Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations

Women with mutations of the genes BRCA1 or BRCA2 are at increased risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they protect against the disease in carriers of these mutations. We obtained self-reported lifetime histories of oral contraceptive use from 451 women who carried mutations of BRCA1 or BRCA2. We used conditional logistic regression to estimate the odds ratios associated with oral contraceptive use, comparing the histories of 147 women with ovarian cancer (cases) to those of 304 women without ovarian cancer (controls) who were matched to cases on year of birth, country of residence and gene (BRCA1 vs BRCA2). Reference ages for controls had to exceed the ages at diagnosis of their matched cases. After adjusting for parity, the odds-ratio for ovarian cancer associated with use of oral contraceptives for at least 1 year was 0.85 (95 percent confidence interval, 0.53-1.36). The risk decreased by 5% (1-9%) with each year of use (P for trend=0.01). Use for 6 or more years was associated with an odds-ratio of 0.62 (0.35-1.09). These data support the hypothesis that long-term oral contraceptive use reduces the risk of ovarian cancer among women who carry mutations of BRCA1 or BRCA2.     

On the regulation of NMDA receptors by nitric oxide

Nitric oxide (NO) is generated in central synapses on activation of N-methyl-D-aspartate (NMDA) receptors and exerts physiological effects by changing cGMP levels. NO has frequently also been claimed to engage a different mechanism, namely the covalent modification of thiol residues (S-nitrosation), and thereby exert a negative feedback on NMDA receptors. Tests of this hypothesis were conducted by recording NMDA receptor-mediated synaptic potentials in the CA1 area of rat hippocampal slices. Manipulations designed to increase or decrease endogenous NO levels had no effect. Addition of exogenous NO using a NONOate donor in concentrations up to 30-fold higher than those needed to evoke maximal cGMP accumulation also had no effect. Nevertheless, in agreement with previous findings, photolysis of a caged NO derivative with UV light led to an enduring block of synaptic NMDA receptors. To address these contradictory results, NMDA receptor-mediated currents were recorded from HEK-293 cells transfected with NR1 and NR2A subunits. As found in slices, photolysis of caged NO inhibited the currents whereas perfusion of NO (up to 5 microM) was ineffective. However, when NO was supplied at a concentration found to be effective when released photolytically (5 microM) and the cells simultaneously exposed to the UV light used for photolysis, NMDA receptor-mediated currents were inhibited. This effect was not observed at more physiological NO concentrations (10 nM range). The results indicate that neither endogenous NO nor exogenous NO in supra-physiological concentration inhibits synaptic NMDA receptors; the combination of high NO concentration and UV light can give an artifactual result.     

The cost-effectiveness of Foscan mediated photodynamic therapy (Foscan-PDT) compared with extensive palliative surgery and palliative chemotherapy for patients with advanced head and neck cancer in the UK

This study aimed to analyse the cost-effectiveness of Foscan mediated photodynamic therapy (Foscan-PDT) compared with palliative chemotherapy, extensive palliative surgery or 'no treatment' for patients with advanced head and neck cancer in the UK. A computerised cost-effectiveness model was constructed using published effectiveness data and unit costs for each of the treatment arms. Where possible, published resource use data were also used. In the absence of such information, expert opinion informed data input. Robust sensitivity analyses were performed to negate the effect of potential over or underestimation of the costs used for any of the interventions. The primary outcome was incremental cost/life year saved (cost/LYS); the secondary outcomes were incremental cost/overall tumour response and incremental cost/remission. Foscan-PDT was associated with the greatest health gains of all three interventions yielding 129 extra days of life compared with no treatment and extensive palliative surgery and 48 extra days of life compared with four cycles of palliative chemotherapy. The unit cost of Foscan-PDT ( pound 5741) was found to be lower than the unit cost for four cycles of palliative chemotherapy ( pound 9924) and extensive palliative surgery ( pound 16912). Foscan-PDT continued to have a lower unit cost than palliative chemotherapy until the number of chemotherapy cycles was reduced to two or fewer. Reducing the number of cycles would be likely to reduce the health gains associated with chemotherapy. However, even with assumed maintenance of chemotherapy efficacy, Foscan-PDT remained cost-effective versus two or fewer chemotherapy cycles. Compared with three or more cycles of palliative chemotherapy and extensive palliative surgery, Foscan-PDT dominated with a lower unit cost and greater health gains. Compared with giving no treatment, Foscan-PDT was a cost-effective treatment option at pound 14206/LYS. Sensitivity analysis showed that Foscan-PDT remained cost-effective when the costs used for the comparators were decreased and/or the costs used for Foscan-PDT were increased. Foscan-PDT is a clinically and cost-effective treatment option for patients with advanced head and neck cancer compared to palliative chemotherapy, extensive palliative surgery or 'no treatment'. Furthermore, Foscan-PDT offers patients, with traditionally very limited treatment options, a unique chance of tumour response, remission and increased life expectancy.     

