Citations

AbstractBackgroundSince the human genome has been sequenced many mysteries of cell biology have been unravelled, thereby clarifying the pathogenesis of several diseases, particularly cancer. In members of kindreds with certain hereditary diseases, it is now possible early in life to predict with great certainty whether or not a family member has inherited the mutated allele causing the disease. In hereditary malignancies this has been particularly important, because in affected family members there is the possibility of removing the organ destined to develop cancer before malignancy develops or while it is in situ. At first consideration, it would appear that “prophylactic surgery” would have a place in many hereditary malignancies; however, the procedure has applicability only if certain criteria are met: (1) the genetic mutation causing the hereditary malignancy must have a very high penetrance and be expressed regardless of environmental factors; (2) there must be a highly reliable test to identify patients who have inherited the mutated gene; (3) the organ must be removed with minimal morbidity and virtually no mortality; (4) there must be a suitable replacement for the function of the removed organ; and (5) there must be a reliable method of determining over time that the patient has been cured by “prophylactic surgery.”ConclusionsIn this monograph we review several hereditary malignancies and consider those where prophylactic surgery might be useful. As we learn, there are various barriers to performing the procedure in many common hereditary cancer syndromes. The archetype disease syndromes, which meet each of the five criteria mentioned above and where prophylactic surgery is most useful, are the type 2 multiple endocrine neoplasia (MEN) syndromes: MEN2A, MEN2B, and the related familial medullary thyroid carcinoma. An additional benefit of the Human Genome Project, has been the development of pharmacologic and biologic compounds that block the metabolic pathway(s) activated by specific genetic mutations. Many of these compounds have shown efficacy in patients with locally advanced or metastatic cancers, and there is the likelihood that they will prove beneficial in preventing the outgrowth of malignant cells in patients destined to develop a hereditary cancer.

Abstract Germ line inactivating mutations in BRCA1 confer susceptibility for breast and ovarian cancer. However, the relevance of the many missense changes in the gene for which the effect on protein function is unknown remains unclear. Determination of which variants are causally associated with cancer is important for assessment of individual risk. We used a functional assay that measures the transactivation activity of BRCA1 in combination with analysis of protein modeling based on the structure of BRCA1 BRCT domains. In addition, the information generated was interpreted in light of genetic data. We determined the predicted cancer association of 22 BRCA1 variants and verified that the common polymorphism S1613G has no effect on BRCA1 function, even when combined with other rare variants. We estimated the specificity and sensitivity of the assay, and by meta-analysis of 47 variants, we show that variants with <45% of wild-type activity can be classified as deleterious whereas variants with >50% can be classified as neutral. In conclusion, we did functional and structure-based analyses on a large series of BRCA1 missense variants and defined a tentative threshold activity for the classification missense variants. By interpreting the validated functional data in light of additional clinical and structural evidence, we conclude that it is possible to classify all missense variants in the BRCA1 COOH-terminal region. These results bring functional assays for BRCA1 closer to clinical applicability. [Cancer Res 2007;67(4):1494–501]

Abstract FKBP52 is a member of the FK506-binding family of immunophilins and serves as a co-chaperone for steroid hormone nuclear receptors to govern appropriate hormone action in target tissues. Male mice missing Fkbp52 are infertile, and this infertility has been ascribed to compromised sensitivity of the anterior prostate, external genitalia, and other accessory sex organs to androgen. Here, we show additional defects contributing to infertility. We found that epididymal Fkbp52−/− sperm are sparse often with aberrant morphology, and they have reduced fertilizing capacity. This phenotype, initially observed in null males on a C57BL/6/129 background, is also maintained on a CD1 background. Expression studies show that while FKBP52 and androgen receptor are co-expressed in similar cell types in the epididymis, FKBP52 is also present in epididymal sperm flagella. Collectively, our results suggest that reduced number and abnormal morphology contribute to compromised fertilizing capacity of Fkbp52−/− sperm. This study is clinically relevant because unraveling the role of immunophilin signaling in male fertility will help identify new targets for male contraceptives and/or alleviate male infertility.

AbstractIn the past 36 months, new developments have occurred both in the understanding of the biology of Waldenström macroglobulinemia (WM) and in therapeutic options for WM. Here, we review the classification, clinical features, and diagnostic criteria of the disease. WM is a B-cell neoplasm characterized by lymphoplasmacytic infiltration of the bone marrow and a monoclonal immunoglobulin M (IgM) protein. The symptoms of WM are attributable to the extent of tumor infiltration and to elevated IgM levels. The most common symptom is fatigue attributable to anemia. The prognostic factors predictive of survival include the patient's age, β2-microglobulin level, monoclonal protein level, hemoglobin concentration, and platelet count. Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. No specific agent or regimen has been shown to be superior to another for treatment of WM. Novel agents such as bortezomib, perifosine, atacicept, oblimersen sodium, and tositumomab show promise as rational targeted therapy for WM.

