Gary G. Schwartz

Sun Exposure and Prostate Cancer Risk: Evidence for a Protective Effect of Early-Life Exposure

Mounting experimental and epidemiologic evidence supports the hypothesis that vitamin D reduces the risk of prostate cancer. Some evidence suggests that prostate cancer risk may be influenced by sun exposure early in life. We analyzed data from the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study to examine associations of prostate cancer risk with early-life and adult residential sun exposure and adult sun exposures that were assessed through self-report, physician report, and dermatologic examination. We used solar radiation in the state of birth as a measure of sun exposure in early life. Follow-up from 1971 to 1975 (baseline) to 1992 identified 161 prostate cancer cases (102 nonfatal and 59 fatal) among non-Hispanic white men for whom sun exposure data were available. Significant inverse associations were found for men born in a region of high solar radiation (relative risk, 0.49, 95% confidence interval, 0.27-0.90 for high versus low solar radiation), with a slightly greater reduction for fatal than for nonfatal prostate cancer. Frequent recreational sun exposure in adulthood was associated with a significantly reduced risk of fatal prostate cancer only (relative risk, 0.47; 95% confidence interval, 0.23-0.99). These findings suggest that, in addition to sun exposure in adulthood, sun exposure in early life protects against prostate cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1283–6)

Serum Calcium and Incident and Fatal Prostate Cancer in the National Health and Nutrition Examination Survey

We examined the association between serum calcium levels and the risk for prostate cancer using a prospective cohort, the National Health and Nutrition Examination Survey (NHANES) and the NHANES Epidemiologic Follow-up Study. Eighty-five incident cases of prostate cancer and 25 prostate cancer deaths occurred over 46,188 person-years of follow-up. Serum calcium was determined an average of 9.9 years before the diagnosis of prostate cancer. Comparing men in the top with men in the bottom tertile of serum calcium, the multivariable-adjusted relative hazard for fatal prostate cancer was 2.68 (95% confidence interval, 1.02-6.99; Ptrend = 0.04). For incident prostate cancer, the relative risk for the same comparison was 1.31 (95% confidence interval, 0.77-2.20; Ptrend = 0.34). These results support the hypothesis that high serum calcium or a factor strongly associated with it (e.g., high serum parathyroid hormone) increases the risk for fatal prostate cancer. Our finding of a >2.5-fold increased risk for men in the highest tertile of serum calcium is comparable in magnitude with the risk associated with family history and could add significantly to our ability to identify men at increased risk for fatal prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2302–5)

Phase I/II Study of 19-nor-1α-25-Dihydroxyvitamin D2 (Paricalcitol) in Advanced, Androgen-Insensitive Prostate Cancer

Purpose: We assessed the safety and efficacy of the vitamin D analogue, 19-nor-1α-25-dihydroxyvitamin D2 (paricalcitol), in patients with androgen-independent prostate cancer. Experimental Design: Patients received paricalcitol i.v. three times per week on an escalating dose of 5 to 25 μg (3-15 μg/m2). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were characterization of toxicity in this population, changes in serum parathyroid hormone (PTH), and survival. Results: A total of 18 patients were enrolled. No patient showed a sustained 50% drop in serum PSA, despite several large declines in PSA (e.g., 1,300 ng/mL). Paricalcitol was well tolerated. One instance of significant hypercalcemia, a serum calcium of 14.3 mg/dL, was observed at the highest dose (25 μg). At entry into the study, seven (41%) of the patients had elevated serum levels of PTH, which were significantly reduced by paricalcitol. Higher levels of serum PTH at study entry were significantly and negatively associated with survival (P < 0.01). Conclusion: No objective responses were seen in the primary end point. However, elevated serum levels of PTH, a common feature of advanced prostate cancer, were reduced by paricalcitol. Because elevated PTH is associated with increased cardiovascular and skeletal morbidity, including an increased risk for pathologic fracture, further evaluation of paricalcitol in the reduction of skeletal morbidity in advanced prostate cancer is warranted.

Surgery versus radiation therapy as single-modality treatment of tonsillar fossa carcinoma: The roswell park cancer institute experience (1971–1991)†

Objective: To compare the efficacy and treatment outcomes in patients with tonsillar fossa cancer using surgery or radiation as a single modality therapy. Methods: From 1971 to 1991 239 patients with oral pharyngeal cancer were treated at Roswell Park Cancer Institute. Of these patients 90 had tonsillar carcinoma. Seventy‐six of these patients received either surgery (SA) (n = 56) or radiation therapy (RA) (n = 20) as single‐modality therapy and are the subject of this review. All patients in the radiation arm of this review were surgical candidates who declined primary surgical therapy. Results: Sixty‐three percent of the SA and 80% of the RA treatment groups presented with either stage III or stage IV disease (P ⩽ .05). Forty‐seven percent of the SA group and 52% of the RA patients had clinically positive regional disease at initial presentation. There was a predictable pattern of nodal presentation, with level II the most frequently involved region. The rate of occult metastasis was 27% and was evenly distributed between T1 and T4 disease. The overall local control rate in the SA group was 75%, compared with 60% in the RA group (P value was not significant). The disease‐specific survival (all stages) was 61% in the SA group and 37% in the RA group (P ⩽ .05). The disease‐free survival for stage III and stage IV disease in the SA group was 47% and in the RA group 27% (P ⩽ .05). Survival measured against clinical response to radiation therapy, in complete responders (all stages) was 83%; by contrast there were no survivors past 24 months in the partial response group (P ⩽ .001). Conclusion: The results from this study suggest that for early disease (stage I/II), surgery or radiation therapy as single‐modality treatment is equally effective. For advanced disease radiation therapy is inferior to surgery as a single‐modality treatment, as measured by ultimate survival and the local control of disease. There is, however, a subset of patients with advanced disease who respond to radiation therapy and whose survival is equivalent to our surgical cohort of patients.

