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BACKGROUND AND OBJECTIVE: There is no standardized regimen for follow-up after radical cystectomy (RC) for bladder cancer (BC). To address this gap, we conducted a multicenter study involving urologist members from the European Association of Urology (EAU) bladder cancer guideline panels. Our objective was to identify consistent post-RC follow-up strategies and develop a practice-based framework based on expert opinion. METHODS: We surveyed 27 urologist members of the EAU guideline panels for non-muscle-invasive bladder cancer and muscle-invasive and metastatic bladder cancer using a pre-tested questionnaire with dichotomous responses. The survey inquired about follow-up strategies after RC and the use of risk-adapted strategies. Consistency was defined as >75% affirmative responses for follow-up practices commencing 3 mo after RC. Descriptive statistics were used for analysis. KEY FINDINGS AND LIMITATIONS: We received responses from 96% of the panel members, who provided data from 21 European hospitals. Risk-adapted follow-up is used in 53% of hospitals, with uniform criteria for high-risk (at least ≥pT3 or pN+) and low-risk ([y]pT0/a/1N0) cases. In the absence of agreement for risk-based follow up, a non-risk-adapted framework for follow-up was developed. Higher conformity was observed within the initial 3 yr, followed by a decline in subsequent follow-up. Follow-up was most frequent during the first year, including patient assessments, physical examinations, and laboratory tests. Computed tomography of the chest and abdomen/pelvis was the most common imaging modality, initially at least biannually, and then annually from years 2 to 5. There was a lack of consistency for continuing follow-up beyond 10 yr after RC. CONCLUSIONS AND CLINICAL IMPLICATIONS: This practice-based post-RC follow-up framework developed by EAU bladder cancer experts may serve as a valuable guide for urologists in the absence of prospective randomized studies. PATIENT SUMMARY: We asked urologists from the EAU bladder cancer guideline panels about their patient follow-up after surgical removal of the bladder for bladder cancer. We found that although urologists have varying approaches, there are also common follow-up practices across the panel. We created a practical follow-up framework that could be useful for urologists in their day-to-day practice.
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Objectives: To evaluate effects of dose intensified salvage radiotherapy (sRT) on erectile function in biochemically recurrent prostate cancer (PC) after radical prostatectomy (RP). Materials and methods: Eligible patients had evidence of biochemical failure after RP and a PSA at randomization of ≤ 2 ng/ml. Erectile dysfunction (ED) was investigated as secondary endpoint within the multicentre randomized trial (February 2011 to April 2014) in patients receiving either 64 Gy or 70 Gy sRT. ED and quality of life (QoL) were assessed using CTCAE v4.0 and the EORTC QoL questionnaires C30 and PR25 at baseline and up to 5 years after sRT. Results: 344 patients were evaluable. After RP 197 (57.3 %) patients had G0-2 ED while G3 ED was recorded in 147 (42.7 %) patients. Subsequently, sexual activity and functioning was impaired. 5 years after sRT, 101 (29.4 %) patients noted G0-2 ED. During follow-up, 44.2 % of patients with baseline G3 ED showed any improvement and 61.4 % of patients with baseline G0-2 ED showed worsening. Shorter time interval between RP and start of sRT (p = 0.007) and older age at randomization (p = 0.005) were significant predictors to more baseline ED and low sexual activity in the long-term. Age (p = 0.010) and RT technique (p = 0.031) had a significant impact on occurrence of long-term ED grade 3 and worse sexual functioning. During follow-up, no differences were found in erectile function, sexual activity, and sexual functioning between the 64 Gy and 70 Gy arm. Conclusion: ED after RP is a known long-term side effect with significant impact on patients' QoL. ED was further affected by sRT, but dose intensification of sRT showed no significant impact on erectile function recovery or prevalence of de novo ED after sRT. Age, tumor stage, prostatectomy and RT-techniques, nerve-sparing and observation time were associated with long-term erectile function outcome.ClinicalTrials.gov. Identifier: NCT01272050.