Acellularization of human placenta with preservation of the basement membrane: a potential matrix for tissue engineering

Basement membrane directs cell migration, cell adherence, and tissue organization in vivo. These qualities would be advantageous in tissue engineering, during which repopulation of scaffolds by functional cells is a common problem. The purpose of this study was to expose human term placenta to a chemical acellularization protocol using the isolated cotyledon perfusion technique to develop an acellular scaffold rich in extracellular matrix components for tissue engineering applications. The processed blocks of tissue demonstrated no cellular material on histologic examination. Periodic acid-Schiff staining, type IV collagen labeling, and transmission electron microscopy demonstrated preservation of the extracellular matrix and basement membrane. Maintenance of the extracellular matrix architecture was seen on scanning electron microscopy. Placenta-derived acellular matrix is a potential volume scaffold for tissue engineering. It is rich in extracellular matrix, has a complex architecture of vascular channels, and has unique donor opportunities.     

Long-term in vivo wear performance of porous-coated acetabular components sterilized with gamma irradiation in air or ethylene oxide

This study evaluated the long-term in vivo wear performance of 2 groups of well-functioning cementless acetabular cups sterilized by different methods. The first group included 31 hips that were implanted with AML TriSpike cups (DePuy, Warsaw, IN) sterilized by gamma-irradiation in air. The second group included 28 hips implanted with Arthropor cups (Joint Medical Products, Stamford, CT) that were sterilized with ethylene oxide. Time-dependent variations in the radiographic wear rates were compared within each group. Changes in the wear rates between 4- and 16-year follow-up times for the TriSpike cups were not significant (P=.09), and there was no evidence to suggest a trend toward substantially increasing wear rates with longer follow-up times. Among the Arthropor cups, the wear rates remained relatively constant between 2 and 14 years of follow-up evaluation. Although clinically apparent late increases in radiographic head penetration rates were not evident, we will continue to monitor all patients for evidence of accelerated wear at late follow-up.     

Can component and patient factors account for the variance in wear rates among bilateral total hip arthroplasty patients?

The purpose of this study was to indirectly quantify the effect of patient and component factors on polyethylene wear in patients with bilateral hip arthroplasties. Assuming that both hips experience similar levels of activity, the confounding influence of activity on wear can be removed by comparing wear rates within subjects. We studied temporal wear patterns in 21 patients with bilateral hip arthroplasty with a mean follow-up of 102 months. Each patient had matching acetabular cup and femoral head components implanted in both hips. Regression analyses were used to assess the variation in wear rates between the first and second implanted hips. The r(2) value demonstrated that matched components and patient factors accounted for 61% of the variance in wear rates. The remaining 39% of the variance, which is unaccounted for, indicates that factors other than those related to the components and patient also play a role.     

