Single institution followed by national implementation of systematic surgical quality control and feedback for radical prostatectomy: a 20-year journey.

PURPOSE: The demand for objective and outcome-based facts about surgical results after radical prostatectomy (RP) is increasing. Systematic feedback is also essential for each surgeon to improve his/her performance. METHODS: RP outcome data (e.g., pT-stage and margin status) have been registered at Sahlgrenska University Hospital (SUH) since 1988 and patient-related outcome measures (PROM) have been registered since 2001. The National Prostate Cancer Registry (NPCR) has covered all Regions in Sweden since 1998 and includes PROM-data from 2008. Initially PROM was on-paper questionnaires but due since 2018 all PROMs are collected electronically. In 2014 an on-line "dashboard" panel was introduced, showing the results for ten quality-control variables in real-time. Since 2017 all RP data on hospital, regional, and national levels are publicly accessible on-line on "www.npcr.se/RATTEN". RESULTS: The early PROM-data from SUH have been used for internal quality control. As national clinical and PROM-data from the NPCR have been made accessible on-line and in real-time we have incorporated this into our pre-existing protocol. Our data are now internally available as real-time NPCR reports on the individual surgeons' results, as well as ePROM data. We can compare the results of each surgeon internally and to other departments' aggregated data. The public can access data and compare hospital level data on "RATTEN". CONCLUSIONS: The process of quality control of RP locally at SUH, and nationally through the NPCR, has been long but fruitful. The online design, with direct real-time feedback to the institutions that report the data, is essential.

Serum inflammatory markers in relation to prostate cancer severity and death in the Swedish AMORIS study.

Inflammation is a well-documented driver of cancer development and progression. However, little is known about its role in prostate carcinogenesis. Thus, we examined the association of C-reactive protein (CRP), haptoglobin, albumin and white blood cells (WBC) with prostate cancer (PCa) severity (defined by PCa risk category and clinicopathological characteristics) and progression (defined by PCa death). We selected 8,471 Swedish men with newly diagnosed PCa who had exposure measurements taken approximately 14 years prior to diagnosis. We calculated odds ratio (OR) and 95% confidence interval (CI) for the associations between the inflammatory markers and PCa severity using logistic regression, while Cox proportional hazard regression was used for the associations with overall and PCa death. Serum CRP levels were associated with increased odds of high risk and metastatic PCa, and high PSA levels (≥20 µg/L) (OR: 1.29; 95% CI: 1.06-1.56, 1.32; 1.05-1.65 and 1.51; 1.26-1.81, respectively). Similarly, higher haptoglobin levels were associated with increased odds of metastatic PCa, high PSA level and possibly high grade PCa (1.38; 1.10-1.74, 1.50; 1.17-1.93 and 1.25; 1.00-1.56, respectively). Albumin was positively associated with Gleason 4 + 3 tumour (1.38; 1.02-1.86) and overall death (HRunit increase in log : 1.60; 95% CI: 1.11-2.30), but inversely associated with high risk PCa and high PSA levels (≥20 µg/L) (0.71; 0.56-0.89 and 0.72; 0.5 9-0.90). WBC was associated with increased odds of T3-T4 PCa. Except for albumin, none of these markers were associated with PCa death or overall death. Systemic inflammation as early as 14 years prior to diagnosis may influence prostate cancer severity.

Age at diagnosis and prostate cancer treatment and prognosis: a population-based cohort study.

Background: Old age at prostate cancer diagnosis has been associated with poor prognosis in several studies. We aimed to investigate the association between age at diagnosis and prognosis, and if it is independent of tumor characteristics, primary treatment, year of diagnosis, mode of detection and comorbidity. Patients and methods: We conducted a nation-wide cohort study including 121 392 Swedish men aged 55-95 years in Prostate Cancer data Base Sweden 3.0 diagnosed with prostate cancer in 1998-2012 and followed for prostate cancer death through 2014. Data were available on age, stage, grade, prostate-specific antigen (PSA)-level, mode of detection, comorbidity, educational level and primary treatment. We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: With increasing age at diagnosis, men had more comorbidity, fewer PSA-detected cancers, more advanced cancers and were less often treated with curative intent. Among men with high-risk or regionally metastatic disease, the proportion of men with unknown M stage was higher among old men versus young men. During a follow-up of 751 000 person-years, 23 649 men died of prostate cancer. In multivariable Cox-regression analyses stratified by treatment, old age at diagnosis was associated with poorer prognosis among men treated with deferred treatment (HRage 85+ versus 60-64: 7.19; 95% CI: 5.61-9.20), androgen deprivation therapy (HRage 85+ versus 60-64: 1.72; 95% CI: 1.61-1.84) or radical prostatectomy (HRage 75+ versus 60-64: 2.20; 95% CI: 1.01-4.77), but not radiotherapy (HRage 75+ versus 60-64: 1.08; 95% CI: 0.76-1.53). Conclusion: Our findings argue against a strong inherent effect of age on risk of prostate cancer death, but indicate that in current clinical practice, old men with prostate cancer receive insufficient diagnostic workup and subsequent curative treatment.

