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1.
Eur Urol Oncol ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33436325

RESUMO

BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.

2.
BMC Cancer ; 20(1): 805, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32842975

RESUMO

BACKGROUND: Patients who have undergone radical cystectomy for urinary bladder cancer are not sufficiently physically active and therefore may suffer complications leading to readmissions. A physical rehabilitation programme early postoperatively might prevent or at least alleviate these potential complications and improve physical function. The main aim of the CanMoRe trial is to evaluate the impact of a standardised and individually adapted exercise intervention in primary health care to improve physical function (primary outcome) and habitual physical activity, health-related quality of life, fatigue, psychological wellbeing and readmissions due to complications in patients undergoing robotic-assisted radical cystectomy for urinary bladder cancer. METHODS: In total, 120 patients will be included and assigned to either intervention or control arm of the study. All patients will receive preoperative information on the importance of early mobilisation and during the hospital stay they will follow a standard protocol for enhanced mobilisation. The intervention group will be given a referral to a physiotherapist in primary health care close to their home. Within the third week after discharge, the intervention group will begin 12 weeks of biweekly exercise. The exercise programme includes aerobic and strengthening exercises. The control group will receive oral and written information about a home-based exercise programme. Physical function will serve as the primary outcome and will be measured using the Six-minute walk test. Secondary outcomes are gait speed, handgrip strength, leg strength, habitual physical activity, health-related quality of life, fatigue, psychological wellbeing and readmissions due to complications. The measurements will be conducted at discharge (i.e. baseline), post-intervention and 1 year after surgery. To evaluate the effects of the intervention mixed or linear regression models according to the intention to treat procedure will be used. DISCUSSION: This proposed randomised controlled trial has the potential to provide new knowledge within rehabilitation after radical cystectomy for urinary bladder cancer. The programme should be easy to apply to other patient groups undergoing abdominal surgery for cancer and has the potential to change the health care chain for these patients. TRIAL REGISTRATION: ClinicalTrials.gov. Clinical trial registration number NCT03998579 . First posted June 26, 2019.

3.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1731-1738, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32581112

RESUMO

BACKGROUND: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. METHODS: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. RESULTS: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. CONCLUSIONS: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. IMPACT: Personalized genetic risk assessments could inform prostate cancer screening decisions.

4.
Eur J Hum Genet ; 28(10): 1467-1475, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32514134

RESUMO

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

5.
Scand J Urol ; 54(2): 115-121, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32266854

RESUMO

Background: This study investigated prostate cancer (PC)-specific survival and overall survival (OS) in a population-based castration-resistant PC (CRPC) cohort.Methods: Data from Stockholm Prostate-Specific Antigen (PSA) and Biopsy Register patients with increasing PSA despite gonadotropin-releasing hormone treatment or surgical castration (n = 1,712) included PSA values and biopsies from 2003 to 2015 and were linked to the National Prostate Cancer Register and Prescribed Drug Register. Kaplan-Meier method estimated PC-specific survival and OS, stratified by metastasis at PC diagnosis, and Cox regression estimated hazard ratios (HRs) for Gleason score and T-stage at PC diagnosis and for age and calendar period at CRPC onset by metastasis status at diagnosis.Results: Median OS after CRPC onset was 23.2 months (95% CI = 21.0-25.9) among patients without metastases (M0) at primary diagnosis, and 13.2 months (11.3-14.5) among patients with metastases (M1). Median PC-specific survival from CRPC onset was 30.3 (27.5-34.1) months and 13.3 (12.1-15.8) months for M0 and M1 patients, respectively. Biopsy Gleason score ≥ 8 was associated with higher all-cause mortality than ≤6 (HR = 2.07 [95% CI = 1.43-3.01]) and PC-specific mortality (2.07 [1.27-3.40]) after CRPC among patients with M0 disease. Patients developing CRPC from 2012 onward had lower all-cause mortality (HR = 0.71 [95% CI = 0.60-0.85] [M0]; 0.60 [0.47-0.77] [M1]) and PC-specific mortality (0.73 [0.57-0.94] [M0]; 0.62 [0.46-0.84] [M1]) compared with those prior to 2012.Conclusions: M1 disease at PC diagnosis was associated with worse survival after CRPC onset versus M0. Higher Gleason score at diagnosis was associated with higher mortality after CRPC onset in M0 patients at diagnosis.

