Loss of heterozygosity of chromosome 3p21 is associated with mutant TP53 and better patient survival in non-small-cell lung cancer

Allelic loss of chromosome region 3p21.3 occurs early and frequently in non-small-cell lung cancer, and numerous tumor suppressor genes at this locus may be targets of inactivation. Using an incident case series study of non-small-cell lung cancer, we sought to determine the prevalence of loss of heterozygosity (LOH) in the 3p21.3 region and to examine the associations between this alteration and patient outcome, exposure to tobacco smoke, occupational asbestos exposure, and additional molecular alterations in these tumors. We examined LOH at 7 microsatellite markers in the chromosome 3p21.3 region, and LOH was present in at least one of the loci examined in 60% (156 of 258) of the tumors, with the prevalence of LOH at individual loci ranging from 15 to 56%. Occupational asbestos exposure and TP53 mutation were significantly associated with more extensive 3p21 LOH. In squamous cell carcinomas, measures of cumulative smoking dose were significantly lower in patients with LOH at 3p21, particularly in TP53 mutant tumors. Examining patient outcome, we found that in squamous cell carcinomas, having any LOH in this region was associated with a better overall survival (log-rank test, P < 0.04). Together, these results indicate that allelic loss at 3p21 can affect patient outcome, and that this loss may initially be related to carcinogen exposure, but that extension of this loss is related to TP53 mutation status and occupational asbestos exposure.     

Surgical lung cancer. Risk operative analysis

STUDY OBJECTIVE: To identify those variables that are associated with operative morbidity or mortality in cases of thoracotomy in lung cancer. SETTING: Third level university hospital. PATIENTS: Consecutive patients with thoracotomy due to lung cancer operated on between 1994 and 1997 (n = 115). METHODS: Pre- and postoperative variables potentially associated with operative morbidity or mortality were retrieved prospectively as follows: demographic and clinical characteristics of the patients, cardiopulmonary function characteristics, tumour characteristics, and treatment characteristics. A bivariate analysis of all variables under evaluation was carried out in order to identify those variables associated with operative morbidity and mortality. A multivariable analysis of the selected variables was then conducted using a logistic model. RESULTS: The predicted postoperative product (predicted FEV1 x predicting diffusing capacity of carbon monoxide), the carbon monoxide diffusion coefficient (Kco) and the contralateral pulmonary perfusion are variables that relate to the overall morbidity or mortality (number of events 63, 55%) (-2 log likelihood chi2 = 22.9; R2 = 0.27). For variables associated with postoperative morbidity, the best associative model combines functional variables (diffusion, predicted FEV1), endoscopic variables (obstructed segments to be resected), clinical variables (comorbidity) and an important postoperative variable, the pathological tumoural staging (pN) (number of events 49, 43%) (-2 log likelihood chi2 = 32.9; R2 = 0.36). CONCLUSION: The numerous variables under analysis are poorly associated with morbidity or mortality after thoracotomy in lung cancer. With regard to postoperative morbidity, the best associative models combine information that is known pre- and postoperatively and which is provided by both the patient and the tumour.     

Radiobiology of radioimmunotherapy: targeting CD20 B-cell antigen in non-Hodgkin's lymphoma

The radiobiology of radioimmunotherapy is an important determinant of both the toxicity and the efficacy associated with the treatment of B-cell non-Hodgkin's lymphoma with radiolabeled anti-CD20 monoclonal antibodies. The properties of the target, CD20, and the mechanisms of action of both the monoclonal antibodies and the associated exponentially decreasing low-dose-rate radiotherapy are described. The radiation dose and dose-rate effects are discussed and related to both the tumor responses and normal organ toxicity. Finally, the use of either unlabeled or radiolabeled anti-CD20 monoclonal antibodies as a component of combined modality therapy (including the sequential or concurrent use of sensitizers) and future directions of the field are discussed.     

