A standardised protocol for relative SARS-CoV-2 variant severity assessment, applied to Omicron BA.1 and Delta in six European countries, October 2021 to February 2022.

Several SARS-CoV-2 variants that evolved during the COVID-19 pandemic have appeared to differ in severity, based on analyses of single-country datasets. With decreased testing and sequencing, international collaborative studies will become increasingly important for timely assessment of the severity of new variants. Therefore, a joint WHO Regional Office for Europe and ECDC working group was formed to produce and pilot a standardised study protocol to estimate relative case-severity of SARS-CoV-2 variants during periods when two variants were co-circulating. The study protocol and its associated statistical analysis code was applied by investigators in Denmark, England, Luxembourg, Norway, Portugal and Scotland to assess the severity of cases with the Omicron BA.1 virus variant relative to Delta. After pooling estimates using meta-analysis methods (random effects estimates), the risk of hospital admission (adjusted hazard ratio (aHR) = 0.41; 95% confidence interval (CI): 0.31-0.54), admission to intensive care unit (aHR = 0.12; 95% CI: 0.05-0.27) and death (aHR = 0.31; 95% CI: 0.28-0.35) was lower for Omicron BA.1 compared with Delta cases. The aHRs varied by age group and vaccination status. In conclusion, this study demonstrates the feasibility of conducting variant severity analyses in a multinational collaborative framework and adds evidence for the reduced severity of the Omicron BA.1 variant.

Directions of change in intrinsic case severity across successive SARS-CoV-2 variant waves have been inconsistent.

OBJECTIVES: To determine how the intrinsic severity of successively dominant SARS-CoV-2 variants changed over the course of the pandemic. METHODS: A retrospective cohort analysis in the NHS Greater Glasgow and Clyde (NHS GGC) Health Board. All sequenced non-nosocomial adult COVID-19 cases in NHS GGC with relevant SARS-CoV-2 lineages (B.1.177/Alpha, Alpha/Delta, AY.4.2 Delta/non-AY.4.2 Delta, non-AY.4.2 Delta/Omicron, and BA.1 Omicron/BA.2 Omicron) during analysis periods were included. Outcome measures were hospital admission, ICU admission, or death within 28 days of positive COVID-19 test. We report the cumulative odds ratio; the ratio of the odds that an individual experiences a severity event of a given level vs all lower severity levels for the resident and the replacement variant after adjustment. RESULTS: After adjustment for covariates, the cumulative odds ratio was 1.51 (95% CI: 1.08-2.11) for Alpha versus B.1.177, 2.09 (95% CI: 1.42-3.08) for Delta versus Alpha, 0.99 (95% CI: 0.76-1.27) for AY.4.2 Delta versus non-AY.4.2 Delta, 0.49 (95% CI: 0.22-1.06) for Omicron versus non-AY.4.2 Delta, and 0.86 (95% CI: 0.68-1.09) for BA.2 Omicron versus BA.1 Omicron. CONCLUSIONS: The direction of change in intrinsic severity between successively emerging SARS-CoV-2 variants was inconsistent, reminding us that the intrinsic severity of future SARS-CoV-2 variants remains uncertain.

CanRisk-Prostate: A Comprehensive, Externally Validated Risk Model for the Prediction of Future Prostate Cancer.

PURPOSE: Prostate cancer (PCa) is highly heritable. No validated PCa risk model currently exists. We therefore sought to develop a genetic risk model that can provide personalized predicted PCa risks on the basis of known moderate- to high-risk pathogenic variants, low-risk common genetic variants, and explicit cancer family history, and to externally validate the model in an independent prospective cohort. MATERIALS AND METHODS: We developed a risk model using a kin-cohort comprising individuals from 16,633 PCa families ascertained in the United Kingdom from 1993 to 2017 from the UK Genetic Prostate Cancer Study, and complex segregation analysis adjusting for ascertainment. The model was externally validated in 170,850 unaffected men (7,624 incident PCas) recruited from 2006 to 2010 to the independent UK Biobank prospective cohort study. RESULTS: The most parsimonious model included the effects of pathogenic variants in BRCA2, HOXB13, and BRCA1, and a polygenic score on the basis of 268 common low-risk variants. Residual familial risk was modeled by a hypothetical recessively inherited variant and a polygenic component whose standard deviation decreased log-linearly with age. The model predicted familial risks that were consistent with those reported in previous observational studies. In the validation cohort, the model discriminated well between unaffected men and men with incident PCas within 5 years (C-index, 0.790; 95% CI, 0.783 to 0.797) and 10 years (C-index, 0.772; 95% CI, 0.768 to 0.777). The 50% of men with highest predicted risks captured 86.3% of PCa cases within 10 years. CONCLUSION: To our knowledge, this is the first validated risk model offering personalized PCa risks. The model will assist in counseling men concerned about their risk and can facilitate future risk-stratified population screening approaches.