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We performed a urine cytology analysis of a pharmacologically induced diuresis for the diagnosis of upper tract urothelial carcinoma. To evaluate the diagnostic value of cytology of pharmacologically forced diuresis, an initial cohort of 77 consecutive patients with primary upper tract urothelial carcinoma treated via radical surgery was enrolled. To evaluate pharmacologically forced diuresis cytology as a follow-up procedure, a second cohort of 1250 patients who underwent a radical cystectomy for bladder cancer was selected. In the first cohort, the sensitivity of cytology of pharmacologically forced diuresis in patients with invasive, high-grade, low-grade, and concomitant carcinoma in situ was 8%, 9%, 0%, and 14%, respectively. In the second cohort, cytology of pharmacologically forced diuresis was positive in 30/689 (4.3%) patients, in whom upper urinary tract recurrence was present in 21/30 (70%) of cases, and urethral recurrence was present in 8/30 (26%) of cases. As a follow-up tool, cytology of pharmacologically forced diuresis showed a sensitivity, specificity, and positive and negative predictive values of 60%, 99%, 70%, and 98%, respectively. Overall, as a diagnostic tool, the sensitivity of cytology of pharmacologically forced diuresis is slightly better in patients with invasive upper tract urothelial carcinoma and concomitant carcinoma in situ. As a follow-up method, positive cytology of pharmacologically forced diuresis is strongly related to cancer recurrence and can reveal urethral recurrence. Cytology of pharmacologically forced diuresis might be useful in cases with contraindications for imaging or when achieving endoscopic access to the upper urinary tract is difficult.
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CONTEXT: We present an overview of the updated 2023 European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC). OBJECTIVE: To provide practical evidence-based recommendations and consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment. EVIDENCE ACQUISITION: A broad and comprehensive scoping exercise covering all areas of the MMIBC guidelines has been performed annually since 2017. Searches cover the Medline, EMBASE, and Cochrane Libraries databases for yearly guideline updates. A level of evidence and strength of recommendation are assigned. The evidence cutoff date for the 2023 MIBC guidelines was May 4, 2022. EVIDENCE SYNTHESIS: Patients should be counselled regarding risk factors for bladder cancer. Pathologists should describe tumour and lymph nodes in detail, including the presence of histological subtypes. The importance of the presence or absence of urothelial carcinoma (UC) in the prostatic urethra is emphasised. Magnetic resonance imaging (MRI) of the bladder is superior to computed tomography (CT) for disease staging, specifically in differentiating T1 from T2 disease, and may lead to a change in treatment approach in patients at high risk of an invasive tumour. Imaging of the upper urinary tract, lymph nodes, and distant metastasis is performed with CT or MRI; the additional value of flurodeoxyglucose positron emission tomography/CT still needs to be determined. Frail and comorbid patients should be evaluated by a multidisciplinary team. Postoperative histology remains the most important prognostic variable, while circulating tumour DNA appears to be an interesting predictive marker. Neoadjuvant systemic therapy remains cisplatin-based. In motivated and selected women and men, sexual organ-preserving cystectomy results in better functional outcomes without compromising oncological outcomes. Robotic and open cystectomy have comparable outcomes and should be combined with (extended) lymph node dissection. The diversion type is an individual choice after taking patient and tumour characteristics into account. Radical cystectomy remains a highly complex procedure with considerable morbidity and risk of mortality, although lower rates are observed for higher hospital volumes (>20 cases/yr). With proper patient selection, trimodal therapy (chemoradiation) has comparable outcomes to radical cystectomy. Adjuvant chemotherapy after surgery improves disease-specific survival and overall survival (OS) in patients with high-risk disease who did not receive neoadjuvant treatment, and is strongly recommended. There is a weak recommendation for adjuvant nivolumab, as OS data are not yet available. Health-related quality of life should be assessed using validated questionnaires at baseline and after treatment. Surveillance is needed to monitor for recurrent cancer and functional outcomes. Recurrences detected on follow-up seem to have better prognosis than symptomatic recurrences. CONCLUSIONS: This summary of the 2023 EAU guidelines provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice. PATIENT SUMMARY: The European Association of Urology guidelines panel on muscle-invasive and metastatic bladder cancer has released an updated version of the guideline containing information on diagnosis and treatment of this disease. Recommendations are based on studies published up to May 4, 2022. Surgical removal of the bladder and bladder preservation are discussed, as well as updates on the use of chemotherapy and immunotherapy in localised and metastatic disease.