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Laurence H Klotz

Publications and source records attributed to Laurence H Klotz.

At least 19 recordsLinked to original sources
PubMed2007

Expression of TMPRSS2:ERG gene fusion in prostate cancer cells is an important prognostic factor for cancer progression.

The prostate-specific gene, TMPRSS2, is fused with the transcription factor gene, ERG in a high proportion of prostate cancers. However, the clinical significance of TMPRSS2:ERG gene fusion among prostate cancer patients is unknown. We assayed for the presence of the TMPRSS2:ERG gene fusion product among 26 patients who underwent surgery for clinically localized prostate cancer using RT-PCR and direct DNA sequencing, and evaluated its prognostic significance. All 26 patients had cancers of the same histologic grade (Gleason score 7). The fusion protein was present within prostate cancer tumor cells in eleven patients (42.3%). Nine patients experienced biochemical disease relapse (elevated PSA) after a mean follow-up of 12 months (range 1 to 48 months). Patients with the fusion protein had a significantly higher rate of recurrence (5-year recurrence rate 79.5%) compared to patients who lacked the fusion protein (five-year recurrence rate 37.5%, p = 0.009). The adjusted hazard ratio for disease relapse for patients with the fusion protein was 7.1 (95% C.I.: 1.1-45, p = 0.03) compared to patients without the fusion protein. In multivariate analysis, the presence of gene fusion was the single most important prognostic factor. Our study indicates that the expression of TMPRSS2:ERG fusion gene among prostate cancer patients treated with surgery is a strong prognostic factor for disease relapse, and may have important clinical implications.

Biomarkers, Tumor↗
PubMed2006

Variants of the hK2 protein gene (KLK2) are associated with serum hK2 levels and predict the presence of prostate cancer at biopsy.

PURPOSE: Increased levels of serum human kallikrein-2 (hK2) and an hK2 gene (KLK2) variant are positively associated for prostate cancer, but the relationships between them remain unclear. We examined five variants of the KLK2 gene to further define its relevance to prostate cancer susceptibility and hK2 levels. EXPERIMENTAL DESIGN: We genotyped 645 men with biopsy-proven prostate cancer (cases) and 606 males with biopsies negative for prostate cancer (controls) for five additional single nucleotide polymorphisms (SNP) across the KLK2 gene and also tested for serum hK2 levels. These SNPs were identified from sequencing the KLK2 gene among 20 patients with aggressive prostate cancer. Odds ratios (OR) for prostate cancer detection and haplotype analysis were done. RESULTS: Among the SNPs studied, the A allele of the KLK2-SNP1 (G>A, rs2664155) and the T allele of the KLK2-SNP5 (C>T, rs198977) polymorphisms showed positive associations with prostate cancer, adjusted ORs for KLK2-SNP1 AG and AA genotypes being 1.4 [95% confidence interval (95% CI), 1.2-1.8; P=0.002] and for KLK2-SNP5 TT or CT genotypes being 1.3 (95% CI, 1.1-1.6; P=0.05). Haplotype analyses also revealed a significant association between prostate cancer and the haplotype containing both risk alleles (ACCTT), OR being 5.1 (95% CI, 1.6-6.5; P=0.005). Analysis of serum hK2 revealed hK2 levels to be significantly increased in association with KLK2-SNP1 AA and AG risk genotypes compared with the GG genotype (P=0.001) and also in association with the ACCTT risk haplotype compared with the most common non-risk haplotype (P=0.05). CONCLUSIONS: These findings suggest a role for the KLK2 gene in prostate cancer susceptibility and imply that this role may be realized at least in part by the induction of increases in hK2 production.

Adenocarcinoma↗
PubMed2006

Making sense of prostate specific antigen: improving its predictive value in patients undergoing prostate biopsy.

PURPOSE: The clinical usefulness of PSA for prostate cancer screening is unclear, although the test remains in common use. New methods to interpret PSA are needed. MATERIALS AND METHODS: We examined a cohort of 2,637 men who underwent prostate biopsies for abnormal DRE or PSA between 1999 and 2004. Using risk factors for prostate cancer, including patient age, ethnicity, family history of prostate cancer, previous negative biopsy, voiding symptoms and prostate volume, we developed risk groups for prostate cancer using recursive partitioning modeling independent of PSA or DRE. We then compared prostate cancer probabilities by PSA ranges by risk group. RESULTS: Of the 2,637 men 1,282 (48.6%) had prostate cancer. Age, ethnicity, family history, previous negative biopsy and prostate volume were predictive for cancer. We constructed 6 risk groups by combining these factors and created tables to assign patients to these groups. Independent of PSA and DRE the probability of cancer ranged from 15% in patients in group 1 to 78% in patients in group 6 (p <0.0001). By adding PSA and DRE to each risk group prostate cancer probabilities were refined from 0% to 100%. Patients in the higher risk groups also had higher grade cancer (p <0.0001). CONCLUSIONS: We generated 6 risk groups based on simple risk factors for prostate cancer. When used in the right context and patient, PSA is highly accurate for predicting prostate cancer and permitting rational decision making in patients with abnormal PSA.

