from non-heart beating minipig donors

BACKGROUND The use of lung grafts from non-heart-beating donors (NHBD) is one way of solving the donor organ shortage problem. In this experiment, we studied the effect of retrograde flush (RF) from the left atrium before harvest, inhaled nitric oxide (NO), and gabexate mesilate (FOY), a protease inhibitor, in the lung grafts from NHBD. METHODS Forty-eight Lee-Sung, small-ear, miniature pigs (15-20 kg) were divided into 24 pairs (donor and recipient) and four groups. The donor lungs were flushed and harvested 90 min after cardiac arrest. No i.v. heparin was administered until the time before flush and harvest. Left single lung transplantation was undertaken, and the recipients were observed for 18 hr. The grafts warm and cold ischemia times were 90 (controlled) and 183+/-23.4 min. Group 1 (untreated control, UC, n=6) had core perfusion through a Swan-Ganz catheter followed by a single, antegrade flush with modified Euro-Collins solution containing heparin, urokinase, and PGE1. Group 2 (RF group, n=6) had the same as group 1, except that one additive retrograde flush through the left atrium was administered. Group 3 (NO group, n=6) had the same as group 1, except that 20 parts per million (ppm) inhaled NO was administered for the cadaver donors before the graft harvest, and for the recipients after the grafts reperfusion. Group 4 (FOY group, n=6) had the same as group 1, except that the recipients received FOY i.v. infusion from the beginning of the recipients operation and continuously throughout the experiments. RESULTS Compared with the group 1 (control), group 2 (RF) had significantly (P<0.05) lower mean pulmonary artery pressure, pulmonary vascular resistance (PVR), lung wet/dry ratio, histological lung injury score, and higher PaO2/FiO2 and pulmonary dynamic compliance. Group 3 (NO) had significantly lower mean pulmonary arterial pressure, PVR, lung injury score, degree of tissue neutrophils infiltration (histological and myeloperoxidase assay), bronchoalveolar lavage fluid protein content and neutrophils (PMNs) percentage, and higher PaO2/FiO2 and pulmonary dynamic compliance. Group 4 (FOY) had significantly lower PMNs infiltration, lung injury score, wet/dry ratio, bronchoalveolar lavage fluid protein and PMNs percentage, and higher PaO2/FiO2. Group 2 (RF) revealed better gas exchange (PaO2/FiO2) than the control (group 1) at earlier reperfusion periods (1st and 5th hr). On the contrary, group 4 (FOY) had higher PaO2/FiO2 than group 1 only at later period (18th hr). Pathologically, retrograde flush (group 2, RF) inhibited the intravascular thrombi formation more effectively than the NO or FOY treatment. However, the NO or FOY treatment inhibited the neutrophil infiltration more effectively than did the retrograde flush. CONCLUSION The retrograde flush, inhaled NO and FOY infusion are beneficial to the protection of the NHBD lung grafts at an early reperfusion period, through different mechanisms. The use of these treatments in combination might help us to find a better way to protect the NHBD grafts against the preservation and reperfusion injury.

Protective effects of inhaled nitric oxide and gabexate mesilate in lung reperfusion injury after transplantation from non-heart-beat donors

BACKGROUND The use of lung grafts from non-heart-beat donors (NHBDs) is one way of solving the critical donor organ shortage. Inhaled nitric oxide (NO) and gabexate mesilate (FOY), a protease inhibitor, can attenuate some types of neutrophil-mediated tissue injury. Using an isolated lung ventilation and perfusion model, we studied the effects of these agents on reperfusion injury following lung transplantation from NHBDs. METHODS Five groups of minipigs were studied. In group 1(n = 6), the lungs were flushed and harvested after cardiac arrest, and were reperfused for 2 hours after 2 hours of cold ischemia. In group 2 (n = 6), the lungs were harvested after 2 hours of in situ warm ischemia, followed by 2 hours of cold ischemia and 2 hours of reperfusion. In groups 3 (n = 7), 4 (n = 7), and 5 (n = 6), the procedure was the same as in group 2, except in group 3, NO was inhaled before and after ischemia, in group 4, FOY was given intravenously, and in group 5, a combination of inhaled NO and intravenous FOY were administered. RESULTS Compared with group 1, group 2 had higher mean pulmonary arterial pressure, vascular resistance, and lower arterial blood oxygen tension. Furthermore, these negative effects of warm ischemia were also reflected in the contents of bronchoalveolar lavage fluid, tissue myeloperoxidase (MPO) activity, histology, and permeability change. Either FOY or NO administration (groups 3 or 4) ameliorated the associated injury. A combination of FOY and NO use (group5) decreased the parameters of lung reperfusion injury measurement to a larger degree than either agent individually. CONCLUSIONS The inhaled NO and FOY can protect NHBD lung grafts at an early reperfusion period. Their use in combination has an additive protective effect that might be applied to the protection of NHBD grafts from preservation and reperfusion injury.