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Urologia , Masculino , Humanos , Feminino , Neoplasias da Bexiga Urinária/patologia , Carcinoma de Células de Transição/patologia , Qualidade de Vida , Cistectomia/métodos , Músculos/patologia , Invasividade NeoplásicaRESUMO
OBJECTIVE: To assess the long-term safety of nerve-sparing radical prostatectomy (NSRP) in men with high-risk prostate cancer (PCa) by comparing survival outcomes, disease recurrence, the need for additional therapy, and perioperative outcomes of patients undergoing NSRP to those having non-NSRP. PATIENTS AND METHODS: We included consecutive patients at a single, academic centre who underwent open RP for high-risk PCa, defined as preoperative prostate-specific antigen level of > 20 ng/mL and/or postoperative International Society of Urological Pathology Grade Group 4 or 5 (i.e., Gleason score ≥ 8) and/or ≥pT3 and/or pN1 assessing the RP and lymph node specimen. We calculated a propensity score and used inverse probability of treatment weighting to match baseline characteristics of patients with high-risk PCa who underwent NSRP vs non-NSRP. We analysed oncological outcome as time-to-event and calculated hazard ratios (HRs). RESULTS: A total of 726 patients were included in this analysis of which 84% (n = 609) underwent NSRP. There was no evidence for the positive surgical margin rate being different between the NSRP and non-NSRP groups (47% vs 49%, P = 0.64). Likewise, there was no evidence for the need for postoperative radiotherapy being different in men who underwent NSRP from those who underwent non-NSRP (HR 0.78, 95% confidence interval [CI] 0.53-1.15). NSRP did not impact the risk of any recurrence (HR 0.99, 95% CI 0.73-1.34, P = 0.09) and there was no evidence for survival being different in men who underwent NSRP to those who underwent non-NSRP (HR 0.65, 95% CI 0.39-1.08). There was also no evidence for the cancer-specific survival (HR 0.56, 95% CI 0.29-1.11) or progression-free survival (HR 0.99, 95% CI 0.73-1.34) being different between the groups. CONCLUSION: In patients with high-risk PCa, NSRP can be attempted without compromising long-term oncological outcomes provided a comprehensive assessment of objective (e.g., T Stage) and subjective (e.g., intraoperative appraisal of tissue planes) criteria are conducted.
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Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Recidiva Local de Neoplasia/patologia , Prostatectomia/efeitos adversos , Estudos Longitudinais , Gradação de TumoresRESUMO
Nerve sparing (NS) is a surgical technique to optimize functional outcomes of radical prostatectomy (RP). However, it is not recommended in high risk (HR) cases because of the risk of a positive surgical margin that may increase the risk of cancer recurrence. In the last two decades there has been a change of perspective to the effect that in well-selected cases NS could be an oncologically safe option with better functional outcomes. Therefore, we aim to compare the functional outcomes and oncological safety of NS during RP in men with HR disease. A total of 1340 patients were included in this analysis, of which 12% (n = 158) underwent non-NSRP and 39% (n = 516) and 50% (n = 666) uni- and bilateral NSRP, respectively. We calculated a propensity score and used inverse probability of treatment weighting (IPTW) to balance the baseline characteristics of Pca patients undergoing non-NSRP and those having uni- and bilateral NSRP, respectively. NS improved functional outcomes; after IPTW, only 3% of patients having non-NSRP reached complete erectile function recovery (without erectile aid) at 24 months, whereas 22% reached erectile function recovery (with erectile aid), while 87% were continent. Unilateral NS increased the probability of functional recovery in all outcomes (OR 1.1 or 1.2, respectively), bilateral NS slightly more so (OR 1.1 to 1.4). NSRP did not impact the risk of any recurrence (HR 0.99, 95%CI 0.73-1.34, p = 0.09), and there was no difference in survival for men who underwent NSRP (HR 0.65, 95%CI 0.39-1.08). There was no difference in cancer-specific survival (0.56, 95%CI 0.29-1.11). Our study found that NSRP significantly improved functional outcomes and can be safely performed in carefully selected patients with HR-PCa without compromising long term oncological outcomes.
