Manish I. Patel

Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma.

BackgroundThe clinical staging of renal cortical tumors traditionally has not evaluated the potential effect of histological subtypes on survival. Evidence suggests that conventional clear cell renal cell carcinoma (RCC) and nonconventional clear cell RCC (chromophobe and papillary) have different metastatic potential. Using a large renal tumor database, we examined the effect of tumor histology on the pattern of metastasis and patient survival.MethodsAll patients with nonmetastatic renal cortical tumors undergoing partial or radical nephrectomy were identified from a renal tumor database between July 1989 and July 2002. Kaplan-Meier and Cox regression tests were used for statistical analysis.ResultsAnalysis revealed 1057 patients: 794 with conventional clear cell RCC, 157 with papillary RCC, and 106 with chromophobe RCC. Metastasis occurred in 95 conventional clear cell RCC, 9 papillary RCC, and 6 chromophobe RCC. Metastasis occurred in 95 conventional clear cell RCC, 9 papillary RCC, and 6 chromophobe RCC with a median follow-up of 34.6, 43.0, and 33.2 months, respectively. Using log-rank analysis, chromophobe and papillary RCC were associated with an improved disease-free survival at 5 years (P=.009 and .015, respectively). Multivariate analysis revealed tumor size, stage, and chromophobe histology as significant variables for disease progression.ConclusionsRenal cortical tumors have distinct histological subtypes with varying degrees of metastatic potential. Conventional clear cell RCC, which comprises two thirds of renal cortical tumors presenting with localized disease, has a less favorable outcome when compared with papillary and chromophobe RCC. Controlling for size and stage, chromophobe, and not papillary, RCC was a significant variable for disease progression compared with conventional clear cell RCC. Knowledge of renal cortical tumor histological subtype is critical for projecting prognosis, tailoring follow-up strategies, and designing clinical trials.

Celecoxib Inhibits Prostate Cancer Growth: Evidence of a Cyclooxygenase-2-Independent Mechanism

Purpose: Selective cyclooxygenase-2 (COX-2) inhibitors may suppress carcinogenesis by both COX-2-dependent and COX-2-independent mechanisms. The primary purpose of this study was to evaluate whether celecoxib or rofecoxib, two widely used selective COX-2 inhibitors, possess COX-2-independent antitumor activity. Experimental Design: PC3 and LNCaP human prostate cancer cell lines were used to investigate the growth inhibitory effects of selective COX-2 inhibitors in vitro. To complement these studies, we evaluated the effect of celecoxib on the growth of PC3 xenografts. Results: COX-1 but not COX-2 was detected in PC3 and LNCaP cells. Clinically achievable concentrations (2.5-5.0 μmol/L) of celecoxib inhibited the growth of both cell lines in vitro, whereas rofecoxib had no effect over the same concentration range. Celecoxib inhibited cell growth by inducing a G1 cell cycle block and reducing DNA synthesis. Treatment with celecoxib also led to dose-dependent inhibition of PC3 xenograft growth without causing a reduction in intratumor prostaglandin E2. Inhibition of tumor growth occurred at concentrations (2.37-5.70 μmol/L) of celecoxib in plasma that were comparable with the concentrations required to inhibit cell growth in vitro. The highest dose of celecoxib led to a 52% reduction in tumor volume and an ∼50% decrease in both cell proliferation and microvessel density. Treatment with celecoxib caused a marked decrease in amounts of cyclin D1 both in vitro and in vivo. Conclusions: Two clinically available selective COX-2 inhibitors possess different COX-2-independent anticancer properties. The anticancer activity of celecoxib may reflect COX-2-independent in addition to COX-2-dependent effects.

