The survival curves suggest a more aggressive cancer than pancreatic endocrine neoplasms but one that is less aggressive than ductal adenocarcinoma of the pancreas. Those patients who present with localized disease have a much better prognosis than those who present with metastases. There is a high recurrence rate after complete surgical resection, suggesting that micrometastases are present even in localized disease and that adjuvant therapies may be indicated. Chemotherapy and radiation afford disappointing results, however, and novel therapies are needed.

Objective To assess quadriceps strength and fatigability by using femoral nerve magnetic stimulation (FNMS) and their relationship to exercise capacity in patients with fibromyalgia syndrome (FMS) and healthy controls. Methods Twenty‐two women (11 with FMS, 11 controls) performed a maximal incremental cycling test and a quadriceps fatigue test on 2 separate visits. For quadriceps assessment, we used FNMS during and after maximum voluntary contraction (MVC) to evaluate central and peripheral factors of neuromuscular fatigue. Subjects performed sets of 10 intermittent (5 seconds on/5 seconds off) isometric contractions starting at 10% MVC, in 10% MVC increments from one set to another until exhaustion. Neuromuscular fatigue was assessed with FNMS after each set. Results FMS patients had reduced initial MVC compared to controls (mean ± SD 102 ± 18 versus 120 ± 24 Nm; P < 0.05) without significant impairment of voluntary activation (mean ± SD 93.5% ± 3.0% versus 93.1% ± 3.4%; P = 0.74). During the fatigue task, FMS patients exhibited a greater fall in evoked muscular responses (mean ± SD −26% ± 6% versus −16% ± 8% at set 50% MVC; P < 0.05), but not in MVC (mean ± SD −24% ± 7% versus −19% ± 4% at set 50% MVC; P = 0.12). During the cycling test, FMS patients had lowered maximal exercise capacity and an enhanced rate of perceived exertion (RPE) compared to controls. The percent reduction in evoked muscular responses during the quadriceps fatigue test correlated with maximum oxygen consumption (r = 0.56, P < 0.05) and RPE at submaximal intensity (r = 0.84, P < 0.05) during cycling. Conclusion Greater impairment in muscle contractility is associated with enhanced perception of exertion and reduced maximal exercise capacity in FMS patients. Neuromuscular impairments should be considered as an important factor underlying functional limitations in FMS patients.

breast cancer in carriers of mutations in BRCA1 or BRCA2 is critical for guiding decisions concerning cancer prevention options. Many previous studies have reported on the cumulative risk to various ages (penetrance) of breast cancer in carriers. The recent literature primarily has involved studies of breast cancer incidence in the relatives of probands identified without consideration of family history. This literature has included studies of self-selected volunteers,1 but there appears to be some degree of consensus that the most reliable approach is to use populationbased ascertainment.2-8 Most of this literature has been focused on the magnitude of the risk, with relatively little attention being paid to the degree by which risk may vary among carriers.Population-based studies to date have used incident cases from existing casecontrol investigations as probands. Estimates of risk based on studies of in- ContextThe risk of breast cancer in BRCA1 and BRCA2 mutation carriers has been examined in many studies, but relatively little attention has been paid to the degree to which the risk may vary among carriers.Objectives To determine the extent to which risks for BRCA1 and BRCA2 carriers vary with respect to observable and unobservable characteristics. Main Outcome Measure Incidence of breast cancer in first-degree female relatives of the probands was examined and compared on the basis of proband characteristics and on the basis of variation between families.Results Among the 1394 participants with unilateral breast cancer, 73 (5.2%) were identified as carriers of deleterious mutations (42 with BRCA1 and 31 with BRCA2). Among the 704 participants with contralateral breast cancer, 108 (15.3%) were identified as carriers of deleterious mutations (67 with BRCA1 and 41 with BRCA2). Among relatives of carriers, risk was significantly associated with younger age at diagnosis in the proband (P=.04), and there was a trend toward higher risk for relatives of contralateral breast cancer vs unilateral breast cancer participants (odds ratio, 1.4 [95% confidence interval, 0.8-2.4]; P=.28). In addition, there were significant differences in risk between carrier families after adjusting for these observed characteristics. ConclusionThere exists broad variation in breast cancer risk among carriers of BRCA1 and BRCA2 mutations.

