Rolf Lundgren

Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer.

In a recent study by Tomlins et al., (2005), it was shown that a large subset of prostate cancer harbors the fusion genes TMPRSS2/ERG and TMPRSS2/ ETV1, generated through cryptic interand intrachromosomal rearrangements. A gene fusion of the 50 untranslated region of TMPRSS2 to ERG or ETV1 was identified in 23 (79%) of 29 prostate cancer samples. As yet, however, there have not been any confirmatory reports. In the present study, total RNA was extracted from 18 prostate adenocarcinoma biopsies using the Trizol reagent (Invitrogen, Carlsbad, CA) and cDNA synthesis was conducted in a 20 ll reaction mixture which contained 2.5 lg of total RNA, 13 first strand buffer, 10 mM DTT, 1 mM of each dNTP, 20 U RNase inhibitor (RNA guard, Amersham, Biosciences, Piscataway, NJ), 500 pmol random hexamers, and 200 U M-MLV reverse transcriptase (Invitrogen). The reaction was carried out at 378C for 60 min, heated for 10 min at 658C, and then kept at 48C. PCR amplifications were performed using 1 ll cDNA as template in a final volume of 50 ll containing 13 PCR buffer, 0.2 mM of each dNTP, 1.25 mM MgCl2, 0.5 lM of each of the TMPRSS2-1F and ERG-541R primers (Table 1) for the amplification of the TMPRSS2/ERG transcript or TMPRSS2-1F and ETV1-580R for the TMPRSS2/ETV1 transcript, and 1U Platinum Taq DNA polymerase (Invitrogen). One microliter of the first PCR product was then used as template in a second PCR with primers TMPRSS2-20F and ERG-450R (for TMPRSS2/ERG) or TMPRSS220F and ETV1-502R (TMPRSS2/ETV1). The PCR was run on a PCT-200 DNA Engine (MJ Research, Waltham, MA), and both amplifications had an identical cycling profile: an initial denaturation at 948C for 5 min, followed by 30 cycles of 1 min at 948C, 1 min at 608C, and 1 min at 728C, and a final extension for 10 min at 728C. Amplified fragments were run on a 1.5% agarose gel, stained with ethidium bromide, purified using the QIAquick gel extraction kit (Qiagen, Hilden, Germany), and directly sequenced using the dideoxy procedure with an ABI Prism BigDye terminator v1.1 cycle sequencing ready reaction kit (Applied Biosystems, Foster City, CA) on the Applied Biosystems

Familial and hereditary prostate cancer in southern Sweden. A population-based case–control study

The objectives of this study were to investigate the effect of family history on prostate cancer risk, to estimate the incidence of hereditary prostate cancer in southern Sweden and to assess the reliability of self-reported family history of prostate cancer. The study included consecutive prostate cancer patients and age-matched control subjects from a geographically defined population. The controls consisted of 1 male patient with malignant melanoma or non-Hodgkins lymphoma and 1 male from the community per prostate cancer case. Family history was assessed with questionnaires, and diagnoses of fathers and brothers of cases were validated by the Southern Swedish Regional Tumour Registry. Among fathers and brothers whose names and birth dates were available, 56 (92%) of the 61 reported prostate cancer diagnoses were verified. Fifteen per cent of 356 cases and 5.0% of 712 controls reported at least 1 case of prostate cancer among their brothers or fathers, giving a relative risk of 3.2 (95% confidence interval 2.1-5.1). The relative risk increased with decreasing age at diagnosis of the patient. Based on the pedigree, 3.1% of the 356 patients were classified as having hereditary prostate cancer. This proportion was significantly higher among patients diagnosed before the age of 60 years (7.1%) than among older patients (2.2%). We conclude that there is a substantially increased risk of prostate cancer for sons and brothers of prostate cancer patients. The risk increases with decreasing age at diagnosis of the patient as an effect of a higher prevalence of hereditary prostate among early onset cases. Furthermore, we found self-reported family history of prostate cancer to be a valid estimate of the true incidence of prostate cancer in fathers and brothers of men with prostate cancer.

Clinical Course of Early Onset Prostate Cancer with Special Reference to Family History as a Prognostic Factor

Objective: The aim of this study was to describe the clinical characteristics of early onset prostate cancer, with special reference to family history as a possible prognostic factor. Material and Methods: We identified all cases of prostate cancer diagnosed before the age of 51 in the Southern health care region in Sweden between 1958 and 1994. Clinical data were collected retrospectively from medical records. Data about family history of prostate cancer were also collected from the parish authorities and the Regional Cancer Registry. Results: In all, 89 cases were included. The median time of follow-up was 17 years. During the time of follow-up, 65 patients died, 57 of whom died from prostate cancer. At diagnosis, 34% of the patients had localized, 22% had locallly advanced, and 40% had metastatic tumours. The tumours were well differentiated in 30% of the cases, moderately differentiated in 38%, and poorly differentiated in 28%. Information on tumour grade and stage was missing in 3 cases. The cause-specific survival was 48% at 5 years and 29% at 10 years. The 18 patients with a family history of prostate cancer had a somewhat better prognosis than the patients with a negative family history, though the difference did not reach statistical significance (p = 0.08). Conclusions: Early onset prostate cancer is a serious disease with high mortality. The proportions of patients with poorly differentiated and metastatic tumours appeared to be larger than for cases diagnosed later in life, but this could be explained by selection bias since younger men may have a lower probability of having asymptomatic localized tumours diagnosed. Family history of prostate cancer was not significantly associated with prognosis.

