Citations

Abstract Current users of postmenopausal hormones (PMH) have ∼30% to 40% lower risk of colorectal cancer (CRC), although associations with specific types of hormones have been inconsistent. Further, it is not clear whether some tumor types have a different risk. We conducted a case-control study to examine the relationship between PMH and CRC. Cases (n = 1,004), ages 50 to 74 years, were identified from the Surveillance Epidemiology and End Results registry in Washington from 1998 to 2002; controls (n = 1,062) were randomly selected from population lists. Case tissue samples were obtained for microsatellite instability (MSI) analyses. Interviews collected risk-factor data for CRC, including detailed information on PMH. Multivariable logistic regression models estimated odds ratios (OR) and 95% confidence intervals (95% CI). Current use of any PMH was associated with a 20% reduction in CRC risk (95% CI 0.6–0.9). This reduction in risk was limited to women who had taken estrogen plus progestin (EP) preparations only (OR = 0.6, 95% CI 0.5–0.9); there was no association with estrogen-only (E alone) use (OR = 0.9, 95% CI 0.7–1.1). For women with MSI-low or MSI-stable tumors, there was a statistically significant 40% reduction in CRC risk associated with EP use (95% CI 0.4–0.9); there was no clear association with MSI-high tumors. EP use was associated with a decreased risk of CRC; however, there seemed to be no association with E alone data that are consistent with the recent Women's Health Initiative findings. Progestin may enhance the estrogenic effect of conjugated estrogen so the combination may be more biologically active in the colon than E alone. [Cancer Res 2007;67(15):7534–9]

The transseptal/transsphenoidal approach to the pituitary gland has been the most commonly used approach for resection of pituitary adenomas for the last 50 years. This procedure has a low morbidity and provides direct midline access to the sella and pituitary gland. Recent advancements in endoscopic surgery, however, suggest that a lower morbidity approach to the sella would be possible via transnasal endoscopic route. Prior reports have confirmed effectiveness of this approach to the pituitary gland and we report here an early series of endoscopic transnasal pituitary surgery from our institution. We report seven cases of transnasal endoscopic pituitary surgery. Our technique consists of endoscopic exposure of the sphenoid ostium unilaterally, excision of the posterior septum anterior to the rostrum of the sphenoid sinus with resection of the sphenoid rostrum for bilateral exposure of the sphenoid sinus. A specially designed nasal speculum is positioned to displace the posterior septum and lateralize the middle turbinates, permitting direct midline exposure of the sphenoid sinus and sella. We have progressively modified the technique over the seven cases that we present and will discuss our specific instrumentation, indications, and technique for this procedure. We have encountered one cerebrospinal fluid leak in this series. Patient satisfaction has been high and hospitalization is less than with the conventional transseptal approach, averaging 1 day. Our impression is that the transnasal endoscopic approach to pituitary adenomas is a safe technique with reduced morbidity permitting shortened hospital stay.

AbstractMany congenital disorders of glycosylation (CDG) can be diagnosed by observing the extent of glycosylation of the abundant serum glycoprotein transferrin (Trf). Trf is an N‐glycosylated protein with two asparagine glycation sites. CDG types I are those genetic defects which occur prior to transfer of the complex oligosaccharide to the acceptor asparagine in the cotranslated polypeptide chain. CDG Ia constitutes by far the most frequent form of CDG and is the result of mutations in the phosphomannomutase gene. CDG Ia and the Ib subtype (Phosphomannoisomerase deficiency) result in low cellular mannose‐1‐phosphate levels, a required precursor for oligosaccharide assembly in the endoplasmic reticulum. The deficiency in oligosaccharides with branched mannose structures is thereafter expressed by the appearance of glycoproteins with unoccupied N‐glycosylation sites (hypoglycosylation). Currently, there have been at least 11 Type I defects, type Ia being by far the most frequently occurring. Most, if not all type I defects result in unoccupied N‐glycation sites. Hypoglycosylated Trf, also known as carbohydrate‐deficient Trf (CDT), can be detected using mass spectrometry (MS) to measure the masses of the serum Trf. The methods for sample preparation using affinity chromatography and MS analysis are described in this unit. Curr. Protoc. Hum. Genet. 54:17.4.1‐17.4.9 © 2007 by John Wiley & Sons, Inc.

Purpose To evaluate the outcome of patients with limited-stage small-cell lung cancer (L-SCLC) treated with cisplatin and etoposide (PE), early prophylactic cranial irradiation (PCI), and high-dose twice-daily thoracic radiotherapy (bid RT). Patients and Methods A total of 76 assessable patients were treated on this phase II trial, which included six cycles of PE. PCI (25 Gy/10 fractions) was delivered during cycle 3 to responding patients. Cycles 4 and 5 included concurrent chemotherapy and thoracic RT (30 Gy/20 bid fractions, a 2-week break, and another 30 Gy/20 bid fractions). Results Of the 76 assessable patients, 74 patients (97%) suffered grade 3 or greater (3+) toxicity and 61 patients (80%) had grade 4 or greater (4+) toxicity. Of these adverse events, grade 3+ hematologic toxicity occurred in 72 patients (95%), and grade 3+ nonhematologic toxicity occurred in 55 patients (72%). Only one (2%) of the 61 patients who received PCI experienced treatment failure in the brain. The 5-year survival rate of the 76 assessable patients was 24% (median, 20 months). The 5-year survival rate of the 64 patients who received thoracic RT was 29% (median, 22 months). The 5-year cumulative incidence of in-field treatment failure was 34%. Conclusion This regimen included a high total dose of bid TRT, which resulted in a favorable 5-year survival rate. Local failure remains a problem that will require additional investigation. Newer technology should allow the safe administration of greater doses of RT, which should improve patient outcome. Data from eight trials were combined to demonstrate a relationship between RT dose fractionation and 5-year survival.