AbstractBackgroundThe purpose of the present study was to compare surgical and endovascular revascularization for chronic mesenteric ischemia (CMI).MethodsForty‐nine patients underwent surgical (SG) or endovascular (EG) treatment. Relief of symptoms was considered the primary endpoint; patency, morbidity, and mortality were secondary endpoints. For statistical analysis, significance was assumed if P values ≤ 0.05.ResultsTwenty‐six patients (53%) underwent surgical revascularization; 23 patients (47%), endovascular repair. Mean follow‐up was 25 ± 21 months (SG) versus 10 ± 10 (EG) months (P = 0.07). Except for body mass indices (SG 18.9 ± 2.7 versus EG 23.6 ± 4.8; P = 0.001), preoperative data were comparable. Freedom from symptoms was 100% (SG) versus 90% (EG) after intervention (P = 0.194), and 89% (SG) versus 75% (EG) at the end of follow‐up. Reocclusion or re‐stenosis occurred in 8% (SG) versus 25% (EG) (log‐rank test: P = 0.003), and mesenteric ischemia developed in 0% (SG) versus 9% (EG) (P = 0.04). Reintervention for CMI was required in 0% (SG) versus 13% (EG) (P = 0.01). Surgical patients experienced more early complications (42% versus EG 4%; P = 0.02) and longer hospital stays (11.6 ± 10.9 days versus EG 1.3 ± 0.5 days; P < 0.001). Overall mortality at the end of follow‐up was 31% (SG) versus 4% (EG) (log‐rank test: P = 0.08), including all patients with combined open mesenteric and aortic reconstruction (P = 0.001).ConclusionsSurgical treatment has superior long‐term patency and requires fewer reinterventions, but it is also more invasive with greater morbidity and mortality compared to endovascular treatment. Endovascular techniques may be preferable in patients with significant co‐morbidities, concomitant aortic disease, or indeterminate symptoms.

AbstractMutations in the BRCA2 gene have been implicated in pancreatic cancer susceptibility through studies of high-risk breast and ovarian cancer families. To determine the contribution of mutations in BRCA2 to familial pancreatic cancer, we screened affected probands from 151 high-risk families identified through pancreatic cancer clinics for germ-line BRCA2 mutations. Of these families, 118 had two or more first- and second-degree relatives with pancreatic cancer, and an additional 33 had two or more affected second-degree relatives. The average age of onset for pancreatic cancer was 62.8 years. Five BRCA2 truncating mutations were identified, three in families with two or more first- and second-degree relatives with pancreatic cancer. Three of the families with mutations had a history of breast cancer but not ovarian cancer. Four of five families with mutations were identified through probands with early-onset (&lt;55 years) pancreatic cancer. The results of this study were combined with those from a BRCA2 mutation study of 29 other families from the same Johns Hopkins University National Familial Pancreatic Tumor Registry to estimate the frequency of BRCA2 mutations. A total of 10 carriers from 180 families were identified, suggesting that BRCA2 mutations account for 6% of moderate and high-risk pancreatic cancer families. (Cancer Epidemiol Biomarkers Prev 2007;16(2):342–6)

Abstract After acute estrogen withdrawal in postmenopausal women, administration of anakinra or etanercept, specific blockers of IL-1 and TNF-α, respectively, reduced the rise in bone resorption markers to about one half of that in controls. This is consistent with an important role for these immune cytokines in mediating the effect of estrogen deficiency on bone. Introduction: Studies in rodents have implicated increased production of interleukin (IL)-1β and TNF-α as mediators of bone loss after ovariectomy, but their roles are unclear in humans whose immune system differs markedly from that of rodents. Materials and Methods: We administered transdermal estradiol, 0.1 mg/d, for 60 days to 42 early postmenopausal women. Estrogen treatment was discontinued, and subjects were randomly assigned to intervention groups receiving 3 wk of injections with 0.9% saline, anakinra 100 mg/d, or etanercept 25 mg/twice weekly. Bone turnover was assessed by measuring serum carboxyl-terminal telopeptide of type 1 collagen (CTX) and amino-terminal telopeptide of type 1 collagen (NTX), markers for bone resorption, and serum amino-terminal propeptide of type 1 collagen (P1NP), a marker for bone formation. Results were expressed as percent change in markers from baseline (last 2 days of estrogen treatment and days 20 and 21 of intervention). Results: The percent changes from baseline during intervention for serum CTX, urine NTX, and serum PINP, respectively, were 43.3 ± 8.0%, 12.0 ± 7.1%, and −41.0 ± 2.5% for the control group; 25.9 ± 6.3%, 9.5 ± 4.0%, and −37.8 ± 3.0% for the anakinra group; and 21.7 ± 5.0%, 0.32 ± 3.82%, and −34.5 ± 3.9% for the etanercept group. Compared with the control group, the blunting of the increase in serum CTX fell just below the level of significance (p = 0.10) after anakinra treatment, whereas the blunting of the increase in serum CTX (p = 0.034) and in urine NTX (p = 0.048) were significant after etanercept treatment. Other changes were not significant. Conclusions: The data are consistent with a role for TNF-α, and possibly for IL-1β, in mediating increased bone resorption during estrogen deficiency in women. Although either cytokine blocker reduced serum CTX by about one half, the effect of combined blockade could not be tested because of concerns about toxicity. The data do not exclude direct or indirect contributory roles for RANKL or for other cytokines.