Adjusting for time of infection or positive test when estimating the risk of a post-infection outcome in an epidemic.

When comparing the risk of a post-infection binary outcome, for example, hospitalisation, for two variants of an infectious pathogen, it is important to adjust for calendar time of infection. Typically, the infection time is unknown and positive test time used as a proxy for it. Positive test time may also be used when assessing how risk of the outcome changes over calendar time. We show that if time from infection to positive test is correlated with the outcome, the risk conditional on positive test time is a function of the trajectory of infection incidence. Hence, a risk ratio adjusted for positive test time can be quite different from the risk ratio adjusted for infection time. We propose a simple sensitivity analysis that indicates how risk ratios adjusted for positive test time and infection time may differ. This involves adjusting for a shifted positive test time, shifted to make the difference between it and infection time uncorrelated with the outcome. We illustrate this method by reanalysing published results on the relative risk of hospitalisation following infection with the Alpha versus pre-existing variants of SARS-CoV-2. Results indicate the relative risk adjusted for infection time may be lower than that adjusted for positive test time.

Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study.

BACKGROUND: The omicron variant (B.1.1.529) of SARS-CoV-2 has demonstrated partial vaccine escape and high transmissibility, with early studies indicating lower severity of infection than that of the delta variant (B.1.617.2). We aimed to better characterise omicron severity relative to delta by assessing the relative risk of hospital attendance, hospital admission, or death in a large national cohort. METHODS: Individual-level data on laboratory-confirmed COVID-19 cases resident in England between Nov 29, 2021, and Jan 9, 2022, were linked to routine datasets on vaccination status, hospital attendance and admission, and mortality. The relative risk of hospital attendance or admission within 14 days, or death within 28 days after confirmed infection, was estimated using proportional hazards regression. Analyses were stratified by test date, 10-year age band, ethnicity, residential region, and vaccination status, and were further adjusted for sex, index of multiple deprivation decile, evidence of a previous infection, and year of age within each age band. A secondary analysis estimated variant-specific and vaccine-specific vaccine effectiveness and the intrinsic relative severity of omicron infection compared with delta (ie, the relative risk in unvaccinated cases). FINDINGS: The adjusted hazard ratio (HR) of hospital attendance (not necessarily resulting in admission) with omicron compared with delta was 0·56 (95% CI 0·54-0·58); for hospital admission and death, HR estimates were 0·41 (0·39-0·43) and 0·31 (0·26-0·37), respectively. Omicron versus delta HR estimates varied with age for all endpoints examined. The adjusted HR for hospital admission was 1·10 (0·85-1·42) in those younger than 10 years, decreasing to 0·25 (0·21-0·30) in 60-69-year-olds, and then increasing to 0·47 (0·40-0·56) in those aged at least 80 years. For both variants, past infection gave some protection against death both in vaccinated (HR 0·47 [0·32-0·68]) and unvaccinated (0·18 [0·06-0·57]) cases. In vaccinated cases, past infection offered no additional protection against hospital admission beyond that provided by vaccination (HR 0·96 [0·88-1·04]); however, for unvaccinated cases, past infection gave moderate protection (HR 0·55 [0·48-0·63]). Omicron versus delta HR estimates were lower for hospital admission (0·30 [0·28-0·32]) in unvaccinated cases than the corresponding HR estimated for all cases in the primary analysis. Booster vaccination with an mRNA vaccine was highly protective against hospitalisation and death in omicron cases (HR for hospital admission 8-11 weeks post-booster vs unvaccinated: 0·22 [0·20-0·24]), with the protection afforded after a booster not being affected by the vaccine used for doses 1 and 2. INTERPRETATION: The risk of severe outcomes following SARS-CoV-2 infection is substantially lower for omicron than for delta, with higher reductions for more severe endpoints and significant variation with age. Underlying the observed risks is a larger reduction in intrinsic severity (in unvaccinated individuals) counterbalanced by a reduction in vaccine effectiveness. Documented previous SARS-CoV-2 infection offered some protection against hospitalisation and high protection against death in unvaccinated individuals, but only offered additional protection in vaccinated individuals for the death endpoint. Booster vaccination with mRNA vaccines maintains over 70% protection against hospitalisation and death in breakthrough confirmed omicron infections. FUNDING: Medical Research Council, UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research, Community Jameel, and Engineering and Physical Sciences Research Council.