Adjuvant immunotherapy with intrapleural Streptococcus pyogenes (OK-432) in lung cancer patients after resection

A prospective randomized study to evaluate the effect of adjuvant intrapleural OK-432 immunotherapy after resection of lung tumor was conducted in 93 patients with primary lung cancer. Among them, 46 patients had had intrapleural OK-432 injection, 47 had not. In the meantime, serial measurements of serum immunosuppressive acidic protein, of serum interleukin-2 receptor and of the sub-population of the peripheral blood cells and lymphocytes were performed in all these patients. Patient characteristics in these two groups (sex, age, histological type, pathological stage, type of operation, and performance status) were compatible. The results showed that adjuvant intrapleural OK-432 injection after resection had no beneficial effect on a patients survival time. Patients who received intrapleural OK-432, had an increase in blood leukocytes, granulocytes and monocytes and serum immunosuppressive acidic protein level. But the cell numbers of total T cells, suppressor/cytoxic cells, helper/inducer cells and natural killer cells of peripheral blood were decreased in the OK-432 positive group. Over half of the patients had transient 1- or 2-day febrile reactions after intrapleural OK-432 injection. It was concluded that neither clinical observation nor immunological monitoring of peripheral blood could demonstrate a beneficial effect from intrapleural OK-432 immunotherapy after complete resection of the tumor.

Lung transplantation for patients with end-stage Sauropus androgynus-induced bronchiolitis obliterans (SABO) syndrome

Sauropus androgynus (SA), a vegetable of the Euphorbiaceae family, is a common food source in Malaysia. In Taiwan, over 30 patients have developed progressive respiratory failure after consuming the extract from raw SA leaves as a means of losing weight. Symptoms consistent with a severe obstructive ventilatory defect progressed, despite cessation of SA intake and treatment with bronchodilators, corticosteroids, cytotoxic agents and plasmaphresis. Five patients with end‐stage Sauropus androgynus‐induced bronchiolitis obliterans (SABO) syndrome underwent lung transplantation. There was no early mortality. One patient died of post‐transplant lymphoproliferative disorder and another patient died of bronchial stenosis with infection, 5 and 3.5 months, respectively, post‐transplantation. The remaining 3 patients have been followed from 29 to 34 months, with improved general condition and pulmonary function. Perfusion/ventilation scans revealed that these improvements were exclusively attributed to the functional grafts. We believe that lung transplantation is the only effective modality of treatment for patients with end‐stage SABO syndrome.

Comparison of Histidine-Tryptophan-Ketoglutarate and Euro-Collins Solutions for Lung preservation Using the Minipig In Situ Warm Ischemia Model

BACKGROUND AND PURPOSE Reperfusion injury remains a common problem in lung transplantation. This study compared the effect of lung preservation with histidine-tryptophan-ketoglutarate (HTK), a relatively low potassium solution, and Euro-Collins (EC) solution by using a minipig in situ model of warm ischemia. METHODS The left lungs of 5 minipigs were selectively flushed with EC solution. HTK was used for flush perfusion in 6 other minipigs. After 60 minutes of warm ischemia, the left lungs were reperfused. Hemodynamics, aerodynamics, and arterial blood gas were measured after the blood flow and ventilation of the contralateral lungs were temporally blocked. Bronchoalveolar lavage fluid (BALF) analysis, lung wet-to-dry weight ratio (W/D ratio) and histological analysis were done before perfusion (right lung) and 2 hours after reperfusion (left lung). RESULTS This in situ model of warm ischemia induced significantly increased pulmonary arterial pressure, pulmonary vascular resistance, BALF albumin contents and neutrophil counts, histological injury score, lung W/D ratio and tissue myeloperoxidase assay. The HTK perfusion group had a significantly lower degree of lung injury than the EC perfusion group. CONCLUSIONS Lung preservation with HTK solution resulted in better lung function after reperfusion than preservation by EC solution in this minipig model.

Local Excision of Well-defined Esophageal Leiomyosarcoma: Case Report and Literature Review

Leiomyosarcomas are uncommon tumors, and even rarer are esophageal leiomyosarcomas. For patients with respectable esophageal leiomyosarcomas, standard treatment is usually esophagectomy. Herein, however, we report a case of pedunculated esophageal leiomyosarcoma that was successfully removed by local excision without esophagectomy, which is interesting in that only four such cases of local excision of esophageal leiomyosarcoma has been reported. Our patient underwent postoperative irradiation and, as of his two-year follow-up, was still alive and without symptom. After describing the case, we review the literature on the clinical behavior and management of leiomyosarcoma. In cases of well-defined esophageal leiomyosarcoma, local excision might be as effective as radical resection and have fewer postoperative complications and less morbidity.

The Association of GSTT1 Genetic Polymorphism with the Risk of Esophageal Cancer-Interactive with Environmental Exposure

In this study, we investigated the association of the genetic polymorphisms of CYPlAl, CYP2E1, GSTMl and GSTTl with the risk of esophageal cancer in Taiwan. We recruited 105 cases of esophageal squamous cell carcinoma and 266 persons of healthy controls during 1996-1999. The genotypes of the xenobiotic metabolizing enzymes were determined by PCR or PCR-RFLP. There was no significant difference in distribution of these genotypes between the patients and controls. However, among the cigarette smokers, GSTTl null genotype was found to associate a higher risk of esophageal cancer, after adjustment with other environmental confounders (OR: 2.44;95% CI:1.17-5.08). Our results revealed that the GSTTl genetic polymorphism might interact with cigarette smoke to modulate the risk of esophageal cancer in Taiwan.