Transition from open to robotically assisted approach on radical prostatectomies in Iceland. A nationwide, population-based study.

OBJECTIVES: In January 2015, radical prostatectomies (RPs) in Iceland changed almost entirely from being performed as open (ORP) to robotically assisted (RARP). This study assesses early surgical and short-term oncological outcome after ORP and RARP and evaluates the safety of transition between the two surgical techniques. METHODS: The study population involved 160/163 (98%) of all radical prostatectomies performed in Iceland between January 2013 and April 2016. Data on patients was collected retrospectively from medical records. Early surgical and short-term oncological outcomes were compared between the two surgical techniques. RESULTS: The ORP and RARP cohorts were comparable with respect to all clinical and pathological variables, except for median prostate volume, which was 45 mL in the ORP cohort and 37 mL in the RARP cohort (p = 0.03). Intraoperative blood loss was higher, hospital stay longer, catheterization time longer, and risk of complications within 30 days of surgery higher after ORP than RARP (p < 0.01). The operative time, positive surgical margin rate and recurrence free survival, within two years, was comparable between the two surgical techniques. CONCLUSIONS: The transition from ORP to RARP in Iceland was safe and resulted in improved early surgical outcome. However, no conclusion can be drawn from this study regarding oncological outcome, due to short follow up and a small sample size.

Exploratory assessment of pineal gland volume, composition, and urinary 6-sulfatoxymelatonin levels on prostate cancer risk.

INTRODUCTION: Melatonin levels are partially driven by the parenchyma volume of the pineal gland. Low urinary levels of 6-sulfatoxymelatonin have been associated with increased risk of advanced prostate cancer, but the relationship between pineal gland volume and composition and prostate cancer risk has not been examined. MATERIALS AND METHODS: We utilized data from 864 men from the AGES-Reykjavik Study with complete pineal gland volumes and urinary 6-sulfatoxymelatonin measurements. Pineal parenchyma, calcification, and cyst volumes were calculated from brain magnetic resonance imaging. Levels of 6-sulfatoxymelatonin were assayed from prediagnostic urine samples. We calculated Pearson correlation coefficients between parenchyma volume and urinary 6-sulfatoxymelatonin levels. We used Cox proportional hazards regression to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) comparing prostate cancer risk across parenchyma volume tertiles and across categories factoring in parenchyma volume, gland composition, and urinary 6-sulfatoxymelatonin level. RESULTS: Parenchyma volume was moderately correlated with urinary 6-sulfatoxymelatonin level (r = .24; p < .01). There was no statistically significant association between parenchyma volume tertile and prostate cancer risk. Men with high parenchyma volume, pineal cysts and calcifications, and low urinary 6-sulfatoxymelatonin levels had almost twice the risk of total prostate cancer as men with low parenchyma volume, no pineal calcifications or cysts, and low urinary 6-sulfatoxymelatonin levels (HR: 1.98; 95% CI: 1.02, 3.84; p: .04). CONCLUSIONS: Although parenchyma volume is not associated with prostate cancer risk, pineal gland composition and other circadian dynamics may influence risk for prostate cancer. Additional studies are needed to examine the interplay of pineal gland volume, composition, and melatonin levels on prostate cancer risk.

Operative management in patients with upper tract urothelial carcinoma in Iceland: a population-based study.

OBJECTIVE: Radical nephroureterectomy is the standard treatment of organ-confined upper tract urothelial carcinoma (UTUC). The objective of this study was to investigate survival and bladder recurrence rate in Icelandic patients with UTUC who underwent radical nephroureterctomy (RNU) or other procedures with curative intent. MATERIAL AND METHODS: All patients who were diagnosed with UTUC in Iceland from 2003 to 2016 and treated with curative intent were included in the study. Information on patients was obtained retrospectively from patients' medical records and from the Icelandic Cause of Death Registry. RESULTS: Overall 63 patients underwent a procedure for UTUC with curative intent in Iceland during the study period. The median age was 71 years and the majority were male (65%). In 50 patients (79%), the tumor was a primary UTUC. The most common procedure was RNU (78%) and eight patients (13%) underwent a kidney-sparing procedure. No patient died within 90 d of surgery. Twenty-eight patients (44%) had pathological stage T2 or higher, whereas 35 patients (56%) had pathological stage T1 or lower. The median follow-up time was 98.8 months . During the follow-up time 25 patients (40%) were diagnosed with recurrence in the bladder. Five-year cancer-specific survival (CSS) was 67%. CONCLUSIONS: This population-based study shows that the oncologic outcome in Icelandic patients with UTUC is similar to what has been reported in other countries. Bladder recurrence rate is high and can hopefully be reduced by improvements in surgical and intravesical instillation treatment. Possibly more kidney-sparing surgeries could have been done during the study period; however, careful selection for those procedures is mandatory.

Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA.

Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, rg = 0.77 (P = 2.6 × 10-11), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6×10-55). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels.

Docetaxel Versus Surveillance After Radical Prostatectomy for High-risk Prostate Cancer: Results from the Prospective Randomised, Open-label Phase 3 Scandinavian Prostate Cancer Group 12 Trial.

BACKGROUND: Adjuvant chemotherapy is standard treatment for other solid tumours, but to date has not proven effective in prostate cancer. OBJECTIVE: o evaluate whether six cycles of docetaxel alone improve biochemical disease-free survival after radical prostatectomy for high-risk prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Open-label, randomised multinational phase 3 trial. Enrolment of 459 patients after prostatectomy. INCLUSION CRITERIA: high-risk pT2 margin positive or pT3a Gleason score ≥4+3, pT3b, or lymph node positive disease Gleason score ≥3+4. Patients assigned (1:1) to either six cycles of adjuvant docetaxel 75mg/m2 every 3 wk without daily prednisone (Arm A) or surveillance (Arm B) until endpoint was reached. Primary endpoint was prostate-specific antigen progression ≥0.5 ng/ml. INTERVENTION: Docetaxel treatment after prostatectomy. RESULTS AND LIMITATIONS: Median time to progression, death, or last follow-up was 56.8 mo. Primary endpoint was reached in 190/459 patients-the risk of progression at 5 yr being 41% (45% in Arm A and 38% in Arm B). There was evidence of nonproportional hazards in Kaplan-Meier analysis, so we used the difference in restricted mean survival time as the primary estimate of effect. Restricted mean survival time to endpoint was 43 mo in Arm A versus 46 mo in Arm B (p=0.06), a nonsignificant difference of 3.2 mo (95% confidence interval: 6.7 to -1.5 mo). A total of 116 serious adverse events were recorded in Arm A and 41 in Arm B with no treatment-related deaths. Not all patients received docetaxel by protocol. The endpoint is biochemical progression and some patients received radiation treatment before the endpoint. CONCLUSIONS: Docetaxel without hormonal therapy did not significantly improve biochemical disease-free survival after radical prostatectomy. PATIENT SUMMARY: In this randomised trial, we tested whether chemotherapy after surgery for high-risk prostate cancer decreases the risk of a rising prostate-specific antigen. We found no benefit from docetaxel given after radical prostatectomy.

Occupation as a risk factor for renal cell cancer: a nationwide, prospective epidemiological study.

Objective Using centralized registries in Iceland, the aim of this study was to prospectively investigate multiple risk factors for renal cell carcinoma (RCC), including occupational history. Materials and methods From the Reykjavik study database, 18,840 men and women born in the period 1907-1935 were linked with a population-based registry containing all RCCs diagnosed in Iceland from 1971 to 2005 (n = 910). From this cross-reference, altogether 225 cases were identified. A prospective analysis of the risk factors for RCC was performed using Cox regression analysis, from the time of entry into the Reykjavik study to the diagnosis of RCC, death or end of follow-up, with a median follow-up time of 25 years. The hazard ratio (HR) was then calculated for multiple risk factors including occupational history. Results Male gender [HR 1.65, 95% confidence interval (CI) 1.14-2.38], body mass index (BMI) over 25 kg/m² (HR 1.41, 95% CI 1.06-1.88) and age (HR 1.04, 95% CI 1.03-1.07) increased the risk of RCC, as did severe hypertension (>160/100 mmHg) (HR 1.46, 95% CI 1.05-2.03) and history of kidney disease (HR 1.55, 95% CI 1.11-2.16); however, smoking and type 2 diabetes were not significantly associated with the disease. The risk of RCC was significantly increased in painters (HR 2.97, 95% CI 1.31-6.74), aircraft mechanics (HR 4.51, 95% CI 1.11-18.28) and shipbuilders (HR 2.03, 95% CI 1.06-3.84). Conclusions Together with male gender, advanced age, hypertension, BMI over 25 kg/m² and history of kidney disease, the risk of RCC was significantly increased in painters, aircraft mechanics and shipbuilders, suggesting a link to occupational exposure.

Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.

Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r(2) = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10(-32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10(-7)).

Radical cystectomy in the treatment of bladder cancer in Iceland: A population-based study.

OBJECTIVE: Radical cystectomy (RC) is the standard treatment for muscle-invasive bladder cancer. Postoperative complications are reported to be as high as 65%. The objective of this study was to investigate complications and survival in Icelandic patients with bladder cancer who underwent RC. MATERIALS AND METHODS: All patients who had bladder cancer and underwent RC in Iceland from 2003 to 2012 were included. Information was obtained retrospectively from patients' medical records and from the Icelandic Cause of Death Registry. Complications were classified according to the Clavien-Dindo classification system. The Kaplan-Meier method was used in the survival analysis. Only patients with transitional cell carcinoma (TCC) were included in the survival analysis. RESULTS: Overall, 108 patients (male 81%, median age 68 years) underwent the procedure during the study period and 100 of them had TCC. Ileal conduit was performed in 86% of procedures and orthotopic neobladder in 14%. The median operation time was 266 min and the median blood loss during the procedure was 1000 ml. No patient died within 30 days of surgery, but one patient (0.9%) died within 90 days of surgery from complications of the surgery. Complications were reported for 62 patients (57%) overall. Major complications (Clavien 3-5) were reported in 32 patients (29%), and 30 patients (28%) had only minor complications (Clavien 1-2). Twenty-four patients (22%) had to undergo reoperation. Overall 5 year survival was 54%. CONCLUSION: Morbidity after RC is high but similar to that seen in other studies. Long-term survival of Icelandic patients is comparable to that in neighboring countries.

The impact of tumour size on the probability of synchronous metastasis and survival in renal cell carcinoma patients: a population-based study.

BACKGROUND: The observed low metastatic potential and favorable survival of small incidentally detected renal cell carcinomas (RCCs) have been a part of the rationale for recommending partial nephrectomy as a first treatment option and active surveillance in selected patients. We examined the relationship between tumor size and the odds of synchronous metastases (SMs) (primary outcome) and disease specific survival (secondary outcome) in a nationwide RCC registry. METHODS: Retrospective study of the 794 RCC patients diagnosed in Iceland between 1971 and 2005. Histological material and TNM staging were reviewed centrally. The presence of SM and survival were recorded. Cubic spline analysis was used to assess relationship between tumor size and probability of SM. Univariate and multivariate statistics were used to estimate prognostic factors for SM and survival. RESULTS: The probability of SM increased in a non-linear fashion with increasing tumor size (11, 25, 35, and 50%) for patients with tumors of ≤4, 4.1-7.0, 7.1-10.0, and >10 cm, respectively. On multivariate analysis, tumor size was an independent prognostic factor for disease-specific survival (HR = 1.05, 95% CI 1.02-1.09, p < 0.001), but not for SM. CONCLUSION: Tumor size affected the probability of disease-specific mortality but not SM, after correcting for TNM staging in multivariate analysis. This confirms the prognostic ability of the 2010 TNM staging system for renal cell cancer in the Icelandic population.

Explosion of the urinary bladder during transurethral resection of the prostate.

Transurethral resection of the prostate (TURP) remains the gold standard for the surgical treatment of benign prostatic hyperplasia. Complications during the procedure are rare. An extremely rare complication is a rupture of the urinary bladder. This article reports a case where an explosion occurred during TURP, resulting in a large intraperitoneal rupture of the urinary bladder. The patient underwent emergency laparotomy to repair the bladder.

Functional results after orthotopic bladder substitution: a prospective multicentre study comparing four types of neobladder.