Adult↗
PubMed2006

Active surveillance with selective delayed intervention for favorable risk prostate cancer: clinical experience and a 'number needed to treat' analysis.

This is a summary of the case for active surveillance for 'favorable-risk' prostate cancer with selective delayed intervention for rapid biochemical progression, assessed by rising prostate-specific antigen (PSA) levels, or grade progression. The results of a large phase II trial using this approach are reviewed. To date, this study has shown that virtually all men with 'favorable-risk' prostate cancer managed in this fashion will die of unrelated causes. Based on the Swedish randomized trial of radical prostatectomy versus watchful waiting, the Connecticut observation series, and the Toronto active surveillance experience, a number needed to treat analysis of the benefit of radical treatment of all newly diagnosed favorable risk prostate cancer patients, compared to a strategy of active surveillance with selective delayed intervention, is presented. This suggests that approximately 100 patients will require radical treatment for each prostate cancer death averted. This translates into a 2-3 week survival benefit, unadjusted for quality of life. This figure is confirmed based on an analysis of the D'Amico PSA velocity data in favorable risk disease. The approach of active surveillance with selective delayed intervention based on PSADT and repeat biopsy represents a practical compromise between radical therapy for all patients, (which results in overtreatment for patients with indolent disease), and watchful waiting with palliative therapy only, (which results in undertreatment for those with aggressive disease).

Disease Progression↗
PubMed2006

Prostate sparing radical cystectomy--not for all, but an option for some.

OBJECTIVES: Prostate sparing radical cystectomy (PSRC) is a controversial surgical approach for the treatment of male bladder cancer. The objective of this review is to address some of the concerns related to the potential compromise of oncological outcome compared to radical cystoprostatectomy (RCP)-the gold standard procedure. METHODS: Review of series published in the English literature. Only studies that address PSRC for transitional cell carcinoma of the bladder were included. RESULTS: There are only a limited number of studies addressing this approach. All are retrospective, non-comparative and not uniform in terms of patient selection and technique. Long-term follow-up is lacking. The incidence of synchronous and or metachronous prostate cancer and TCC of the prostatic urethra is lower than that found in RCP due to pre-operative screening. The local recurrence rate is 5%- comparable with RCP. Stage for stage, recurrence free and overall survival are compatible. CONCLUSIONS: The experience with PSRC is too limited to allow firm conclusions as to whether the outcome with respect to disease free and disease specific survival is comparable to that achieved by RCP. However, with proper patient screening and selection the short-term results appear promising.

Carcinoma, Transitional Cell↗
PubMed2006

Nomogram prediction for prostate cancer and aggressive prostate cancer at time of biopsy: utilizing all risk factors and tumor markers for prostate cancer.

BACKGROUND: There is a large amount of confusion in interpreting prostate specific antigen (PSA) values for prostate cancer. More precise risk assessments for prostate cancer detection are needed for men faced with an abnormal PSA. METHODS: We studied a sample of 2,637 men who underwent a prostate biopsy for an abnormal digital rectal exam (DRE) or PSA. Using factors including age, ethnicity, family history of prostate cancer, previous negative biopsy, presence of voiding symptoms, prostate volume, DRE and PSA, we constructed nomograms to predict the probability of prostate cancer at biopsy. RESULTS: Of the 2,637 men, 1,282 men (48.6%) had prostate cancer detected. Age, ethnicity, family history of prostate cancer, a previous negative biopsy, prostate volume, DRE and PSA were all significant predictors of prostate cancer. Nomograms were constructed based on these factors to predict the risk of prostate cancer and of aggressive prostate cancer (defined as a Gleason Score 7 or more). The positive predictive value varied from 5% to 95% based on the nomograms. The nomograms were validated using bootstrapping methods and the expected and observed proportions were found to be highly concordant. CONCLUSIONS: For men with an abnormal PSA or DRE, the risk for prostate cancer can be accurately estimated using a nomogram based on age, ethnicity, family history of prostate cancer, previous negative biopsy, presence of voiding symptoms, prostate volume, DRE and PSA. This tool will aid physicians and patients in determining the need for prostate biopsy.

