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Eric A Klein

Publications and source records attributed to Eric A Klein.

At least 19 recordsLinked to original sources

The Pseudomonas aeruginosa sphBC genes are important for growth in the presence of sphingosine by promoting sphingosine metabolism.

Sphingoid bases, including sphingosine, are important components of the antimicrobial barrier at epithelial surfaces where they can cause growth inhibition and killing of susceptible bacteria. Pseudomonas aeruginosa is a common opportunistic pathogen that is less susceptible to sphingosine than many Gram-negative bacteria. Here, we determined that the deletion of the sphBCD operon reduced growth in the presence of sphingosine. Using deletion mutants, complementation and growth assays in P. aeruginosa PAO1, we determined that the sphC and sphB genes, encoding a periplasmic oxidase and periplasmic cytochrome c, respectively, were important for growth on sphingosine, while sphD was dispensable under these conditions. Deletion of sphBCD in P. aeruginosa PA14, Pseudomonas protegens Pf-5 and Pseudomonas fluorescens Pf01 also showed reduced growth in the presence of sphingosine. The P. aeruginosa sphBC genes were also important for growth in the presence of two other sphingoid bases, phytosphingosine and sphinganine. In WT P. aeruginosa, sphingosine is metabolized to an unknown non-inhibitory product, as sphingosine concentrations drop in the culture. However, in the absence of sphBC, sphingosine accumulates, pointing to SphC and SphB as having a role in sphingosine metabolism. Finally, the metabolism of sphingosine by WT P. aeruginosa protected susceptible cells from full growth inhibition by sphingosine, pointing to a role for sphingosine metabolism as a public good. This work shows that the metabolism of sphingosine by P. aeruginosa presents a novel pathway by which bacteria can alter host-derived sphingolipids, but it remains an open question whether SphB and SphC act directly on sphingosine.

Sphingosine↗

Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy.

CONTEXT: Salvage radiotherapy may potentially cure patients with disease recurrence after radical prostatectomy, but previous evidence has suggested that it is ineffective in patients at the highest risk of metastatic disease progression. OBJECTIVE: To delineate patients who may benefit from salvage radiotherapy for prostate cancer recurrence by identifying variables associated with a durable response. DESIGN, SETTING, AND PATIENTS: Retrospective review of a cohort of 501 patients at 5 US academic tertiary referral centers who received salvage radiotherapy between June 1987 and November 2002 for detectable and increasing prostate-specific antigen (PSA) levels after radical prostatectomy. MAIN OUTCOME MEASURE: Disease progression after salvage radiotherapy, defined as a serum PSA value > or =0.1 ng/mL above the postradiotherapy PSA nadir confirmed by a second PSA measurement that was higher than the first by any amount, by a continued increase in PSA level after treatment, or by the initiation of androgen deprivation therapy after treatment. RESULTS: Over a median follow-up of 45 months, 250 patients (50%) experienced disease progression after treatment, 49 (10%) developed distant metastases, 20 (4%) died from prostate cancer, and 21 (4%) died from other or unknown causes. The 4-year progression-free probability (PFP) was 45% (95% confidence interval [CI], 40%-50%). By multivariable analysis, predictors of progression were Gleason score of 8 to 10 (hazard ratio [HR], 2.6; 95% CI, 1.7-4.1; P<.001), preradiotherapy PSA level greater than 2.0 ng/mL (HR, 2.3; 95% CI, 1.7-3.2; P<.001), negative surgical margins (HR, 1.9; 95% CI, 1.4-2.5; P<.001), PSA doubling time (PSADT) of 10 months or less (HR, 1.7; 95% CI, 1.2-2.2; P =.001), and seminal vesicle invasion (HR, 1.4; 95% CI, 1.1-1.9; P =.02). Patients with no adverse features had a 4-year PFP of 77% (95% CI, 64%-91%). When treatment was given for early recurrence (PSA level < or =2.0 ng/mL), patients with Gleason scores of 4 to 7 and a rapid PSADT had a 4-year PFP of 64% (95% CI, 51%-76%) and of 22% (95% CI, 6%-38%) when the surgical margins were positive and negative, respectively. Patients with Gleason scores of 8 to 10, positive margins, and receiving early salvage radiotherapy had a 4-year PFP of 81% (95% CI, 57%-100%) when the PSADT was longer than 10 months and of 37% (95% CI, 16%-58%) when the PSADT was 10 months or less. CONCLUSIONS: Gleason score, preradiotherapy PSA level, surgical margins, PSADT, and seminal vesicle invasion are prognostic variables for a durable response to salvage radiotherapy. Selected patients with high-grade disease and/or a rapid PSADT who were previously thought to be destined to develop progressive metastatic disease may achieve a durable response to salvage radiotherapy.