Intussusception After Rotavirus Vaccines Reported to US VAERS, 2006–2012

BACKGROUND: In 2006 and 2008, 2 new rotavirus vaccines (RotaTeq [RV5] and Rotarix [RV1]) were introduced in the United States. METHODS: We assessed intussusception events reported to the Vaccine Adverse Event Reporting System from February 2006 through April 2012 for RV5 and from April 2008 through April 2012 for RV1. For RV5, we conducted a self-controlled risk interval analysis using Poisson regression to estimate the daily reporting ratio (DRR) of intussusception comparing average daily reports 3 to 6 versus 0 to 2 days after vaccination. We calculated reporting rate differences based on DRRs and background rates of intussusception. Sensitivity analyses were conducted to assess effects of differential reporting completeness and inaccuracy of baseline rates. Few reports were submitted after RV1, allowing only a descriptive analysis. RESULTS: The Vaccine Adverse Event Reporting System received 584 confirmed intussusception reports after RV5 and 52 after RV1, with clustering 3 to 6 days after both vaccines. The DRR comparing the 3- to 6-day and the 0- to 2-day periods after RV5 dose 1 was 3.75 (95% confidence interval = 1.90 to 7.39). There was no significant increase in reporting after dose 2 or dose 3. Over all 3 doses, the excess risk of intussusception was 0.79 events (95% confidence interval = –0.04 to 1.62) per 100 000 vaccinations. From the sensitivity analyses, we conclude that under a worst-case scenario, the DRR could be 5.00 and excess risk per 100 000 doses could be 1.36. CONCLUSIONS: We observed a persistent clustering of reported intussusception events 3 to 6 days after the first dose of RV5 vaccination. This clustering could translate to a small increased risk of intussusception, which is outweighed by the benefits of rotavirus vaccination.

Primary treatment of the prostate improves local palliation in men who ultimately develop castrate‐resistant prostate cancer

To determine whether local treatment of primary prostate cancer gives palliative benefit to men who later develop castrate‐resistant prostate cancer (CRPC). Local treatments of primary prostate cancer are defined as radical retropubic prostatectomy (RRP) or external beam radiation therapy (EBRT).

Long-term follow-up of bilateral sporadic renal tumors

OBJECTIVES To assess the clinical characteristics, pathology, and long-term follow-up of patients with bilateral nonfamilial renal tumors (BNFRTs). METHODS Patients with BNFRTs and unilateral tumors were identified from a prospective surgery database. The Mann-Whitney U test, Cox proportional hazards regression analysis, and the log-rank test were used to compare groups. RESULTS From a database of 1082 patients with nonmetastatic renal tumors, 46 were identified with BNFRTs (4.25%). Thirty-three had synchronous tumors and 13 had asynchronous tumors. The median patient age of BNFRT patients was 61 years. Of the 92 renal tumors in these 46 patients, 42% were managed with radical nephrectomy (RN) and 58% with partial nephrectomy (PN); 7 underwent bilateral PN. The tumors were conventional clear cell carcinoma in 66% (n = 61), papillary carcinoma in 14% (n = 13), and the remaining 20% were of varied histologic origin. A 76.2% concordance was noted between the histologic subtypes of the two renal tumors in each patient. Median follow-up was 74 months. Thirty-three patients (72%) were disease-free and 7 patients had recurrence (2 local, 5 metastatic). Compared with patients having unilateral disease, BNFRT patients had an equivalent disease-free survival (DFS) (bilateral: 3-year DFS 90%, 5-year DFS 83%; unilateral: 3-year DFS 92%, 5-year DFS 82% [P = 0.449]). No difference in DFS was observed between synchronous and asynchronous tumors. CONCLUSIONS BNFRTs were present in 4.25% of patients with sporadic renal tumors. Conventional clear cell histology was the most common histologic subtype; concordance among tumors was found to be 76%. DFS rates comparable to those of unilateral tumors can be obtained by using combinations of PN and RN.

Location and Pathological Characteristics of Cancers in Radical Prostatectomy Specimens Identified by Transperineal Biopsy Compared to Transrectal Biopsy