OBJECTIVE: The aim of this study was to evaluate enterocystometry, voiding pattern and urine leakage of four types of orthotopic bladder substitute. MATERIAL AND METHODS: At eight urological departments, 78 consecutive men were studied: 66 with an ileal neobladder [30 Studer pouches (S), 24 Hautmann pouches (H) and 12 T-pouches (T)] and 12 with a right colonic [Goldwasser type (G)] neobladder. Enterocystometry, determination of residual urine, micturition protocol and 24 h pad weight test were performed 6 and 12 months postoperatively. RESULTS: Colonic neobladders had higher pouch pressure at first desire, normal desire and strong desire than ileal neobladders (except at first and normal desire at 12 months) (p < 0.02) and contraction was present more often at both 6 and 12 months (p < 0.01 and p < 0.01). Compliance was good in all types of pouch. Intermittent self-catheterization was more common in H patients at 6 months (p = 0.033). All patients with colonic neobladders used pads during the day and night. In patients with ileal pouches 32% used pads during the day and 70% during the night at 12 months. Urine leakage was higher in patients with colonic bladders at 6 and 12 months during the day (mean/median of 98/31 ml and 82/16 ml versus 10/0 ml and 4/0 ml, p < 0.001). T-pouches had excellent day-time continence, but nocturnal leakage was high. CONCLUSIONS: The Hautmann pouch and the Studer pouch behaved similarly at enterocystometry and clinically, and continence was good in the majority of patients. The low number of patients with the other two types of pouch precludes definitive statements.

A common variant at 8q24.21 is associated with renal cell cancer.

Renal cell carcinoma (RCC) represents between 80 and 90% of kidney cancers. Previous genome-wide association studies of RCC have identified five variants conferring risk of the disease. Here we report the results from a discovery RCC genome-wide association study and replication analysis, including a total of 2,411 patients and 71,497 controls. One variant, rs35252396[CG] located at 8q24.21, is significantly associated with RCC after combining discovery and replication results (OR=1.27, P(combined)=5.4 × 10(-11)) and has an average risk allele frequency in controls of 46%. rs35252396[CG] does not have any strongly correlated variants in the genome and is located within a region predicted to have regulatory functions in several cell lines, including six originating from the kidney. This is the first RCC variant reported at 8q24.21 and it is largely independent (r(2)≤0.02) of the numerous previously reported cancer risk variants at this locus.

Kidney function following partial or radical nephrectomy for renal cell carcinoma: a population-based study.

OBJECTIVE: The aim of this retrospective study was to compare kidney function in a population-based cohort of renal cell carcinoma (RCC) patients after partial (PN) or radical nephrectomy (RN). MATERIAL AND METHODS: Forty-four consecutive RCC patients who had undergone PN in Iceland between 2000 and 2010 were compared with 44 controls matched for tumour, node, metastasis (TNM) stage who had undergone RN during the same period. Estimated glomerular filtration rate (eGFR) and survival were calculated, and predictors of chronic kidney disease (CKD) were evaluated with multivariate analysis. RESULTS: In 16 cases (36%), PN was performed for imperative reasons (single kidney, decreased kidney function or bilateral kidney tumours) but 28 patients had a normal contralateral kidney. The groups were similar regarding preoperative eGFR, median follow-up and TNM stage, but age and American Society of Anesthesiologists (ASA) score were significantly higher in the RN group. Six months after surgery, eGFR was significantly higher in the PN group. By multivariate analysis, RN contributed negatively to eGFR 6 months after surgery (-12.6 ml/1.73 m², p < 0.001) and increased the risk of new-onset CKD (odds ratio = 3.07, 95% confidence interval 1.03-9.79, p = 0.04), compared to PN. At median follow-up of 44 months, no patients in either group had a recurrence of RCC. The 5-year overall survival (Kaplan-Meier) was 100% and 65% in the PN and RN groups, respectively (log-rank test, p < 0.001). CONCLUSION: eGFR was significantly lower after RN, and these patients were three times more likely to develop new-onset CKD. These findings suggest that PN successfully preserves kidney function compared to RN, with good oncological outcome and survival.

Consumption of fish products across the lifespan and prostate cancer risk.