Hospitalization and Mortality Risk for COVID-19 Cases With SARS-CoV-2 AY.4.2 (VUI-21OCT-01) Compared to Non-AY.4.2 Delta Variant Sublineages.

To investigate if the AY.4.2 sublineage of the SARS-CoV-2 delta variant is associated with hospitalization and mortality risks that differ from non-AY.4.2 delta risks, we performed a retrospective cohort study of sequencing-confirmed COVID-19 cases in England based on linkage of routine health care datasets. Using stratified Cox regression, we estimated adjusted hazard ratios (aHR) of hospital admission (aHR = 0.85; 95% confidence interval [CI], .77-.94), hospital admission or emergency care attendance (aHR = 0.87; 95% CI, .81-.94), and COVID-19 mortality (aHR = 0.85; 95% CI, .71-1.03). The results indicate that the risks of hospitalization and mortality are similar or lower for AY.4.2 compared to cases with other delta sublineages.

BRCA1 and BRCA2 pathogenic variants and prostate cancer risk: systematic review and meta-analysis.

BACKGROUND: BRCA1 and BRCA2 pathogenic variants (PVs) are associated with prostate cancer (PCa) risk, but a wide range of relative risks (RRs) has been reported. METHODS: We systematically searched PubMed, Embase, MEDLINE and Cochrane Library in June 2021 for studies that estimated PCa RRs for male BRCA1/2 carriers, with no time or language restrictions. The literature search identified 27 studies (BRCA1: n = 20, BRCA2: n = 21). RESULTS: The heterogeneity between the published estimates was high (BRCA1: I2 = 30%, BRCA2: I2 = 83%); this could partly be explained by selection for age, family history or aggressive disease, and study-level differences in ethnicity composition, use of historical controls, and location of PVs within BRCA2. The pooled RRs were 2.08 (95% CI 1.38-3.12) for Ashkenazi Jewish BRCA2 carriers, 4.35 (95% CI 3.50-5.41) for non-Ashkenazi European ancestry BRCA2 carriers, and 1.18 (95% CI 0.95-1.47) for BRCA1 carriers. At ages <65 years, the RRs were 7.14 (95% CI 5.33-9.56) for non-Ashkenazi European ancestry BRCA2 and 1.78 (95% CI 1.09-2.91) for BRCA1 carriers. CONCLUSIONS: These PCa risk estimates will assist in guiding clinical management. The study-level subgroup analyses indicate that risks may be modified by age and ethnicity, and for BRCA2 carriers by PV location within the gene, which may guide future risk-estimation studies.

Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study.

BACKGROUND: The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes. METHODS: This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status. FINDINGS: Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17-43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32-3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08-1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47-8·05] and for hospital admission or emergency care attendance 1·58 [0·69-3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29-4·16] and 1·43 [1·04-1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low. INTERPRETATION: This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant. FUNDING: Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

Risk of hospital admission for patients with SARS-CoV-2 variant B.1.1.7: cohort analysis.

OBJECTIVE: To evaluate the relation between diagnosis of covid-19 with SARS-CoV-2 variant B.1.1.7 (also known as variant of concern 202012/01) and the risk of hospital admission compared with diagnosis with wild-type SARS-CoV-2 variants. DESIGN: Retrospective cohort analysis. SETTING: Community based SARS-CoV-2 testing in England, individually linked with hospital admission data. PARTICIPANTS: 839 278 patients with laboratory confirmed covid-19, of whom 36 233 had been admitted to hospital within 14 days, tested between 23 November 2020 and 31 January 2021 and analysed at a laboratory with an available TaqPath assay that enables assessment of S-gene target failure (SGTF), a proxy test for the B.1.1.7 variant. Patient data were stratified by age, sex, ethnicity, deprivation, region of residence, and date of positive test. MAIN OUTCOME MEASURES: Hospital admission between one and 14 days after the first positive SARS-CoV-2 test. RESULTS: 27 710 (4.7%) of 592 409 patients with SGTF variants and 8523 (3.5%) of 246 869 patients without SGTF variants had been admitted to hospital within one to 14 days. The stratum adjusted hazard ratio of hospital admission was 1.52 (95% confidence interval 1.47 to 1.57) for patients with covid-19 infected with SGTF variants, compared with those infected with non-SGTF variants. The effect was modified by age (P<0.001), with hazard ratios of 0.93-1.21 in patients younger than 20 years with versus without SGTF variants, 1.29 in those aged 20-29, and 1.45-1.65 in those aged ≥30 years. The adjusted absolute risk of hospital admission within 14 days was 4.7% (95% confidence interval 4.6% to 4.7%) for patients with SGTF variants and 3.5% (3.4% to 3.5%) for those with non-SGTF variants. CONCLUSIONS: The results suggest that the risk of hospital admission is higher for people infected with the B.1.1.7 variant compared with wild-type SARS-CoV-2, likely reflecting a more severe disease. The higher severity may be specific to adults older than 30 years.

