Association between PSA kinetics and cancer-specific mortality in patients with localised prostate cancer: analysis of the placebo arm of the SPCG-6 study.

BACKGROUND: The prognostic value of prostate-specific antigen (PSA) kinetics in untreated prostate cancer (PCa) patients is debatable. We investigated the association between PSA doubling time (PSAdt), PSA velocity (PSAvel) and PSAvel risk count (PSAvRC) and PCa mortality in a cohort of patients with localised PCa managed on watchful waiting. PATIENTS AND METHODS: Patients with clinically localised PCa managed observationally, who were randomised to and remained on placebo for minimum 18 months in the SPCG-6 study, were included. All patients survived at least 2 years and had a minimum of three PSA determinations available. The prognostic value of PSA kinetics was analysed and patients were stratified according to their PSA at consent: ≤10, 10.1-25, and >25 ng/ml. Cumulative incidences of PCa-specific mortality were estimated with the Aalen-Johansen method. RESULTS: Two hundred and sixty-three patients were included of which 116, 76 and 71 had a PSA at consent ≤10, 10.1-25, and >25 ng/ml, respectively. Median follow-up was 13.6 years. For patients with PSA at consent between 10.1 and 25 ng/ml, the 13-year risks of PCa mortality were associated with PSA kinetics: PSAdt ≤3 years: 62.0% versus PSAdt >3 years: 16.3% (Gray's test: P < 0.0001), PSAvel ≥2 ng/ml/year: 48.0% versus PSAvel <2 ng/ml/year: 11.0% (Gray's test: P = 0.0008), and PSAvRC 2: 45.0% versus 0-1: 3.8% (Gray's test: P = 0.001). In contrast, none of the PSA kinetics were significantly associated with changes of 13-year risks of PCa mortality in patients with PSA at consent ≤10 or >25 ng/ml. CONCLUSION: We found that magnitude changes in 13-year risks of PCa mortality that can be indicated by PSA kinetics depend on PSA level in patients with localised PCa who were managed observationally. Our results question PSA kinetics as surrogate marker for PCa mortality in patients with low and high PSA values. CLINICAL TRIAL NUMBER: NCT00672282.

RNA quality in fresh frozen prostate tissue from patients operated with radical prostatectomy.

BACKGROUND: High-throughput technologies such as microarray have enhanced the discovery of new biomarkers in prostate cancer. However, the reliability of transcriptome analyses is limited by the RNA quality. OBJECTIVE: Identification of variables influencing the RNA quality in radical prostatectomy specimens. MATERIAL AND METHODS: RNA was extracted using an automatic extraction method for 354 samples from 38 fresh frozen prostate slices, and by manual extraction for 28 samples from 5 slices. RNA quality was measured using the RIN method (RNA Integrity Number). Evaluation of tissue composition was performed by light-microscopy for each sample. Age, total operative time, estimated blood loss, prostate volume, prostate specific antigen (s-PSA) and postoperative Gleason score were registered. The independent variables were correlated to the RIN score in a multiple linear regression model, taking p < 0.05 as the significance limit. RESULTS: The amount of blood loss during prostatectomy and the amount of stroma in the tissue sample both correlated negatively with the RIN score (p = 0.03 and 0.02). Automatically extracted samples which were exposed to heat according to the RNA extraction protocol, had lower mean RNA quality (5.5, 1.46 SD) than manually extracted samples, not exposed to heat (8.7, 0.86 SD), suggesting degradation by temperature sensitive RNases, mainly residing in the stroma. CONCLUSION: The highest RNA quality isolated by an automatic method from fresh frozen prostate tissue is obtained from patients with low peroperative blood loss and from samples with a low stromal fraction.

Regional trends in prostate cancer incidence, treatment with curative intent and mortality in Norway 1980-2007.

OBJECTIVES: To compare the trends in prostate cancer incidence, treatment with curative intent and mortality across regions and counties in Norway, and to consider changes in incidence (an indicator for early diagnosis) and treatment with curative intent as explanatory factors for the decreasing prostate cancer mortality rates. PATIENTS AND METHODS: Prostate cancer incidence and mortality data (1980-2007) alongside treatment data (1987-2005) were obtained from the national, population-based Cancer Registry of Norway. Joinpoint regression models were fitted to age-adjusted incidence, treatment and mortality rates to identify linear changes in the trends. RESULTS: Both age-adjusted incidence rates and rates of curative treatment of prostate cancer increased significantly in all five regions of Norway since the early 1990s. There was a strong positive correlation between increasing incidence and increasing use of curative treatment. The frequency of curative treatment in Western Norway was almost threefold that in the Northern and Central regions around year 2000. Subsequently, the regional trends converged and only minor differences in prostate cancer incidence and use of curative treatment were observed by 2005. The declines in mortality were observed earliest in the regions with the highest incidence and the most frequent use of curative treatment, while the largest decreases in mortality were found in counties where the largest increases in curative treatment were observed. CONCLUSIONS: The elucidation of the prostate cancer mortality trends is hindered by an inability to tease out the potential effects of early treatment from the more general impact of improved and more active treatment. However, it is likely that both sets of intervention have contributed to the decline in prostate cancer mortality in Norway since 1996.

