Dirk F. Moore

Relative risk of prostate cancer for men with affected relatives: systematic review and meta-analysis.

An increased risk of prostate cancer associated with a family history of prostate cancer has been documented in multiple published reports. Risk has been shown to vary by degree of relationship and age of onset of disease in the affected relative. Several studies, using various designs, have estimated the relative risk (RR) for these associations. The purpose of our study was to identify and summarize published reports on the relationship between risk of prostate cancer and family history, which is defined as having a father, brother, any first‐ or second‐degree relative or other relative affected with prostate cancer. A Medline and manual search from 1982 to 2000 identified 24 studies that reported RR and confidence intervals (CI) and satisfied inclusion criteria. Pooled RR estimates based upon a weighted average model were as follows: any affected family member RR = 1.93, CI 1.65–2.26; affected first‐degree relative RR = 2.22, CI 2.06–2.40; affected second‐degree relative RR = 1.88, CI 1.54–2.30; father with prostate cancer RR = 2.12, CI 1.82–2.51; and brother with prostate cancer RR = 2.87, CI 2.21–3.73). Statistical comparison of pooled data demonstrated that the RR is significantly higher for affected brother than for affected father (p < 0.03). A sensitivity analysis demonstrated that these results are robust with respect to population bias. This meta‐analysis confirms that risk of prostate cancer is associated with family history of disease and improves the quantification of this risk.

The Analysis of Multiple Correlated Binary Outcomes: Application to Rodent Teratology Experiments

Abstract In a developmental toxicity study, pregnant animals are exposed to the test substance and their offspring are assessed for defects. Often, multiple observations are made on each fetus, in which case the data are doubly nested. In this article we adapt the approach of Liang and Zeger (1986) and Zeger and Liang (1986) to yield an analysis, which appropriately allows for the correlation structure.

miR-320 targets transferrin receptor 1 (CD71) and inhibits cell proliferation

OBJECTIVE MicroRNAs (miRNAs) have been implicated in complex vertebrate developmental systems, such as hematopoiesis, and may play an integral role in the development of human cancers. Based on these observations, we investigated the contribution of miRNAs to acute myelogenous leukemia cell lineage-specific differentiation. MATERIALS AND METHODS To facilitate the identification of miRNAs and their targets relevant to leukemic cell differentiation, changes miRNA expression were analyzed in the human leukemia cell line HL-60, which historically has been utilized to study lineage-specific changes in response to the differentiation agent 12-O-tetradecanoylphorbol-13-acetate (TPA). RESULTS Using this approach, we have identified a panel of TPA-induced miRNAs that are expressed coincident with HL-60 stereotypic morphological changes characteristic of monocytic differentiation. The transferrin receptor 1(TfR-1; CD71), whose surface expression is downregulated during TPA-mediated HL-60 cell differentiation, has been identified as a target of the TPA-induced miRNA miR-320. Cell culture experiments indicate that enforced miR-320 expression can suppress TfR-1 expression and cell proliferation. CONCLUSION TPA induces the expression of several miRNAs in HL-60 cells, one such miRNA (miR-320) contributes to downregulation of TfR-1 surface expression characteristically seen during HL-60 monocytic differentiation. Moreover, TfR-1-targeting miRNAs, such as miR-320, may have potential as novel therapeutic agents for cancer due to their inhibitory effects on cell proliferation.

Late Gastrointestinal Toxicities Following Radiation Therapy for Prostate Cancer

BACKGROUND Radiation therapy is commonly used to treat localized prostate cancer; however, representative data regarding treatment-related toxicities compared with conservative management are sparse. OBJECTIVE To evaluate gastrointestinal (GI) toxicities in men treated with either primary radiation or conservative management for T1-T2 prostate cancer. DESIGN, SETTING, AND PARTICIPANTS We performed a population-based cohort study, using Medicare claims data linked to the Surveillance Epidemiology and End Results data. Competing risk models were used to evaluate the risks. MEASUREMENTS GI toxicities requiring interventional procedures occurring at least 6 mo after cancer diagnosis. RESULTS AND LIMITATIONS Among 41,737 patients in this study, 28,088 patients received radiation therapy. The most common GI toxicity was GI bleeding or ulceration. GI toxicity rates were 9.3 per 1000 person-years after three-dimensional conformal radiotherapy, 8.9 per 1000 person-years after intensity-modulated radiotherapy, 5.3 per 1000 person-years after brachytherapy alone, 20.1 per 1000 person-years after proton therapy, and 2.1 per 1000 person-years for conservative management patients. Radiation therapy is the most significant factor associated with an increased risk of GI toxicities (hazard ratio [HR]: 4.74; 95% confidence interval [CI], 3.97-5.66). Even after 5 yr, the radiation group continued to experience significantly higher rates of new GI toxicities than the conservative management group (HR: 3.01; 95% CI, 2.06-4.39). Because our cohort of patients were between 66 and 85 yr of age, these results may not be applicable to younger patients. CONCLUSIONS Patients treated with radiation therapy are more likely to have procedural interventions for GI toxicities than patients with conservative management, and the elevated risk persists beyond 5 yr.