Acute and long-term grief reactions and experiences in parentally cancer-bereaved teenagers.

BACKGROUND: Previous research shows that many cancer-bereaved youths report unresolved grief several years after the death of a parent. Grief work hypothesis suggests that, in order to heal, the bereaved needs to process the pain of grief in some way. This study explored acute grief experiences and reactions in the first 6 months post-loss among cancer-bereaved teenagers. We further explored long-term grief resolution and potential predictors of having had "an okay way to grieve" in the first months post-loss. METHODS: We used a population-based nationwide, study-specific survey to investigate acute and long-term grief experiences in 622 (73% response rate) bereaved young adults (age > 18) who, 6-9 years earlier, at ages 13-16 years, had lost a parent to cancer. Associations were assessed using bivariable and multivariable logistic regression. RESULTS: Fifty-seven per cent of the participants reported that they did not have a way to grieve that felt okay during the first 6 months after the death of their parent. This was associated with increased risk for long-term unresolved grief (odds ratio (OR): 4.32, 95% confidence interval (CI): 2.99-6.28). An association with long-term unresolved grief was also found for those who reported to have been numbing and postponing (42%, OR: 1.73, 95% CI: 1.22-2.47), overwhelmed by grief (24%, OR: 2.02, 95% CI: 1.35-3.04) and discouraged from grieving (15%, OR: 2.68, 95% CI: 1.62-4.56) or to have concealed their grief to protect the other parent (24%, OR: 1.83, 95% CI: 1.23-2.73). Predictors of having had an okay way to grieve included being male, having had good family cohesion, and having talked about what was important with the dying parent. CONCLUSION: More than half of the cancer-bereaved teenagers did not find a way to grieve that felt okay during the first 6 months after the death of their parent and the acute grief experiences and reaction were associated with their grief resolution long-term, i.e. 6-9 years post-loss. Facilitating a last conversation with their dying parent, good family cohesion, and providing teenagers with knowledge about common grief experiences may help to prevent long-term unresolved grief.

Prostate Cancer Risk by BRCA2 Genomic Regions.

A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval [CI] 4.46-15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR = 3.31, 95% CI 1.97-5.57; hazard ratio = 2.34, 95% CI 1.09-5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23-72%) by the age of 75 yr and 78% (95% CI 54-94%) by the age of 85 yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort. PATIENT SUMMARY: In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene.

Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study.

BACKGROUND: BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies. OBJECTIVE: To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods. RESULTS AND LIMITATIONS: Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute PCa risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20-8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24-7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses. CONCLUSIONS: The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers. PATIENT SUMMARY: In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.

Losing a parent to cancer as a teenager: Family cohesion in childhood, teenage, and young adulthood as perceived by bereaved and non-bereaved youths.

OBJECTIVE: The aim of this study was to investigate levels of perceived family cohesion during childhood, teenage years, and young adulthood in cancer-bereaved youths compared with non-bereaved peers. METHODS: In this nationwide, population-based study, 622 (73%) young adults (aged 18-26) who had lost a parent to cancer 6 to 9 years previously, when they were teenagers (aged 13-16), and 330 (78%) non-bereaved peers from a matched random sample answered a study-specific questionnaire. Associations were assessed using multivariable logistic regression. RESULTS: Compared with non-bereaved youths, the cancer-bereaved participants were more likely to report poor family cohesion during teenage years (odds ratio [OR] 1.6, 95% CI, 1.0-2.4, and 2.3, 95% CI, 1.5-3.5, for paternally and maternally bereaved youths, respectively). This was also seen in young adulthood among maternally bereaved participants (OR 2.5; 95% CI, 1.6-4.1), while there was no difference between paternally bereaved and non-bereaved youths. After controlling for a number of covariates (eg, year of birth, number of siblings, and depression), the adjusted ORs for poor family cohesion remained statistically significant. In a further analysis stratified for gender, this difference in perceived poor family cohesion was only noted in females. CONCLUSION: Teenage loss of a parent to cancer was associated with perceived poor family cohesion during teenage years. This was also noted in young adulthood among the maternally bereaved. Females were more likely to report poor family cohesion. Our results indicate a need for increased awareness of family cohesion in bereaved-to-be families with teenage offspring, with special attention to gender roles.