Nocturia: A new perspective on an old symptom

The purpose of this review is to make urologists aware of the fact that nocturia among elderly men has a multifactorial aetiology and does not always depends on bladder outlet obstruction. After diagnosis of the underlying cause, specific treatments can be offered to the patient, one of which is transurethral resection of the prostate. Nocturia, defined as waking up at night to void, is a very common and bothersome symptom, affecting >50% of both men and women aged >60 years. Nocturnal polyuria is one reason for nocturia. Recent studies have shown that this condition can now be treated successfully with desmopressin acetate, a synthetic analogue of arginine vasopressin, which for many years has been used in the treatment of enuresis in children.

Non-systematic screening for Prostate Cancer in Sweden: Survey from the National Prostate Cancer Registry

Objective: The large increase in the incidence of prostate cancer is largely due to testing of serum levels of prostate‐specific antigen (PSA). Little is known about how PSA testing is used in clinical practice outside of screening programmes. Essentially, PSA can be used in the health check‐ups of men without symptoms as a form of non‐systematic screening or in the work‐up of symptomatic patients. The aim of this study was to investigate the cause of initiating a work‐up leading to a diagnosis of prostate cancer, with emphasis on T1c tumours. Material and Methods: Data on the cause of initiation of work‐up leading to a diagnosis of prostate cancer were retrieved from the National Prostate Cancer Registry for 6361 incident cases in tumour category T1c and local stages T2, T3 and T4 registered in Sweden in 2000. Results: For 1496 cases in tumour category T1c (non‐palpable tumours detected during work‐up of elevated PSA), the cause of PSA testing was health check‐ups in 32% of cases, work‐up of symptoms suspected to emanate from the prostate in 51% and other causes/not reported in 17%. For all stages combined, the cause of initiation of the diagnostic work‐up was health check‐ups in 18% of cases, symptoms in 68% and other causes/not reported in 14%. Conclusion: Non‐systematic screening using PSA testing has been introduced in Sweden. However, prostate cancer is still most commonly diagnosed during the work‐up of symptomatic patients.

Cardiovascular complications of estrogen therapy for nondisseminated prostatic carcinoma. A preliminary report from a randomized multicenter study.

In a prospective multicenter study, 244 men with highly or moderately differentiated prostatic cancer in stage I, II or III (VACURG) were consecutively randomized to three groups of treatment: Group A (77 patients) received polyestradiol phosphate (Estradurin, Leo) 80 mg i.m. every fourth week + ethinyl estradiol (Etivex, Leo) 150 micrograms daily, group B (72 patients) estramustine phosphate (Estracyt, Leo) 280 mg twice daily, and group C (76 patients) no therapy. Only men without current or previous other malignancy and without cardiovascular disease were admitted to the study. After 4 1/2 years 125 of the 244 patients had left the study, 9 because of cancer progression (stage IV, VACURG). The most serious complications were cardiovascular, including ischemic heart disease, cardiac decompensation, cerebral ischemia and venous thromboembolism, which occurred in 24 patients from group A and 9 from group B as compared to only one patient in group C. The subgroup superficial or deep venous thrombosis comprised 11 group A and 2 group B patients. Estrogens (E + e) offered as palliative treatment to patients with non-generalized prostatic carcinoma is burdened with a high incidence of serious cardiovascular complications.

Geographical variation in incidence of prostate cancer in Sweden.

Objective. To investigate the geographical variation in prostate cancer incidence in Sweden, in particular the incidences of screening-detected tumours and curative treatment of prostate cancer. Material and methods. Data were retrieved from the National Prostate Cancer Register of Sweden for all cases of prostate cancer diagnosed in the year 2000–01. There were a total of 14 376 cases of prostate cancer and the mean total annual age-adjusted incidence was 197/100 000 men. There were 3318 cases in tumour category T1c, i.e. non-palpable tumours diagnosed during work-up for an elevated serum level of prostate-specific antigen, 1006 of which (30%) were asymptomatic and detected at a health check-up. Results. The difference between the counties with the lowest and highest age-adjusted incidences per 100 000 men of total prostate cancer was almost twofold (128 vs 217). The corresponding variation in incidence of category T1c tumours was more than fourfold (13 vs 60); the difference in incidence of T1c tumours detected in asymptomatic men was up to 10-fold (2 vs 20); and there was more than a fourfold variation in incidence of curative treatment between counties (13 vs 67). Measured incidences were mostly highest in urban regions and in counties with university hospitals. Conclusion. There are large geographical variations in prostate cancer incidence and in the frequency of curative treatment for prostate cancer in Sweden and there appear to be large geographical variations in the uptake of prostate cancer screening.