6.
Scand J Urol ; 54(1): 1-6, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31876229

RESUMO

Background: There is conflicting evidence about the association between prostate cancer and Lower Urinary Tract Symptoms (LUTS). We aimed to describe the prevalence of LUTS and its association with prostate cancer risk.Methods: We studied the association between International Prostate Symptom Score (IPSS) and prostate cancer in a population-based sample of men (n = 45,595) aged 50-69 years from the Stockholm3 study. Men with PSA ≥3 ng/ml (n = 4579) underwent systematic prostate biopsies. We used the International Society of Urological Pathology Gleason Grading (ISUP grade) and performed regression analysis for risk of any cancer (n = 1797), ISUP grade ≥2 (n = 840) and advanced cancer, defined as ISUP grade ≥3 or cT ≥3 (n = 353).Results: 74.6% of all men had no or mild LUTS (IPSS ≤7) and 3.2% had severe LUTS (IPSS >19). Men with any, ISUP grade ≥2 or advanced cancer had lower median IPSS compared to men with benign biopsy (any cancer: 4 (IQR 2-9); ISUP grade ≥2: 4 (2-8); advanced cancer: 4 (2-8); benign biopsy: 6 (3-11); p < 0.05). IPSS was not associated with increased risk of cancer in multivariate analyses (OR (any cancer) 0.97; 95% CI 0.96-0.98; OR (ISUP grade ≥2) 0.97; 95% CI 0.96-0.99; OR (advanced cancer) 0.99; 95% CI 0.99-1.01).Conclusions: Three-quarters of men aged 50-69 years report no or mild LUTS. Our data do not support any clinically meaningful association between LUTS and prostate cancer. Specifically, men with advanced prostate cancer did not exhibit more urinary symptoms than men without cancer.

7.
JAMA Netw Open ; 2(11): e1914689, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31693126

RESUMO

Importance: Diabetic men appear to have a lower risk of prostate cancer. Whether antidiabetic medications are protective or potentially mask prostate cancer by lowering prostate-specific antigen (PSA) levels is unclear. Objective: To examine the associations of antidiabetic medication use with (1) PSA levels, (2) frequency of PSA testing, (3) receipt of biopsy following elevated PSA results, and (4) prostate cancer detection at biopsy. Design, Setting, and Participants: Population-based cohort study using data from the Stockholm PSA and Biopsy Register. Participants were all prostate cancer-free men aged 40 to 79 years residing in Stockholm County, Sweden, between January 1, 2006, and December 31, 2015. Data were analyzed from November 2018 to March 2019. Exposures: One or more prescription for metformin, sulfonylurea, or insulin, as recorded in Sweden's National Prescribed Drug Register. Main Outcomes and Measures: Levels of PSA following first exposure to antidiabetic medications were assessed using multivariable linear regression. Frequency of PSA testing was assessed via multivariable Poisson regression. Biopsy following elevated PSA (≥3.0 ng/mL) and prostate cancer detection at biopsy were assessed via multivariable logistic regression. Results: The cohort of 564 666 men (median [range] age, 65 [40-79] years) consisted of 4583 men initially exposed to metformin, 1104 exposed to sulfonylurea, and 978 exposed to insulin who were age matched with unexposed men (1:5). Exposed men had lower median (interquartile range) PSA levels before starting antidiabetic medications compared with unexposed men (1.2 [0.7-2.5] vs 1.6 [0.8-3.2] ng/mL). After accounting for baseline differences, PSA levels did not vary from those of unexposed men following exposure to antidiabetic medications. Frequency of PSA testing was higher for those receiving metformin (rate ratio, 1.07; 95% CI, 1.06-1.09) and sulfonylurea (rate ratio, 1.06; 95% CI, 1.03-1.08) but was lower for those receiving insulin (rate ratio, 0.79; 95% CI, 0.77- 0.81). Likelihood of biopsy after elevated PSA was lower among men receiving metformin (odds ratio, 0.87; 95% CI, 0.80-0.96) and insulin (odds ratio, 0.83; 95% CI, 0.74-0.93). There were no differences in prostate cancer detection at biopsy, regardless of PSA levels that triggered the biopsy. Conclusions and Relevance: This study's findings do not support the hypothesis that the inverse association between diabetes and prostate cancer is mediated through antidiabetic medications lowering PSA levels to mask prostate cancer. They do suggest potential detection bias due to fewer biopsies among men receiving antidiabetic medications, which may explain the lower prostate cancer risk in men with diabetes.