Rethinking the causes of deforestation: lessons from economic models.

PIP: Concern is rising over the deleterious effects of tropical deforestation. For example, the loss of forest cover influences the climate and reduces biodiversity, while reduced timber supplies, siltation, flooding, and soil degradation affect economic activity and threaten the livelihoods and cultural integrity of forest-dependent people. Such concerns have led economists to expand their efforts to model why, where, and to what extent forests are being converted to other land uses. This synthesis of the results of more than 140 economic models analyzing the causes of tropical deforestation brings into question many conventional hypotheses upon deforestation. More roads, higher agricultural prices, lower wages, and a shortage of off-farm employment generally lead to more deforestation. However, it is not known how technical change, agricultural input prices, household income levels, and tenure security affect deforestation. The role of macroeconomic factors such as population growth, poverty reduction, national income, economic growth, and foreign debt is also unclear. The authors nonetheless determine through their review that policy reforms included in current economic liberalization and adjustment efforts may increase pressure upon forests.^ieng

[Percutaneous pyeloplasty of ureteropelvic junction stenoses]. / Perkutan spalting av overgangstenoser i nyrebekken.

From March 1990 to November 1993, percutaneous endopyelotomy was performed in 22 patients for treatment of symptomatic ureteropelvic obstruction. One patient was treated bilaterally. In three patients renal pelvic stones were removed during the same procedure. Clinical findings, intravenous pyelography and isotope renography were considered in preoperative and postoperative evaluation. Overall, 18 of 23 procedures (79%) were successful. The success rate was lowest in patients with enlarged renal pelvis. Failed procedures became evident less than six months after operation.

[Prostate-specific antigen]. / Prostataspesifikt antigen.

BACKGROUND: Serum PSA has been commercially available for more than ten years, and has proved to be the most important tumour marker for prostate cancer. We review the clinical usefulness and limitations of serum PSA as a tumour marker of prostate cancer. MATERIAL AND METHODS: The international literature and medical databases were searched for studies on the contributions and limitations of PSA in clinical practice. RESULTS: Serum PSA > or = 4.0 ng/ml is commonly regarded as elevated, and give rise suspicion of prostate cancer. However, only one out of four men with serum PSA level between 4.0 ng/ml and 10.0 ng/ml has prostate cancer. The most common cause of elevated serum PSA value in this group is benign prostatic hyperplasia. In an attempt to increase the sensitivity as well as the specificity for serum PSA in the detection of prostate cancer, the serum PSA level has been combined with age of patients (age-specific serum PSA), time (PSA velocity), prostate volume (PSA density), different molecular PSA forms, like per cent of free PSA. Some of these new methods have shown promising results. INTERPRETATION: PSA is the best and most widely used tumour marker in urology. However, it is important that clinicians know the limitations of this marker.

Hypertension and pseudoaneurism on the renal artery following retrograde endopyelotomy (Acucise).

Acucise endopyelotomy has gained widespread use in the treatment of ureteropelvic junction obstruction. Acute postoperative bleeding is a well-known complication. We report one case with a delayed postoperative formation of pseudoaneurism, and one case which developed arterial hypertension postoperatively.

[Collaborated admission to a surgical department]. / Samordnet pasientmottak i en kirurgisk avdeling.

BACKGROUND: The medical case record is an important tool for securing high quality in treatment and care of patients. Efficient and accurate documentation of diagnostic and therapeutic procedures, patient information etc. is crucial. MATERIAL AND METHODS: We have prospectively studied how time and patient satisfaction are influenced when nurse and doctor together ("combined model") take the patient's medical history, perform a clinical examination, and inform the patient, compared to separate history-taking by nurse and doctor ("separate model"). RESULTS: The mean nurse time per patient increased from 17 min in the separate model to 21 min in the combined model (p = 0.01). Corresponding time use by the doctor was 26 min and 21 min (p = 0.04), and for the patient 43 min and 23 min (p < 0.001). Patients reported the two models to be comparable in quality. INTERPRETATION: The "combined registration model" secures high quality of the medical case record, respects the patient's time, and signals professional collaboration to the patient.

[Urinary problems and prostate-specific antigen in a Norwegian normal population]. / Vannlatingsplager og prostataspesifikt antigen i en norsk normalpopulasjon.