Quality of Life After Open Radical Prostatectomy Compared with Robot-assisted Radical Prostatectomy.

BACKGROUND: Surgery for prostate cancer has a large impact on quality of life (QoL). OBJECTIVE: To evaluate predictors for the level of self-assessed QoL at 3 mo, 12 mo, and 24 mo after robot-assisted laparoscopic (RALP) and open radical prostatectomy (ORP). DESIGN, SETTING, AND PARTICIPANTS: The LAParoscopic Prostatectomy Robot Open study, a prospective, controlled, nonrandomised trial of more than 4000 men who underwent radical prostatectomy at 14 centres. Here we report on QoL issues after RALP and ORP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was self-assessed QoL preoperatively and at 3 mo, 12 mo, and 24 mo postoperatively. A direct validated question of self-assessed QoL on a seven-digit visual scale was used. Differences in QoL were analysed using logistic regression, with adjustment for confounders. RESULTS AND LIMITATIONS: QoL did not differ between RALP and ORP postoperatively. Men undergoing ORP had a preoperatively significantly lower level of self-assessed QoL in a multivariable analysis compared with men undergoing RALP (odds ratio: 1.21, 95% confidence interval: 1.02-1.43), that disappeared when adjusted for preoperative preparedness for incontinence, erectile dysfunction, and certainty of being cured (odds ratio: 1.18, 95% confidence interval: 0.99-1.40). Incontinence and erectile dysfunction increased the risk for poor QoL at 3 mo, 12 mo, and 24 mo postoperatively. Biochemical recurrence did not affect QoL. A limitation of the study is the nonrandomised design. CONCLUSIONS: QoL at 3 mo, 12 mo, and 24 mo after RALP or ORP did not differ significantly between the two techniques. Poor QoL was associated with postoperative incontinence and erectile dysfunction but not with early cancer relapse, which was related to thoughts of death and waking up at night with worry. PATIENT SUMMARY: We did not find any difference in quality of life at 3 mo, 12 mo, and 24 mo when open and robot-assisted surgery for prostate cancer were compared. Postoperative incontinence and erectile dysfunction were associated with poor quality of life.

Homeobox B13 G84E Mutation and Prostate Cancer Risk.

BACKGROUND: The homeobox B13 (HOXB13) G84E mutation has been recommended for use in genetic counselling for prostate cancer (PCa), but the magnitude of PCa risk conferred by this mutation is uncertain. OBJECTIVE: To obtain precise risk estimates for mutation carriers and information on how these vary by family history and other factors. DESIGN, SETTING, AND PARTICIPANTS: Two-fold: a systematic review and meta-analysis of published risk estimates, and a kin-cohort study comprising pedigree data on 11983 PCa patients enrolled during 1993-2014 from 189 UK hospitals and who had been genotyped for HOXB13 G84E. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relative and absolute PCa risks. Complex segregation analysis with ascertainment adjustment to derive age-specific risks applicable to the population, and to investigate how these vary by family history and birth cohort. RESULTS AND LIMITATIONS: A meta-analysis of case-control studies revealed significant heterogeneity between reported relative risks (RRs; range: 0.95-33.0, p<0.001) and differences by case selection (p=0.007). Based on case-control studies unselected for PCa family history, the pooled RR estimate was 3.43 (95% confidence interval [CI] 2.78-4.23). In the kin-cohort study, PCa risk for mutation carriers varied by family history (p<0.001). There was a suggestion that RRs decrease with age, but this was not significant (p=0.068). We found higher RR estimates for men from more recent birth cohorts (p=0.004): 3.09 (95% CI 2.03-4.71) for men born in 1929 or earlier and 5.96 (95% CI 4.01-8.88) for men born in 1930 or later. The absolute PCa risk by age 85 for a male HOXB13 G84E carrier varied from 60% for those with no PCa family history to 98% for those with two relatives diagnosed at young ages, compared with an average risk of 15% for noncarriers. Limitations include the reliance on self-reported cancer family history. CONCLUSIONS: PCa risks for HOXB13 G84E mutation carriers are heterogeneous. Counselling should not be based on average risk estimates but on age-specific absolute risk estimates tailored to individual mutation carriers' family history and birth cohort. PATIENT SUMMARY: Men who carry a hereditary mutation in the homeobox B13 (HOXB13) gene have a higher than average risk for developing prostate cancer. In our study, we examined a large number of families of men with prostate cancer recruited across UK hospitals, to assess what other factors may contribute to this risk and to assess whether we could create a precise model to help in predicting a man's prostate cancer risk. We found that the risk of developing prostate cancer in men who carry this genetic mutation is also affected by a family history of prostate cancer and their year of birth. This information can be used to assess more personalised prostate cancer risks to men who carry HOXB13 mutations and hence better counsel them on more personalised risk management options, such as tailoring prostate cancer screening frequency.