Assuntos
Hipoglicemiantes/uso terapêutico , Antígeno Prostático Específico/sangue , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Adulto , Idoso , Biópsia/estatística & dados numéricos , Estudos de Casos e Controles , Estudos de Coortes , Diabetes Mellitus/tratamento farmacológico , Escolaridade , Predisposição Genética para Doença , Humanos , Insulina/uso terapêutico , Masculino , Estado Civil , Metformina/uso terapêutico , Pessoa de Meia-Idade , Neoplasias da Próstata/epidemiologia , Sistema de Registros , Compostos de Sulfonilureia/uso terapêutico , Suécia/epidemiologia
8.
BMC Urol ; 19(1): 73, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383015

RESUMO

BACKGROUND: Patient-related factors such as concern about cancer are believed to influence both men's decisions to undergo prostate specific antigen (PSA) testing and to have definitive treatment if diagnosed with low risk prostate cancer (PCa). The potential link between screening frequency and choice of active surveillance (AS) for low risk disease has not been studied previously. Our aim was to investigate whether there is any association between PCa screening frequency or previous negative prostate biopsy and uptake of AS among men with low risk PCa. METHODS: This register-based study included all men ≤75 years from Stockholm who were diagnosed with low risk PCa from 2008 to 2014 (n = 4336). Pre-diagnostic PSA testing and biopsy histories were obtained from the Stockholm PSA and Biopsy Register, a population-based register for the Stockholm country. The association between previous screening/biopsy history and AS uptake (based on primary treatment recorded in the National Prostate Cancer Register) was examined using multivariable logistic regression. RESULTS: Forty seven percent of men with low risk PCa underwent AS. Uptake was associated with older age, very low risk disease, more recent diagnosis and absence of family history. None of the screening/biopsy measures (testing frequency, mean interval, PSA velocity, highest pre-diagnostic PSA or prior negative biopsy) were associated with uptake of AS among men with low risk PCa. Generalisability to settings with different policies and practices may be limited. CONCLUSION: We found no evidence that screening frequency and negative biopsy influence uptake of AS among Swedish men with low risk PCa. Further research is required to determine factors that still present barriers for men taking up AS.


Assuntos
Detecção Precoce de Câncer/estatística & dados numéricos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Conduta Expectante/estatística & dados numéricos , Idoso , Biópsia , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/patologia , Medição de Risco
9.
Eur Urol Oncol ; 2(5): 490-496, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31412016