Fruits and vegetables and endometrial cancer risk: a systematic literature review and meta-analysis.

Abstract: Endometrial cancer is the most common female gynecological cancer in the United States. Although obesity is a well-established risk factor, the role of other dietary factors is not well understood. The purpose of this study was to summarize and quantify the current evidence for fruit and vegetable intake and endometrial cancer by conducting a systematic literature review and meta-analysis. Searches were conducted to identify relevant papers published up to June 2006 in various databases. We included peer-reviewed manuscripts published in any language. Random and fixed-effects pooled risk estimates were estimated. We found one cohort study and 16 case-control studies evaluating various aspects of consumption. The random-effects summary estimates (95% CI) comparing high vs. low categories of intake reported were 0.71 (0.55–0.91) for total vegetables based on 10 studies, 0.85 (0.74–0.97) for cruciferous vegetables based on seven studies, and 0.90 (0.72–1.12) for total fruit based on 14 studies. For 100 g/day intake, summary ORs were 0.90 (0.86–0.95) for total vegetables, 0.79 (0.69–0.90) for cruciferous vegetables, and 0.97 (0.92–1.02) for total fruit. Excluding studies not meeting certain quality criteria provided similar results. The current evidence, based solely on case-control studies, with less than half being population-based, suggests a modest inverse association with vegetable consumption, particularly for cruciferous vegetables. We did not find any cohort studies evaluating fruit and vegetables separately. No firm conclusion can be drawn at this time in the absence of additional well-conducted population-based studies and, particularly, prospective data.

Patterns and Correlates of Prostate Cancer Treatment in Older Men

BACKGROUND Although elderly men, particularly patients with low-risk prostate cancer and a life expectancy less than 10 years, are unlikely to benefit from prostate cancer active therapy, treatment rates in this group are high. METHODS By using the population-based Surveillance, Epidemiology, and End Results program linked to Medicare data from 2004 to 2005, we examined the effects of clinical and nonclinical factors on the selection of prostate cancer active therapy (ie, radical prostatectomy, external beam radiation therapy, brachytherapy, or androgen deprivation therapy) in men aged≥75 years with a new diagnosis of localized prostate cancer. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for receiving prostate cancer active therapy. RESULTS The majority of men aged≥75 years were treated with prostate cancer active therapy (81.7%), which varied by disease risk level: low, 72.2%; intermediate, 83.7%; and high, 86.4%. Overall, in older men, the percentage of the total variance in the use of prostate cancer active therapy attributable to clinical and nonclinical factors was minimal, 5.1% and 2.6%, respectively. In men with low-risk disease, comorbidity status did not affect treatment selection, such that patients with 1 or 2+ comorbidities were as likely to receive prostate cancer active therapy as healthy men: OR=0.98; 95% CI, 0.76-1.27 and OR=1.19; 95% CI, 0.84-1.68, respectively. Geographic location was the most powerful predictor of treatment selection (Northeast vs Greater California: OR=2.41; 95% CI, 1.75-3.32). CONCLUSION Clinical factors play a limited role in treatment selection among elderly patients with localized prostate cancer.

A proportional hazards model for truncated AIDS data

An important source of information on the latency period for AIDS is the data from individuals infected by contaminated blood transfusion. However, a difficulty in the analysis and interpretation of these data is that information is available only on individuals who are infected and develop the disease prior to some specific time. In this paper, we propose an approach to the analysis of such data under a proportional hazards model. The proposed approach allows testing for group effects in the presence of multiple explanatory variables.

