Hiromi Wada

Prognostic Significance of Apoptotic Index in Completely Resected Non–Small-Cell Lung Cancer

PURPOSEnTo evaluate the significance of apoptotic index (AI) as a prognostic factor after surgery for non-small-cell lung cancer (NSCLC).nnnPATIENTS AND METHODSnA total of 236 patients who underwent surgery for previously untreated pathologic stage I to IIIa NSCLC between 1985 and 1990 were reviewed. AI was defined as the number of apoptotic cells, detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling, per 1,000 tumor cells. Proliferative index (PI) and aberrant p53 expression were also evaluated immunohistochemically.nnnRESULTSnThe 5-year survival rate for the lowest-AI group (AI < 5.0) was 74.7%; those for the lower-AI group (5.0 < or = AI < 11.0) and the higher-AI group (11.0 < or = AI < 25.0) were 51.6% and 57.8%, respectively. These survival rates were significantly lower than that of the lowest-AI group (P =.021 and P =.043, respectively). The highest-AI group (25.0 < or = AI), however, showed the most favorable prognosis, with a 5-year survival rate of 83.2%. Multivariate analysis confirmed that a moderate AI (5.0 < or = AI < 11.0 or 11.0 < or = AI < 25.0) was a significant factor to predict poor prognosis. The PIs for the lowest-, the lower-, the higher-, and the highest-AI groups were 32.3%, 48.0%, 54.3%, and 50.7%, respectively. The lowest-AI group showed a favorable prognosis because of its low PI, whereas the lower- and the higher-AI groups had a poor prognosis caused by increased cancer-cell proliferation. The highest-AI group showed the most favorable prognosis because apoptotic cell death overcame cell proliferation. No significant correlation was observed between AI and aberrant p53 expression.nnnCONCLUSIONnAI proved to be an independent prognostic factor in NSCLC.

Apoptosis and p53 status predict the efficacy of postoperative administration of UFT in non-small cell lung cancer

To examine whether efficacy of postoperative oral administration of UFT, a 5-fluorouracil derivative chemotherapeutic agent, may be influenced by incidence of apoptosis (apoptosis index) or apoptosis-related gene status (p53 and bcl-2) of the tumour, a total of 162 patients with pathologic stage I non-small cell lung cancer were retrospectively reviewed. UFT was administrated postoperatively to 44 patients (UFT group), and not to the other 118 patients (Control group). For all patients, 5-year survival rate of the UFT group (79.9%) seemed higher than that of the Control group (69.8%), although without significant difference (P=0.054). For patients with higher apoptotic index, 5-year survival rate of the UFT group (83.3%) was significantly higher than that of the Control group (67.6%, P=0.039); for patients with lower apoptotic index, however, there was no difference in the prognosis between these two groups. Similarly, UFT was effective for patients without p53 aberrant expression (5-year survival rates: 95.2% for the UFT group and 74.3% for the Control group, P=0.022), whereas not effective for patients with p53 aberrant expression. Bcl-2 status did not influence the efficacy of UFT. In conclusion, apoptotic index and p53 status are useful factors to predict the efficacy of postoperative adjuvant therapy using UFT.

Role Of Saccharides On Lung Preservation

BACKGROUNDnSaccharides are considered to play a role as osmotic impermeants and serve as an energy source for the organ during ischemia. However, previous studies on the effectiveness of saccharides on organ preservation have yielded conflicting results. We compared the preservative effects of a monosaccharide (glucose), disaccharides (trehalose, maltose, sucrose), and a trisaccharide (raffinose) to investigate whether the effects of saccharides on lung preservation depend on their molecular weight, energy-level maintenance, and cytoprotective effects.nnnMETHODSnWe used an ex vivo rat lung model using homologous blood as the perfusate. In the fresh group, the lungs were reperfused immediately after flush. In the other groups, the lungs were flushed with one of the solutions containing glucose, trehalose, maltose, sucrose, or raffinose and preserved for 14 hours.nnnRESULTSnThe results of the trehalose group were comparable to those of the fresh group. The glucose, maltose, and raffinose groups showed significantly higher levels of shunt fraction, pulmonary artery pressure, and peak inspiratory pressure compared with the fresh and trehalose groups. There were no differences among the groups in the levels of total adenine nucleotides, adenosine triphosphate of the lung after flush, and preservation. However, after reperfusion, levels of total adenine nucleotides became significantly lower in the glucose, sucrose, maltose, and raffinose groups. Ultrastructural examination revealed endothelial cell injury in the glucose, sucrose, maltose, and raffinose groups.nnnCONCLUSIONSnThese results show that the effects of saccharides may depend on their cytoprotective effect rather than on impermeant activity or energy-level maintenance of the preserved lung. Trehalose proved to be superior to the other saccharides.

Chemical preconditioning by 3-nitropropionate reduces ischemia-reperfusion injury in cardiac-arrested rat lungs

Background. Chemical preconditioning was defined as the induction of resistance to massive disruption of energy metabolism through prior chemical suppression of oxidative phosphorylation, by which phenomena similar to those resulting from increased ischemic tolerance as a result of ischemic preconditioning can be induced. It could be induced by the inhibitor of either mitochondrial complex I or II. We investigated whether or not chemical preconditioning by 3-nitropropionate (an inhibitor of the mitochondrial complex II) can suppress ischemia-reperfusion injury in cardiac-arrested lungs, which will be the major problem in lung transplants donated from non-heart-beating cadavers. Methods and Results. In an isolated rat lung perfusion model with fresh rat blood as perfusate, administration of 3-nitropropionate (20 mg/kg) immediately before the induction of cardiac arrest attenuated pulmonary dysfunction during reperfusion after 1 hr postmortem warm ischemia and 1 hr cold preservation. 3-Nitropropionate administration reduced the mitochondrial respiratory functions (state 3 and state 4 respiration, and the respiratory control ratio) before cardiac arrest and kept them at a lower level of activity than when decreased by ischemia alone. 3-Nitropropionate administration also reduced the ATP levels immediately after drug administration. However, 3-nitropropionate did not significantly reduce lipid peroxidation in the lung tissue and mitochondria. Conclusions. These results demonstrated that chemical preconditioning by 3-nitropropionate administration immediately before cardiac arrest suppressed succinate-related oxidation during postmortem warm ischemia and reduced ischemia-reperfusion injury in cardiac arrested rat lungs.

Biological features and preoperative evaluation of mediastinal nodal status in non–small cell lung cancer

BACKGROUNDnTo examine whether biological features of primary tumor can help preoperative evaluation of mediastinal nodal status in non-small cell lung cancer.nnnMETHODSnA total of 450 patients who underwent tumor resection and mediastinal dissection were reviewed. p53 status and proliferative fraction (PI) were evaluated immunohistochemically.nnnRESULTSnThe accuracy of preoperative evaluation of mediastinal nodal status with computed tomography (CT) was 72.2%; mediastinal nodal metastases had not been revealed until operation in 59 patients (13.1%) (false-negative), and no metastasis was revealed in 66 patients (14.7%) although mediastinal nodal enlargement had been demonstrated by CT (false-positive). The number of false-negative patients was significantly larger when p53 aberrant expression was positive or when PI was higher. Combined with p53 status and PI, there were 27 false-negatives (24.1%) among patients with aberrant p53 expression and higher PI, whereas only two false-negatives (1.5%) among those with negative p53 expression and lower PI.nnnCONCLUSIONSnMediastinoscopy may be recommended for tumor showing aberrant p53 expression and higher PI, even when CT demonstrates no mediastinal nodal enlargement.