RESUMO

BACKGROUND: Risk prediction models and magnetic resonance imaging (MRI) of the prostate can reduce unnecessary biopsies and overdiagnosis of low-risk prostate cancer. However, it is unclear how these tools should be used in concert. OBJECTIVE: To develop a unified risk prediction model (S3M-MRI) that combines the Stockholm3 score (based on protein and genetic markers and clinical variables) and Prostate Imaging-Reporting and Data System v.2 scores modified for MRI without contrast (modPI-RADS). DESIGN, SETTING, AND PARTICIPANTS: We used data for 532 men from the prospective multicentre STHLM3-MRI diagnostic study to construct S3M-MRI. We compared S3M-MRI to Stockholm3 and modPI-RADS alone with respect to model discrimination, calibration, and net benefit. We also compared clinical outcomes for five diagnostic strategies according to the use of combinations of the three models. RESULTS AND LIMITATIONS: The area under the receiver operating characteristic curve (AUC) was 0.88 (95% confidence interval [CI] 0.85-0.91) for S3M-MRI, which was significantly higher (p=0.04) than for Stockholm3 (0.86, 95% CI 0.83-0.89) and modPI-RADS (0.83, 95% CI 0.79-0.87). S3M-MRI had a higher net benefit on decision curve analysis for clinically relevant probability thresholds for biopsy recommendation in comparison to Stockholm3 and modPI-RADS. However, for different diagnostic strategies, sequential use of Stockholm3 followed by MRI only for Stockholm3-positive men resulted in a similar number of unnecessary biopsies (64 vs 69) and diagnosed International Society of Urological Pathology (ISUP) grade group 1 cancers (56 vs 51) at similar sensitivity for ISUP grade group ≥2 cancers, while avoiding 38% of MRI scans. Limitations include the ethnically homogeneous study population. CONCLUSIONS: The unified S3M-MRI model was superior to the Stockholm3 model and modPI-RADS alone. However, the S3M-MRI improvement was marginal compared to sequential use of Stockholm3 followed by MRI, and resulted in 60% more MRI scans. PATIENT SUMMARY: A new risk prediction model combining clinical variables, genetic and protein biomarkers, and results from prostate magnetic resonance imaging improved the clinical outcome performance of prostate cancer diagnostics.


Assuntos
Biomarcadores Tumorais/sangue , Imagem por Ressonância Magnética/estatística & dados numéricos , Modelos Biológicos , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico , Idoso , Biópsia com Agulha de Grande Calibre/efeitos adversos , Biópsia com Agulha de Grande Calibre/estatística & dados numéricos , Humanos , Masculino , Sobremedicalização/prevenção & controle , Sobremedicalização/estatística & dados numéricos , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Próstata/patologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Curva ROC , Medição de Risco/métodos
10.
PLoS One ; 14(6): e0218280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31194822

RESUMO

BACKGROUND: Knowledge about the relationship between PSA, age and ISUP grade group (ISUP) 1 prostate cancer can improve clinical and biological understanding of prostate cancer. We aimed to investigate the associations between PSA and age and the risk of ISUP 1 and ISUP ≥ 2 prostate cancer, respectively. METHODS: We included 6 083 men aged 50-69 biopsied with a total of 72 996 individual biopsy cores from the prospective and population based Stockholm3 diagnostic study. We computed the risk of ISUP 1 and ISUP ≥ 2 prostate cancer and their respective associations with PSA and age. Since lower Gleason grades often are masked by higher grades in the overall Gleason score, we compared associations both for overall Gleason score and for Gleason on individual biopsy cores. RESULTS: ISUP 1 prostate cancer was not significantly associated with PSA at diagnosis: odds ratios ranged from 0.82 (95%CI: 0.68-1.00) for PSA 3-4 ng/mL, 0.96 (95%CI: 0.79-1.16) for PSA 4-6 ng/mL, 0.95 (95%CI: 0.75-1.21) for PSA 6-10 ng/mL, and 0.92 (95%CI: 0.58-1.45) for PSA 10-15 ng/mL compared with PSA 2-3 ng/mL. Age was not significantly associated with risk of ISUP 1 cancer. This contrasts to the strong relationship between ISUP ≥ 2 prostate cancer and its respective associations with PSA and age. CONCLUSIONS: We find no significant association between the risk of ISUP 1 prostate cancer and PSA and age at diagnosis indicating that PSA contribution from ISUP 1 prostate cancer is closer to that of benign prostate tissue than to that of ISUP ≥ 2 prostate cancer.