Metaphase cytogenetics and DNA flow cytometry with analysis of S-phase fraction in prostate cancer: influence on prognosis

OBJECTIVES To compare the prognostic significance of chromosome aberrations, DNA ploidy, and S-phase fraction (SPF) in prostate adenocarcinomas and to compare the sensitivity of metaphase cytogenetics with flow cytometry (FCM) in detecting abnormal tumor clones. METHODS Prostate adenocarcinomas from 57 men were previously successfully analyzed with metaphase cytogenetics. Archival material from these tumors were further analyzed with FCM for DNA content and SPF. RESULTS The patients were followed for 4.5 to 7.7 years. DNA ploidy was analyzed in 51, and SPF in 45 of the 57 tumors. Clonal chromosomal aberrations, DNA aneuploidy, and high SPF were all significantly associated with poor survival. Of these three variables, SPF was the best predictor of survival, but compared with tumor stage and grade in multivariate analysis, SPF was not an independent prognostic factor. Patients with locally advanced tumors or metastatic disease with SPF less than 8% had a median survival of 5.9 years, compared with only 1.3 years for those with SPF more than 8%. Twenty-eight abnormal clones were detected with FCM and 20 with cytogenetic analysis, but only for two of these clones could the results from the two different methods be regarded as concordant. CONCLUSIONS SPF was superior to karyotype and ploidy in predicting death in prostate cancer, but it remains to be shown whether SPF analysis adds prognostic information to tumor stage and grade. The cytogenetic analyses correlated poorly with results of FCM, indicating low sensitivity of both methods.

Morbidity of Pelvic Lymphadenectomy, Radical Retropubic Prostatectomy and External Radiotherapy in Patients with Localised Prostatic Cancer

Staging pelvic lymphadenectomy (PLND) was performed in 210 prostatic cancer patients (mean age 67 years, clinical stage T0-T3 M0). A radical retropubic prostatectomy was subsequently performed in 54 men, ten of whom also received postoperative radiotherapy due to positive surgical margins. Ninety-eight patients were treated with external beam radiation alone (70 Gy in 35 fractions) and the remaining 58 received endocrine therapy. The complications of PLND alone (156 patients), consisted of wound infection in eight patients, hematoma or lymphocele in seven, venous thrombosis in three, and cardiac infarction in one patient. Early side-effects of radiotherapy included mild to moderate proctitis and/or cystitis in 57 patients. One year after completion of therapy, 48 of the irradiated men had proctitis, but only six had severe symptoms. Four patients developed radiation cystitis and two urethral stricture. Following prostatectomy (54 patients), two patients died in pulmonary embolism and another one developed a deep venous thrombosis. Hematoma occurred in five patients. Of the 42 surviving patients who did not receive postoperative radiotherapy, eight developed anastomotic strictures and four had severe stress incontinence. Only five were fully potent one year after surgery. Eight of the ten patients receiving radiotherapy after prostatectomy developed side-effects from the intestine and/or the urinary bladder. Two of them became totally incontinent. One developed a severe hemorrhagic cystitis necessitating urinary diversion. All ten were impotent after treatment.

Prostate-Specific Antigen for Prostate Cancer Staging in a Population-based Register

Objective: Previous studies have shown a relationship between serum prostate-specific antigen (PSA) level and prostate tumour volume. Reports based on selected case series have also indicated that serum PSA may be used for staging, although a varying prevalence of metastasizing tumours complicates the interpretation of these studies. In order to determine the accuracy of the serum level of PSA in predicting the presence of metastases we performed a prospective cohort study of a geographically defined population of men with prostate cancer. Methods: Serum level of PSA and the results of investigations for regional lymph node and distant metastases were recorded for all 8328 men with prostate cancer registered in the Swedish National Prostate Cancer Register 1996-1997. Results: The prevalence of lymph node metastases among men who had undergone lymph node exploration was 4%, 16% and 33% for well, moderately and poorly differentiated tumours. The corresponding prevalence of distant metastases was 12%, 30% and 48%. With serum PSA <20 ng/ml as a cut-off point the negative likelihood ratios for well and moderately differentiated tumours were found to be 0.47 and 0.45 for lymph node metastases and 0.24 and 0.18 for distant metastases, resulting in post-test probabilities >92% for the exclusion of metastases. In men with poorly differentiated tumours, the negative likelihood ratio would need to be even lower to safely exclude disseminated disease. Conclusion: For well to moderately differentiated tumours, further investigations to assess the presence of metastases may be omitted with no great risk for understaging if serum PSA <20 ng/ml.