Increasing trends of cervical adenocarcinoma incidence in Central Italy despite Extensive Screening Programme, 1985-2000

Incidence rates of adenocarcinoma of the uterine cervix have been reported to be increasing in several countries, but not in Italy. The aim of the present study was to analyse trends in cervical cancer incidence by histological type in two districts of Central Italy (Florence and Prato), covered by the Tuscany Cancer Registry (RTT), where cytological screening had been available since the 1970s. Incident cervical cancers during 1985-2000 were 1012. Estimated Annual Percent Change (EAPC) by age-groups and histological type were computed. Incidence increased for adenocarcinoma (EAPC = +5.7%; 95% confidence interval (CI)+2.8; +8.6); whereas, it decreased for squamous cancer (EAPC = -1.9%; 95% CI-3.8; 0) and for other or not specified types (EAPC = -4.4%; 95% CI-10.0; +1.5). Adenocarcinoma increased significantly among younger women (<55 years) but not among older ones, whereas squamous cell cancer decreased among older women only. The burden of cervical cancers might increase in the future if no specific preventive strategies for adenocarcinoma are implemented.     

Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival

Inactivation of the FANC-BRCA pathway via promoter methylation of the FANCF gene renders cells sensitive to DNA crosslinking agents, and has been identified in ovarian cancer cell lines and sporadic primary tumor tissues. We investigated epigenetic alterations in the FANC-BRCA pathway in head and neck squamous cell carcinomas (HNSCC) and non-small-cell lung cancers (NSCLC) using methylation-specific PCR. Promoter methylation of FANCF occurred in 15% (13/89) of HNSCCs and 14% (22/158) of NSCLCs. Methylation of BRCA1 occurred only in 6/158 NSCLC, and was limited to adenocarcinomas and large-cell carcinomas of the lung. No methylation of BRCA2 was detected. FANCF methylation was associated with a shorter duration of tobacco use (P=0.03) and a younger age of starting smoking (P=0.06) in NSCLC, and with a greater number of years of alcohol drinking (P=0.02) in HNSCC. In adenocarcinomas of the lung, FANCF promoter methylation was a significant predictor of poor survival with a hazard ratio of 3.1 (95% CI 1.2-7.9). This study demonstrates that inactivation of the FANC-BRCA pathway is relatively common in solid tumors and may be related to tobacco and alcohol exposure and survival of these patients.     

AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis

Cyclophilin A (CypA) was determined to interact with apoptosis-inducing factor (AIF) by mass spectroscopy, coimmunoprecipitation, pull-down assays, and molecular modeling. During the initial, caspase-independent stage of chromatin condensation that accompanies apoptosis, AIF and CypA were found to coimmunolocalize in the nucleus. Recombinant AIF and CypA proteins synergized in vitro in the degradation of plasmid DNA, as well as in the capacity to induce DNA loss in purified nuclei. The apoptogenic cooperation between AIF and CypA did not rely on the CypA peptidyl-prolyl cis-trans isomerase activity. In Cyp-expressing cells, AIF overexpression augmented apoptotic chromatinolysis. The AIF-dependent large-scale DNA fragmentation was less pronounced in CypA knockout cells as compared to controls. AIF mutants lacking the CypA-binding domain were inefficient apoptosis sensitizers in transfection experiments. Moreover, AIF failed to sensitize CypA knockout cells to apoptosis induction, and this defect in the AIF response was reversed by reintroduction of the CypA gene into CypA-deficient cells. In summary, AIF and CypA collaborate in chromatinolysis.     

Bullous pemphigoid associated with mantle cell lymphoma

BACKGROUND: Bullous pemphigoid has developed in association with different types of malignant diseases, including a few cases of B-cell lymphoproliferative disorders. However, the paraneoplastic significance of this association is still controversial. OBSERVATIONS: We describe a 39-year-old patient who presented with a bullous eruption and generalized lymphadenopathy. The results of histologic, immunofluorescence, and antigenic studies confirmed the diagnosis of bullous pemphigoid. The histopathologic and immunophenotypic features of a lymph node biopsy specimen were consistent with mantle cell lymphoma. There was total resolution of the mucocutaneous lesions when mantle cell lymphoma went into remission. CONCLUSION: The age of the patient and the concomitant appearance and simultaneous remission of both diseases strongly suggest that bullous pemphigoid was a paraneoplastic phenomenon in the present case.