Intake of vitamins D and A and calcium and risk of non-Hodgkin lymphoma: San Francisco Bay Area population-based case-control study.

Several nutrients identified as potentially cancer protective have been inconsistently associated with non-Hodgkin lymphoma (NHL) risk. Dietary history data, including use of vitamin supplements, were collected using a semiquantitative food frequency questionnaire administered during in-person interviews with 4,133 participants (2,052 cases, 2,081 controls) in a San Francisco Bay Area population-based case-control study. Data were used to determine the association of intake levels of vitamins D and A and calcium with risk of NHL and NHL subtypes. Odds ratios (OR) and 95% confidence intervals (CI) were computed as estimates of relative risk using adjusted unconditional logistic regression. Increasing vitamin D intake from food and supplements was positively associated with NHL risk in men (5th quintile: OR = 1.6, 95% CI = 1.0-2.4, P(trend) = 0.07) and with diffuse large B-cell lymphoma (DLBCL) in women and men (5th quintile: OR = 1.6, 95% CI = 1.0-2.5, P(trend) = 0.02); that was largely due to the effect in men (P(trend) = 0.03). These results do not support a strong role for vitamin D intake with NHL risk, with the exception of a potential association for DLBCL risk in men. Our results should be interpreted conservatively until further investigation in larger pooled studies can be conducted to better assess the role of vitamin D intake in lymphomagenesis.

Angiopoietin-like 4 (ANGPTL4) gene polymorphisms and risk of brain arteriovenous malformations.

BACKGROUND: Brain arteriovenous malformations (BAVM) are high-flow vascular lesions prone to intracranial hemorrhage (ICH). Abnormal angiogenesis is a key characteristic of BAVM tissue. Angiopoietin-like 4 (ANGPTL4), a secreted glycoprotein, is thought to be involved in angiogenesis and required for proper postnatal blood vessel partitioning. We investigated whether common single nucleotide polymorphisms (SNPs) in ANGPTL4 were associated with risk of BAVM or ICH. METHODS AND RESULTS: We conducted a case-control study of 216 Caucasian BAVM cases and 246 healthy controls, and a secondary case-only analysis, comparing 83 ruptured (ICH) with 133 unruptured BAVM cases at presentation. Four tagSNPs in ANGPTL4 captured variation over a 10-kb region (rs2278236, rs1044250, rs11672433, and rs1808536) and were tested for association with BAVM or ICH. The minor allele (A) of rs11672433 (exon 6, Pro389Pro) was associated with an increased risk of BAVM (p = 0.006), which persisted after adjusting for multiple comparisons (p = 0.03). After adjustments for age and sex, carriers of the minor allele (A) remained at higher risk for BAVM compared to noncarriers (odds ratio, OR = 1.56; 95% confidence interval, CI = 1.01-2.41; p = 0.046) and risk of BAVM was increased with increasing copy of the minor A allele (OR = 1.49, 95% CI = 1.03-2.15; p(trend) = 0.03). Five common haplotypes (frequency >1%) were inferred; overall haplotype distribution differed between BAVM cases and controls (χ(2) = 12.2, d.f. = 4, p = 0.02). Neither SNPs (p > 0.05) nor haplotype distribution (χ(2) = 1.1, d.f. = 4, p = 0.89) were associated with risk of ICH among BAVM cases. CONCLUSION: A synonymous SNP in ANGPTL4 and haplotypes carrying it are associated with risk of BAVM but not with ICH presentation in BAVM cases.

Manganese superoxide dismutase (MnSOD) gene polymorphism, interactions with carotenoid levels and prostate cancer risk.

BACKGROUND: The manganese superoxide dismutase (MnSOD) gene encodes an antioxidant enzyme (SOD2) that may protect cells from oxidative damage. The MnSOD allele with Val as amino acid 16 encodes a protein that has 30-40% lower activity compared with the MnSOD Ala variant, hence possibly increasing susceptibility to oxidative stress. On the other hand, some epidemiologic studies suggest that the Ala allele is associated with a higher risk of cancer, including prostate cancer. METHODS: We conducted a nested case-control study in the Health Professionals Follow-up Study with 612 incident prostate cancer cases and 612 matched controls to investigate the role of the MnSOD gene Ala16Val polymorphism and its joint association with plasma carotenoid concentrations in relation to risk of total prostate cancer and aggressive prostate cancer (advanced stage or Gleason sum > or =7). RESULTS: The allele frequencies in the controls were 49.8% for Ala and 50.2% for Val. No association was found between the MnSOD genotype and risk of total and aggressive prostate cancer. Furthermore, no statistically significant interaction was observed between the MnSOD genotype and any of the plasma carotenoids in relation to risk of total and aggressive prostate cancer. In analyses in which we combined data from plasma and dietary carotenoids and created a quintile score to reflect long-term carotenoid status, a 3-fold [95% confidence interval: 1.37-7.02] increased risk of aggressive prostate cancer was observed among men with the Ala/Ala genotype in the presence of low long-term lycopene status (P-value, test for interaction = 0.02) as compared with men with the Ala/Val+Val/Val genotypes with low long-term lycopene status. CONCLUSION: In this cohort of mainly white men, the MnSOD gene Ala16Val polymorphism was not associated with total or aggressive prostate cancer risk. However, men with the MnSOD Ala/Ala genotype who had low long-term lycopene status had a higher risk of aggressive prostate cancer compared with individuals with the other genotypes. These results are consistent with findings from earlier studies that reported when antioxidant status is low, the MnSOD Ala/Ala genotype may be associated with an increased risk of aggressive prostate cancer.