Adult↗

Recurrence-free survival rates after external-beam radiotherapy for patients with clinical T1-T3 prostate carcinoma in the prostate-specific antigen era: what should we expect?

BACKGROUND: The objective of the current study was to report biochemical recurrence-free survival (bRFS) rates among men with T1-T3 prostate carcinoma who were treated with external-beam radiotherapy (RT) at the Cleveland Clinic Foundation (Cleveland, OH). METHODS: In total, 1352 patients were identified between 1987 and 2000 with a minimum follow-up of 1 year (median follow-up, 55 months; range, 12-189 months). The median radiation dose was 74.0 grays (Gy) (range, 63.0-83.0 Gy). The median radiation doses for patients who received < 68.0 Gy (n = 201), 68.0-72.0 Gy (n = 373), and > or = 72.0 Gy (n = 778) were 66.6 Gy, 70.0 Gy, and 78.0 Gy, respectively. The RT techniques used were standard RT in 41% of patients, 3-dimensional conformal RT in 34% of patients, and intensity-modulated RT in 25% of patients. Androgen-deprivation (AD) therapy lasting < or = 6 months was administered to 34% of patients. RESULTS: The 5-year and 7-year bRFS rates were 63% and 59%, respectively. On multivariate analysis, T classification (P < 0.001), pretreatment prostate-specific antigen level (P < 0.001), biopsy Gleason score (P = 0.001), radiation dose (P < 0.001), and year of therapy (P < 0.001) were independent predictors of biochemical failure. Age, race, AD therapy, and RT technique did not predict for biochemical failure. For patients with low-risk tumors, the 5-year bRFS rates for those who received RT doses of < or = 68.0 Gy, 68.0-72.0 Gy, and > or = 72.0 Gy were 52%, 82%, and 93%, respectively (P < 0.001); for patients with intermediate-risk tumors, the respective 5-year bRFS rates were 27%, 51%, and 83% (P < 0.001); and for patients with high-risk tumors, the respective 5-year bRFS rates were 21%, 29%, and 71%, respectively (P < 0.001). CONCLUSIONS: The most significant therapeutic factor affecting bRFS rates after RT was radiation dose, rather than AD therapy use or radiation technique.

Adult↗

Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy > or =72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1-T2 prostate cancer.