The Cambridge Prognostic Groups for improved prediction of disease mortality at diagnosis in primary non-metastatic prostate cancer: a validation study.

BACKGROUND: The purpose of this study is to validate a new five-tiered prognostic classification system to better discriminate cancer-specific mortality in men diagnosed with primary non-metastatic prostate cancer. METHODS: We applied a recently described five-strata model, the Cambridge Prognostic Groups (CPGs 1-5), in two international cohorts and tested prognostic performance against the current standard three-strata classification of low-, intermediate- or high-risk disease. Diagnostic clinico-pathological data for men obtained from the Prostate Cancer data Base Sweden (PCBaSe) and the Singapore Health Study were used. The main outcome measure was prostate cancer mortality (PCM) stratified by age group and treatment modality. RESULTS: The PCBaSe cohort included 72,337 men, of whom 7162 died of prostate cancer. The CPG model successfully classified men with different risks of PCM with competing risk regression confirming significant intergroup distinction (p < 0.0001). The CPGs were significantly better at stratified prediction of PCM compared to the current three-tiered system (concordance index (C-index) 0.81 vs. 0.77, p < 0.0001). This superiority was maintained for every age group division (p < 0.0001). Also in the ethnically different Singapore cohort of 2550 men with 142 prostate cancer deaths, the CPG model outperformed the three strata categories (C-index 0.79 vs. 0.76, p < 0.0001). The model also retained superior prognostic discrimination in the treatment sub-groups: radical prostatectomy (n = 20,586), C-index 0.77 vs. 074; radiotherapy (n = 11,872), C-index 0.73 vs. 0.69; and conservative management (n = 14,950), C-index 0.74 vs. 0.73. The CPG groups that sub-divided the old intermediate-risk (CPG2 vs. CPG3) and high-risk categories (CPG4 vs. CPG5) significantly discriminated PCM outcomes after radical therapy or conservative management (p < 0.0001). CONCLUSIONS: This validation study of nearly 75,000 men confirms that the CPG five-tiered prognostic model has superior discrimination compared to the three-tiered model in predicting prostate cancer death across different age and treatment groups. Crucially, it identifies distinct sub-groups of men within the old intermediate-risk and high-risk criteria who have very different prognostic outcomes. We therefore propose adoption of the CPG model as a simple-to-use but more accurate prognostic stratification tool to help guide management for men with newly diagnosed prostate cancer.

International cancer seminars: a focus on kidney cancer.

Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.

Smoking and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Smoking is not associated with prostate cancer incidence in most studies, but associations between smoking and fatal prostate cancer have been reported. METHODS: During 1992 and 2000, lifestyle information was assessed via questionnaires and personal interview in a cohort of 145,112 European men. Until 2009, 4623 incident cases of prostate cancer were identified, including 1517 cases of low-grade, 396 cases of high grade, 1516 cases of localised, 808 cases of advanced disease, and 432 fatal cases. Multivariable Cox proportional hazards regression models were used to examine the association of smoking status, smoking intensity, and smoking duration with the risk of incident and fatal prostate cancer. RESULTS: Compared with never smokers, current smokers had a reduced risk of prostate cancer (RR=0.90, 95% CI: 0.83-0.97), which was statistically significant for localised and low-grade disease, but not for advanced or high-grade disease. In contrast, heavy smokers (25+ cigarettes per day) and men who had smoked for a long time (40+ years) had a higher risk of prostate cancer death (RR=1.81, 95% CI: 1.11-2.93; RR=1.38, 95% CI: 1.01-1.87, respectively). CONCLUSION: The observation of an increased prostate cancer mortality among heavy smokers confirms the results of previous prospective studies.

Metabolic risk factors and skin cancer in the Metabolic Syndrome and Cancer Project (Me-Can).

