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.

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.

¹8F-fluorocholine PET/CT compared with extended pelvic lymph node dissection in high-risk prostate cancer.

PURPOSE: To compare (18)F-fluorocholine positron-emission tomography/computed tomography (PET/CT) with extended pelvic lymph node dissection (ePLND) for the detection of lymph node metastases in a large cohort of patients with high-risk prostate cancer. MATERIALS AND METHODS: Patients with prostate-specific antigen levels between 20 and 99 ng/mL and/or Gleason score 8-10 cancers, planned for treatment with curative intent following a negative or inconclusive standard bone scan, were investigated with (18)F-fluorocholine PET/CT followed by an ePLND. None of the patients received hormonal therapy prior to these staging procedures. Results for PET/CT were compared on a per-patient basis with histopathology from ePLND. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: PET/CT detected a total of 76 suspected lymph node metastases and four suspected bone metastases in 33 (29 %) of the 112 included patients. Of these, 35 suspected lymph node metastases, only within the anatomical template area of an ePLND, were found in 21 of the patients. Histopathology of the ePLND specimens detected 117 lymph node metastases in 48 (43 %) of the 112 patients. Per-patient sensitivity, specificity, positive and negative predictive values for (18)F-fluorocholine PET/CT for lymph node metastases within the ePLND template were 0.33, 0.92, 0.76 and 0.65, respectively. Only 11 patients had lymph nodes larger than 10 mm that would have been reported by CT alone. CONCLUSIONS: (18)F-fluorocholine PET/CT detects lymph node metastases in a significant proportion of patients with high-risk prostate cancer with a high specificity, but low sensitivity.

Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer.

BACKGROUND: Tasquinimod is a quinoline-3-carboxamide derivative with anti-angiogenic activity. Two open-label phase I clinical trials in patients were conducted to evaluate the safety and tolerability of tasquinimod, with additional pharmacokinetic and efficacy assessments. METHODS: Patients with castration-resistant prostate cancer with no previous chemotherapy were enrolled in this study. The patients received tasquinimod up to 1 year either at fixed doses of 0.5 or 1.0 mg per day or at an initial dose of 0.25 mg per day that escalated to 1.0 mg per day. RESULTS: A total of 32 patients were enrolled; 21 patients were maintained for >or=4 months. The maximum tolerated dose was determined to be 0.5 mg per day; but when using stepwise intra-patient dose escalation, a dose of 1.0 mg per day was well tolerated. The dose-limiting toxicity was sinus tachycardia and asymptomatic elevation in amylase. Common treatment-emergent adverse events included transient laboratory abnormalities, anaemia, nausea, fatigue, myalgia and pain. A serum prostate-specific antigen (PSA) decline of >or=50% was noted in two patients. The median time to PSA progression (>25%) was 19 weeks. Only 3 out of 15 patients (median time on study: 34 weeks) developed new bone lesions. CONCLUSION: Long-term continuous oral administration of tasquinimod seems to be safe, and the overall efficacy results indicate that tasquinimod might delay disease progression.

CHEK2*1100delC is not an important high-risk gene in families with hereditary prostate cancer in southern Sweden.

OBJECTIVE: CHEK2*1100delC is a frame-shifting germ-line mutation which abolishes the function of cell-cycle-checkpoint kinase 2 (chk2) and hence impairs the cells' response to DNA damage. This variant occurs in 1% of the general Western population but has been reported to be more common among patients with breast and prostate cancer. The aim of this study was to investigate the significance of CHEK2*1100delC as a possible high-risk gene for hereditary prostate cancer in the population of southern Sweden. MATERIAL AND METHODS: We screened for the CHEK2*1100delC variant in 419 men diagnosed with prostate cancer in southern Sweden, 145 of whom were sporadic cases that were divided into two subgroups depending on whether they were diagnosed before (n=64) or after (n=81) the age of 55 years. A further 126 men were classified as familial prostate cancer cases and 148 as hereditary prostate cancer cases. The control group consisted of 305 military conscripts aged 18 years (range 18-21 years). RESULTS: The CHEK2*1100delC variant was found in 1.2% of the cases (sporadic: 0.7%; familial: 1.6%; hereditary: 1.4%) and in 1.0% of the controls. CONCLUSION: The CHEK2 1100delC mutation is not a clinically important high-risk gene for hereditary prostate cancer susceptibility in the population of southern Sweden.

Acupuncture fails to reduce but increases anaesthetic gas required to prevent movement in response to surgical incision.