PURPOSE: To review the biochemical relapse-free survival (bRFS) rates after treatment with permanent seed implantation (PI), external beam radiotherapy (EBRT) <72 Gy (EBRT <72), EBRT > or =72 Gy (EBRT > or =72), combined seeds and EBRT (COMB), or radical prostatectomy (RP) for clinical Stage T1-T2 localized prostate cancer treated between 1990 and 1998. METHODS AND MATERIALS: The study population comprised 2991 consecutive patients treated at the Cleveland Clinic Foundation or Memorial Sloan Kettering at Mercy Medical Center. All cases had pretreatment prostate-specific antigen (iPSA) levels and biopsy Gleason scores (bGSs). Neoadjuvant androgen deprivation for < or =6 months was given in 622 cases (21%). No adjuvant therapy was given after local therapy. RP was used for 1034 patients (35%), EBRT <72 for 484 (16%), EBRT > or =72 for 301 (10%), PI for 950 (32%), and COMB for 222 patients (7%). The RP, EBRT <72, EBRT > or =72, and 154 PI patients were treated at Cleveland Clinic Foundation. The median radiation doses in EBRT <72 and EBRT > or =72 case was 68.4 and 78.0 Gy, respectively. The median follow-up time for all cases was 56 months (range 12-145). The median follow-up time for RP, EBRT <72, EBRT > or =72, PI, and COMB was 66, 75, 49, 47, and 46 months, respectively. Biochemical relapse was defined as PSA levels >0.2 for RP cases and three consecutive rising PSA levels (American Society for Therapeutic Radiology Oncology consensus definition) for all other cases. A multivariate analysis for factors affecting the bRFS rates was performed using the following variables: clinical T stage, iPSA, bGS, androgen deprivation, year of treatment, and treatment modality. The multivariate analysis was repeated excluding the EBRT <72 cases. RESULTS: The 5-year bRFS rate for RP, EBRT <72, EBRT > or =72, PI, and COMB was 81%, 51%, 81%, 83%, and 77%, respectively (p <0.001). The 7-year bRFS rate for RP, EBRT <72, EBRT > or =72, PI, and COMB was 76%, 48%, 81%, 75%, and 77%, respectively. Multivariate analysis, including all cases, showed iPSA (p <0.001), bGS (p <0.001), year of therapy (p <0.001), and treatment modality (p <0.001) to be independent predictors of relapse. Because EBRT <72 cases had distinctly worse outcomes, the analysis was repeated after excluding these cases to discern any differences among the other modalities. The multivariate analysis excluding the EBRT <72 cases revealed iPSA (p <0.001), bGS (p <0.001), and year of therapy (p = 0.001) to be the only independent predictors of relapse. Treatment modality (p = 0.95), clinical T stage (p = 0.09), and androgen deprivation (p = 0.56) were not independent predictors for failure. CONCLUSION: The biochemical failure rates were similar among PI, high-dose (> or =72 Gy) EBRT, COMB, and RP for localized prostate cancer. The outcomes were significantly worse for low-dose (<72 Gy) EBRT.

Aged↗

Monotherapy for stage T1-T2 prostate cancer: radical prostatectomy, external beam radiotherapy, or permanent seed implantation.

BACKGROUND AND PURPOSE: To review the freedom from biochemical recurrence (FBR) rates after permanent prostate brachytherapy (PPB), external beam radiotherapy (RT) to a minimum 70Gy, or radical prostatectomy (RP) for clinically localized stage T1-T2 adenocarcinoma of the prostate. PATIENTS AND METHODS: The study cohort consisted of 1819 consecutively treated clinical stage T1-T2 (AJCC 1997) localized prostate cancer patients between 1992 and 1998. All patients received monotherapy treatment without additional adjuvant therapy. The distribution by treatment modality was as follows: RT for 340, RP for 746, and PPB for 733 cases. The median follow-up time was 58 months for all cases (51 months for PPB cases, 56 months for RT cases, and 64 months for RP cases). Biochemical relapse was defined as to be detectable PSA levels in RP cases, and the ASTRO consensus panel definition for the RT and PPB cases. RESULTS: The 7-year FBR rates for PPB vs EBRT vs RP were 74, 77, and 79%, respectively. Multivariate analysis identified iPSA (P < 0.001) and bGS (P < 0.001) as independent predictors of relapse. Treatment modality, age, clinical T-stage, and race were not independent predictors of failure. CONCLUSIONS: Pretreatment PSA levels, and biopsy Gleason score determined outcome in this study cohort. Biochemical failure rates in this study cohort are similar between PPB, RT, and RP as monotherapy for clinically localized prostate cancer.

Adenocarcinoma↗

PSA bounce predicts early success in patients with permanent iodine-125 prostate implant.