Malignant melanomas often contain BRAF or NRAS mutations, but the relationship of these mutations to ambient UV exposure in combination with phenotypic characteristics is unknown. In a population-based case series from North Carolina, 214 first primary invasive melanoma patients in the year 2000 were interviewed regarding their risk factors. Ambient solar UV exposures were estimated using residential histories and a satellite-based model. Cases were grouped on the basis of BRAF and NRAS somatic mutations, determined using single-strand conformation polymorphism analysis and radiolabeled DNA sequencing, and the risk profiles of these groups were compared. Mutually exclusive BRAF-mutant and NRAS-mutant cases occurred at frequencies of 43.0% and 13.6% with mean ages at diagnosis of 47.3 and 62.1 years, respectively. Tumors from patients with >14 back nevi were more likely to harbor either a BRAF mutation [age-adjusted odds ratio (OR), 3.2; 95% confidence interval (95% CI), 1.4-7.0] or an NRAS mutation (age-adjusted OR, 1.7; 95% CI, 0.6-4.8) compared with patients with 0 to 4 back nevi. However, BRAF-mutant and NRAS-mutant tumors were distinctive in that BRAF-mutant tumors were characteristic of patients with high early-life ambient UV exposure (adjusted OR, 2.6; 95% CI, 1.2-5.3). When ambient UV irradiance was analyzed by decadal age, high exposure at ages 0 to 20 years was associated with BRAF-mutant cases, whereas high exposure at ages 50 and 60 years was characteristic of NRAS-mutant cases. Our results suggest that although nevus propensity is important for the occurrence of both BRAF and NRAS-mutant melanomas, ambient UV irradiance influences risk differently based on the age of exposure. The association of BRAF mutations with early-life UV exposure provides evidence in support of childhood sun protection for melanoma prevention.

Many endometrial adenocarcinomas, particularly those of endometrioid type, express estrogen receptors (ERs), progesterone receptors (PRs), and vimentin. This typical immunophenotype is frequently considered a standard against which others are compared when immunohistochemistry is used for differential diagnosis. We tested large numbers of endometrial cancers, enriched for high-grade tumors, to determine whether this reported immunophenotype was valid and whether expression differences between types of endometrial carcinoma could be exploited for diagnostic purposes. Immunohistochemical stains were performed on the following types of endometrial cancers using established methodology: International Federation of Gynecology and Obstetrics (FIGO) grades 1 and 2 endometrioid-42; FIGO grade 3 endometrioid-40; serous-24; clear cell-11; carcinosarcoma-9. In total, 92% of serous carcinomas expressed p16 strongly compared to weak-tomoderate expression of p16 in 7-67% of other tumors (FIGO grades 1 and 2 carcinoma and carcinosarcoma, respectively). A total of 84% of FIGO grades 1 and 2 carcinomas expressed ER compared to 9-54% of other tumors (clear cell and serous carcinomas respectively); 83% of FIGO grades 1 and 2 expressed PR compared to 11-54% of other carcinomas (carcinosarcoma and serous carcinoma, respectively). Most carcinomas were negative for monoclonal carcinoembryonic antigen (mCEA), and those that were positive showed mostly only focal membrane expression. Vimentin was expressed in nearly every tumor. Most tumors were diffusely vimentin positive, but a large range of expression patterns, from focal to diffuse and from weak to strong, was noted. Only 70% of FIGO grades 1 and 2 endometrioid carcinomas and 26% of grade 3 endometrioid carcinomas possessed the reportedly characteristic endometrial cancer immunophenotype p16 (À), ER ( þ ), PR ( þ ), mCEA (À), and vimentin ( þ ). Endometrial cancers demonstrate substantial immunophenotypic diversity that remained apparent even within groups of similar histologic subtype and grade. ER, PR, and p16 expression was more illustrative of tumor type and degree of differentiation than they were of endometrial origin. In contrast, the vimentin-positive/CEA-negative phenotype remained the most constant among all endometrial cancers.