BACKGROUND: Little is known about the associations of metabolic aberrations with malignant melanoma (MM) and nonmelanoma skin cancer (NMSC). OBJECTIVES: To assess the associations between metabolic factors (both individually and combined) and the risk of skin cancer in the large prospective Metabolic Syndrome and Cancer Project (Me-Can). METHODS: During a mean follow-up of 12 years of the Me-Can cohort, 1728 (41% women) incident MM, 230 (23% women) fatal MM and 1145 (33% women) NMSC were identified. Most NMSC cases (76%) were squamous cell carcinoma (SCC) (873, 33% women). Hazard ratios (HRs) were estimated by Cox proportional hazards regression for quintiles and standardized z-scores (with a mean of 0 and SD of 1) of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and for a combined metabolic syndrome score. Risk estimates were corrected for random error in the measurements. RESULTS: Blood pressure per unit increase of z-score was associated with an increased risk of incident MM cases in men and women [HR 1·17, 95% confidence interval (CI) 1·04-1·31 and HR 1·18, 95% CI 1·03-1·36, respectively] and fatal MM cases among women (HR 2·39, 95% CI 1·58-3·64). In men, all quintiles for BMI above the reference were associated with a higher risk of incident MM. In women, SCC NMSC risk increased across quintiles for glucose levels (P-trend 0·02) and there was a trend with triglyceride concentration (P-trend 0·09). CONCLUSION: These findings suggest that mechanisms linked to blood pressure may be involved in the pathogenesis of MM. SCC NMSC in women could be related to glucose and lipid metabolism.

Anti-androgen prescribing patterns, patient treatment adherence and influencing factors; results from the nationwide PCBaSe Sweden.

PURPOSE: Adherence has not been studied in male oncology populations. The aim of this study on both the prescriber and user perspectives in prostate cancer treatment was to analyse real-life prescribing patterns of anti-androgens (AA), primarily bicalutamide, and factors influencing the patients' adherence to treatment. METHODS: A nationwide clinical cohort of incident prostate cancer, PCBaSe, was linked to the Swedish Prescribed Drug Register. Men with a planned first line monotherapy AA treatment were identified; dosages and extent of off-label treatment were investigated. Cumulative incidence proportions for reasons for drug discontinuation were calculated. Factors potentially influencing adherence were explored using the medical possession ratio based on the individual prescribed daily dose. RESULTS: First line monotherapy AA was planned in 4.4 % of all incident cases and in 2.1 % of low risk disease cases. Among 1,406 men prescribed bicalutamide, 1,109 (79 %) received the approved daily dose of 150 mg. Discontinuation reasons differed with disease severity. Off-label, low-dose prescription associated with age above 75 years and disease categorised as low risk was noted in 297 men (21 %). Sixty percent of the men adhered well, i.e. to ≥80 %. Age above 75 years and less severe disease were both negatively associated with adherence. CONCLUSIONS: Patient age and tumour risk group influenced the prescriber's choice of dose, pointing to important issues for critical reflection. Possible over-treatment was noted in low risk disease. Interventions to increase adherence in older men and in men with less severe disease are worth considering after critically reviewing the appropriateness of the treatment indication, especially in the latter case.

Dietary supplement use patterns in men with prostate cancer: the Cancer Prostate Sweden study.

BACKGROUND: In a European setting, we know little about the use of dietary supplements among men with prostate cancer (PCa) and to what extent lifestyle, disease or other factors influence such use. PATIENTS AND METHODS: We evaluated supplement use in 1127 men with incident PCa and in 900 population controls in Sweden. Age-adjusted binary regression with an identity link was carried out to estimate prevalence differences and corresponding 95% confidence intervals (CIs). Modifying effects of lifestyle- and diet-related factors were explored by statistical assessment of additive interaction. RESULTS: Among men with PCa, 542 individuals (48%) had used supplements, which was a 10% (95% CI: 5.9%-15%) higher prevalence than among population controls. Among individuals with high intake of fatty fish, vegetables, and phytoestrogens, but low intake of saturated fat, supplement use was 29% (95% CI: 18%-41%) more common in men with PCa than in population controls. We found no evidence of heterogeneity by categories of education, smoking history, body mass index, fiber, fruit, or phytoestrogen intake, treatment, or disease stage. CONCLUSION: Supplement use is common in Swedish men with PCa, especially among those with a healthy dietary pattern.

Metabolic syndrome and rare gynecological cancers in the metabolic syndrome and cancer project (Me-Can).

