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.

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)).

Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24.

Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.

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.

Kidney transplantation in Icelandic patients, 2000-2019: are outcomes affected by low volume?

Background: In Iceland, a small number of kidney transplants from living donors (LDs) are performed at Landspitali University Hospital (LUH) in Reykjavik, while deceased donor transplants have until recently invariably been carried out abroad. In this study, we evaluated the outcome of kidney transplantation in Icelandic patients. Methods: This was a retrospective study that included all Icelandic residents who underwent kidney transplantation between 1 January 2000 and 31 December 2019. Data were obtained from the Icelandic End-Stage Kidney Disease Registry, medical records at LUH, and the Scandiatransplant database. The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate estimated glomerular filtration rate from serum creatinine for recipients and donors aged >18 years, and the modified Schwartz equation for those aged ≤18 years. Survival was estimated using the Kaplan-Meier method, and the log-rank test was employed for group comparisons. Results: A total of 229 kidney transplants in 221 patients were performed during the 20-year period, of which 135 (58.9%) were from LDs. Transplants carried out at LUH were 118 (51.5%), of which 116 were from LDs. During a median follow-up of 7.4 years (range 0.1-20), 27 (12.2%) patients died, 20 (74%) of whom had a functioning graft. One-year patient survival was 99.1% [95% confidence interval (CI), 97.9-100], 5-year survival was 95.7% (95% CI, 92.7-98.7), and 10-year survival was 87.7% (95% CI, 82.4-93.4). Death-censored graft survival was 98.3% (95% CI, 96.6-100), 96.8% (95% CI, 94.4-99.2), and 89.2% (95% CI, 84.1-94.7) at 1, 5, and 10 years, respectively. Conclusions: Patient and graft survival are comparable with those of large transplant centers, demonstrating the feasibility of running a quality kidney transplant program in a small nation in collaboration with a larger center abroad.

European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.

Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.

Milk intake in early life and risk of advanced prostate cancer.

The authors investigated whether early-life residency in certain areas of Iceland marked by distinct differences in milk intake was associated with risk of prostate cancer in a population-based cohort of 8,894 men born between 1907 and 1935. Through linkage to cancer and mortality registers, the men were followed for prostate cancer diagnosis and mortality from study entry (in waves from 1967 to 1987) through 2009. In 2002-2006, a subgroup of 2,268 participants reported their milk intake in early, mid-, and current life. During a mean follow-up period of 24.3 years, 1,123 men were diagnosed with prostate cancer, including 371 with advanced disease (stage 3 or higher or prostate cancer death). Compared with early-life residency in the capital area, rural residency in the first 20 years of life was marginally associated with increased risk of advanced prostate cancer (hazard ratio = 1.29, 95% confidence interval (CI): 0.97, 1.73), particularly among men born before 1920 (hazard ratio = 1.64, 95% CI: 1.06, 2.56). Daily milk consumption in adolescence (vs. less than daily), but not in midlife or currently, was associated with a 3.2-fold risk of advanced prostate cancer (95% CI: 1.25, 8.28). These data suggest that frequent milk intake in adolescence increases risk of advanced prostate cancer.

Rye bread consumption in early life and reduced risk of advanced prostate cancer.

OBJECTIVE: To determine whether consumption of whole-grain rye bread, oatmeal, and whole-wheat bread, during different periods of life, is associated with risk of prostate cancer (PCa). METHODS: From 2002 to 2006, 2,268 men, aged 67-96 years, reported their dietary habits in the AGES-Reykjavik cohort study. Dietary habits were assessed for early life, midlife, and current life using a validated food frequency questionnaire. Through linkage to cancer and mortality registers, we retrieved information on PCa diagnosis and mortality through 2009. We used regression models to estimate odds ratios (ORs) and hazard ratios (HRs) for PCa according to whole-grain consumption, adjusted for possible confounding factors including fish, fish liver oil, meat, and milk intake. RESULTS: Of the 2,268 men, 347 had or were diagnosed with PCa during follow-up, 63 with advanced disease (stage 3+ or died of PCa). Daily rye bread consumption in adolescence (vs. less than daily) was associated with a decreased risk of PCa diagnosis (OR = 0.76, 95 % confidence interval (CI): 0.59-0.98) and of advanced PCa (OR = 0.47, 95 % CI: 0.27-0.84). High intake of oatmeal in adolescence (≥5 vs. ≤4 times/week) was not significantly associated with risk of PCa diagnosis (OR = 0.99, 95 % CI: 0.77-1.27) nor advanced PCa (OR = 0.67, 95 % CI: 0.37-1.20). Midlife and late life consumption of rye bread, oatmeal, or whole-wheat bread was not associated with PCa risk. CONCLUSION: Our results suggest that rye bread consumption in adolescence may be associated with reduced risk of PCa, particularly advanced disease.