PURPOSE Anterior tumors are estimated to constitute 20% of prostate cancers. Current data indicate that transperineal biopsy is more reliable than transrectal biopsy in identifying these tumors. If correct, this superior reliability should result in an increased proportion of anterior tumors identified by transperineal biopsy. We investigated this hypothesis with reference to prostatectomy specimens. MATERIALS AND METHODS Radical prostatectomy histopathology records were retrospectively examined. Patients were grouped based on primary transperineal or transrectal biopsy as the modality used to identify the initial cancer. After grouping, tumor location and size were recorded and, thus, the proportion of anterior tumors was determined. RESULTS A total of 1,132 (414 transperineal and 718 transrectal) prostatectomy specimens were examined. Overall mean tumor size (1.8 and 2.0 cm(3)), stage (pT2 63.3% and 61%) and significance (5.1% and 5.1%) for the transperineal and transrectal methods were similar. However, the transperineal method was associated with proportionally more anterior tumors (16.2% vs 12%, p = 0.046), and identified them at a smaller size (1.4 vs 2.1 cm(3), p = 0.03) and lower stage (extracapsular extension 13% vs 28%, p = 0.03) compared to the transrectal method. The pT3 positive surgical margin rate for anterior vs other tumors was 69% vs 34.9%, respectively. CONCLUSIONS Overall transrectal and transperineal biopsy identify cancers that are similar in size, stage and significance. However, transperineal biopsy detected proportionally more anterior tumors (16.2% vs 12%), and identified them at a smaller size (1.4 vs 2.1 cm(3)) and stage (extracapsular extension 13% vs 28%) compared to transrectal biopsy. Identifying anterior tumors early is important because the positive surgical margin rate for anterior pT3 lesions is significantly higher.

The Arachidonic Acid Pathway and its Role in Prostate Cancer Development and Progression

PURPOSE The arachidonic acid pathway incorporates phospholipase, cyclooxygenase, lipoxygenase and epoxygenase enzymes. This pathway has been shown to have a major role in the development and progression of a number of cancers, including prostate cancer. We discuss the current status of research of this pathway in the area of prostate cancer, ranging from preclinical in vitro studies to human clinical trials. MATERIALS AND METHODS We performed an online search of the current and past peer reviewed literature on prostate cancer and arachidonic acid, phospholipase, cyclooxygenase, lipoxygenase, epoxygenase, platelet activating factor, prostaglandin and eicosanoid. We retrieved and evaluated all full-length articles published in English from the 1980s to January 2007. RESULTS Epidemiological evidence suggested that nonsteroidal anti-inflammatory drugs may decrease the risk of prostate cancer. This effect, presumably through the inhibition of cyclooxygenase-2, has been validated in preclinical studies. Cyclooxygenase-2 inhibition has also decreased the rate of prostate specific antigen increase in men with biochemical recurrence after treatment for prostate cancer. Although lipoxygenase and secretory phospholipase A2 inhibition was also effective for decreasing prostate cancer growth in preclinical studies, to our knowledge these strategies have not yet been used in clinical trials. Cytosolic phospholipase A2, platelet activating factor and epoxygenase need further investigation to determine a role in prostate cancer. CONCLUSIONS Evolving data suggest a significant role for some areas of the arachidonic acid pathway in prostate cancer. Inhibiting 1 or a number of these enzymes in combination may hold promise for future prostate cancer treatment.

Duration of protection of pentavalent rotavirus vaccination in Nicaragua.

OBJECTIVE: To evaluate the duration of protection of pentavaent rotavirus vaccine (RV5) against rotavirus hospitalizations in Nicaragua, a developing country in Central America. METHODS: We conducted a case-control study at 4 hospitals from 2007 through 2010, including 1016 children hospitalized with laboratory-confirmed rotavirus diarrhea, 4930 controls with nonrotavirus diarrhea (ie, “test-negative”), and 5627 controls without diarrhea. All cases and controls were aged ≥6 months and born after August 2006. Outcomes included odds of antecedent vaccination between case-patients and controls, and effectiveness of vaccination (1 – adjusted odds ratio [OR] × 100). Duration of protection was assessed by comparing effectiveness among children aged <1 year compared with ≥1 year. RESULTS: Indicators of socioeconomic conditions and nonrotavirus vaccination (oral polio vaccine and diphtheria/tetanus/pertussis/hepatitis A/hepatitis B) for test-negative controls were more comparable to the rotavirus case-patients than nondiarrhea controls. RV5 vaccination was associated with a significantly lower risk of rotavirus hospitalization by using test-negative controls (OR: 0.55; 95% confidence interval [CI]: 0.41–0.74) and nondiarrhea controls (OR: 0.30; 95% CI: 0.22–0.40). Risk of rotavirus hospitalization was twofold lower among RV5 vaccinated children aged <1 year (OR: 0.36; 95% CI: 0.22–0.57) compared with RV5 vaccinated children aged ≥1 year (OR: 0.70; 95% CI: 0.47–1.05). CONCLUSIONS: RV5 provided good protection against severe rotavirus disease in Nicaragua during the first year of life, when most severe and fatal rotavirus disease in developing countries occurs. However, the decline in protection with age warrants monitoring of disease among older children and consideration of a booster dose evaluation at the end of infancy.