BACKGROUND: Risk factors for rare gynecological cancers are largely unknown. Initial research has indicated that the metabolic syndrome (MetS) or individual components could play a role. MATERIALS AND METHODS: The Metabolic syndrome and Cancer project cohort includes 288,834 women. During an average follow-up of 11 years, 82 vulvar, 26 vaginal and 43 other rare gynecological cancers were identified. Hazard ratios (HRs) were estimated fitting Cox proportional hazards regression models for tertiles and standardized z-scores [with a mean of 0 and a standard deviation (SD) of 1] of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and MetS. Risk estimates were corrected for random error in the measurement of metabolic factors. RESULTS: The MetS was associated with increased risk of vulvar [HR 1.78, 95% confidence interval (CI) 1.30-2.41) and vaginal cancer (HR 1.87, 95% CI 1.07-3.25). Among separate MetS components, 1 SD increase in BMI was associated with overall risk (HR 1.43, 95% CI 1.23-1.66), vulvar (HR 1.36, 95% CI 1.11-1.69) and vaginal cancer (HR 1.79, 95% CI 1.30-2.46). Blood glucose and triglyceride concentrations were associated with increased risk of vulvar cancer (HR 1.98, 95% CI 1.10-3.58 and HR 2.09, 95% CI 1.39-3.15, respectively). CONCLUSION: The results from this first prospective study on rare gynecological cancers suggest that the MetS and its individual components may play a role in the development of these tumors.

Plasma phyto-oestrogens and prostate cancer in the European Prospective Investigation into Cancer and Nutrition.

We examined plasma concentrations of phyto-oestrogens in relation to risk for subsequent prostate cancer in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition. Concentrations of isoflavones genistein, daidzein and equol, and that of lignans enterolactone and enterodiol, were measured in plasma samples for 950 prostate cancer cases and 1042 matched control participants. Relative risks (RRs) for prostate cancer in relation to plasma concentrations of these phyto-oestrogens were estimated by conditional logistic regression. Higher plasma concentrations of genistein were associated with lower risk of prostate cancer: RR among men in the highest vs the lowest fifth, 0.71 (95% confidence interval (CI) 0.53-0.96, P trend=0.03). After adjustment for potential confounders this RR was 0.74 (95% CI 0.54-1.00, P trend=0.05). No statistically significant associations were observed for circulating concentrations of daidzein, equol, enterolactone or enterodiol in relation to overall risk for prostate cancer. There was no evidence of heterogeneity in these results by age at blood collection or country of recruitment, nor by cancer stage or grade. These results suggest that higher concentrations of circulating genistein may reduce the risk of prostate cancer but do not support an association with plasma lignans.

Animal foods, protein, calcium and prostate cancer risk: the European Prospective Investigation into Cancer and Nutrition.

We examined consumption of animal foods, protein and calcium in relation to risk of prostate cancer among 142 251 men in the European Prospective Investigation into Cancer and Nutrition. Associations were examined using Cox regression, stratified by recruitment centre and adjusted for height, weight, education, marital status and energy intake. After an average of 8.7 years of follow-up, there were 2727 incident cases of prostate cancer, of which 1131 were known to be localised and 541 advanced-stage disease. A high intake of dairy protein was associated with an increased risk, with a hazard ratio for the top versus the bottom fifth of intake of 1.22 (95% confidence interval (CI): 1.07-1.41, P(trend)=0.02). After calibration to allow for measurement error, we estimated that a 35-g day(-1) increase in consumption of dairy protein was associated with an increase in the risk of prostate cancer of 32% (95% CI: 1-72%, P(trend)=0.04). Calcium from dairy products was also positively associated with risk, but not calcium from other foods. The results support the hypothesis that a high intake of protein or calcium from dairy products may increase the risk for prostate cancer.

Components of the metabolic syndrome and colorectal cancer risk; a prospective study.