Incidental detection of renal cell carcinoma is an independent prognostic marker: results of a long-term, whole population study.

PURPOSE: The true effect of incidental detection on the survival of patients with renal cell carcinoma has been debated. We used centralized databases in Iceland to study prognostic factors of survival, focusing on the effect of incidental detection. MATERIALS AND METHODS: This retrospective study included all living patients diagnosed with renal cell carcinoma in Iceland from 1971 to 2005. Hospital charts and histology were reviewed. Incidentally diagnosed renal cell carcinomas were compared to symptomatic tumors and prognostic factors were evaluated using Cox multivariate analysis. RESULTS: Of the 910 patients 254 (27.9%) were diagnosed incidentally, most often by abdominal ultrasound (29.5%) or computerized tomography (28.3%). The incidental detection rate increased from 11.1% in 1971 through 1975 to 39.2% in 2001 through 2005 (p <0.001). During the same period the incidence increased significantly in males but in females only during the last 5 study years. Mortality remained unchanged for each gender. Incidentally detected tumors were an average of 2.6 cm smaller and diagnosed at lower stage and lower grade than symptomatic tumors. Age and histology were similar in each group. TNM stage was by far the strongest independent prognostic factor of survival but age, calendar year of diagnosis and ESR were also significant. After correcting for confounders patients with symptomatic renal cell carcinoma had worse survival than those diagnosed incidentally. CONCLUSIONS: With increased incidence and unchanged mortality the survival of patients with renal cell carcinoma has improved. This is mainly related to a steep increase in incidental detection. Incidental detection affects survival favorably and to a greater extent than can be explained by lower stage compared to the survival of patients diagnosed with symptoms.

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.

Chromophobe renal cell carcinoma in Iceland: an epidemiological and clinicopathological study.

OBJECTIVE: Numerous studies have suggested that the rare chromophobe renal cell carcinoma (CRCC) has a more favourable prognosis than the other more common subtypes of RCC, clear cell RCC (CCRCC) and papillary RCC (PRCC). These studies have, however, usually involved selected patient cohorts and not whole populations. This study compared CRCC patients with patients with the other two major histological subtypes and established a population-based age-standardized incidence rate (ASR). MATERIAL AND METHODS: Of 828 histopathologically confirmed RCCs diagnosed between 1971 and 2005 in Iceland, 15 CRCC cases were identified. Histological material was reviewed, the TNM system was used for staging and cancer-specific survival was estimated. Univariate and multivariate analysis was used to compare CRCC to both CCRCC (n = 740) and PRCC (n = 66). Mean follow-up was 6.7 years. RESULTS: CRCC accounted for 1.8% of RCCs, the ASR being 0.17/100,000 per year. Compared to other subtypes, CRCC was detected incidentally less often (7% vs 29%, p = 0.02), but was more often diagnosed at lower stages (73% vs 45% at stage I + II, p < 0.001). One patient had synchronous metastasis and another developed recurrent CRCC; both died of CRCC. Five-year survival for CRCC, CCRCC and PRCC was 86%, 59% and 50%, respectively (p = 0.004). After correcting for TNM stage (odds ratio 1.98), multivariate analysis did not indicate that CRCC subtype was an independent predictive factor for survival. CONCLUSION: CRCC is a rare neoplasm with an ASR of 0.17/100,000 per year. These tumours often present with symptoms despite being at lower stages than the other RCC subtypes. The more favourable survival of the CRCC subtype appears to be explained by these tumours being diagnosed at low stages. These findings may suggest that CRCC has a different biological behaviour.

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.

Arteriovenous fistula in an autotransplanted kidney segment: successful angiographic management.

Autotransplantation is a management option in complex renal or ureteral diseases. This report describes a case of bilateral renal cell carcinoma treated with partial nephrectomy using bench surgery followed by a contralateral total nephrectomy. This procedure was complicated by an arteriovenous fistula in the transplanted segment that was successively embolized angiographically.

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.

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.

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.

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.