Biomedical subjects

Eric A Klein

Publications and source records attributed to Eric A Klein.

At least 73 records · Page 4Linked to original sources

PubMed2003

Clinical models for testing chemopreventative agents in prostate cancer and overview of SELECT: the Selenium and Vitamin E Cancer Prevention Trial.

Target populations for chemoprevention trials should include those at higher than average risk for the development of prostate cancer as defined by explicit epidemiologic and genetic criteria. Such populations include a "primary prevention" group without histologic or clinical evidence of cancer, and several clinical models of "secondary prevention," including those with clinically evident disease prior to definitive therapy and those at high risk of recurrence after therapy based on histology and/or biochemical status. Each risk group and clinical model has potential advantages and disadvantages, and the mechanisms which underlie disease development and progression in each group may be unique. These observations give rise to many potential clinical trials of specific agents. These trials should also include collection of data on potentially confounding influences on disease development and progression. Preclinical, epidemiologic, and Phase II data suggest that both selenium and vitamin E have potential efficacy in prostate cancer prevention. The experience of the Prostate Cancer Prevention Trial (PCPT) demonstrates the interest and dedication of healthy men to long-term studies of cancer prevention. SELECT, the Selenium and Vitamin E Cancer Prevention Trial, is an intergroup phase III, randomized, double-blind, placebo-controlled, population-based clinical trial designed to test the efficacy of selenium and vitamin E alone and in combination in the prevention of prostate cancer which builds on secondary analyses of large-scale chemoprevention trials for other cancers and the lessons of PCPT.

Antioxidants↗

PubMed2003

Prevention of prostate cancer with finasteride: US/European perspective.

PURPOSE: Prostate cancer is the most common male cancer, affecting one man in six. Prevention of this disease, even in a subset of patients would have a significant impact on public health. The results of the National Cancer Institute-sponsored Prostate Cancer Prevention Trial demonstrate that finasteride causes a substantial risk reduction across all known risk groups. We herein amplify on the results of this trial to assist patients and physicians in reaching individualized decisions. MATERIALS AND METHODS: The results of the Prostate Cancer Prevention Trial were reviewed. RESULTS: The PCPT demonstrated a 24.8% reduction in prostate cancer risk with the administration of finasteride. High-grade cancers were noted in 6.4% of finasteride patients compared to 5.1% of men receiving placebo. The increase in high-grade tumors was seen within one year of finasteride exposure and did not increase over time. This observation, combined with previous evidence demonstrating an alteration in cytologic and architectural features of prostate cancer with hormonal therapy suggests that the differences in high-grade disease may be an artifact and that application of Gleason grading to these tumors may not be appropriate. DISCUSSION: Men should be presented the benefits and risks of taking finasteride and be assisted in integrating their sexual and urinary symptoms into their decision-making process. Blanket statements for or against the use of this medication ignore patient preferences and differential risk-benefit profiles from finasteride.

Aged↗

PubMed2003

Effect of anatomic, procedural, and dosimetric variables on urinary retention after permanent iodine-125 prostate brachytherapy.

OBJECTIVES: To correlate anatomic, procedural, and dosimetric parameters with the rate of intermittent self-catheterization (ISC). METHODS: The records of 402 patients with a median age of 69 years treated with 125I prostate seed implantation from 1996 to 2001 were reviewed for the use of ISC. The records were examined for the preimplant factors: prostate volume, use of androgen deprivation, and prostate length. The intraprocedural factor reviewed was the number of needles used. The following postimplant information was also collected: preimplant transrectal ultrasound-generated prostate volume/postimplant computed tomography-generated prostate volume ratio, V100, V150, V200, V300, V400, D90, and D100. Correlation was assessed using logistic regression analysis. RESULTS: Forty-four patients had to use ISC (10.9%). The mean and median duration of ISC was 11.9 and 6 weeks, respectively. From univariate analysis, prostate length and prostate volume were found to be statistically significant predictors of ISC after 125I prostate seed implantation with a P value of 0.0002 and 0.0042, respectively. With multivariate analysis, only prostate length was a statistically significant predictor of ISC use after 125I prostate seed implantation (P = 0.0095). CONCLUSIONS: Prostate length is an important predictor of ISC after 125I prostate seed implantation.

