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Multiple molecularly targeted agents (MTAs) have been approved for the management of metastatic renal cell carcinoma (mRCC). Sunitinib and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) are primarily metabolized in the liver, whereas the metabolism of bevacizumab is unclear. There are limited data on the toxicity profile and the efficacy of these agents in patients with renal insufficiency (RI). This is clinically relevant, especially as about one-third of patients with mRCC have renal dysfunction. The primary objective was to assess the safety and efficacy of targeted agents in patients with mRCC with RI. Medical records of patients with mRCC at Wayne State University, started on sunitinib, temsirolimus, everolimus, or bevacizumab, were reviewed. Patients with a calculated creatinine clearance of less than or equal to 60 ml/min were deemed to have RI. Data on safety and efficacy of MTA therapy were collected and analyzed with respect to renal function. RI was observed in 33% of our patients with mRCC. The incidence of toxicities, responses, time to progression, and overall survival were not significantly different in patients with RI compared with patients with normal renal function. Patients with RI had larger median increases in blood pressure with sunitinib and bevacizumab, increased incidence of thyroid dysfunction with sunitinib, and increased incidence of rash and dose interruptions with mammalian target of rapamycin inhibitors, than did patients with normal renal function. In conclusion, RI was commonly observed in our patients with mRCC. Molecularly targeted agents are well tolerated, and efficacy seems to be maintained in patients with RI. Vigilant monitoring of hypertension would be recommended for patients receiving sunitinib and bevacizumab.

Background: Pancreatic cancer ranks as the fourth leading cause of cancer death in the United States with 5-year survival ranging from 1% to 5%. Positron emission tomography (PET) is a metabolic imaging system that is widely used for the initial staging of cancer and detecting residual disease after treatment. There are limited data, however, on the use of this molecular imaging technique to assess early tumor response after treatment in pancreatic cancer. Methods: The objective of the study was to explore the relationship of early treatment response using the 18 F-fluorodeoxyglucose (FDG) PET with surgical outcome and overall survival in patients with locally advanced pancreatic cancer. FDG-PET measurements of maximum standardized uptake value and kinetic parameters were compared with the clinical outcome. Results: Twenty patients were enrolled in the study evaluating neoadjuvant induction chemotherapy followed by concurrent chemoradiotherapy (chemo-RT) for locally advanced pancreatic cancer. All 20 patients had prestudy PET scans and a total of fifty PET scans were performed. Among patients who were PET responders (≥50% decrease in standardized uptake value after cycle 1), 100% (2/2) had complete surgical resection. Only 6% (1/16) had surgical resection in the PET nonresponders (

Synergy is observed with the combination of capecitabine and docetaxel due to docetaxel mediated up-regulation of thymidine phosphorylase. A phase II trial was performed with the combination for metastatic, castrate resistant prostate cancer.Eligible patients had metastatic, castrate resistant prostate cancer, no prior chemotherapy for metastatic disease and normal organ function. Docetaxel (36 mg/m(2) per week intravenously) on days 1, 8 and 15, and capecitabine (1,250 mg/m(2) per day in 2 divided doses) on days 5 to 18 were administered in 28-day cycles. The response was assessed every 2 cycles. Biomarker correlative studies were performed on blood dihydropyrimidine dehydrogenase, and the thymidine phosphorylase-to-dihydropyrimidine dehydrogenase and thymidine synthase-to-dihydropyrimidine dehydrogenase ratios in available prostate tumor tissue.A total of 30 patients with a median age of 69 years were enrolled in the study. We noted bone pain in 21 patients (70%), Gleason score 8 or higher in 18 (60%), measurable disease progression in 9, bone scan progression in 18 and prostate specific antigen progression in 22. Grade 3 or 4 neutropenia was seen in 3 patients and grade 3 hand-foot syndrome was found in 2. No treatment related deaths occurred. A prostate specific antigen response of 50% or greater decrease was observed in 22 patients (73%), of whom 9 (30%) had 90% or greater decrease. A partial response was noted in 5 of 9 patients (56%) with measurable disease. Median time to progression was 6.7 months (90% CI 4.2-7.7) and median overall survival was 22.0 months (90% CI 18.4-25.3).The combination was well tolerated and it demonstrated favorable response rates with durable remission and survival outcomes.

Prostate cancer is an androgen sensitive disease. Cytochrome P450 3A4 (CYP3A4) oxidatively deactivates testosterone by converting it to biologically less active metabolites. Previous studies suggest that a germline genetic variant in the 5' regulatory region of the gene may interfere with deactivation and increase the risk of clinically advanced prostate cancer. We investigated the impact of this polymorphism on the risk of recurrence after prostatectomy.We assembled clinical data and analyzed specimens from a large series of patients who underwent prostatectomy who were carefully staged at a single institution and had 5 to 10 years of prospective clinical followup. The series included 428 white men and 309 black men.Stage, Gleason score or preoperative prostate specific antigen strongly predicted progression-free survival (PFS) but were not associated with CYP3A4 genotypes. There was a strong association between race and genotype (p = 0.00002) in that 8% of white men and 83% of black men had 1 or more copies of the G allele. When both races were included genotype was associated with PFS (hazard ratio [HR] 1.27, CI 1.08-1.27, p = 0.005). In race specific analyses increasing copies of the G allele were associated with poorer PFS among white men (HR 1.98, CI 1.06-3.70, p = 0.03) but had little impact on PFS among black men (HR 1.004, CI 0.77-1.32, p = 0.97).The CYP3A4 genotype studied was not associated with pathological features of prostate cancer for men of either race. Unstratified analyses of men of both races and stratified analyses of white men demonstrated poorer PFS after prostatectomy for those with the G allele, but the G allele did not predict PFS among black men.