OBJECTIVES: To determine the clinical and dosimetric factors that predict prostate-specific antigen (PSA) bounce after iodine-125 prostate brachytherapy and to determine the predictive value of PSA bounce relative to biochemical relapse-free survival (bRFS). METHODS: A multivariate analysis of factors thought to predict for PSA bounce was performed in 295 consecutive patients with T1-T2 prostate cancer treated by prostate brachytherapy as the sole radiotherapeutic modality and a minimum follow-up of 2 years. The variables examined included age, initial PSA level, biopsy Gleason score, use of androgen deprivation, occurrence of PSA bounce, dose received by 90% of the prostate gland, and volume of gland receiving 100% of the prescribed dose. A PSA bounce was defined as a rise of at least 0.2 ng/mL greater than a previous PSA level with a subsequent decline equal to, or less than, the initial nadir. A second analysis investigating the same factors and adding PSA bounce as a predictor of bRFS was also performed. RESULTS: The median follow-up was 38 months. A PSA bounce was noted in 82 (28%) of 295 patients. On multivariate analysis, only younger age (younger than 65 years) significantly predicted for a PSA bounce. Patients who experienced a PSA bounce were less likely to have biochemical failure (P = 0.037). Overall, the bRFS rate at 5 years in those experiencing a PSA bounce was 100% versus 92% in those with no bounce. CONCLUSIONS: Immediate salvage therapy in patients with a rising PSA level after permanent prostate brachytherapy should not be initiated provided the PSA increase does not exceed the pretreatment PSA value. A PSA bounce may be associated with improved bRFS but was not associated with any of the pretreatment clinical and dosimetric factors examined.

Adenocarcinoma↗

No difference in six-year biochemical failure rates with or without pelvic lymph node dissection during radical prostatectomy in low-risk patients with localized prostate cancer.

OBJECTIVES: To compare differences in the actuarial biochemical relapse-free survival rates at 6 years in a contemporary series of patients who underwent radical prostatectomy with and without pelvic lymph node dissection (PLND). Biochemical failure was defined as a serum prostate-specific antigen level greater than 0.2 ng/mL confirmed at least 1 week later. METHODS: The records of 806 consecutive radical prostatectomy cases performed between January 1995 and June 1999 were reviewed. A total of 336 patients with favorable tumor characteristics (prostate-specific antigen 10 ng/mL or less, biopsy Gleason score 6 or less, and clinical Stage T1 or T2) not receiving adjuvant or neoadjuvant therapy were divided into two groups according to whether PLND was performed (PLND group, n = 140) or omitted (no-PLND group, n = 196). A Cox proportional hazards model was used to analyze the effect of age, race, family history, initial prostate-specific antigen level, tumor stage, biopsy Gleason score, PLND, extracapsular extension, and seminal vesicle invasion on the likelihood of biochemical failure. Biochemical relapse-free survival for each group was estimated by Kaplan-Meier analysis. The mean follow-up time for the entire group was 60.0 months, with a similar follow-up for both cohorts (mean 61.8 and 58.2 months, respectively, P value not statistically significant). Follow-up information was obtained through an institutional review board-approved prospective patient registry. RESULTS: The 6-year biochemical relapse-free rate for the PLND versus no-PLND group was 86% and 88%, respectively (P = 0.28). On multivariate analysis, PLND was not an independent predictor of outcome (P = 0.33). CONCLUSIONS: Our study results demonstrated that the omission of PLND in patients with favorable tumor characteristics does not adversely affect biochemical relapse rates at 6 years after surgery. Such patients can be spared the morbidity and cost of PLND without affecting the chance for cure.

Adenocarcinoma↗

Phase II trial of neoadjuvant docetaxel before radical prostatectomy for locally advanced prostate cancer.

OBJECTIVES: To perform a Phase II trial of docetaxel administered on a weekly schedule for 6 weeks before radical prostatectomy (RP) in patients with locally advanced prostate cancer. METHODS: Treatment consisted of six doses of docetaxel 40 mg/m(2) intravenously administered weekly for 6 weeks followed by RP. Eligibility criteria included clinical Stage T2b, prostate-specific antigen (PSA) level 15 ng/mL or greater or Gleason sum 8 or greater, and no evidence of metastatic disease. The primary endpoint was feasibility and drug-related and surgical-related toxicities. Secondary endpoints included pre-RP PSA level, local response, pathologic outcomes, and time to PSA failure. RESULTS: Twenty-nine patients were entered; 80% completed all 6 weeks of therapy and 97% underwent RP. The median PSA level was 12 ng/mL (range 2.5 to 43.3), the median Gleason sum was 8 (range 6 to 9), and all had Stage T2b or greater disease. A statistically significant reduction in the prechemotherapy versus postchemotherapy mean PSA level was observed (12.00 +/- 1.86 ng/mL versus 8.42 +/- 1.63 ng/mL, P <0.03), with 79% of patients experiencing some reduction and 24% a more than 50% reduction in PSA level in response to docetaxel alone. No unexpected toxicities and no intraoperative complications occurred. Pathologic analysis demonstrated residual carcinoma in all cases. Three patients (11%) had organ-confined disease, and 26 (93%) had achieved an undetectable PSA postoperatively. At a median follow-up of 23 months (range 1.5 to 36), 20 patients were disease free with no additional therapy. CONCLUSIONS: This trial establishes the baseline effect of short-course high-dose docetaxel alone on locally advanced prostate cancer. Additional study of this paradigm with other agents alone and in combination with docetaxel seems warranted.