Aged↗

PubMed2003

Age and PSA predict likelihood of organ-confined disease in men presenting with PSA less than 10 ng/mL: implications for screening.

OBJECTIVES: To examine age and pretreatment prostate-specific antigen (PSA) level as predictors of organ-confined disease in a large multinational database of men with pretreatment PSA levels less than 10 ng/mL who were treated with radical prostatectomy. The optimal PSA and age cutoffs for triggering prostate biopsy are controversial. Although a PSA level greater than 4.0 ng/mL is generally accepted, recent observations suggest that PSA values between 2.5 and 4.0 ng/mL are associated with a 20% detection rate. Furthermore, age has been shown to represent an independent predictor of outcome after radical prostatectomy. METHODS: We analyzed a cohort of 3198 patients from five institutions, who underwent radical prostatectomy between 1985 and 2001 for clinically localized prostate cancer. All presented with a pretreatment PSA level of less than 10 ng/mL. Multivariate analyses addressed age, preoperative PSA, year of treatment, biopsy Gleason sum, and clinical stage as independent predictors of non-organ-confined disease (NOCD). RESULTS: Twenty-nine percent of patients had NOCD. All tested variables were independent, multivariate predictors of NOCD (age, P = 0.004; year of treatment, P <0.0001; PSA, P <0.0001; Gleason sum, P <0.0001; clinical stage, P <0.0001). A linear relationship between age and the risk of NOCD was noted. The likelihood of NOCD remained constant for PSA levels between 0.1 and 4.0 ng/mL and rose substantially for PSA levels greater than 4.0 ng/mL. CONCLUSIONS: After controlling for other covariates, the rate of NOCD increased in proportion to age and pretreatment PSA level in men initially diagnosed with a serum PSA level less than 10 ng/mL. These observations suggest that younger men with a lower PSA are more likely to have organ-confined and curable disease at diagnosis. This information has important implications for counseling and screening.

Adenocarcinoma↗

PubMed2003

Paracolic recurrence of stage I seminoma.

Paracolic recurrence of testicular germ cell tumors is rare and is usually related to incomplete excision of the ipsilateral spermatic cord. We describe a paracolic recurrence outside of the standard radiation field of a low-stage pure seminoma that was managed by chemotherapy and surgical excision, rendering the patient disease free with short-term follow-up.

Adult↗

PubMed2003

Localized prostate cancer: radiation or surgery?

The treatment of localized prostate cancer remains controversial because of the lack of conclusive well-controlled or randomized studies comparing outcomes of radiotherapy to outcomes of radical prostatectomy. A comparison of different therapies should include issues of cancer control, morbidity, quality of life (QOL), salvage of primary treatment failures, late effects, and cost. The available data suggest that these two modalities provide similar rates of cancer control at 10 years, and that except for the youngest patients, choice of therapy should be based on toxicity and QOL issues.

Counseling↗

PubMed2003

Nuclear translocation of LIM kinase mediates Rho-Rho kinase regulation of cyclin D1 expression.

We previously reported that the Rho-Rho kinase pathway controls cyclin D1 expression by preventing its early G1 phase induction in response to Rac and/or Cdc42, thus increasing its dependence on ERK signaling and actin stress fiber formation. We now show that the Rho kinase effector LIM kinase is responsible for this effect. Surprisingly, inhibition of Rac-dependent cyclin D1 expression by LIM kinase is independent of both cofilin phosphorylation and actin polymerization. Instead, specific mutation of its nuclear localization and export sequences showed that LIM kinase acts in the nucleus to suppress Rac/Cdc42-dependent cyclin D1 expression. Our results therefore describe an unexpected role for LIM kinase that requires nuclear translocation. The effect of nuclear LIM kinase on cyclin D1 expression ultimately regulates the duration of G1 phase and the degree to which G1 phase progression depends on actin stress fiber formation and imposition of cellular tension.

Actin Depolymerizing Factors↗

PubMed2003

Laparoscopic radical nephrectomy: incorporating advantages of hand assisted and standard laparoscopy.