BACKGROUND: Acupuncture is used for clinical pain relief but has not been evaluated under clinical anaesthesia. This study was designed to compare movement in response to surgical incision in anaesthetized patients subjected to electro-acupuncture (EA) or sham procedures. Our hypothesis was that EA stimulation would reduce the requirements for anaesthetic gas. METHODS: Forty-six healthy women, scheduled for laparoscopic sterilization at a Swedish county hospital, were randomized to have either the electro-acupuncture (n = 23) or sham (n = 23) procedure between the induction of general anaesthesia and the start of surgery. The minimal alveolar concentration (MAC) of sevoflurane required to prevent neck or major limb movements in response to surgical incision was determined in each group of patients. RESULTS: The MAC for sevoflurane was found to be higher in the group given acupuncture than in the control group (2.1 +/- 0.3% vs. 1.8 +/- 0.4%; P = 0.008). CONCLUSION: Electro-acupuncture given during general anaesthesia with sevoflurane failed to reduce but instead increased the clinical need for anaesthetic gas, possibly by reducing the anaesthetic effect of sevoflurane and/or by facilitating nociceptive transmission and/or reflex activity.

Hereditary prostate cancer: clinical characteristics and survival.

PURPOSE: Hereditary prostate cancer accounts for 5% to 10% of all prostate cancer cases. We assessed clinical characteristics and survival in patients with hereditary prostate cancer MATERIALS AND METHODS: The study comprised 201 patients from 62 Swedish hereditary prostate cancer families and 402 controls with prostate cancer who were matched for age and calendar year at diagnosis, and the hospital where the diagnosis was made. Clinical data were obtained from the National Cancer Registry, Causes of Death Registry and medical records. RESULTS: Median age at the diagnosis of hereditary prostate cancer was 68 years, which was 6 years less than in patients with prostate cancer in the general population in Sweden. Distributions of tumor grade, symptoms at diagnosis and initial therapy were similar in hereditary prostate cancer cases and controls. More controls were classified with localized disease but it may have been due to methodological problems. Overall and cancer specific survival was similar in patients with hereditary prostate cancer and controls as well as in subgroup analyses including those with early onset and those diagnosed before 1990. Prostate cancer was the cause of death in 75% of patients with hereditary prostate cancer, in contrast to 55% with prostate cancer in the Swedish population. This difference was completely explained by the earlier age at the diagnosis of hereditary prostate cancer. CONCLUSIONS: Hereditary prostate cancer has an earlier onset than sporadic prostate cancer but this study did not indicate any other important difference in clinical characteristics or survival in patients with hereditary prostate cancer and those with sporadic prostate cancer. However, it cannot be excluded that individual hereditary prostate cancer genes may have specific biological characteristics.

Amplification of EIF3S3 gene is associated with advanced stage in prostate cancer.

Gain of the long arm of chromosome 8 (8q) is one of the most common gains found in the advanced prostate cancer by comparative genomic hybridization. We have previously identified a putative target gene for the 8q gain, EIF3S3, that encodes a p40 subunit of eukaryotic translation initiation factor 3 (eIF3). Here, we studied the frequency of the EIF3S3 amplification in different stages of prostate cancer and co-amplification of EIF3S3 and oncogene MYC. In addition, prognostic utility of the EIF3S3 copy number alteration was evaluated. The analyses were done with fluorescence in situ hybridization and tissue microarray technology. High-level amplification of EIF3S3 was found in 11 of 125 (9%) of pT1/pT2 tumors, 12 of 44 (27%) of pT3/pT4 tumors, and 8 of 37 (22%) of lymph node metastases as well as in 26 of 78 (33%) and 15 of 30 (50%) of hormone refractory locally recurrent tumors and metastases, respectively. The amplification was associated with high Gleason score (P < 0.001). One of the 79 tumors with EIF3S3 amplification had only two copies of MYC, whereas all tumors with amplification of MYC had also amplification of EIF3S3 indicating common co-amplification of the genes. Gain of EIF3S3 was associated with poor cancer-specific survival in incidentally found prostate carcinomas (P = 0.023). In the analyses of prostatectomy-treated patients, the amplification was not statistically significantly associated with progression-free time. In conclusion, amplification of EIF3S3 gene is common in late-stage prostate cancer suggesting that it may be functionally involved in the progression of the disease.

Amplification of hypoxia-inducible factor 1alpha gene in prostate cancer.

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates the expression of genes associated with adaptation to reduced oxygen pressure. Increased expression of HIF-1alpha gene (HIF1A) has been found in the majority of prostate carcinomas. In addition, the PC-3 prostate cancer cell line has been shown to express the gene even under normoxic conditions. By comparative genomic hybridization (CGH), we have earlier shown that the PC-3 cell line contains a high-level amplification in the chromosomal region harboring the HIF1A gene. Here, we first fine mapped the gene to locus 14q23 by fluorescence in situ hybridization (FISH). The gene was then shown to be highly amplified in the PC-3 cell line. Subsequently, the copy number of the HIF1A gene was studied in 5 other prostate cancer cell lines (LNCaP, DU-145, NCI-H660, Tsu-Pr, JCA-1) and in 117 prostate tumors representing both hormone-dependent and -refractory disease as well as primary and metastatic lesions. No high-level amplifications of the HIF1A gene were found. Additional copies of the gene were seen in all of the cell lines and in 36% of the tumors. There was no association between the tumor type and the copy number alterations of the gene. In conclusion, high-level amplification of the HIF1A gene may explain the overexpression of the gene in the PC-3 prostate cancer cell line. However, such high-level amplification seems to be very rare in prostate cancer.

