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.     

Breast cancer risk in primary care: implications for chemoprevention

BACKGROUND: Some women may benefit from taking tamoxifen citrate for breast cancer prevention if the probability of benefit outweighs that of adverse events. We determined the proportion of women aged 40 to 69 years attending general internal medicine practices who were potentially eligible for tamoxifen chemoprevention and calculated the maximum proportion of breast cancers that could be prevented. METHODS: Six hundred five women aged 40 to 69 completed self-administered questionnaires in the waiting rooms of 10 general internal medicine practices in North Carolina in 2001. RESULTS: Among white women, 9.0% (95% confidence interval [CI], 5.1%-15.2%) in their 40s, 24.0% (95% CI, 18.2%-31.0%) in their 50s, and 53.4% (95% CI, 46.1%-61.3%) in their 60s had a 5-year Gail model estimated breast cancer risk of 1.66% or greater. Among black women, 2.9% (95% CI, 0%-15.0%) in their 40s, 7.1% (95% CI, 1.1%-24.4%) in their 50s, and 13.0% (95% CI, 3.1%-34.3%) in their 60s had a similar risk. When adverse events were considered in white women, 10% or fewer in all age groups were potentially eligible for chemoprevention. The maximum proportion of breast cancers prevented in eligible women was 6.0% to 8.3%. CONCLUSIONS: Small numbers of women in primary care practices are eligible for discussions about chemoprevention; the maximum proportion of breast cancers prevented if eligible women take tamoxifen is also small. Challenges lie in targeting discussions to the most appropriate women and in finding new chemoprevention strategies that have less risk of harms.     

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.