PURPOSE: We present an approach to laparoscopic radical nephrectomy and intact specimen extraction, which incorporates hand assisted and standard laparoscopic techniques. MATERIALS AND METHODS: A refined approach to laparoscopic radical nephrectomy is described and our experience is reviewed. A low, muscle splitting Gibson incision is made just lateral to the rectus muscle and the hand port is inserted. A trocar is placed through the hand port and pneumoperitoneum is established. With the laparoscope in the hand port trocar 2 additional trocars are placed under direct vision. The laparoscope is then repositioned through the middle trocar and standard laparoscopic instruments are used through the other 2 trocars including the one in the hand port. If at any time during the procedure the surgeon believes the hand would be useful or needed, the trocar is removed from the hand port and the hand is inserted. RESULTS: This approach has been applied to 7 patients. Mean estimated blood loss was 200 cc (range 50 to 300) and mean operative time was 276.7 minutes (range 247 to 360). Mean specimen weight was 767 gm. (range 538 to 1,170). Pathologically 6 specimens were renal cell carcinoma (grades 2 to 4) and 1 was oncocytoma. Mean length of hospital stay was 3.71 days (range 2 to 7). There were no major complications. CONCLUSIONS: We believe that this approach enables the surgeon to incorporate the advantages of the hand assisted and standard laparoscopic approaches.

Blood Loss, Surgical↗

PubMed2003

Supplements and the prostate: widespread use, little evidence.

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Adult↗

PubMed2003

Initial experience with single-agent docetaxel as neoadjuvant therapy in men with locally advanced prostate cancer.

Patients with locally advanced prostate cancer have worse outcomes after radical prostatectomy (RP) than patients with more favorable parameters. The findings of large, contemporary, RP series have led investigators at a number of centers to evaluate the potential role of neoadjuvant chemotherapy in patients with locally advanced disease. A currently ongoing study of 28 patients explores the antitumor response of a regimen of single-agent, docetaxel, 40 mg/m(2), administered intravenously on a weekly schedule for 6 weeks to patients with locally advanced prostate cancer before RP. Docetaxel has demonstrated significant antitumor activity in patients with advanced, androgen-independent disease. Study results showed that 75% of patients had reductions in prostate-specific antigen (PSA) levels ranging from 9%-79% at the completion of docetaxel therapy. In 25% of the patients, PSA levels increased by 2%-18% from baseline to completion of chemotherapy. In addition, noncastrate levels of testosterone were maintained in all patients. The docetaxel therapy has also been relatively well tolerated. Reporting of the primary endpoint of pathologic response is pending completion of accrual and surgery.

Journal Article↗

PubMed2003

Initial experience with single-agent docetaxel as neoadjuvant therapy in men with locally advanced prostate cancer.

Journal Article↗

PubMed2002

The use of treatments for erectile dysfunction among survivors of prostate carcinoma.

BACKGROUND: The objectives of this survey were to describe the prevalence of using a treatment for erectile dysfunction (ED) among men after therapy for localized prostate carcinoma and to construct models explaining the variance in trying a treatment, treatment success, and adherence to treatment. METHODS: A postal survey was sent to 2636 men in The Cleveland Clinic Foundation's Prostate Cancer Registry who were treated initially with either definitive radiotherapy or prostatectomy for localized prostate carcinoma. The survey asked about demographic items, past and current sexual functioning, and the partner's sexual function. Men were asked about their current and intended use of medical treatments for ED. Standardized questionnaires included the Sexual Self-Schema Scale-Male Version, the International Index of Erectile Function, urinary and bowel symptom scales from the Los Angeles Prostate Cancer Index), and the Short-Form Health Survey. RESULTS: The return rate was 49%. Differences between men who returned the questionnaire and men who did not respond suggest that the sample was weighted toward men who were more interested in staying active sexually. ED was a problem for 85% of men, and 59% of this group used at least 1 treatment for ED. Only 38% of men found that a medical treatment was at least somewhat helpful in improving their sex lives, however, and 30% of respondents still were using at least 1 treatment at the time of the survey. Factors that were associated with the efficacy of treatments for ED and with their continued use included having a sexual partner, younger age, choosing a treatment for prostate carcinoma that was more likely to spare some sexual function, and not having had neoadjuvant or current antiandrogen therapy. Men who tried a greater number of treatments for ED were more likely to find one that worked. Men were more likely to continue using treatments for ED that produced greater improvements in sexual function. CONCLUSIONS: The success of medical treatments for men with ED among long-term survivors of prostate carcinoma is limited. Men prefer noninvasive treatments, although invasive treatments are more effective. Sexual counseling for men and their partners is recommended, because it may increase the use of medical therapies for ED. Creating more realistic expectations in both partners also may enhance treatment adherence.

