Pulmonary metastases from uterine malignancies: results of surgical resection in 133 patients

OBJECTIVE: The long-term results of the surgical treatment for patients with pulmonary metastases from uterine malignancies were clarified. METHODS: A total of 133 patients who underwent pulmonary metastasectomy for uterine malignancies were enrolled in the Metastatic Lung Tumor Study Group of Japan between March 1984 and February 2002. These patients constituted the study population, and their clinical, pathologic, and prognostic data were retrospectively analyzed. RESULTS: The morbidity and mortality rates related to the operation were minimal (1% and 1%, respectively). The 5- and 10-year survivals after the surgical resection in all cases were 54.6% and 44.9%, respectively. The 5-year survivals for each histologic type were estimated to be 46.8% for squamous cell carcinoma (n = 58), 40.3% for cervical adenocarcinoma (n = 13), 75.7% for endometrial adenocarcinoma (n = 23), 86.5% for choriocarcinoma (n = 16), and 37.9% for leiomyosarcoma (n = 11). In the univariate analysis, the following were shown to be associated with poor survival: primary tumor in the cervix, short disease-free interval (<12 months), large number of resected metastases (> or =4), and large tumor size (> or =3 cm). After mutual adjustment, short disease-free interval (<12 months) alone was related to risk of death (hazard ratio = 2.26, 95% confidence interval = 1.06-4.78) for 105 patients, excluding patients with choriocarcinoma and miscellaneous histologic types. CONCLUSION: Pulmonary metastasectomy for uterine malignancies is a safe and acceptable treatment to improve survival. Patients with a disease-free interval of 12 months or more are good candidates for this treatment if there is adequate control of the primary tumor without extrapulmonary metastasis.     

Benefits of resection for metachronous lung cancer

OBJECTIVES: The benefits of resection for metachronous lung cancer are not well described. The objective of this study was to evaluate the safety and efficacy of surgical resection for metachronous lung cancers. METHODS: We reviewed the charts of all patients who underwent a second resection for a metachronous lung cancer from July 1, 1988, to December 31, 2002. Type of resection, operative morbidity, mortality, and survival by stage were analyzed. Survival was determined by using the Kaplan-Meier survival method. All patients were pathologically staged by using the 1997 American Joint Committee on Cancer standards. RESULTS: Pulmonary resections were performed in 69 patients who had undergone a previous resection. The mean interval between the first and second resection was 2.4 +/- 2.5 years. Seventy-three percent of patients presented with stage I cancers, 9% with stage II cancers, and 17% with stage III cancers. Lobectomy and wedge resection were performed with equal frequency (42% each) for the metachronous cancers. Operative mortality for the second resection was 5.8%. The mean follow-up after the second resection was 37 months. Overall 5-year actuarial survival for the entire group after the second resection was 33.4%. CONCLUSIONS: Operations for metachronous cancers provided survival that approximated the expected survival for lung cancer. Surgical intervention should be considered as a safe and effective treatment for resectable metachronous lung cancer in patients with adequate physiologic pulmonary reserve.     

Visceral pleural invasion classification in non-small cell lung cancer: a proposal on the basis of outcome assessment

OBJECTIVE: The definition of visceral pleural invasion in lung cancer TNM classification of the International Union Against Cancer lacks detail. The purpose of this study was to evaluate the significance of the extent of pleural involvement as a prognostic factor and to propose a refined TNM classification on the basis of visceral pleural invasion. METHODS: We reviewed 1653 consecutive patients with T1, T2, and T3 surgically resected non-small cell lung cancer for their clinicopathologic characteristics and prognoses. Visceral pleural invasion was classified by using the Japan Lung Cancer Society criteria: p0, tumor with no pleural involvement beyond its elastic layer; p1, tumor extension beyond the elastic layer but no exposure on the pleural surface; and p2, tumor exposure on the pleural surface. RESULTS: The 5-year survivals for patients with p1 or p2 tumors of 3 cm or less were identical and significantly worse than those for patients with p0 tumors of the same size. Patients with p1 or p2 tumors of greater than 3 cm and patients with T3 cancers had essentially identical survivals. CONCLUSIONS: Visceral pleural invasion should be defined as tumor extension beyond the elastic layer of the visceral pleura, regardless of its exposure on the pleural surface. A tumor of 3 cm or less with visceral pleural invasion should remain classified as a T2 tumor, as presently occurs in the International Union Against Cancer staging system, and tumors of greater than 3 cm with visceral pleural invasion should be upgraded to T3 status in the International Union Against Cancer TNM classification.     