Phase I/II trial of an allogeneic cellular immunotherapy in hormone-naïve prostate cancer.

PURPOSE: To determine the toxicity, immunologic, and clinical activity of immunotherapy with irradiated, allogeneic, prostate cancer cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with recurrent prostate cancer. PATIENTS AND METHODS: A single-institution phase I/II trial was done in hormone therapy-naïve patients with prostate-specific antigen (PSA) relapse following radical prostatectomy and absence of radiologic metastases. Treatments were administered weekly via intradermal injections of 1.2 x 10(8) GM-CSF gene-transduced, irradiated, cancer cells (6 x 10(7) LNCaP cells and 6 x 10(7) PC-3 cells) for 8 weeks. RESULTS: Twenty-one patients were enrolled and treated. Toxicities included local injection-site reactions, pruritus, and flu-like symptoms. One patient had a partial PSA response of 7-month duration. At 20 weeks post first treatment, 16 of 21 (76%) patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination (P < 0.001). Injection site biopsies showed intradermal infiltrates consisting of CD1a+ dendritic cells and CD68+ macrophages, similar to previous clinical trials using autologous GM-CSF-transduced cancer cells. Posttreatment, patients developed new oligoclonal antibodies reactive against at least five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody response against a 250-kDa antigen expressed on normal prostate epithelial cells was induced in a patient with partial PSA remission; titers of this antibody decreased when treatment ended, and subsequent PSA relapse occurred. CONCLUSIONS: This non-patient-specific prostate cancer immunotherapy has a favorable safety profile and is immunologically active. Continued clinical investigation at higher doses and with longer boosting schedules is warranted.

A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery.

BACKGROUND: Patient age, hemorrhagic presentation, nidal diffuseness, and deep perforating artery supply are important factors when selecting patients with brain arteriovenous malformations (AVMs) for surgery. OBJECTIVE: We hypothesized that these factors outside of the Spetzler-Martin grading system could be combined into a simple, supplementary grading system that would accurately predict neurologic outcome and refine patient selection. METHODS: A consecutive, single-surgeon series of 300 patients with AVMs treated microsurgically was analyzed in terms of change between preoperative and final postoperative modified Rankin Scale scores. Three different multivariable logistic models (full, Spetzler-Martin, and supplementary models) were constructed to test the association of combined predictor variables with the change in modified Rankin Scale score. A simplified supplementary grading system was developed from the data with points assigned according to each variable and added together for a supplementary AVM grade. RESULTS: Predictive accuracy was highest for the full multivariable model (receiver operating characteristic curve area, 0.78), followed by the supplementary model (0.73), and least for the Spetzler-Martin model (0.66). Predictive accuracy of the simplified supplementary grade was significantly better than that of the Spetzler-Martin grade (P = .042), with receiver operating characteristic curve areas of 0.73 and 0.65, respectively. CONCLUSION: This new AVM grading system supplements rather than replaces the well-established Spetzler-Martin grading system and is a better predictor of neurologic outcomes after AVM surgery. The supplementary grading scale has high predictive accuracy on its own and stratifies surgical risk more evenly. The supplementary grading system is easily applicable at the bedside, where it is intended to improve preoperative risk prediction and patient selection for surgery.

Vitamin D receptor (VDR) gene polymorphisms and haplotypes, interactions with plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and prostate cancer risk.

BACKGROUND: The vitamin D receptor (VDR) is required for actions of vitamin D. The binding of 1,25-dihydroxyvitamin D to the VDR on prostatic epithelial cells prompts the regulation of cancer-related genes. METHODS: We conducted a nested case-control study in the Health Professionals Follow-up Study to investigate the role of the VDR Cdx2, Fok1, and Bsm1 gene polymorphisms and associated haplotypes and their interaction with plasma vitamin D metabolites in relation to prostate cancer (PC) risk. RESULTS: No association was found between these SNPs or their associated haplotypes and all PC subtypes except that haplotype 2 (A-f-b) with Cdx2 A, Fok1 f, and Bsm1 b alleles and haplotype 3 (A-F-B) with Cdx2 A, Fok1 F and Bsm1 B alleles compared to the most common haplotype (A-F-b), were associated with reduced risk of aggressive PC (high stage or Gleason sum > or =7; P = 0.02), both with two alleles suspected of being low risk. Carriers of the variant Cdx2 A allele who were deficient in plasma 25-hydroxyvitamin D (< or =15 ng/ml) compared to non-carriers with normal 25-hydroxyvitamin D, had a lower risk of total and poorly differentiated PCs (Gleason sum > or =7) (P for interaction = 0.02 and 0.04, respectively). Plasma 1,25-dihydroxyvitamin D deficiency (< or =26 pg/ml) was associated with a threefold risk of poorly differentiated PC (P for interaction = 0.01) when comparing carriers of the Cdx2 A allele to non-carriers with normal 1,25-dihydroxyvitamin D. CONCLUSION: In this population of men, none of the VDR polymorphisms studied was associated with susceptibility to PC.