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BACKGROUND: Prostate cancer is morphologically and molecularly heterogeneous. Genomic heterogeneity might be mirrored by variability in DNA ploidy. Aneuploidy is a hallmark of genomic instability and associated with tumor aggressiveness. Little attention has been paid to the biological significance of the diploid tumor cell population that often coexists with aneuploid populations. Here, we investigated the role of DNA ploidy in tumor heterogeneity and clonal evolution. METHODS: Three radical prostatectomy specimens with intratumoral heterogeneity based on nuclear features on H&E were selected. DNA content of each subpopulation was determined by DNA image cytometry and silver in situ hybridization (SISH). Genomic evolution was inferred from array comparative genomic hybridization (aCGH). Additionally, immunohistochemistry was used to examine the stemness-associated marker ALDH1A1. RESULTS: Nuclear morphology reliably predicted DNA ploidy status in all three cases. In one case, aCGH analysis revealed several shared deletions and one amplification in both the diploid and the aneuploid population, suggesting that these populations could be related. In the other two cases, a statement about relatedness was not possible. Furthermore, ALDH1A1 was expressed in 2/3 cases and exclusively observed in their diploid populations. CONCLUSIONS: In this proof-of-concept study, we demonstrate the feasibility to predict the DNA ploidy status of distinct populations within one tumor by H&E morphology. Future studies are needed to further investigate the clonal relationship between the diploid and the aneuploid subpopulation and test the hypothesis that the aneuploid population is derived from the diploid one. Finally, our analyses pointed to an enrichment of the stemness-associated marker ALDH1A1 in diploid populations, which warrants further investigation in future studies.
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INTRODUCTION: Germ-cell cancer (GCC) is curable in the majority of men. However, previous reports have described inferior outcomes in men living in rural as compared to urban residential areas. METHODS: We identified all GCC patients treated at two large university hospitals in Zürich and Bern, both in Switzerland, between 2010 and 2020 by retrospective chart review. In 400 patients from Zürich and 274 patients from Bern, details on presentation, diagnosis, treatment, and outcomes were abstracted from medical records. For follow-up, we contacted referring centers or private physicians. Residential region was allocated according to the Federal Statistical Office of Switzerland. RESULTS: We found no differences in initial presentation (clinical stage I [CSI] versus de novo metastatic), relapse rate in CSI patients, response in metastatic patients (favorable vs. unfavorable), progression-free survival (PFS) or overall survival (OS) between patients from urban as compared to suburban or rural residential areas. PFS at 3 years for CSI patients was 78% (95% confidence interval 72-82%) and OS at 5 years was 98% (95% confidence interval 96-99%). PFS at 3 years for de novo metastatic patients was 74% (95% confidence interval 68-79%) and OS at 5 years was 86% (95% confidence interval 80-90%). CONCLUSION: Treatment outcomes in GCC patients were excellent and comparable to international standards at both centers irrespective of the residential area of patients documenting equal access to high-level oncological care at both centers.
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The evolutionarily conserved minor spliceosome (MiS) is required for protein expression of â¼714 minor intron-containing genes (MIGs) crucial for cell-cycle regulation, DNA repair, and MAP-kinase signaling. We explored the role of MIGs and MiS in cancer, taking prostate cancer (PCa) as an exemplar. Both androgen receptor signaling and elevated levels of U6atac, a MiS small nuclear RNA, regulate MiS activity, which is highest in advanced metastatic PCa. siU6atac-mediated MiS inhibition in PCa in vitro model systems resulted in aberrant minor intron splicing leading to cell-cycle G1 arrest. Small interfering RNA knocking down U6atac was â¼50% more efficient in lowering tumor burden in models of advanced therapy-resistant PCa compared with standard antiandrogen therapy. In lethal PCa, siU6atac disrupted the splicing of a crucial lineage dependency factor, the RE1-silencing factor (REST). Taken together, we have nominated MiS as a vulnerability for lethal PCa and potentially other cancers.
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Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Íntrons/genética , Neoplasias da Próstata/metabolismo , Splicing de RNA/genética , Spliceossomos/metabolismo , Transdução de Sinais , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Linhagem Celular Tumoral , Neoplasias de Próstata Resistentes à Castração/genéticaRESUMO
Despite the advances in bone fracture treatment, a significant fraction of fracture patients will develop non-union. Most non-unions are treated with surgery since identifying the molecular causes of these defects is exceptionally challenging. In this study, compared with marrow bone, we generated a transcriptional atlas of human osteoprogenitor cells derived from healing callus and non-union fractures. Detailed comparison among the three conditions revealed a substantial similarity of callus and nonunion at the gene expression level. Nevertheless, when assayed functionally, they showed different osteogenic potential. Utilizing longitudinal transcriptional profiling of the osteoprogenitor cells, we identified FOS as a putative master regulator of non-union fractures. We validated FOS activity by profiling a validation cohort of 31 tissue samples. Our work identified new molecular targets for non-union classification and treatment while providing a valuable resource to better understand human bone healing biology.