Assuntos
Fatores Etários , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Idoso , Biópsia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia
11.
BMJ Open ; 9(6): e027816, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201191

RESUMO

INTRODUCTION: Prostate cancer is a leading cause of cancer death among men in the Western world. Early detection of prostate cancer has been shown to decrease mortality, but has limitations with low specificity leading to unnecessary biopsies and overdiagnosis of low-risk cancers. The STHLM3 trial has paved way for improved specificity in early detection of prostate cancer using the blood-based STHLM3 test for identifying men at increased risk of harbouring significant prostate cancer. Targeted prostate biopsies based on MRI images have shown non-inferior sensitivity to detect significant prostate cancer and decrease the number of biopsies and non-significant cancers among men referred for prostate biopsy in clinical practice. The strategy of the STHLM3-MRI project is to study an improved diagnostic pathway including an improved blood-based test for identification of men with increased risk of prostate cancer and use of MRI to select men for diagnostic workup with targeted prostate biopsies. METHODS: This study compares prostate cancer detection using prostate-specific antigen (PSA) and systematic biopsies to the improved pathway for prostate cancer detection using the STHLM3 test and targeted biopsies in a screening context. The study will recruit 10 000 participants during 1 June 2018 to 1 June 2020 combining a paired and randomised design. Participants are grouped by PSA and Stockholm3 test level. Men with Stockholm3 ≥11% or PSA ≥3 ng/mL are randomised to systematic or MRI-targeted biopsies. This protocol follows SPIRIT guidelines. Endpoints include the number of detected prostate cancers, number of performed biopsy procedures and number of performed MRIs. Additional aims include to assess the health economic consequences and development of automated image-analysis. ETHICS AND DISSEMINATION: The study is approved by the regional ethical review board in Stockholm (2017-1280/31). The study findings will be published in peer-review journals. Findings will also be disseminated by conference/departmental presentations and by media. TRIAL REGISTRATION NUMBER: NCT03377881; Pre-results.


Assuntos
Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/diagnóstico , Idoso , Biópsia por Agulha/métodos , Procedimentos Clínicos , Detecção Precoce de Câncer , Humanos , Biópsia Guiada por Imagem/métodos , Calicreínas/metabolismo , Imagem por Ressonância Magnética/métodos , Masculino , Sobremedicalização , Pessoa de Meia-Idade , Próstata , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Medição de Risco , Sensibilidade e Especificidade
12.
Eur J Surg Oncol ; 45(10): 1847-1853, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31030805

RESUMO

INTRODUCTION: Mobilisation reduces the risk of complications after abdominal surgery. Despite that, patients spend most of their time immobilised during hospital stay. Hence, the aim of this study was to evaluate a tool called the Activity board, which includes behaviour change techniques, regarding effects on mobilisation and postoperative recovery after abdominal cancer surgery. MATERIAL AND METHODS: Patients who were planned for abdominal surgery due to colorectal, ovarian or urinary bladder cancer, and at least three postoperative days at Karolinska University Hospital were included in this non-randomised controlled trial, from January 2017 to May 2018. The patients were allocated to Activity board or standard treatment when they were admitted to hospital. Mobilisation was evaluated objectively with activity monitor the first three postoperative days, and postoperative recovery was assessed continuously during hospital stay. RESULTS: In total, 133 patients, mean (sd) age 68.1 (12.3) years were included. The patients with the Activity board had postoperatively higher levels of mobilisation, compared to standard treatment, as mean value over the first three days, steps, median (min-max) 1057 (3-10433) and 360 (0-6546), respectively (p = 0.001), and for each day separately. Further, the group with the Activity board had a shorter length of stay, 6 (3-13), compared to standard treatment 7 (3-14) (p = 0.027). CONCLUSION: The Activity board is an effective tool to enhance mobilisation after abdominal surgery due to cancer, in hospital settings. Using the Activity board could lead to improved postoperative recovery.