Adult↗
PubMed2006

PSA recurrence: definitions, PSA kinetics, and identifying patients at risk.

Uncertainty exists for clinicians and patients with respect to choosing the optimal therapy for patients with PSA recurrence. There is no consensus as to what the PSA cutpoint should be to define PSA failure after radical prostatectomy (RP) or radiation therapy (XRT). We do, however, have validated nomograms which allow the stratification of patients according to their risk of disease progression and cancer specific death. This is based in large part on PSA kinetics. A short PSA doubling time (PSA-DT) is associated with a marked increase in the risk of prostate cancer death in the 5-10 year time frame. PSA DT can also be used to identify patients most likely to respond to local salvage therapy.

Humans↗
PubMed2006

Does prolonging the time to testicular cancer surgery impact long-term cancer control: a systematic review of the literature.

BACKGROUND: The wait times for urological cancer surgeries in Canada are beyond those recommended by the Canadian Association of Surgical Oncology. Prolonged wait times have a negative impact on patient quality of life but the effect on long-term cancer control is controversial. We conducted a systematic review of the testicular cancer literature to examine the best available evidence addressing the following key questions: What is the reported time interval for testicular cancer patients from the decision to operate until the day of testicular cancer surgery? Are there recommendations/guidelines in the urological cancer literature and, if so, how do the Canadian times compare? Is there a known association between duration of wait time beyond the recommended standard and clinical outcome (i.e. recurrence free survival, overall survival)? METHODS: A structured literature search of Medline, Pubmed, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews, the Cochrane Database of Abstracts of Reviews of Effects, Healthstar and Google Scholar from January 1980 to September 2005 was conducted for published epidemiological studies and international guidelines/consensus documents that evaluated surgical wait times for testicular cancer. Data extracted from eligible studies included median time to diagnosis and to testicular cancer surgery. RESULTS: Five studies evaluating different components of wait times (e.g. delay in diagnosis, delay in orchiectomy) in testicular cancer patients were identified, four of which measured the impact of prolonged delays on relapse free and overall survival. Differences in study data availability, method of analysis and wait time definitions precluded statistical pooling of the findings. In one study from the United Kingdom, median wait time was 30 days from general practitioner referral to surgery and 4 days from diagnosis to surgery. No Canadian studies specific to testicular cancer were identified. The association between surgical delay and clinical outcomes remained controversial where only one of five epidemiological studies reported an association between treatment delay and relapse free and overall survival CONCLUSIONS: Even though the association between surgical delay and disease related clinical outcomes remains controversial, there is an ongoing concern that the psychological impact of prolonged waiting for urological cancer surgery could negatively impact patient outcomes. Additional research is needed to identify the current wait times for testicular cancer in Canada and to develop guidelines and recommendations on what appropriate wait times should be. To address these important issues, the surgical wait times (SWAT) initiative is mandated to provide the necessary guidance and recommendations to the federal and provincial governments. Through a partnership between the key stakeholders, it is the vision of SWAT to ultimately improve the care and quality of life of cancer patients.

Appointments and Schedules↗
PubMed2005

The use of genetic markers to determine risk for prostate cancer at prostate biopsy.

PURPOSE: We examined a panel of 13 polymorphisms in 13 different genes to determine whether specific genotypes can help predict prostate cancer at the time of biopsy among men prescreened with prostate-specific antigen and digital rectal exam. EXPERIMENTAL DESIGN: We examined 2,088 consecutive men who were referred for prostate biopsy from 1997 to 2003. Thirteen genes were examined, including TNF308, GSTT1, KLK2, endostatin, MCRA, MCRV, tyrosinase, MSR1, CHK2, RNasel, HOGG1-326, HOGG1-11657, and HRAS1. Odds ratio for detection of prostate cancer were adjusted for age, race, prostate-specific antigen, digital rectal exam, family history of prostate cancer, and urinary symptoms. RESULTS: Of the 2,088 men, 996 (47.7%) had cancer detected. Four genes (TNF308, GSTT1, KLK2, and HOGG1-326) were significantly associated with prostate cancer. The adjusted odds ratios (OR) for prostate cancer for patients with the AA genotype of the TNF308 gene was 1.92 [95% confidence interval (95% CI), 1.0-1.5, P = 0.05], compared with those with the GG genotype, and for patients with the TT genotype of the KLK2 gene, the OR was 1.5 (95% confidence interval, 1.0-2.2, P = 0.04), compared with the CC genotype. The OR for patients with a homozygous deletion of the GSTT1 gene was 0.81 (95% CI, 0.6-1.0, P = 0.06) compared with those with the deletion, and the OR for patients with the GG genotype of the HOGG1-326 gene was 0.68 (95% CI, 0.5-1.0, P = 0.05) compared with the CC genotype. Patients who had all four alleles that were positively associated with prostate cancer had an OR of 9.33 (95% CI, 2.4-35.8, P = 0.0005) for prostate cancer compared with patients with alleles that were negatively associated with prostate cancer. CONCLUSIONS: Of the 13 polymorphisms, two were found to be positively associated with prostate cancer (TNF308 and KLK2) and two were negatively associated with prostate cancer (GSTT1 and HOGG1-326). Future studies are required to confirm these results.