Aged↗

Idiopathic ureteral strictures without evidence of malignancy.

Benign strictures of the ureter without known antecedent cause are rare. In the absence of prior instrumentation, infection, radiotherapy, or ureteral calculi, strictures intrinsic to the ureter are usually of malignant origin. We describe two recent cases of idiopathic ureteral strictures without evidence of malignancy.

Anastomosis, Surgical↗

Seeking help for erectile dysfunction after treatment for prostate cancer.

Prostate cancer survivors appear to have higher rates of seeking medical help for erectile dysfunction (ED) than other cohorts of sexually dysfunctional men; however, factors associated with help-seeking for ED after prostate cancer have not been investigated. A group of 1,188 men with ED after prostate cancer responded to a postal survey about their sexuality, including a new questionnaire developed to measure traditional masculine attitudes about sex that could inhibit help-seeking. Respondents had a mean age of 68 years and were an average of 4.3 years postdiagnosis of cancer. At the time of the survey, 46% had sought medical help for ED since their cancer treatment and 44% intended to seek help in the next year. A hierarchical backward selection logistic regression analysis was performed to determine factors correlated with seeking help for ED after prostate cancer. Blocks of factors were entered in to the analysis in order. Factors significant within each step were retained when calculating a final model. Out of 37 factors entered into the model, three retained significance: Men who sought help for ED were more likely to have had a prostate cancer treatment designed to spare sexual function and reported higher distress about postcancer ED. Even with all other factors taken into account, men who had more positive attitudes on the Help-Seeking Questionnaire were significantly more likely to have sought help for ED. A second logistic regression analysis examined correlates of intent to seek help for ED within the next year. Out of 38 factors entered into the analysis, six retained significance in the final model: Men intending to seek help had been treated more recently for their prostate cancer, were more dissatisfied with their sexual function, had higher levels of distress about postcancer ED and loss of sexual desire, and were more likely to have sought help for ED even before their prostate cancer was diagnosed. Even with these factors taken into account, positive attitudes on the Help-Seeking Questionnaire were significantly associated with help-seeking intentions. These results suggest that cognitive-behavioral interventions designed to challenge men's negative beliefs about seeking help for ED could potentially increase help-seeking behavior.

Adult↗

Update on chemoprevention of prostate cancer.

PURPOSE OF REVIEW: Prostate cancer remains the most commonly diagnosed visceral cancer in men in the United States, with almost 200,000 newly diagnosed cases in 2003. Prevention of this disease would have a major impact on disease-associated cost, morbidity, and mortality for a large segment of the population. A major advance in prevention of prostate cancer came in 2003 with the publication of the Prostate Cancer Prevention Trial. This overview summarizes the results of that trial, the design of other large-scale trials, and advances in understanding of the molecular mechanisms underlying the effect of other promising agents. RECENT FINDINGS: The Prostate Cancer Prevention Trial demonstrated that use of finasteride is associated with a 25% reduction in the 7-year period prevalence of prostate cancer in men over age 55 years with normal digital rectal exam and initial prostate specific antigen <3.0 ng/ml. Use of finasteride was associated with a slightly higher risk of Gleason sum 7-10 tumors, some sexual side effects, and fewer urinary symptoms. A substantial body of new molecular evidence supports the existing body of clinical and epidemiological data leading to testing of vitamin E and selenium as preventative agents in men at risk for prostate cancer. Epidemiologic and molecular evidence also makes cyclooxygenase-2 inhibitors, lycopene, soy, and green tea promising agents. SUMMARY: Results of a population-based, randomized phase III trial demonstrates that finasteride can prevent prostate cancer. A large amount of data supports the use of other agents as potential preventatives, including selenium, vitamin E, vitamin D, other 5-alpha-reductase inhibitors, cyclooxygenase-2 inhibitors, lycopene, and green tea. Some of these agents are being tested in new large-scale phase III clinical trials.