Assuntos
Neoplasias Abdominais/cirurgia , Terapia Comportamental/métodos , Procedimentos Cirúrgicos do Sistema Digestório/reabilitação , Modalidades de Fisioterapia , Complicações Pós-Operatórias/prevenção & controle , Cuidados Pré-Operatórios/métodos , Neoplasias Abdominais/reabilitação , Idoso , Feminino , Humanos , Tempo de Internação/tendências , Masculino , Atividade Motora/fisiologia
14.
Prostate Cancer Prostatic Dis ; 22(3): 391-398, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30504811

RESUMO

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.


Assuntos
Imagem por Ressonância Magnética , Margens de Excisão , Próstata/diagnóstico por imagem , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Período Pré-Operatório , Próstata/patologia , Próstata/cirurgia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Fatores de Risco , Sensibilidade e Especificidade
15.
Eur Urol Focus ; 5(5): 842-848, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-29433987

RESUMO

BACKGROUND: Although prostate-specific antigen (PSA) testing is common, little is known about the pattern of retesting by either PSA values or subsequent prostate biopsies. Poor follow-up of high PSA values may lead to delayed diagnosis. OBJECTIVE: To estimate the probabilities of follow-up (including retesting, prostate biopsies, diagnosis, and cause-specific death) for men undergoing prostate cancer testing at a population level. DESIGN, SETTING, AND PARTICIPANTS: Cohort study design for men living in Stockholm with no previous diagnosis of prostate cancer between 2003 and 2015. Men were linked to the national health and population registries in Sweden. We report follow-up for men aged 50-79 yr at 2003 or at their index PSA test. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: State probabilities with 95% confidence intervals (CIs) were calculated using multistate Markov models. RESULTS AND LIMITATIONS: Among men not previously diagnosed with prostate cancer with an initial PSA value of ≥10ng/ml, the proportions at 1 yr with no subsequent testing or only elevated PSA test values >3ng/ml were 21.7% (95% CI: 19.5, 23.9), 25.2% (95% CI: 23.9, 26.6), and 47.7% (95% CI: 46.2, 49.1) for those aged 50-59, 60-69, and 70-79 yr, respectively. No significant changes were noticed when stratifying by comorbidities. Limitations include the lack of detail from patient medical charts. This detail would have allowed for more accurate assessment of appropriate clinical follow-up. CONCLUSIONS: Regardless of medical history, a large proportion of men with PSA≥10ng/ml were not followed appropriately at 1 yr after the index PSA test. This may partially explain why opportunistic testing is not as effective as screening within trials to reduce prostate cancer mortality. PATIENT SUMMARY: For men aged 50-69 yr, who undertake a prostate-specific antigen (PSA) test, a PSA level of >10ng/ml should prompt further investigation. However, we found that one out of 10 of these men did not receive repeat testing within 1 yr of the initial test. This may partially explain why opportunistic prostate cancer testing is less effective than screening trials.


Assuntos
Calicreínas/sangue , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Idoso , Biópsia , Estudos de Coortes , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/mortalidade , Suécia
16.
Eur Urol Focus ; 5(5): 788-798, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-29627197