Adult↗

PubMed2002

Factors affecting recurrence rates after prostatectomy or radiotherapy in localized prostate carcinoma patients with biopsy Gleason score 8 or above.

BACKGROUND: To review the biochemical recurrence-free survival (bRFS) rates of treatment with either external beam radiotherapy or radical prostatectomy in patients with biopsy Gleason score 8 or above in the prostate specific antigen (PSA) era. METHODS: A total of 297 localized prostate carcinoma patients diagnosed with biopsy Gleason score 8 or above were treated between 1987 and 2000 at the Cleveland Clinic with either prostatectomy or radiotherapy (RT). All patients had pretreatment PSA (iPSA) levels. Androgen deprivation was given as part of the initial treatment in 154 patients (52%). Radical prostatectomy (RP) was the primary treatment in 115 patients (39%) and 182 patients (61%) received RT. The median radiation dose was 70.2 Gy (range, 60.0-78.0 Gy). The median follow-up time was 42 months (range, 1-153 months). RESULTS: For the 297 patients, the 5 and 8-year bRFS rates were 45% (95% confidence interval [CI] 38-52%) and 31% (95% CI 20-42%), respectively. The 5-year bRFS rates for iPSA 10 or less versus. iPSA above10 were 66% (95% CI 54-78%) versus 31% (95% CI 22-40%), respectively (P < 0.001). The 5-year bRFS rates for use of androgen deprivation versus no androgen deprivation were 62% (95% CI 52-72%) versus 35% (95% CI 27-42%), respectively (P < 0.001). The 5-year bRFS rates for RT patients versus RP patients were 47% (95% CI 38-57%) versus 42% (95% CI 31-53%), respectively (P = 0.051). For RT patients, the 5-year bRFS rates for use of androgen deprivation versus no androgen deprivation were 71% versus 29%, respectively (P < 0.001). For RP patients, the 5-year bRFS rates for use of androgen deprivation versus no androgen deprivation were 39% versus 43%, respectively (P = 0.90). Multivariate time-to-failure analysis using the proportional hazards model showed iPSA level (P < 0.001) and the use of androgen deprivation (P = 0.001) to be the only independent predictors of biochemical recurrence. Age (P = 0.44), race (P = 0.80), clinical T stage (P = 0.10), biopsy Gleason scores (P = 0.39), and treatment modality (P = 0.13) were not independent predictors of biochemical failure. A total of 104 patients had Stage T1 or T2 disease, low iPSA levels (</= 10 ng/mL), and a high Gleason score (>/= 8). For all 104 patients, the 5-year bRFS rate was 64%. For 52 of the 104 patients who received 6 months of androgen deprivation or less, the 5-year bRFS rate was 78%. CONCLUSION: Patients with localized prostate carcinoma with a biopsy Gleason score 8 or less have lower recurrence rates if iPSA levels are 10 or less. Biochemical control rates were encouraging for patients with biopsy Gleason score 8 or above, clinical Stage T1-T2, and iPSA levels less than or equal to 10 ng/mL treated with adjuvant androgen deprivation given only for 6 months or less. If longer follow-up confirms these findings, these patients might not need prolonged androgen deprivation for periods exceeding 6 months following local therapy.

Adult↗

PubMed2002

RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases.

RNASEL (encoding ribonuclease L) has recently been proposed as a candidate for the hereditary prostate cancer (HPC1) gene. We determined that the RNASEL variant Arg462Gln has three times less enzymatic activity than the wildtype and is significantly associated with prostate cancer risk (P = 0.007). At least one copy of the mutated allele that causes this substitution is carried by nearly 60% of the men in our study. Men that are heterozygous with respect to the mutated allele have 50% greater risk of prostate cancer than non-carriers, and homozygotes have more than double the risk.