Dominant expression of interleukin-10 and transforming growth factor-beta genes in activated T-cells of chronic active Epstein-Barr virus infection

Chronic active Epstein-Barr virus (EBV) infection is a chronic mononucleosis syndrome associated with clonal proliferation of EBV-carrying T-/natural killer (NK)-cells. High levels of circulating EBV and activated T-cells are sustained during the prolonged disease course, whereas it is not clear how ectopic EBV infection in T-/NK-cells has been established and maintained. To assess the biological role of activated T-cells in chronic active EBV infection (CAEBV), EBV DNA and cellular gene expressions in peripheral T-cells were quantified in CAEBV and infectious mononucleosis (IM) patients. In CAEBV, HLA-DR(+) T-cells had higher viral load and larger amounts of IFN gamma, IL-10, transforming growth factor-beta (TGF beta), and cytotoxic T lymphocyte antigen-4 (CTLA4) mRNA than HLA-DR(-)T-cells. HLA-DR(+) T cells of IM patients transcribed more IFN gamma and IL-10 than their HLA-DR(-)T cells. Expression levels of IFN gamma and forkhead box p3 (Foxp3) in CAEBV HLA-DR(+) T-cells were higher than in IM HLA-DR(+) T-cells. The effective variables to discriminate the positivity of HLA-DR were IL-10, IFN gamma, CTLA4, TGF beta, and IL-2 in the order of statistical weight. EBV load in CAEBV T-cells correlated with the expression levels of only IL-10 and TGF beta. These results suggest that CAEBV T-cells are activated to transcribe IFN gamma, IL-10, and TGF beta excessively, and the latter two genes are expressed preferentially in the EBV-infected subsets. The dominant expression of regulatory cytokines in T-cells may imply a viral evasion mechanism in the disease.     

Genotoxicity of PM10 and extracted organics collected in an industrial, urban and rural area in Flanders, Belgium

The variation in the genotoxic potency of PM10 in vitro in relation to the particle source type was investigated. Particles were collected at one urban, one rural, and one industrial site in Flanders. Genotoxicity was assessed using four different in vitro test systems exposed to PM10 in suspension and to the organic extracts of PM10. Two of these systems were bacterial assays: the Salmonella mutagenicity test and the Vitotox test. In addition, the Comet assay and Micronucleus test were performed using human blood cells. Results show that exposure to PM10 and the organic extracts from both urban and industrial areas causes significant genetic damage. The Salmonella mutagenicity test was most suitable for the screening of PM10 and the organic extracts; the Micronucleus test was most suitable only for the screening of organic extracts, and original particles were toxic for the exposed lymphocytes. Clear dose-response curves were not established in the Comet and Vitotox assay, and organic extracts were apparently toxic in the latter. The total polycyclic aromatic hydrocarbon content of the organic extracts, as measured with GC/MS, ranged between 1 and 6 ng/m3. Results obtained in this study suggest that PM10 causes DNA damage and mutations. The use of biological tests for the screening of air samples is useful to complement air quality control by chemical measurements.     

Effects of enhancing mitochondrial oxidative phosphorylation with reducing equivalents and ubiquinone on 1-methyl-4-phenylpyridinium toxicity and complex I-IV damage in neuroblastoma cells