Prostate Cancer, Serum Parathyroid Hormone, and the Progression of Skeletal Metastases

Bony metastases from prostate cancer are a significant cause of morbidity and mortality. These metastases are predominantly blastic (bone-forming) and commonly cause increased serum levels of parathyroid hormone (PTH) as calcium ions are transferred from serum into blastic bone. The epidemiologic and clinical significance of secondary hyperparathyroidism in advanced prostate cancer have not been widely appreciated. Prostate cancer bony metastases show increased expression of the PTH receptor (PTH-IR) and PTH promotes the growth and invasiveness of prostate cancer cells in bone. Thus, blastic metastases appear to induce a “vicious cycle” in which PTH resorbs normal bone to support the growth of blastic bone. Recognition of the potential role of PTH in the progression of skeletal metastases suggests novel opportunities for prostate cancer secondary prevention. In particular, we propose that suppressing serum PTH in advanced prostate cancer may reduce morbidity by decreasing fractures and pain caused by bone resorption and may reduce mortality by retarding the progression of metastatic disease. (Cancer Epidemiol Biomarkers Prev 2008;17(3):478–83)

The Relation of Serum Parathyroid Hormone and Serum Calcium to Serum Levels of Prostate-Specific Antigen: A Population-Based Study

Experimental and clinical data implicate calcium and parathyroid hormone (PTH) in the development of prostate cancer. However, epidemiologic data on the role of these variables in prostate health are sparse. We examined the relationship between serum levels of calcium, PTH, and prostate-specific antigen (PSA), an established marker of prostate growth, in a large, population-based study using multivariate linear regression. We studied 1,273 men in National Health and Nutrition Survey 2005 to 2006 who were ≥40 years of age and who were without clinical prostate cancer. Adjusted for age, race, body mass index, and serum levels of 25-hydroxyvitamin D, serum levels of PTH were significantly positively correlated with serum PSA (P = 0.01). Serum levels of PTH and calcium each were correlated significantly with free PSA (P = 0.05 and 0.008, respectively). The percentage of men who had elevated serum levels of PTH (PTH, ≥66 pg/mL) was significantly greater among African American men (19.2 versus 9.6%, P = 0.04). Compared with men whose PTH was at the lower end of the reference range, the predicted PSA for men with a PTH of 66 pg/mL was increased 43%. These findings support the hypothesis that serum calcium and serum PTH stimulate prostate growth in men without clinical prostate cancer and have implications for the use of PSA as a screening tool for prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2869–73)

Expression of the MRP and MDRI Multidrug Resistance Gene Products in 160 Untreated Human Carcinomas Studied by Immunohistochemical Methods in Formalin-Paraffin Sections

An immunohistochemical method was developed and applied to detect multidrug resistance related protein (MRP) in sections of formalin-fixed, paraffin-embedded human tissues. Monoclonal antibodies MRPm6, MRPrl, and QCRL-1 were used on sections of paraffin-embedded cell pellets of known MRP expression (HL60, HT1080, HeLa). None of the antibodies succeeded without pretreatment, but microwave epitope retrieval with 6M urea resulted in excellent specific staining with MRPm6. Moderate or weak staining was seen with MRPrl and QCRL-1. Various carcinomas were tested for MRP with MRPm6, and for MDRl P-glycoprotein (Pgp) expression with MAb JSB-1, by our previously described method (Am J Pathol 144:227-236, 1994) to investigate the possible coexpression of multidrug resistance markers in the same solid tumor. The incidence of positive immunoreactions/case with MRPm6 and JSB-1 respectively, in various human cancers was as follows: lung, 15 and two of 26; esophagus, eight and two of 15; head and neck, nine and one of 27; colorectal, 13 and 11 of 20; breast, 25 and 23 of 55; bladder, 0 and 0 of seven; ovarian, 0 and 0 of 10 cases. The overall incidence of MRP expression in these tumors was higher 70/160 (44%) than that of Pgp 41/160 (26%). Among Pgp-negative tumors 38% proved to be MRP positive. Coexpression of MRP and Pgp was found in 25/160 cases (16%), which is statistically significant (p=.0 17). A relatively higher incidence of strong MRP-positive staining was found in lung and esophageal cancers (4/26 and 5/15); otherwise staining was weak to moderate. No detectable MRP was found in stromal cells and in normal organs. Thus, MRPm6 by this method allows detection of MRP overexpression versus normal cells in paraffin sections of archived surgical specimens for investigation of the clinical significance of MRP.

Circulating Vitamin D and Risk of Prostate Cancer—Letter

Background: This letter notes that the recent association between prostate cancer and serum 25-OHD by Albanes et al. is due to confounding or interaction with serum calcium. Methods: Results: Conclusions: Impact:

Serum calcium, albumin and tumor stage in cutaneous malignant melanoma

AIM Assess the relationship of serum calcium and serum albumin to tumor stage and other clinical characteristics in patients with cutaneous malignant melanoma (MM). PATIENTS & METHODS A cross-sectional study to evaluate serum calcium as a marker of disease progression (n = 644) in MM. RESULTS Serum albumin was significantly lower among men (p < 0.01) and among patients with stage 4 disease (p < 0.05). In a multivariable regression model adjusted for age, gender and site, albumin-corrected calcium was positively associated with disease stage (odds ratio: 1.46; 95% CI: 1.02-2.07; p = 0.04). The odds of higher stage increased 60% for each 1.0 mg/dl increase in albumin-corrected calcium. CONCLUSION Higher albumin-corrected serum calcium may be a marker of disease progression in MM.