RESUMO

CONTEXT: Until recently, there has been a lack of evidence-based treatment alternatives in men with nonmetastatic castrate-resistant prostate cancer (NM-CRPC). However, new evidence-based treatment alternatives are emerging. OBJECTIVE: We aimed to describe time-to-event outcomes in NM-CRPC patients based on evidence from both prospective and retrospective studies. Second, we aimed to describe predictors of these outcomes in the same patient population. EVIDENCE ACQUISITION: A systematic review was conducted to identify clinical studies (both prospective and retrospective) in NM-CRPC patients. All published Kaplan-Meier curves were digitized, and individual participant data were extracted using a published and validated R code. The following outcomes were considered: overall survival (OS), bone metastasis-free survival (BMFS), time to bone metastasis (TTBM), metastasis-free survival, time to metastasis, time to progression (TTP), progression-free survival, and time to prostate-specific antigen (PSA) progression. Second, we described all predictor/outcome relationships. EVIDENCE SYNTHESIS: Median survival times, in months, for OS, BMFS, TTBM, and TTP in placebo arms of randomized clinical trials are 45.3 (95% confidence interval [CI]: 43.5-46.8), 31.5 (95% CI: 28-33.4), 28.8 (95% CI: 25.2-31.6), and 22.2 (95% CI: 19.3-24.8), respectively. In general, reported outcomes in retrospective studies seemed to be longer than those reported in clinical trials. Baseline PSA nadir levels, PSA doubling time, PSA velocity, and alkaline phosphatase velocity are reliable predictors of time-to-event outcomes in NM-CRPC patients, whereas Gleason score is not. CONCLUSIONS: NM-CRPC is a long-standing condition where effective treatments to slow down disease progression historically have been lacking. Compared with prospective studies, retrospective studies have had limited ability to correctly identify NM-CRPC patients and estimate time to different outcomes in NM-CRPC patients. PATIENT SUMMARY: For patients with nonmetastatic castration-resistant prostate cancer (NM-CRPC), currently no effective treatments resulting in longer survival compared with watchful waiting are available. On average, without additional treatment, half of these patients survive <45 mo after NM-CRPC diagnosis.


Assuntos
Neoplasias de Próstata Resistentes à Castração/terapia , Humanos , Masculino , Metanálise como Assunto , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
17.
Prostate Cancer Prostatic Dis ; 22(1): 137-142, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30171228

RESUMO

BACKGROUND: Several blood-based tests have been suggested to improve prostate cancer testing. The Stockholm3 test has been shown to reduce the number of prostate biopsies, to decrease detection of low-grade cancer and to maintain the detection rate of ISUP Gleason Group (GG) ≥ 2 cancer in a screening-by-invitation setting. We aimed to validate the performance of the Stockholm3 test in an independent, clinical practice cohort. METHODS: The study-population consisted of 533 men in ages 45-75 without previous diagnosis of prostate cancer scheduled for prostate biopsy at any of three centers in Norway and Sweden. Blood samples for Stockholm3 analysis were drawn prior to systematic prostate biopsies. Clinically significant prostate cancer was defined as any finding of ISUP Grade Group (GG) 2 or higher. We calculated area under the curve (AUC) for predicting prostate cancer at biopsy and calculated. Models including PSA and PSA-density (PSA/prostate volume) were compared to a model including also clinical information, protein levels and single nucleotide polymorphisms (SNP). RESULTS: 263 of 533 (49%) participants were diagnosed with prostate cancer. 162 men had prostate cancer with GG ≥ 2. The Stockholm3 test discriminated better for GG ≥ 2 prostate cancer than PSA in combination with PSA-density AUC 8.9 (95% CI 82.7-89.2) and AUC 74.8 (95% CI 70.3-79.3). Using a Stockholm3 cut-off of 10% risk of GG ≥ 2 cancer, 38% of the biopsy procedures were saved, however delaying diagnosis for 6% (n = 10) of men with GG ≥ 2 cancer. Using PSA-density 0.1 as cut-off for biopsy saved 35% of biopsies, delaying diagnosis for 16% (n = 26) of men with GG ≥ 2 cancer. CONCLUSION: A prediction model including clinical information, protein levels and SNPs was independently validated in a clinical practice cohort and reduces the number of un-necessary biopsies while delaying diagnosis for a limited number of men.