Aged↗

PubMed2002

Defining sexual outcomes after treatment for localized prostate carcinoma.

BACKGROUND: The objective of this survey was to identify factors associated with good sexual outcomes in a large group of survivors of localized prostate carcinoma. METHODS: A postal survey was sent to 2636 men in the Cleveland Clinic Foundation's Prostate Cancer Registry who either were treated with definitive radiotherapy or underwent prostatectomy for localized prostate carcinoma. The survey asked about demographic items, past and current sexual functioning, partner's sexual function and health, and a number of factors hypothesized to affect sexual satisfaction. Standardized questionnaires included the Sexual Self-Schema Scale-Male Version, the International Index of Erectile Function (IIEF), urinary and bowel symptom scales from the Los Angeles Prostate Cancer Index, and the Short Form Health Survey (SF-36). RESULTS: The return rate was 49%, yielding a sample of 1236 men at an average of 4.3 years post-treatment. Comparing responders with nonresponders suggested that the sample may have been somewhat biased toward men who were more interested in maintaining sexual function. At the time they were diagnosed with prostate carcinoma, 36% of men had erectile dysfunction (ED). Within the past 6 months, however, 85% of men reported having ED. Only 13% of men were having reliable, firm erections spontaneously, and another 8% of men were having erections with the aid of a medical treatment. Men were as distressed about loss of desire and trouble having satisfying orgasms as they were about ED. Of the 84% of men who reported having a current sexual partner, 66% indicated that she had a sexual problem. Younger age was associated strongly with better sexual outcome (global IIEF score). With demographic factors taken into account, better sexual outcome was related significantly to medical factors, including not having neoadjuvant or current antiandrogen therapy, undergoing bilateral nerve-sparing prostatectomy or brachytherapy, and having better mental and physical health composite scores on the SF-36. Sexual factors that were associated with a better outcome included having normal erections before treatment for prostate carcinoma, choosing a treatment based on the hope that it would preserve sexual function, having more sexual partners in the past year, and having a sexually functional partner. CONCLUSIONS: The great majority of men who survive prostate carcinoma do not achieve a return to functional sexual activity in the years after treatment. The priorities a man places on sexuality and on having a sexually functional partner are important factors in sexual satisfaction at follow-up, over and above the influence of age and medical factors.

Adult↗

PubMed2002

Comparison of the efficacy of local therapies for localized prostate cancer in the prostate-specific antigen era: a large single-institution experience with radical prostatectomy and external-beam radiotherapy.

PURPOSE: To review biochemical relapse-free survival (bRFS) rates after either external-beam radiotherapy (RT) or radical prostatectomy (RP) for localized prostate cancer. PATIENTS AND METHODS: All 1,682 patients had pretreatment prostate-specific antigen (PSA) levels and biopsy Gleason scores (bGS) assigned. No adjuvant therapy was administered after local treatment. RP was the treatment in 1,054 patients (63%) and RT in 628 patients (37%). Median follow-up was 51 months (range, 1 to 134). The median follow-up for RP versus RT patients was 50.5 v 51.0 months. Biochemical relapse was considered detectable PSA levels (> 0.2 ng/mL) in RP patients and three consecutive rising PSA levels in RT patients. The analysis was repeated with a more stringent definition of biochemical control after either RP or RT-namely, reaching and maintaining a PSA level < or = 0.5 ng/mL-and excluding patients receiving any androgen deprivation (AD). RESULTS: Eight-year bRFS rates for RP versus RT were 72% and 70%, respectively (P =.010). Multivariate analysis indicated T stage (P <.001), pretreatment PSA (P <.001), bGS (P <.001), year of therapy (P <.001), and neoadjuvant AD (P =.019) to be the only independent predictors of relapse. Age (P =.78), race (P =.29), prior transurethral resection of prostate (P =.81), and treatment modality (P =.96) were not independent predictors of treatment failure. Fifty-one percent of RP patients had favorable tumors (T1 to T2A, pretreatment PSA < or = 10 ng/mL, bGS < or = 7), compared with only 34% of RT patients (P <.001). Repeat analysis with a stringent definition of biochemical failure and excluding patients receiving AD indicated no impact of treatment modality on outcome. CONCLUSION: Eight-year biochemical failure rates were identical between RT and RP in any subgroup. Outcome is determined mainly by pretreatment PSA levels, bGS, clinical T stage, and, for RT patients, radiation dose.