Cancer-specific Survival After Metastasis Following Primary Radical Prostatectomy Compared with Radiation Therapy in Prostate Cancer Patients: Results of a Population-based, Propensity Score–Matched Analysis

BACKGROUND Data regarding the difference in the clinical course from metastasis to prostate cancer-specific mortality (PCSM) following radical prostatectomy (RP) compared with radiation therapy (RT) are lacking. OBJECTIVE To examine the association between primary treatment modality and prostate cancer-specific survival (PCSS) after metastasis. DESIGN, SETTING, AND PARTICIPANTS We used the Surveillance Epidemiology and End Results-Medicare linked database from 1994 to 2007 for patients diagnosed with localized prostate cancer (PCa). We used cancer stage and Gleason score to stratify patients into low and intermediate-high risks. INTERVENTION Radical prostatectomy or radiation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Our outcome is time from onset of metastases to PCSM. Propensity score matching and Cox regression were used to analyze the PCSM hazard for the RP group compared with the RT group. RESULTS AND LIMITATIONS Our study consisted of 66,492 men diagnosed with PCa, 51,337 men receiving RT, and 15,155 men undergoing RP within 1 yr of cancer diagnosis. During the study period, 2802 men were diagnosed as having metastatic disease. A total of 916 men with metastases were included in the propensity-matched cohort; of these men, 186 died from PCa. During the follow-up, for the low-risk patients, the adjusted PCSS after metastasis was 86.2% and 79.3% in the RP and RT groups, respectively; for the intermediate-high-risk patients, the PCSS after metastasis was 76.3% and 63.3% in the RP and RT groups, respectively. The hazard ratios estimating the risk of PCSM between the RP and RT groups were 0.64 (95% confidence interval [CI], 0.36-1.16) and 0.55 (95% CI, 0.39-0.77) for the low- and intermediate-high-risk groups, respectively. Because of the nature of observational studies, the results may be affected by residual confounders and treatment indication. CONCLUSIONS Following the development of metastases, men who received primary RP have a longer PCSS than men who received primary RT. Our results may have implications for the timing and nature of local PCa treatment.

Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications

Receipt of androgen deprivation therapy (ADT) has been associated with an increased risk of skeletal‐associated complications, such as a decrease in bone mineral density and an increase in fracture risk. Many men with pre‐existing health conditions receive ADT as their primary treatment because they are considered to be inappropriate candidates for attempted curative treatments. However, several chronic health conditions, such as diabetes, rheumatoid disease and chronic liver disease, are strong predictors for osteoporosis and fractures. We undertook the present study aiming to quantify the impact of treating men with ADT who carry known risk factors for skeletal complications. Among these high‐risk men, more than 58% develop at least one fracture after ADT within the 12 years of follow‐up. Men who sustained a fracture within 48 months experienced an almost 40% higher risk of mortality than those who did not. Our findings suggest that treating men with a high fracture risk at baseline with long‐term ADT may have serious adverse consequences.

Classification of Subcellular Location by Comparative Proteomic Analysis of Native and Density-shifted Lysosomes

One approach to the functional characterization of the lysosome lies in the use of proteomic methods to identify proteins in subcellular fractions enriched for this organelle. However, distinguishing between true lysosomal residents and proteins from other cofractionating organelles is challenging. To this end, we implemented a quantitative mass spectrometry approach based on the selective decrease in the buoyant density of liver lysosomes that occurs when animals are treated with Triton-WR1339. Liver lysosome-enriched preparations from control and treated rats were fractionated by isopycnic sucrose density gradient centrifugation. Tryptic peptides derived from gradient fractions were reacted with isobaric tag for relative and absolute quantitation eight-plex labeling reagents and analyzed by two-dimensional liquid chromatography matrix-assisted laser desorption ionization time-of-flight MS. Reporter ion intensities were used to generate relative protein distribution profiles across both types of gradients. A distribution index was calculated for each identified protein and used to determine a probability of lysosomal residence by quadratic discriminant analysis. This analysis suggests that several proteins assigned to the lysosome in other proteomics studies are not true lysosomal residents. Conversely, results support lysosomal residency for other proteins that are either not or only tentatively assigned to this location. The density shift for two proteins, Cu/Zn superoxide dismutase and ATP-binding cassette subfamily B (MDR/TAP) member 6, was corroborated by quantitative Western blotting. Additional balance sheet analyses on differential centrifugation fractions revealed that Cu/Zn superoxide dismutase is predominantly cytosolic with a secondary lysosomal localization whereas ATP-binding cassette subfamily B (MDR/TAP) member 6 is predominantly lysosomal. These results establish a quantitative mass spectrometric/subcellular fractionation approach for identification of lysosomal proteins and underscore the necessity of balance sheet analysis for localization studies.