Aspectos clínicos del cáncer de próstata hereditario / Clinical aspects: hereditary prostate cancer

La historia familiar es el mayor factor de riesgo en el cáncer de próstata. Una pequeña proporción, el 5 a 10 por ciento de los casos de cáncer de próstata, está causado por mutaciones en genes de susceptibilidad con alta penetrancia heredados dominantemente. Con mayor probabilidad, una proporción mucho más grande está causada por variantes genéticas comparativamente más comunes que incrementan moderadamente el riesgo de cáncer de próstata. Este artículo de revisión bosqueja el trasfondo científico del cáncer de próstata hereditario y sus implicaciones clínicas. Los conceptos clave son: • La herencia aumenta el valor predictivo positivo del PSA. Se debería investigar la historia familiar en hombres con PSA entre 3 y 10 ng/mL.• El riesgo vital de cáncer de próstata en los hombres escandinavos varía cinco veces dependiendo del número y la edad de los parientes afectados (8-40 por ciento).• Debido a un comienzo más temprano, muere por la enfermedad una mayor proporción de hombres con cáncer de próstata hereditario ('75 por ciento) que de hombres con cáncer esporádico (=50 por ciento).• Todos los urólogos deberían ser capaces de ofrecer consejo genético basa¡ a los hombres preocupados por una posible predisposición hereditaria al cáncer de próstata.• Se debería recomendar a los hombres con parientes cercanos con cáncer de próstata la realización de PSA anual y tacto rectal (AU)

Risk perception, screening practice and interest in genetic testing among unaffected men in families with hereditary prostate cancer.

Approximately 5-10% of prostate cancer cases are caused by dominantly inherited susceptibility to the disease. Although advances have been made in research concerning the genetic mechanisms of hereditary prostate cancer, little is known about the psychological consequences for men at high risk of developing the disease. The aims of the present study were to examine risk perception, interest in genetic investigations, cancer-specific worry, and screening practice among unaffected men, aged 40-72 years old, with a pedigree consistent with hereditary prostate cancer and an estimated lifetime risk of prostate cancer of 35-45%. A questionnaire was sent by mail to 120 subjects, of whom 110 responded. Most of the men (n = 90, 82%) worried about having an inherited susceptibility to prostate cancer, and 34 (31%) claimed that worry about prostate cancer affected their daily life (3 (3%) fairly much, 31 (28%) slightly). As many as 40% of the study subjects perceived their lifetime risk of prostate cancer as 67% or more. Perceived high risk was associated with symptoms of depression and with cancer worry affecting daily living. Two-thirds of the men aged 50 years old or more were regularly screened for prostate cancer. Subjects with high levels of cancer-specific stress, as measured by the avoidance subscale of the Impact of Event Scale, were less likely to opt for screening. Almost all of the men (94%) were interested in presymptomatic genetic testing (84 (76%) "definitely yes" and 20 (18%) "probably yes"). We conclude that hereditary susceptibility to prostate cancer has significant psychological consequences although it rarely causes psychiatric morbidity. The present study underlines the importance of giving thorough, repeated information to men at high risk of prostate cancer.

CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk.

The length of the polymorphic CAG repeat in the N-terminal of the androgen receptor (AR) gene is inversely correlated with the transactivation function of the AR. Some studies have indicated that short CAG repeats are related to higher risk of prostate cancer. We performed a case-control study to investigate relations between CAG repeat length and prostate cancer risk, tumour grade, tumour stage, age at diagnosis and response to endocrine therapy. The study included 190 AR alleles from prostate cancer patients and 186 AR alleles from female control subjects. All were whites from southern Sweden. The frequency distribution of CAG repeat length was strikingly similar for cases and controls, and no significant correlation between CAG repeat length and prostate cancer risk was detected. However, for men with non-hereditary prostate cancer (n = 160), shorter CAG repeats correlated with younger age at diagnosis (P = 0.03). There were also trends toward associations between short CAG repeats and high grade (P = 0.07) and high stage (P = 0.07) disease. Furthermore, we found that patients with long CAG repeats responded better to endocrine therapy, even after adjusting for pretreatment level of prostate-specific antigen and tumour grade and stage (P = 0.05). We conclude that short CAG repeats in the AR gene correlate with young age at diagnosis of prostate cancer, but not with higher risk of the disease. Selection of patients with early onset prostate cancer in case-control studies could therefore lead to an over-estimation of the risk of prostate cancer for men with short CAG repeats. An association between long CAG repeats and good response to endocrine therapy was also found, but the mechanism and clinical relevance are unclear.

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-Hodgkin's 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 locally 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.