BACKGROUND: Measurements of PSA in serum is crucial in the diagnostic work-up of prostatic diseases. MATERIAL AND METHODS: We have studied the distribution of PSA values in an unselected population of 609 men, and the relation between PSA level and urinary symptoms, age and prostate volume. RESULTS: 87 (14%) men had a PSA concentration at or above the reference value of 4.0 ng/ml. Prostate cancer was verified in 14 (16%) of these men. The probability of having PSA equal to or above 4.0 ng/ml was 12 times greater for men with a prostate volume of 40 cm3 or less than for men with a prostate volume less than 20 cm3. Mean PSA values were higher in men with severe than with mild urinary symptoms, but symptoms were poor predictors of PSA levels. Age was not associated with an increase in PSA level independent of prostate volume. INTERPRETATION: Absence of urinary symptoms does not exclude elevated PSA values and thus not cancer. Most men with PSA equal to or above 10.0 ng/ml will have prostate cancer, but enlarged prostate without cancer can also give elevated PSA values.

NGF-beta, NE-cells and prostatic cancer cell lines. A study of neuroendocrine expression in the human prostatic cancer cell lines DU-145, PC-3, LNCaP, and TSU-pr1 following stimulation of the nerve growth factor-beta.

Neuroendocrine (NE) cells are present in both benign and malignant human prostate. However, their function is poorly understood, mainly due to the lack of suitable experimental models. The nerve growth factor-beta (NGF-beta) promotes the rat pheochromocytoma cell line PC-12 to differentiate into neuronal like cells. We have studied the effect of NGF-beta on four human prostate cancer cell lines, LNCaP, DU-145, PC-3, and TSU-pr1. NGF-beta stimulates the growth rate in all these cell lines, but does not induce a neuronal phenotype. NE tumour markers (chromogranin A [CgA] and chromogranin B[CgB]) could not be demonstrated by immunocytochemistry (CgA and CgB), Northern blotting (CgA), or ELISA techniques (CgA), neither in control nor in NGF-beta stimulated cells. Consequently, other experimental models have to be sought in the study of NE cells in the human prostate.

Pre- and postnatal testosterone administration induces proliferative epithelial lesions with neuroendocrine differentiation in the dorsal lobe of the rat prostate.

BACKGROUND: Androgens are implicated in the pathogenesis of prostatic carcinoma. We have elucidated the role of pre- and postnatal testosterone administration in the occurrence of proliferative lesions as well as neuroendocrine (NE) cells in the rat prostatic complex. METHODS: Female rats were given a single dose of 9 mg testosterone enantate i.m. on day 15 of pregnancy; it gave a high testosterone exposure to the fetus in the early organogenetic period of the rat prostatic complex. One group of the male offspring was followed without further testosterone treatment; a second group received testosterone only in the pubertal period; a third group was given testosterone from puberty and throughout life (46 weeks). These groups were compared to parallel groups (1A-1C) of male offspring without a testosterone supplement in pregnancy. RESULTS: The serum testosterone concentrations in the rats receiving testosterone were significantly higher than those of control rats. Histopathologically, the testosterone-induced proliferative lesions, mainly hyperplastic, were almost exclusively located in the dorsal lobe. Chromogranin A-immunoreactive (CgA-IR) cells were rarely found normally, but occurred more often in the proliferative lesions (P < 0.001). CONCLUSIONS: The incidence of proliferative lesions in rats exposed to testosterone only in puberty was comparable to the incidence found in those rats receiving testosterone in puberty and throughout life. This finding may have clinical implications for young athletes, who use testosterone as an anabolic drug. The occurrence of CgA-IR cells increased in proliferative lesions in the dorsal lobe of the rat prostatic complex.

Neuroendocrine cells in the prostate of the rat, guinea pig, cat, and dog.

BACKGROUND: The neuroendocrine (NE) cells in the human prostate gland probably have a local regulatory role in both prostatic growth and differentiation as well as in the exocrine secretory process. Moreover, NE cells may be involved in the pathogenesis of both prostatic cancer and hyperplasia. To enhance the knowledge of the physiological and pathophysiological role of NE cells in the prostate gland, we wanted to establish an experimental animal model. METHODS: All lobes of the prostatic complex of rats with different serum levels of testosterone, as well as the prostate of the guinea pig, cat, and dog, were studied. Prostatic tissue fixed in different fixatives was studied with regard to NE cells by using cytochemical and immunohistochemical staining techniques, as well as Northern blotting and reverse transcriptase polymerase chain reaction (RT-PCR) for detection of rat chromogranin A (CgA) mRNA. RESULTS: The present study indicates the absence of NE cells in the rat prostatic complex. No expression of CgA RNA was detectable either by Northern blotting or by RT-PCR. Only a few argyrophil cells in the prostatic complex of guinea pig were detected in tissue fixed in Bouin's solution. CONCLUSIONS: Rat, guinea pig, cat, and dog are not suitable animals in physiological studies of NE cells in the prostate gland.