Adenocarcinoma↗
PubMed2005

Active surveillance with selective delayed intervention: walking the line between overtreatment for indolent disease and undertreatment for aggressive disease.

PURPOSE: To summarize the case for active surveillance for good risk prostate cancer with selective delayed intervention for rapid biochemical or grade progression, and review the results of a large phase II experience using this approach. MATERIALS AND METHODS: A prospective phase II study of active surveillance with selective delayed intervention was initiated in 1995. Patients were managed initially with surveillance; those who had a PSA DT of 2 years or less, or grade progression on rebiopsy were offered radical intervention. The remainder were closely monitored. RESULTS: The cohort consists of 299 patients with good risk prostate cancer, or intermediate risk prostate cancer in men over 70. The median PSA doubling time was 7.0 years. 35% had a PSA DT > 10 years. The majority of patients remain on surveillance. At 8 years, overall actuarial survival is 85%, and disease specific survival is 99%. CONCLUSION: Most men with favorable risk prostate cancer will die of unrelated causes. The approach of active surveillance with selective delayed intervention based on PSA DT represents a practical compromise between radical therapy for all (which results in overtreatment for patients with indolent disease), and watchful waiting with palliative therapy only (which results in undertreatment for those with aggressive disease). The results at 8 years are favorable. Longer follow up will be required to confirm the safety of this approach in men with a long (>15 year) life expectancy.

Aged↗
PubMed2005

International regional working groups on prostate cancer: results of consensus development.

UNLABELLED: At the first Global Urologic Oncology Congress--which was held in conjunction with the SIU meeting in Honolulu, Hawaii, on October 2-3, 2004--a total of 250 urologists from nine regions throughout the world participated in working groups to develop consensus statements about the management of prostate cancer patients. The focus was on two areas of prostate cancer: first, screening and detection--including when to do a biopsy, and how to manage low-risk patients--and second, management of high-risk patients. CONCLUSION: Overall, there is marked global diversity of beliefs about optimal screening and management of patients with low- or high-risk localized prostate cancer. This diversity likely reflects regional differences in epidemiologic factors, resources, and treatment patterns. Participating in the process of trying to develop international practice consensus gives urologists the opportunity to broaden their perspective about handling common clinical scenarios.

Adult↗
PubMed2005

Active surveillance for good risk prostate cancer: rationale, method, and results.

BACKGROUND: Many newly diagnosed patients with prostate cancer have "good risk" disease. The challenge is to identify the minority of these patients with aggressive disease and offer them curative treatment, while sparing the remainder the morbidity of unnecessary treatment. PURPOSE: To examine the results of active surveillance with selective delayed intervention in good risk prostate cancer patients. MATERIALS AND METHODS: This was a prospective phase II study of active surveillance of 299 patients. Eighty percent (239 patients) met the criteria for good risk disease: PSA < 10 ng/mL, Gleason < 6, T < 2a. Twenty percent of patients, all of whom who were age 70 or greater, had Gleason 7 cancer or a PSA above 10. RESULTS: At 8 years, overall survival is 85% and disease-specific survival is 99%. A PSA doubling time of < 2 years was linked with likelihood of locally advanced disease. CONCLUSION: Watchful waiting is clearly appropriate for elderly prostate cancer patients with high co-morbidities. For good risk, young, healthy patients, this study supports the feasibility of long-term, close monitoring with early intervention for those who progress rapidly. Approximately two thirds of such patients will remain free of treatment over 8 years.

Aged↗