OBJECTIVE: To examine the relation of well-known factors of the metabolic syndrome (MetS) as well as related circulating factors, with risk of colorectal cancer. METHODS: We performed a case control study of 306 colorectal cancer cases and 595 matched controls nested in the Northern Sweden Health and Disease Cohort. Levels of C-peptide, glycated haemoglobin (HbA1c), leptin and adiponectin were measured in cryopreserved samples. Body mass index (BMI), systolic and diastolic blood pressure and fasting and post-load plasma glucose, had been measured in a subcohort. Conditional logistic regression was used to calculate odds ratios (OR) of disease, including risk assessments for the MetS factors: obesity (BMI>30 kg m(-2)), hypertension (blood pressure > or =140/90 mmHg or use of anti-hypertensive drugs) and hyperglycaemia (fasting glucose > or =6.1 mmol l(-1) or post-load glucose in capillary plasma > or =8.9 mmol l(-1)). RESULTS: None of the studied variables were significantly associated with risk across quartiles. Presence of obesity, hypertension and hyperglycaemia significantly increased the risk of colorectal cancer; OR for three vs null factors was 2.57 (95% Confidence Interval [CI] 1.20-5.52; P (trend)=0.0021), as compared to a 30 to 70% increased risk for the factors in single. Similarly, top decile levels of C-peptide, HbA1c and leptin/adiponectin ratio were associated with an increased risk; ORs for top vs deciles 1-9 were 1.56 (95% CI 0.93-2.62; P=0.090), 1.83 (95% CI 1.00-3.36; P=0.051) and 1.50 (95% CI 0.83-2.71; P=0.18), respectively. CONCLUSIONS: Our study support the view that components of the MetS increase risk of colorectal cancer, and further suggests that only very high levels of metabolic factors confer an increased risk.

Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases.

BACKGROUND: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. METHODS: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

Plasma insulin-like growth factor-I, insulin-like growth factor-binding proteins, and prostate cancer risk: a prospective study.

BACKGROUND: Recent studies have suggested that men with elevated plasma levels of insulin-like growth factor-I (IGF-I) may have an increased risk of prostate cancer. Furthermore, IGF-binding proteins (IGFBPs) and insulin can modulate the activity of IGF-I. In this study, we sought to determine the role of IGF-I as well as IGFBPs-1, -2, and -3 and insulin as possible etiologic factors for prostate cancer. METHODS: We conducted a nested case-control study within the Northern Sweden Health and Disease Cohort Study. We measured levels of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and insulin in plasma samples from 149 men who had a diagnosis of prostate cancer between 1 month and 10 years after blood collection and among 298 control men. All statistical tests are two-sided. RESULTS: Case subjects had statistically significantly higher mean levels of IGF-I than control subjects (229 ng/mL; 95% confidence interval [CI] = 218-240 ng/mL] versus 214 ng/mL [95% CI = 208-221 ng/mL]; P =.02) and IGFBP-3 (2611 ng/mL [95% CI = 2518-2704 ng/mL] versus 2498 ng/mL [95% CI = 2437-2560 ng/mL]; P =.04). Conditional logistic regression analyses showed increases in prostate cancer risk with rising levels of IGF-I (P:(for trend) =.02) and IGFBP-3 (P(for trend) =.03). In case subjects younger than 59 years at the time of blood collection, the risk associated with increased IGF-I was higher (P:(for trend) =.01), whereas the risk associated with increased IGFBP-3 was lower (P(for trend) =.44) than the corresponding risks in the full cohort. Prostate cancer risk was not associated with levels of IGFBP-1, IGFBP-2, or insulin. CONCLUSIONS: Prostate cancer risk is increased in men with elevated plasma IGF-I. This association was particularly strong in younger men in this study, suggesting that circulating IGF-I may be specifically involved in the early pathogenesis of prostate cancer.

Ratios of IGF-I, IGF binding protein-3, and prostate-specific antigen in prostate cancer detection.

Recent studies have suggested that IGF-I and IGF-binding protein (IGFBP)-3, in combination with prostate-specific antigen (PSA), may enhance prostate cancer detection. In this study, we sought to determine the effect on the prediction of future prostate cancer occurrence by incorporating ratios of total and free PSA, IGF-I, IGFBP-3 into PSA testing. Within a population-based prospective cohort study, we investigated the validity (sensitivity and specificity) of plasma concentrations of total and free PSA, IGF-I, and IGFBP-3 and combinations thereof, in 114 cases and 97 controls, in the range of 1.75-13.5 microg/l for PSA, as used by Khosravi et al. (See Ref. 7 ). Validity estimated by the area under the curve in receiver operator characteristics analysis (with 95% confidence interval) for total PSA was 0.78 (range, 0.71-0.84); total/free PSA, 0.69 (range, 0.62-0.76); total PSA/IGF-I, 0.72 (range, 0.65-0.79); free PSA/IGF-I, 0.55 (range, 0.48-0.63); total PSA/IGFBP-3, 0.74 (range, 0.68-0.81); and free PSA/IGFBP-3, 0.57 (range, 0.49-0.64). Analysis of ratios of IGF-I, IGFBP-3, and free and total PSA did not improve validity of PSA testing in the prediction of future occurrence of prostate cancer. It is unlikely that these combinations will improve prostate cancer detection.