Adenocarcinoma↗

PubMed2002

Preoperative combined nested reverse transcriptase polymerase chain reaction for prostate-specific antigen and prostate-specific membrane antigen does not correlate with pathologic stage or biochemical failure in patients with localized prostate cancer undergoing radical prostatectomy.

PURPOSE: We report a prospective study examining the ability of preoperative nested reverse transcriptase polymerase chain reaction (RT-PCR) for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM) to predict pathologic stage and biochemical recurrence in patients with clinically localized prostate cancer treated with radical prostatectomy. PATIENTS AND METHODS: One hundred forty-one patients were entered onto the study. Preoperative evaluation included clinical T stage, serum PSA, biopsy Gleason score, and serum RT-PCR for PSA/PSM. Univariate and multivariate logistic regression models, Kaplan-Meier estimates, and Cox proportional hazards modeling were used to identify predictors of pathologic stage and biochemical failure. RESULTS: Seventy-three patients (51.8%) were RT-PCR positive for PSA, PSM, or both. In the multivariate logistic regression model, only initial PSA was an independent predictor of pathologic stage as defined by organ-confined disease (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00 to 1.13; P =.026) or organ-/specimen-confined disease (OR, 1.09; 95% CI, 1.02 to 1.16; P =.009). Overall Kaplan-Meier biochemical relapse-free survival (bRFS) was 85% at 59 months. Multivariate analysis of predictors for bRFS with the Cox proportional hazards model indicated that only initial PSA (OR, 1.05; 95% CI, 1.02 to 1.09; P =.004) and biopsy Gleason score (OR, 3.57; 95% CI, 1.37 to 9.58; P =.009) were independent predictors of biochemical failure. RT-PCR status did not predict pathologic stage or biochemical failure. Repeat analysis excluding 27 patients who received preoperative androgen-deprivation therapy did not change the results. CONCLUSION: Combined nested RT-PCR for PSA and PSM is not an independent predictor of pathologic stage or biochemical failure in patients with localized prostate cancer undergoing radical prostatectomy. This assay has no clinical utility in this patient population.

Antigens, Surface↗

PubMed2002

Selective interleukin-12 synthesis defect in 12/15-lipoxygenase-deficient macrophages associated with reduced atherosclerosis in a mouse model of familial hypercholesterolemia.

Targeted gene disruption or overexpression of 12/15-lipoxygenase in mice on the genetic background of apolipoprotein E or low density lipoprotein-receptor (LDL-R) deficiency has implicated 12/15-lipoxygenase in atherogenesis. The data support indirectly a role for 12/15-lipoxygenase in the oxidative modification of low density lipoprotein. In this study we set out to explore other potential mechanisms for 12/15-lipoxygenase in atherosclerosis using apolipoprotein B mRNA editing catalytic polypeptide-1/LDL-R double-deficient mice, a model highly related to the human condition of familial hypercholesterolemia. 12/15-Lipoxygenase deficiency in this strain led to approximately 50% decrease in aortic lesions in male and female mice at 8 months on a chow diet in the absence of cholesterol differences. While studying 12/15-lipoxygenase-deficient macrophages in culture, we discovered a remarkable selective defect (75-90% decrease) in interleukin-12 production but not in tumor necrosis factor-alpha or nitric oxide release, in response to lipopolysaccharide in the presence or absence of interferon-gamma priming. The lipopolysaccharide/interferon-gamma response was associated with a 33-50% decrease in nuclear interferon consensus sequence-binding protein, which is consistent with interferon consensus sequence-binding protein containing protein complex-dependent regulation of the interleukin-12 p40 gene. The decrease in interleukin-12 production was recapitulated in vivo in mouse aortas of the triple knockout group and was reflected in a marked decrease in interferon-gamma expression. The data provide support for a novel mechanism linking the 12/15-lipoxygenase pathway to a known immunomodulatory Th1 cytokine in atherogenesis.

APOBEC-1 Deaminase↗