The effects of increasing mitochondrial oxidative phosphorylation (OXPHOS), by enhancing electron transport chain components, were evaluated on 1-methyl-4-phenylpyridinium (MPP+) toxicity in brain neuroblastoma cells. Although glucose is a direct energy source, ultimately nicotinamide and flavin reducing equivalents fuel ATP produced through OXPHOS. The findings indicate that cell respiration/mitochondrial O(2) consumption (MOC) (in cells not treated with MPP+) is not controlled by the supply of glucose, coenzyme Q(10) (Co-Q(10)), NADH+, NAD or nicotinic acid. In contrast, MOC in whole cells is highly regulated by the supply of flavins: riboflavin, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), where cell respiration reached up to 410% of controls. In isolated mitochondria, FAD and FMN drastically increased complex I rate of reaction (1300%) and (450%), respectively, having no effects on complex II or III. MPP+ reduced MOC in whole cells in a dose-dependent manner. In isolated mitochondria, MPP+ exerted mild inhibition at complex I, negligible effects on complexes II-III, and extensive inhibition of complex IV. Kinetic analysis of complex I revealed that MPP+ was competitive with NADH, and partially reversible by FAD and FMN. Co-Q(10) potentiated complex II ( approximately 200%), but not complex I or III. Despite positive influence of flavins and Co-Q(10) on complexes I-II function, neither protected against MPP+ toxicity, indicating inhibition of complex IV as the predominant target. The nicotinamides and glucose prevented MPP+ toxicity by fueling anaerobic glycolysis, evident by accumulation of lactate in the absence of MOC. The data also define a clear anomaly of neuroblastoma, indicating a preference for anaerobic conditions, and an adverse response to aerobic. An increase in CO(2), CO(2)/O(2) ratio, mitochondrial inhibition or O(2) deprivation was not directly toxic, but activated metabolism through glycolysis prompting depletion of glucose and starvation. In conclusion, the results of this study indicate that the mechanism of action for MPP+, involves the inhibition of complex I and and more specifically complex IV, leading to impaired OXPHOS and MOC. Moreover, flavin dervatives control the rate of complex I/cellular respiration and Co-Q10 augments complex II [corrected].     

Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins

We have recently shown that drug conjugation catalysed by UDP-glucuronosyltransferases (UGTs) functions as an intrinsic mechanism of resistance to the topoisomerase I inhibitors 7-ethyl-10-hydroxycamptothecin and NU/ICRF 505 in human colon cancer cells and now report on the role of drug transport in this mechanism. The ability of transport proteins to recognise NU/ICRF 505 as a substrate was evaluated in model systems either transfected with breast cancer-resistance protein 1 (Bcrp1), multidrug-resistance protein 2 (Mrp2) or Mrp3, or overexpressing MRP1 or P-170 glycoprotein. Results from chemosensitivity assays suggested that NU/ICRF 505 was not a substrate for any of the above proteins. In drug accumulation studies in human colon cancer cell lines NU/ICRF 505 was taken up avidly and retained in cells lacking UGTs (HCT116), whereas, following equally rapid uptake, it was cleared rapidly from cells displaying UGT activity (HT29) as glucuronide metabolites. HT29 cells were shown to express MRP1 and 3, but not P-170 glycoprotein, MRP2 or breast cancer-resistance protein. The major glucuronide of NU/ICRF 505 inhibited ATP-dependent transport of estradiol 17-beta-glucuronide in Sf9 insect cell membrane vesicles containing MRP1 or MRP3, while co-incubation of HT29 cells with the MRP antagonist, MK571, significantly restored intracellular concentrations of NU/ICRF 505. These data lead us to conclude that the presence of a glucuronide transporter is essential for glucuronidation to represent a major de novo resistance mechanism and that UGTs will contribute more as a primary resistance mechanism when the parent drug (e.g. NU/ICRF 505) is not itself recognised by transport proteins.     

Stimulation of early gene induction and cell proliferation by lysophosphatidic acid in human amnion-derived WISH cells: role of phospholipase D-mediated pathway

Human-amniotic WISH cells express the lysophosphatidic acid (LPA) receptor, LPA(1), LPA(2) but not LPA(3). When WISH cells were stimulated with LPA, phospholipase D (PLD) activation was dramatically induced via a cytosolic calcium increase and protein kinase C activation. We also found that LPA stimulated two kinds of mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and p38 kinase via PLD-dependent signaling pathways in WISH cells. In terms of the LPA-mediated functional modulation of WISH cells, we observed that LPA stimulates the induction of two early genes (c-Jun and c-Fos) and cellular proliferation in WISH cells. We examined the signaling pathways involved in LPA-mediated cellular responses. LPA-induced early gene induction was completely blocked by normal butanol (n-butanol) but not by t-butanol, suggesting that PLD activity is essentially required for the process. PD98059 (2'-amino-3'-methoxyflavone) but not SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole) also significantly blocked LPA-induced early gene induction, suggesting a crucial role for ERK. Pertussis toxin (PTX) did not affect on the LPA-induced early gene induction and ERK activation, ruling out the role of Gi/o protein(s) in the process. The cellular proliferation of WISH cells was also dramatically inhibited by n-butanol or PD98059. This study demonstrates the physiological role of LPA on the modulation of early gene induction and on WISH cell proliferation, and the crucial role played by PLD in the process.