Aged↗

Selenium: epidemiology and basic science.

PURPOSE: The trace element selenium, a constituent of antioxidant enzymes, has been proposed as a chemopreventive agent for prostate and other cancers. MATERIALS AND METHODS: Published epidemiological and scientific studies relating to the potential clinical and molecular role of selenium in preventing cancer are reviewed and summarized. A unifying hypothesis underlying observations on the effect of selenium on early events in carcinogenesis is presented. RESULTS: A large body of epidemiological evidence, including observational, case-control, cohort and randomized controlled clinical trials, support the proposition that selenium may prevent prostate cancer in humans. The available data suggest a beneficial effect for men with low baseline serum or toenail selenium levels, without preexisting tumors, with serum prostate specific antigen less than 4 ng/ml and in current or former smokers. Molecular data demonstrate that selenium prevents clonal expansion of nascent tumors by causing cell cycle arrest, promoting apoptosis, and modulating p53 dependent DNA repair mechanisms. CONCLUSIONS: These observations give strong scientific support to ongoing clinical trials testing the ability of selenium to prevent prostate cancer and the progression of high grade prostatic intraepithelial neoplasia to cancer.

Animals↗

Alterations of transforming growth factor beta receptor II, insulin growth factor receptor II genes in microsatellite unstable prostate carcinomas.

DNA from 45 primary prostate tumors and corresponding normal tissues were analyzed to detect whether the alterations of transforming growth factor beta receptor II (TGFbetaRII) and insulin growth factor receptor II (IGFRII) are associated with microsatellite instability (MSI). We identified that 25 tumors were microsatellite unstable (55%). The remaining 20 tumors are found to be microsatellite stable. Loss of heterozygosity (LOH) was also tested at various loci. Results indicate that in case of TGFbetaRII, the rate of frame-shift mutation depends on the number of polyadenine [poly(A)] tracts. Twelve percent of the tumors had frame-shift alteration at BAT-RII locus which has 10 poly(A) repeats. Twenty percent of the tumors had frame-shift at BAT-25 locus which has 25 poly(A) repeats. In addition, IGFRII gene was examined for the presence of mutation in the repetitive sequences. Seven of the 25 tumors showed deletion of a G within eight poly(G) repeats. Besides these changes there were two tumors which showed a novel insertion of A within this poly(G) repeat making a change in 9 samples (R4, 36%). On the other hand, 4 tumors showed changes within the 5CT repeats. In addition, 3 tumors showed another novel insertion of C within the CT repeats.

Base Sequence↗

Improvement in relapse-free survival throughout the PSA era in patients with localized prostate cancer treated with definitive radiotherapy: year of treatment an independent predictor of outcome.