Leptin is associated with increased prostate cancer risk: a nested case-referent study.

A Western lifestyle has been implicated in the pathogenesis of prostate cancer. However, no clear association between obesity and prostate cancer has been shown. Leptin may stimulate prostate growth and angiogenesis, and receptors for leptin are present in the prostate. Leptin may, thus, be associated with increased risk of prostate cancer. One hundred forty-nine men with prostate cancer were identified (together with 298 matched referents) who, before diagnosis, had participated in population-based health surveys in Northern Sweden. Blood pressure, body mass index, and use of tobacco were recorded. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-I-binding proteins 1-3, testosterone, and sex hormone-binding globulin were analyzed in stored samples. Their influences on prostate cancer were estimated by conditional logistic regression analysis. Prostate cancer specimens were investigated for immunoreactivity for the leptin receptor. Relative risk (95% confidence intervals) estimates of prostate cancer over the quintiles of leptin were 1.0, 2.1 (1.1-4.1), 2.6 (1.4-4.8), 1.4 (0.7-2.7), and 1.6 (0.8-3.2). Adjustments for metabolic variables, testosterone, and IGF-I and its binding proteins did not attenuate this increased risk. Immunoreactivity for the leptin receptor was detected in normal, high-grade prostatic intraepithelial neoplasia lesions and malignant prostatic epithelium. Moderately elevated plasma leptin concentrations are associated with later development of prostate cancer. This may be due to direct effects of leptin on prostatic intraepithelial neoplasia lesions, or to indirect actions through other mechanisms. A critical fat mass related to an interior milieu favorable for prostate cancer development seems to exist, because intermediate but not high leptin levels are related to prostate cancer risk.

Pretreatment p53 immunoreactivity does not infer radioresistance in prostate cancer patients.

PURPOSE: To test, in a clinical context, the hypothesis that p53 aberrations, assessed by immunoreactivity, are related to radioresistance as suggested by several experimental studies. METHODS AND MATERIALS: Sixty patients with prostate cancer who underwent transurethral resection of the prostate or biopsy prior to definitive external beam therapy were retrospectively identified. The endpoint in the study was cancer specific survival. The nuclear accumulation of the aberrant p53 protein was evaluated by immunohisto-chemistry with the pantropic, monoclonal Ab-6 anti-p53 antibody (clone DO-1) on pretreatment biopsies. Immunoreactivity was related to stage, grade, and cancer-specific survival. RESULTS: There was a correlation between p53 immunoreactivity and low tumor stage (p < 0.001), but no relation between p53 status and grade was found. Moreover, no significant difference was found in cancer-specific survival between the p53 positive tumors (109 months) and the p53 negative tumors (99 months). CONCLUSIONS: No disadvantage regarding survival was seen for patients with p53 immunoreactive tumors, implicating that p53 immunoreactivity does not infer radioresistance in prostate cancer. This suggests that the p53 inactivation may be a less important determinant of tumor response to radiotherapy in some human cancers than in the previously studied experimental situations. Thus, other mechanisms may be more important in determining outcome after radiation. However, the series is small and data should be interpreted with caution.

Predictive value of bcl-2 immunoreactivity in prostate cancer patients treated with radiotherapy.

BACKGROUND AND PURPOSE: Recent experimental evidence suggests that overexpression of bcl-2, a protein functioning by blocking apoptosis, may influence the treatment outcome in human tumours, including prostate cancer. To test the clinical implications of this hypothesis, tumours from patients with prostate cancer treated with external beam radiotherapy were investigated for bcl-2 immunoreactivity (IR) and correlated with prognosis and treatment outcome. MATERIALS AND METHODS: Bcl-2 IR was evaluated in archival tumour specimens obtained through transurethral resection from 42 patients with localized prostate cancer (T0-T4, N0 and M0). Bcl-2 IR expression was related to stage, grade and cancer-specific survival. Specimens were obtained prior to administrating routine radiotherapy for all patients. RESULTS: Bcl-2 IR was present in 19/42 (45%) tumours. The bcl-2-positive patients had a significantly longer cancer-specific survival than the bcl-2-negative patients (10.3 versus 3.4 years, P<0.04). At follow-up (7-19 years), nine patients were still alive, 26 patients had died of prostate cancer and seven patients had died of other causes. CONCLUSIONS: This study indicates that pre-treatment bcl-2 overexpression is related to a favourable outcome in prostate cancer treated with radiotherapy. Low bcl-2 along with a high stage may be a predictor of poor prognosis and these patients might benefit from additional treatment.