Abstract Immune reactivity to self-antigens in both cancer and autoimmune diseases can be enhanced by systemic immune modulation, posing a challenge in cancer immunotherapy. To distinguish the genetic and immune regulation of tumor immunity versus autoimmunity, immune responses to human ErbB-2 (Her-2) and mouse thyroglobulin (mTg) were tested in transgenic mice expressing Her-2 that is overexpressed in several cancers, and HLA-DRB1*0301 (DR3) that is associated with susceptibility to several human autoimmune diseases, as well as experimental autoimmune thyroiditis (EAT). To induce Her-2 response, mice were electrovaccinated with pE2TM and pGM-CSF encoding the extracellular and transmembrane domains of Her-2 and the murine granulocyte macrophage colony-stimulating factor, respectively. To induce EAT, mice received mTg i.v. with or without lipopolysaccharide. Depletion of regulatory T cells (Treg) with anti-CD25 monoclonal antibody enhanced immune reactivity to Her-2 as well as mTg, showing control of both Her-2 and mTg responses by Treg. When immunized with, Her-2xDR3 and B6xDR3 mice expressing H2bxDR3 haplotype developed more profound mTg response and thyroid pathology than Her-2 or B6 mice that expressed the EAT-resistant H2b haplotype. In Her-2xDR3 mice, the response to mTg was further amplified when mice were also immunized with pE2TM and pGM-CSF. On the contrary, Her-2 reactivity was comparable whether mice expressed DR3 or not. Therefore, induction of Her-2 immunity was independent of DR3 but development of EAT was dictated by this allele, whereas Tregs control the responses to both self-antigens. These results warrant close monitoring of autoimmunity during cancer immunotherapy, particularly in patients with susceptible MHC class II alleles. [Cancer Res 2007;67(14):7020–7]

Abstract The majority of candidates for breast cancer prevention have not accepted tamoxifen because of the perception of an unfavorable risk/benefit ratio and the acceptance of raloxifene remains to be determined. One means of improving this ratio is to identify women at very high risk of breast cancer. Family history, age, atypia in a benign biopsy, and reproductive factors are the main parameters currently used to determine risk. The most powerful risk factor, mammographic density, is not presently employed routinely. Other potentially important factors are plasma estrogen and androgen levels, bone density, weight gain, age of menopause, and fracture history, which are also not currently used in a comprehensive risk prediction model because of lack of prospective validation. The Breast Cancer Prevention Collaborative Group (BCPCG) met to critically examine and prioritize risk factors that might be selected for further testing by multivariate analysis using existing clinical material. The BCPCG reached a consensus that quantitative breast density, state of the art plasma estrogen and androgen measurements, history of fracture and height loss, BMI, and waist–hip ratio had sufficient priority for further testing. As a practical approach, these parameters could be added to the existing Tyrer–Cuzick model which encompasses factors included in both the Claus and Gail models. The BCPCG analyzed potentially available clinical material from previous prospective studies and determined that a large case/control study to evaluate these new factors might be feasible at this time.

Unlike healthy subjects, overt congestive heart failure cannot “escape” the sodium- and water-retaining actions of mineralocorticoid excess. It is undefined whether escape occurs in asymptomatic left ventricular dysfunction (ALVD), which is characterized by preserved sodium homeostasis, natriuretic peptide activation, and normal circulating aldosterone. We hypothesized that, in ALVD, mineralocorticoid excess with exogenous deoxycorticosterone acetate (DOCA) would overwhelm renal compensatory mechanisms, resulting in sodium and water retention, and promote renal and cardiac collagen deposition. ALVD was induced in 2 groups (N=5 each) of dogs by tachypacing at 180 bpm. Urine was collected daily and blood drawn at baseline and days 2, 5, 8, and 11. One group served as control (ALVD), and the other received DOCA (ALVD+DOCA) starting at day 2 of pacing. Urine flow and sodium excretion were unchanged in the ALVD group. In ALVD+DOCA, urine flow and sodium excretion decreased on the first 2 days DOCA was given but normalized starting day 4. Urine flow and urinary cGMP excretion increased in ALVD+DOCA after DOCA escape. Plasma atrial natriuretic peptide, B-type natriuretic peptide, and cGMP increased equally in both groups. There were no differences in cardiorenal and hemodynamic parameters in an acute study on day 11. Although renal collagen area fraction was similar, left ventricular collagen area fraction in ALVD+DOCA was significantly higher than in ALVD (3.3±0.4% versus 2.0±0.2%; P =0.012). We conclude that ALVD can escape the sodium- and water-retaining effects of mineralocorticoid excess. Despite renal escape, increased left ventricular collagen deposition suggests that the heart but not the kidney failed to escape the tissue effects of DOCA.