Regressive logistic and proportional hazards disease models for within-family analyses of measured genotypes,with application to a CYP17 polymorphism and breast cancer

Various statistical methods have been proposed to evaluate associations between measured genetic variants and disease, including some using family designs. For breast cancer and rare variants, we applied a modified segregation analysis method that uses the population cancer incidence and population-based case families in which a mutation is known to be segregating. Here we extend the method to a common polymorphism, and use a regressive logistic approach to model familial aggregation by conditioning each individual on their mother's breast cancer history. We considered three models: 1) class A regressive logistic model; 2) age-of-onset regressive logistic model; and 3) proportional hazards familial model. Maximum likelihood estimates were calculated using the software MENDEL. We applied these methods to data from the Australian Breast Cancer Family Study on the CYP17 5'UTR T-->C MspA1 polymorphism measured for 1,447 case probands, 787 controls, and 213 relatives of case probands found to have the CC genotype. Breast cancer data for first- and second-degree relatives of case probands were used. The three methods gave consistent estimates. The best-fitting model involved a recessive inheritance, with homozygotes being at an increased risk of 47% (95% CI, 28-68%). The cumulative risk of the disease up to age 70 years was estimated to be 10% or 22% for a CYP17 homozygote whose mother was unaffected or affected, respectively. This analytical approach is well-suited to the data that arise from population-based case-control-family studies, in which cases, controls and relatives are studied, and genotype is measured for some but not all subjects.     

18F]Fluorodeoxyglucose positron emission tomography surveillance of hepatic metastases from prostate cancer following radiofrequency ablation: a case report

The liver is the organ most commonly involved with metastatic disease. Surgical resection of hepatic metastases is the only potentially curative therapy, but it is possible in only 20 per cent of the patients. Radiofrequency ablation (RFA) of hepatic lesions is a therapeutic option for unresectable hepatic metastases. Today there is no clear consensus about which imaging technique is the most reliable to monitor RFA therapy. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is a new imaging modality allowing evaluation of glucose metabolism that has become established for monitoring therapy and early detection of recurrence of various types of malignant tumors. We present a case report of a 61-year-old man treated for prostate carcinoma 3 years earlier who presented with rising serum prostate-specific antigen (PSA) levels. A CT scan demonstrated two hepatic metastases that were treated with RFA because the patient refused surgery. During 3 years of follow-up hepatic recurrence was monitored with serum PSA levels, CT of the abdomen, and FDG-PET imaging on multiple occasions. On three separate occasions FDG-PET revealed hypermetabolic foci despite no definite evidence of recurrence on CT. Furthermore FDG-PET imaging 2 months after the last RFA therapy showed two large photopenic areas without evidence of hypermetabolism consistent with successful RFA therapy. Serum PSA levels correlated better with FDG-PET than CT results. We conclude that in this patient FDG-PET imaging was more accurate than CT for monitoring recurrence of hepatic metastases from prostate carcinoma after RFA therapy. PET demonstrated hypermetabolic foci when there was recurrence and no evidence of hypermetabolism early after successful RFA therapy. In addition FDG-PET imaging helped to guide the placement of the RFA probe to the most metabolically active part of the tumor.     

Early growth,adult body size and prostate cancer risk

The role of growth from birth through puberty and through adult life has been the subject of epidemiologic investigation in regard to the risk of prostate cancer but the evidence remains weak and inconsistent. We investigated associations between prostate cancer risk and a number of markers of body growth, size and changes to size in a population-based, case-control study in Australia from 1994 to 1998. We analyzed data obtained in face-to-face interviews from 1,476 cases and 1,409 controls. The main outcomes of interest were the timing of the growth spurt in adolescence, the experience of acne and interviewer observation of facial acne scarring, body size at age 21, body size in reference year, maximum body weight and rate of body size change since age 21 years. Analysis was performed on all cases and also by tumour grade. We found no associations with measures of body size including body mass index and lean body mass at age 21 or later in adult life. Having a growth spurt later than friends reduced risk (odds ratio [OR] 0.79 [0.63-0.97]) and some measures of acne also gave odds ratios less than 1, for example, having facial acne scarring gave an OR of 0.67 (0.45-1.00). We conclude that markers of delayed androgen action, such as delayed growth spurt in puberty, and markers of other androgen-dependent activity in puberty, such as facial acne scarring, are associated with prostate cancer risk but we could detect no associations with markers of adult body size and growth including lean body mass.