Oxidative DNA damage (ODD) can result from numerous endogenous metabolic processes as well as from exposure to environmental and dietary oxidants. One important type of ODD that may have a role in carcinogenesis is the formation of hydroxylated DNA bases. Our major purpose was to determine the potential for subject accrual for a multisite case-control study of ODD and breast cancer risk within a large urban university medical center. We examined the levels of a hydroxylated thymine residue, 5-hydroxymethyl-2'-deoxyuridine in DNA obtained from the peripheral blood of 26 women with breast cancer and an age-matched group of 29 control women without breast cancer. The isolated DNA was analyzed for levels of 5-hydroxymethyl-2'-deoxyuridine by gas chromatography with mass spectral detection. Our recruitment methods resulted in a relatively high yield of eligible cases (72%) and a lower yield of controls (46%). We evaluated the dose-response relationship of ODD level to breast cancer risk, using quartiles of ODD. The covariate-adjusted odds ratio of breast cancer exceeded 2.0 for women in the highest quartile of ODD (compared with the lowest quartile), although this result was not statistically significant. ODD levels were significantly more variable among African-American controls (SD = 224.1) than among white controls (SD = 57.5), p < 0.001. Overall, these results suggest a possible slight increase in breast cancer risk among women in the highest ODD quartile, after adjusting for race, menopausal status, and family history of breast cancer.

INTRODUCTION AND OBJECTIVES: The prostate cancer (PCa) mortality rate is more than twice as high among African American men (AAM) compared to European American men (EAM) and is unchanged from 1995 to 2007. The Behavioral Risk Factor Surveillance Study (BRFSS) from CDC reports similar PSA testing among AAM and EAM age 50 and above, and from 2000 to 2006 81% and 88% of AAM and EAM, respectively, have insurance. Thus access to care appears to have had minimal effect on the significant mortality disparity. Since metastatic PCa most likely contributes to PCa specific mortality, we examined metastatic PCa incidence and survival. METHODS: We used SEER data to select primary distant stage prostate cancers diagnosed 1995–2002 (survival follow-up through December 31, 2007), to calculate age-adjusted 5-year relative survival rates by year of diagnosis and race. We then calculated age-specific incidence rates of distant prostate cancer in AAM and EAM for ages 40–79. Rate ratios were calculated comparing AAM to EAM within each age stratum. RESULTS: The final dataset for the survival analysis included N 2,133 black (African-American) and N 8,961 white (European-American) cases. 95% confidence intervals indicated no statistical difference in survival rates between AAM and EAM by year of diagnosis of distant stage prostate cancer for this time period. (Graph 1). The incidence analysis included N 2,134 AAM and N 7,919 EAM cases. In each age group, AAM with distant disease had significantly higher incidence than EAM. (Table 1). CONCLUSIONS: The recent Swedish PCa screening study has reported a 44% decrease in mortality among men screened for PCa. We report similar survival among AAM and EAM diagnosed with metastatic PCa but yet a 3-fold disproportionate incidence of metastatic disease in AAM compared to EAM for ages 40 to 59 and above. We recently reported that PCa grows faster among AAM compared to EAM because of biological/genetic factors. We hypothesize that if the cancer is diagnosed early enough these factors may not be contributory. Therefore we conclude that earlier age for more robust screening among AAM is necessary to significantly reduce or eliminate racial PCa mortality disparity.

Serum samples were obtained from 6860 men during their study examination from 1971 to 1975. After a surveillance period of about 14 years, 98 incident cases of prostate cancer were identified. Their stored sera and that of 98 matched controls from the study population were tested for the following: testosterone, dihydrotestosterone, estrone, estradiol, and sex hormone globulin. There was a suggestion that serum dihydrotestosterone levels were lower and the testosterone/dihydrotestosterone ratios were higher in the prostate cancer cases compared with their controls. However, none of these associations or that of the other hormones was strongly significant. Further work is needed to clarify the relationship between sex hormones and prostate cancer risk.

WILLIAMS, JUDITH ANN, JOHN WAGNER, RICHARD WASNICH, and LANCE HEILBRUN. The effect of long-distance running upon appendicular bone mineral content. Med. Sci. Sports Exerc., Vol. 16, No. 3, pp. 223–227, 1984. The bone mineral content (BMC) of the os calcis was measured for a group of 20 male runners at the beginning and the end of a 9-month marathon training program. The participants had no previous running experience. The percent change in bone mineral in the runners was compared with that of a control group of male subjects of the same age range (38–68 yr). The consistent runners showed a significant increase in bone mineral over that of the controls; the increase was not significant for inconsistent runners. The data suggest that those runners with longer, more consistent distances gained more bone mineral than those with shorter, more inconsistent distances.

Commonly known risk factors have been shown to correlate with mean bone mass in populations, but none of these risk factors, either alone or in combination, have been shown to be predictive of future fracture risk in an individual. In order to evaluate the predictive power of bone mineral measurements at various sites, bone mineral content (BMC) has been measured at four skeletal sites and compared to subsequent fracture incidence at all skeletal locations, including spine and appendicular sites. Os calcis BMC has the most consistent monotonic relationship to unadjusted fracture incidence rates; os calcis BMC also has the strongest (p = 0.009) relation to levels of relative risk, after adjustment for age, height, and weight. Based on actual ability to predict fracture risk prospectively, along with such secondary criteria as cost, ease of performance, precision, and radiation exposure, the os calcis appears to be an optimal BMC measurement site for routine screening of perimenopausal women.