Lower urinary tract symptoms, prostate volume and uroflow in norwegian community men.

OBJECTIVE: To describe lower urinary tract symptoms, prostate volume and peak urinary flow rate, and investigate the relationships among urological variables in a community sample of Norwegian men. MATERIALS AND METHODS: A cross-sectional study of 611 men, aged 55-70 years, who underwent a clinical urological examination including uroflowmetry, residual urine measurement, and transrectal ultrasonography of the prostate. All the men completed a questionnaire which included the International Prostate Symptom Score (IPSS). RESULTS: Severe symptoms were reported by 5%, while 23.6% reported moderate symptoms, and the overall median IPSS was 4 (q1 = 25th percentile, 1; q3 = 75th percentile, 9). The median peak flow rate was 15 ml/s (q1 = 11; q2 = 22) while median prostate volume was 30 cm(3) (q1 = 23; q3 = 38), with little variation evident across the narrow age range of 55-70 years. A positive modest correlation (r = 0.176) was found between IPSS and prostate volume, and a negative correlation between IPSS and peak flow rate (r = -0.278). There was a modest correlation between body mass index (BMI) and prostate size, but no significant correlation between BMI and IPSS. CONCLUSION: In this population-based study, moderate lower urinary tract symptoms were reported by 24% and severe symptoms by 5% of community men. The distribution of lower urinary tract symptoms, prostate volume and peak urinary flow rate in Norwegian men is comparable to that described in similar studies conducted in Spain, Holland and USA.

Neuroendocrine differentiation in carcinomas of the prostate: do neuroendocrine serum markers reflect immunohistochemical findings?

The aim of the present study was to examine the correlation between the immunohistochemical findings and the serum markers for neuroendocrine (NE) cells in patients with carcinoma of the prostate. Preoperative serum values of chromogranin A (CgA), chromogranin B (CgB), pancreastatin (Pst), neuron-specific enolase (NSE), and prostatic specific antigen (PSA) were determined in 22 patients. The tissue specimens were obtained by a palliative transurethral resection of the prostate (TURP) because of urinary outflow obstruction. Immunohistochemistry was performed by using antibodies against CgA, CgB, NSE,.serotonin, thyroid-stimulating hormone (TSH), and somatostatin. Tumor cells with NE differentiation were found in 91% of the cases. No patient had elevated serum values of NSE, despite the presence of NSE-positive tumor cells in 77% of the tumors. Neither did CgB in serum correlate with the immunohistochemical findings. Elevated serum values of CgA were found in 59% of patients. A positive correlation between the number of CgA-staining cells and the serum values of CgA was found, as seven out of eight patients with groups of CgA-positive tumor cells had elevated serum values of CgA. We conclude that CgA, in contrast to NSE, CgB, and Pst, seems to be a useful serum marker in predicting the extent of NE differentiation in prostatic tumors.

Use of neuroendocrine serum markers in the follow-up of patients with cancer of the prostate.

Neuroendocrine (NE) differentiation of prostatic adenocarcinomas has received increasing attention in recent years as a result of possible implications on prognosis and therapy. The incidence of NE cells in tumors has been reported from 10% up to 100%. Several studies have shown chromogranin A (CgA) to be the most reliable serum marker of NE differentiation. We have followed 22 patients with prostatic adenocarcinoma over a 2-year period. The patients underwent a palliative transurethral resection of the prostate (TURP) because of urinary outflow obstruction. The prostatic tissue specimens were stained immunohistochemically using antibodies against CgA, chromogranin B (CgB), neuron-specific enolase (NSE), thyroid-stimulating hormone (TSH), serotonin, and somatostatin. In addition, each specimen was stained with hematoxylin & eosin (H & E), and saffran for tumor grading. Blood samples were taken preoperatively and after 1, 3, 6, and 24 months. The serum values of CgA, CgB, pancreastatin (Pst), NSE, and prostate-specific antigen (PSA) were determined from each sample. Carcinomas with groups of CgA-positive cells had higher serum levels of CgA compared to carcinomas with no or only scattered CgA-positive NE cells. During the 2-year period, there were no statistical significant variations in serum levels of CgA, NSE, Pst, and PSA. However, there was a significant increase in serum levels of CgB during the same period, P = 0.002, possibly due to an increase in number of NE cells in tumor or to a relative increase in production of CgB in the NE cells.