OBJECTIVE: To examine whether fish and fish oil consumption across the lifespan is associated with a lower risk of prostate cancer. DESIGN: The study was nested among 2268 men aged 67-96 years in the AGES-Reykjavik cohort study. In 2002 to 2006, dietary habits were assessed, for early life, midlife and later life using a validated food frequency questionnaire. Participants were followed for prostate cancer diagnosis and mortality through 2009 via linkage to nationwide cancer- and mortality registers. Adjusting for potential confounders, we used regression models to estimate odds ratios (ORs) and hazard ratios (HRs) for prostate cancer according to fish and fish oil consumption. RESULTS: Among the 2268 men, we ascertained 214 prevalent and 133 incident prostate cancer cases, of which 63 had advanced disease. High fish consumption in early- and midlife was not associated with overall or advanced prostate cancer. High intake of salted or smoked fish was associated with a 2-fold increased risk of advanced prostate cancer both in early life (95% CI: 1.08, 3.62) and in later life (95% CI: 1.04, 5.00). Men consuming fish oil in later life had a lower risk of advanced prostate cancer [HR (95%CI): 0.43 (0.19, 0.95)], no association was found for early life or midlife consumption. CONCLUSIONS: Salted or smoked fish may increase risk of advanced prostate cancer, whereas fish oil consumption may be protective against progression of prostate cancer in elderly men. In a setting with very high fish consumption, no association was found between overall fish consumption in early or midlife and prostate cancer risk.

Differences in survival from prostate cancer in Denmark, Iceland and Sweden.

INTRODUCTION: Register-based studies have shown large survival differences among prostate cancer patients in the Nordic countries. The aim of this study was to determine the background of such differences in Denmark, Iceland and Sweden. MATERIAL AND METHODS: Patients with prostate cancer were identified through population-based cancer registers in the three countries. Clinical findings at diagnosis were retrieved from hospital records. In Sweden, clinical information was gathered from regional population-based prostate cancer registers. Country-specific incidence and excess mortality rates were compared, with adjustment for prognostic factors. RESULTS: The relative survival in the cohorts was comparable to that in previous population-based studies. Significant differences in excess mortality rates were found across countries, which diminished or disappeared after adjustment for patient characteristics, i.e. metastatic status, clinical T stage and prostate-specific antigen level. A difference in the proportion of patients with metastatic disease was the main explanation of the differences in survival among countries, while the incidence rates of metastatic cancer were similar. DISCUSSION: Register-based studies of the relative survival of prostate cancer patients are influenced by national differences in clinical presentation at diagnosis. Differences in the proportion of patients with metastatic spread explained most of the difference in relative survival among patients in Denmark, Iceland and Sweden. Future country comparisons of relative survival should include adjustment for differences in patient characteristics, such as stage, prostate-specific antigen level and screening intensity.

[Small renal cell carcinomas and synchronous metastases]. / Litil nyrnafrumukrabbamein og fjarmeinvorp.

OBJECTIVE: The incidence of renal cell carcinoma (RCC) is rising in part due to small tumors (≤4cm) detected incidentally with abdominal imaging. Survival for small RCCs has been regarded as favorable and guidelines recommend partial rather than total nephrecteomy. We studied the frequency of synchronous metastasis in patients with small RCCs in Iceland. MATERIALS AND METHODS: A retrospective study on 257 patients with RCC ≤4cm out of 1102 RCC patients diagnosed in Iceland 1971-2010. Patients with metastasis were compared to those with localized disease. Hospital charts were reviewed and histology, TNM-stage and disease-specific survival compared between groups. RESULTS: The proportion of small tumors increased from 9% in 1971-1980 to 33% in 2001-2010 (p<0,001) and incidental detection increased from 14% to 39% during the same period. Out of the 257 patients with small RCCs, 25 (10%) had synchronous metastases, most frequently in lungs or bones. Patients with metastases were on average 1.9 years older, their tumors were 0.2 cm larger and more often located in the right kidney, their hemoglobin was lower and nuclear grade and T-stage higher. Histology was similar in both groups. Five-year survival of patients with and without metastases was 7 vs. 94%, respectively (p<0.001). CONCLUSIONS: One out of ten patients with small RCC has synchronous metastases at diagnosis. This is higher than in most previous reports that usually include surgical patients only. Patients with metastases are significantly older, more often symptomatic, their tumor are larger and their prognosis worse. Our results indicate that small RCC is a potentially systemic disease at diagnosis that has to be taken seriously.

A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer.

In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 × 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.