A Model of Prostate-Specific Antigen Screening Outcomes for Low- to High-Risk Men: Information to Support Informed Choices

BACKGROUND Information is needed to aid individual decision making about prostate-specific antigen (PSA) screening. METHODS We aimed to provide such information for men aged 40, 50, 60, and 70 years at low, moderate, and high risk for prostate cancer. A Markov model compared patients with vs without annual PSA screening using a 20% relative risk (RR) reduction (RR = 0.8) in prostate cancer mortality as a best-case scenario. The model estimated numbers of biopsies, prostate cancers, and deaths from prostate cancer per 1000 men over 10 years and cumulated to age 85 years. RESULTS Benefits and harms vary substantially with age and familial risk. Using 60-year-old men with low risk as an example, of 1000 men screened annually, we estimate that 115 men will undergo biopsy triggered by an abnormal PSA screen result and that 53 men will be diagnosed as having prostate cancer over 10 years compared with 23 men diagnosed as having prostate cancer among 1000 unscreened men. Among screened men, 3.5 will die of prostate cancer over 10 years compared with 4.4 deaths in unscreened men. For 1000 men screened from 40 to 69 years of age, there will be 27.9 prostate cancer deaths and 639.5 deaths overall by age 85 years compared with 29.9 prostate cancer deaths and 640.4 deaths overall in unscreened men. Higher-risk men have more prostate cancer deaths averted but also more prostate cancers diagnosed and related harms. CONCLUSIONS Men should be informed of the likely benefits and harms of PSA screening. These estimates can be used to support individual decision making.

Cytosolic Phospholipase A2-α: A Potential Therapeutic Target for Prostate Cancer

Purpose: Cytosolic phospholipase A2-α (cPLA2-α) provides intracellular arachidonic acid to supply both cyclooxygenase and lipoxygenase pathways. We aim to determine the expression and activation of cPLA2-α in prostate cancer cell lines and tissue and the effect of targeting cPLA2-α in vitro and in vivo. Experimental Design: The expression of cPLA2-α was determined in prostate cancer cells by reverse transcription-PCR, Western blot, and immunocytochemistry. Growth inhibition, apoptosis, and cPLA2-α activity were determined after inhibition with cPLA2-α small interfering RNA or inhibitor (Wyeth-1). Cytosolic PLA2-α inhibitor or vehicle was also administered to prostate cancer xenograft mouse models. Finally, the expression of phosphorylated cPLA2-α was determined by immunohistochemistry in human normal, androgen-sensitive and androgen-insensitive prostate cancer specimens. Results: cPLA2-α is present in all prostate cancer cells lines, but increased in androgen-insensitive cells. Inhibition with small interfering RNA or Wyeth-1 results in significant reductions in prostate cancer cell numbers, as a result of reduced proliferation as well as increased apoptosis, and this was also associated with a reduction in cPLA2-α activity. Expression of cyclin D1 and phosphorylation of Akt were also observed to decrease. Wyeth-1 inhibited PC3 xenograft growth by ∼33% and again, also reduced cyclin D1. Immunohistochemistry of human prostate tissue revealed that phosphorylated cPLA2-α is increased when hormone refractory is reached. Conclusions: Expression and activation of cPLA2-α are increased in the androgen-insensitive cancer cell line and tissue. Inhibition of cPLA2-α results in cells and xenograft tumor growth inhibition and serves as a potentially effective therapy for hormone refractory prostate cancer.