PURPOSE: In patients treated with radical prostatectomy in the prostate-specific antigen (PSA) era, it has been demonstrated that the year of treatment in the PSA era is associated with better pathologic parameters and outcomes, independently of other well-recognized parameters such as clinical stage, pretreatment PSA level, or Gleason score. The purpose of the present study was to study a similar phenomenon with definitive radiotherapy (RT). METHODS AND MATERIALS: The inclusion criteria were as follows: clinical Stage T1-T2, available pretreatment PSA level and biopsy Gleason score, treatment delivered before January 2000 with standard fractionation external beam radiotherapy to at least 70 Gy, no adjuvant androgen deprivation (AD), all neoadjuvant AD limited to < or =6 months, and a minimum of 3 years of PSA follow-up. A total of 467 cases treated between January 1986 and December 1999 were included. Short-course AD in the adjuvant or neoadjuvant setting for < or =6 months was given in 124 cases (27%). The median radiation dose was 74 Gy (range 70.0-78.0). A conformal technique was used in 293 cases (63%). The median follow-up was 62 months (range 37-189). A total of 4931 follow-up PSA levels were available for analysis (average 11 per patient). A multivariate analysis for factors affecting biochemical relapse-free survival rates using the proportional hazards model was performed for all cases using the following variables: age (continuous variable), race (black vs. white), clinical T stage (T1-T2a vs. T2b-T2c), pretreatment PSA (continuous variable), biopsy Gleason score (continuous variable), use of AD (yes vs. no), radiation dose (continuous variable), and year of treatment (continuous variable: 1986-1999). RESULTS: The projected 8-year biochemical relapse-free survival rate was 74%. The projected 5-year biochemical relapse-free survival rate for the 143 patients treated in the 1986-1995 period was 58% vs. 82% for the 324 patients treated in the 1996-1999 period (p <0.001). The difference was attributable to a multitude of factors (earlier stage cancer, higher radiation doses, shorter follow-up). To study the confounding effects of these factors on the year of therapy, a multivariate analysis was performed. The multivariate analysis revealed the initial PSA level (p <0.001), Gleason score (p <0.001), RT dose (p = 0.045), and year of treatment (p <0.001) to be independent predictors of outcome. Age (p = 0.41), race (p = 0.14), T stage (p = 0.10), and use of AD (p = 0.58) were not. CONCLUSION: When controlling for tumor, treatment, and follow-up parameters, the year in which RT was performed was still an independent predictor of outcome, consistent with observations made for radical prostatectomy patients. This indicates a more favorable presentation of localized prostate in current years probably related to a combination of factors such as screening and increased patient awareness leading to earlier diagnosis. Outcome predictions should be based on contemporaneous series.

Adenocarcinoma↗

Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates.

The RNASEL gene, a strong candidate for the hereditary prostate cancer 1 allele (HPC1), encodes a single-stranded specific endoribonuclease involved in the antiviral actions of IFNs. RNase L is activated enzymatically after binding to unusual 5'-phosphorylated, 2',5'-linked oligoadenylates (2-5A). Biostable phosphorothioate analogues of 2-5A were synthesized chemically and used to study the effects of naturally occurring mutations and polymorphisms in RNASEL. The 2-5A analogues induced RNase L activity and caused apoptosis in cultures of late-stage, metastatic human prostate cancer cell lines DU145, PC3, and LNCaP. However, DU145 and PC3 cells were more sensitive to 2-5A than LNCaP cells, which are heterozygous for an inactivating deletion mutation in RNase L. The RNase activities of missense variants of human RNase L were compared after expression in a mouse RNase L(-/-) cell line. Several variants (G59S, I97L, I220V, G296V, S322F, Y529C, and D541E) produced similar levels of RNase L activity as wild-type enzyme. In contrast, the R462Q variant, previously implicated in up to 13% of unselected prostate cancer cases, bound 2-5A at wild-type levels but had a 3-fold decrease in RNase activity. The deficiency in RNase L(R462Q) activity was correlated with a reduction in its ability to dimerize into a catalytically active form. Furthermore, RNase L(R462Q) was deficient in causing apoptosis in response to 2-5A consistent with its possible role in prostate cancer development. Our findings support the notion that RNASEL mutations and some variants allow tumor cells to escape a potent apoptotic pathway.

Adenine Nucleotides↗

The selenium and vitamin E cancer prevention trial.

BACKGROUND: Evidence suggests that both selenium and vitamin E reduce the risk of prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a randomized, prospective, double-blind study designed to determine whether selenium and vitamin E alone and in combination can reduce the risk of prostate cancer among healthy men. MATERIALS AND METHODS: The preclinical and epidemiological evidence supporting a role for selenium and vitamin E as chemopreventive agents in prostate cancer are reviewed, and details of the trial design are presented. RESULTS. Preclinical, epidemiological, and phase III data from randomized, placebo-controlled clinical trials suggest that both selenium and vitamin E have potential efficacy in prostate cancer prevention. SELECT is a 2x2 factorial study with an accrual goal of 32,400 men with nonsuspicious DRE and serum PSA of 4 ng/ml or lower. CONCLUSIONS: SELECT is the second large-scale study of chemoprevention for prostate cancer. Enrollment began in 2001 with final results anticipated in 2013.

Clinical Trials as Topic↗