Assuntos
Biomarcadores Tumorais/sangue , Testes Hematológicos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Idoso , Biópsia , Diagnóstico Diferencial , Testes Hematológicos/métodos , Testes Hematológicos/normas , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Noruega , Polimorfismo de Nucleotídeo Único , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Curva ROC , Suécia
18.
Genome Med ; 10(1): 85, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30458854

RESUMO

BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.


Assuntos
Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Impressões Digitais de DNA , Rearranjo Gênico , Genômica , Hematopoese , Humanos , Masculino , Instabilidade de Microssatélites , PTEN Fosfo-Hidrolase/genética , Receptores Androgênicos/genética , Proteínas de Ligação a Retinoblastoma/genética , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética
19.
Eur Urol ; 74(6): 722-728, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30001824

RESUMO

BACKGROUND: More specific diagnostic for prostate cancer is needed to decrease overdetection and number of diagnostic procedures. OBJECTIVE: To assess the performance of combining a blood-based biomarker panel and magnetic resonance imaging (MRI)-targeted biopsies for prostate cancer detection. DESIGN, SETTING, AND PARTICIPANTS: We used a prospective, multicenter, paired diagnostic study design. A total of 532 men aged 45-74 yr referred for prostate cancer workup were included during 2016-2017. INTERVENTION: Participants underwent blood sampling for analysis of the Stockholm3 test including protein biomarkers, genetic polymorphisms, and clinical variables; 1.5 T MRI; systematic prostate biopsies; and MRI-targeted biopsies to lesions with Prostate Imaging Reporting and Data System version 2 ≥3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main outcome was numbers of detected prostate cancer characterized by grade group (GG) and the number of performed biopsies using relative sensitivity (RS). RESULTS AND LIMITATIONS: Median prostate-specific antigen was 6.3 ng/ml, and mean age was 63.9 yr. Targeted and systematic biopsies detected 170 and 162 GG ≥2 tumors, respectively (RS 1.05; 95% confidence interval [CI] 0.96-1.14). Compared with performing systematic biopsies on all men, performing targeted and systematic biopsies only on men with >10% risk of GG ≥2 cancer, as predicted by the Stockholm3 test, required 62% (95% CI 58-66) of the biopsy procedures and detected 58% (95% CI 48-70) of GG 1 disease, with increased sensitivity for GG ≥2 detection (RS 1.10; 95% CI 1.02-1.17). Performing only targeted biopsies in men with elevated Stockholm3 test altered these results only slightly. Compared with performing systematic and targeted biopsies on all men, performing this only for men with an elevated Stockholm3 test decreased detection of GG ≥2 cancer slightly (RS 0.92; 95% CI 0.88-0.95). Limitations include lacking knowledge of true disease prevalence. CONCLUSIONS: These findings provide evidence that strategies combining the blood-based Stockholm3 test and MRI-targeted biopsies can be used to inform biopsy decision making. PATIENT SUMMARY: In this study, 532 men coming for prostate cancer workup underwent blood sampling, and both traditional and magnetic resonance imaging/fusion-guided prostate biopsies. We report that performing targeted biopsies only in men with an elevated risk as assessed by the Stockholm3 test saved biopsies, decreased overdetection, and maintained the number of detected high-grade cancers.


Assuntos
Biomarcadores Tumorais/sangue , Calicreínas/sangue , Imagem por Ressonância Magnética , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico por imagem , Idoso , Biomarcadores Tumorais/genética , Tomada de Decisão Clínica , Dinamarca , Predisposição Genética para Doença , Humanos , Biópsia Guiada por Imagem , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fenótipo , Polimorfismo Genético , Valor Preditivo dos Testes , Estudos Prospectivos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Reprodutibilidade dos Testes , Suécia , Fatores de Tempo
20.
Nat Genet ; 50(7): 928-936, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29892016

RESUMO

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.


Assuntos
Neoplasias da Próstata/genética , Estudos de Casos e Controles , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Risco
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