Preoperative staging using magnetic resonance imaging and risk of positive surgical margins after prostate-cancer surgery.

BACKGROUND: It is unclear whether preoperative staging using Magnetic Resonance Imaging (MRI) reduces the risk of positive margins in prostate cancer. We aimed to assess the effect on surgical margins and degree of nerve sparing of a pelvic MRI presented at a preoperative MRI conference. METHODS: Single institution, observational cohort study including 1037 men that underwent robot assisted radical prostatectomy between October 2013 and June 2015. Of these, 557 underwent a preoperative MRI combined with a preoperative MRI conference and 410 did not. With whole-mount prostate specimen histopathology as gold standard we assessed the ability of MRI in finding the index tumor and the sensitivity and specificity for extra prostatic extension. We calculated relative risks for positive surgical margins and non-nerve sparing procedure, adjusting for preoperative risk factors using stabilized inverse-probability weighting. RESULTS: MRI detected the index tumor in 80% of the cases. Non-organ confined disease (pT3) at histology was present in the MRI and the non-MRI group in 42% and 24%, respectively. Rate of positive surgical margins comparing the MRI and non-MRI groups was 26.7% and 33.7%, respectively, relative risk 0.79 [95% CI 0.65-0.96], weighted relative risk (wRR) 0.69 [95% CI 0.55-0.86]. The wRR of extensive positive surgical margins was 0.45 [95% CI 0.31-0.67]. Undergoing MRI was also associated with an increased risk of being operated with a non-nerve sparing technique (wRR, 1.84 [95% CI 1.11-3.03]). CONCLUSIONS: Our study suggests that preoperative prostate MRI in combination with a preoperative MRI conference affects the degree of nerve-sparing surgery and reduces positive surgical margins.

Accuracy in local staging of prostate cancer by adding a three-dimensional T2-weighted sequence with radial reconstructions in magnetic resonance imaging.

BACKGROUND: The evidence supporting the use of magnetic resonance imaging (MRI) in prostate cancer detection has been established, but its accuracy in local staging is questioned. PURPOSE: To investigate the additional value of multi-planar radial reconstructions of a three-dimensional (3D) T2-weighted (T2W) MRI sequence, intercepting the prostate capsule perpendicularly, for improving local staging of prostate cancer. MATERIAL AND METHODS: Preoperative, bi-parametric prostate MRI examinations in 94 patients operated between June 2014 and January 2015 where retrospectively reviewed by two experienced abdominal radiologists. Each patient was presented in two separate sets including diffusion-weighted imaging, without and with the 3D T2W set that included radial reconstructions. Each set was read at least two months apart. Extraprostatic tumor extension (EPE) was assessed according to a 5-point grading scale. Sensitivity and specificity for EPE was calculated and presented as receiver operating characteristics (ROC) with area under the curve (AUC), using histology from whole-mount prostate specimen as gold standard. Inter-rater agreement was calculated for the two different reading modes using Cohen's kappa. RESULTS: The AUC for detection of EPE for Readers 1 and 2 in the two-dimensional (2D) set was 0.70 and 0.68, respectively, and for the 2D + 3D set 0.62 and 0.65, respectively. Inter-rater agreement (Reader 1 vs. Reader 2) on EPE using Cohen's kappa for the 2D and 2D + 3D set, respectively, was 0.42 and 0.17 (i.e. moderate and poor agreement, respectively). CONCLUSION: The addition of 3D T2W MRI with radial reconstructions did not improve local staging in prostate cancer.