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Calo Ósseo , Consolidação da Fratura , Humanos , Consolidação da Fratura/genética , Calo Ósseo/metabolismo , Osteogênese/genéticaRESUMO
Bladder Cancer (BLCa) inter-patient heterogeneity is the primary cause of treatment failure, suggesting that patients could benefit from a more personalized treatment approach. Patient-derived organoids (PDOs) have been successfully used as a functional model for predicting drug response in different cancers. In our study, we establish PDO cultures from different BLCa stages and grades. PDOs preserve the histological and molecular heterogeneity of the parental tumors, including their multiclonal genetic landscapes, and consistently share key genetic alterations, mirroring tumor evolution in longitudinal sampling. Our drug screening pipeline is implemented using PDOs, testing standard-of-care and FDA-approved compounds for other tumors. Integrative analysis of drug response profiles with matched PDO genomic analysis is used to determine enrichment thresholds for candidate markers of therapy response and resistance. Finally, by assessing the clinical history of longitudinally sampled cases, we can determine whether the disease clonal evolution matched with drug response.
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Neoplasias da Bexiga Urinária , Humanos , Avaliação Pré-Clínica de Medicamentos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Organoides/patologiaRESUMO
BACKGROUND: Post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) is an integral part of the management of patients with metastatic non-seminoma and residual masses >1 cm after chemotherapy. AIMS: To assess perioperative complications and oncological outcomes at two major referral centres in Switzerland. METHODS: This was a retrospective chart review of 136 patients with non-seminoma who underwent PC-RPLND between 2010 and 2020 at the university hospitals of Bern and Zürich. Patient, treatment and tumour characteristics as well as the types and frequencies of intra- and postoperative complications were registered and compared using the chi-square test. Oncological outcomes consisted of the time and location of relapses as well as progression-free and overall survival, which were compared using the log-rank test. RESULTS: Overall, 70 patients from Bern and 66 patients from Zürich were included; 5 patients had a previous retroperitoneal lymph node dissection (RPLND) (2 Bern, 3 Zürich). Vascular injuries were the most frequent intraoperative complication, occurring in 27/136 (19.9%) patients. Postoperative complications were observed in 42/136 (30.9%) patients, ileus being the most common. Perioperative mortality was 2.2%. A retroperitoneal mass ≥50 mm was significantly associated with intraoperative complications (p = 0.004) and increased resource demands (p = 0.021). Postoperative morbidity was higher according to age at post-chemotherapy retroperitoneal lymph node dissection ≥40 years (p = 0.028) and retroperitoneal mass ≥20 mm (p = 0.005). The median follow-up time was 37 months (interquartile range [IQR] 18-64 months). The median progression-free survival at 5 years was 76% (95% confidence interval [CI]: 64-85%) in Bern and 69% (95% CI: 54-80%) in Zürich (p = 0.464). The median overall survival at 5 years was 88% (95% CI: 76-94%) in Bern and 77% (95% CI: 60-87%) in Zürich (p = 0.335). Patients with progressive disease or a tumour marker increase before retroperitoneal lymph node dissection had significantly inferior progression-free and overall survival compared to non-progressing patients. The presence of teratoma in resected specimens did not confer inferior survival probabilities compared to necrosis only, whereas the presence of vital undifferentiated tumour conferred inferior progression-free and overall survival. Patients with a previous retroperitoneal lymph node dissection and patients operated for late relapses >2 years after chemotherapy also had significantly inferior progression-free and overall survival. CONCLUSIONS: We found a relevant rate of severe perioperative complications at PC-RPLND at even experienced high-volume centres. The oncological outcomes at two major university urological centres in Switzerland were similar and determined by preoperative risk factors and intraoperative histology.
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Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Masculino , Humanos , Estudos Retrospectivos , Suíça/epidemiologia , Espaço Retroperitoneal/patologia , Espaço Retroperitoneal/cirurgia , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/cirurgia , Recidiva Local de Neoplasia , Excisão de Linfonodo/efeitos adversos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do TratamentoRESUMO
Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive SPOP-mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion sampling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in SPOP-mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand-receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation. SIGNIFICANCE: DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases.
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Neoplasias Encefálicas , Neoplasias da Próstata , Humanos , Masculino , Metilação de DNA , Neoplasias da Próstata/patologia , Ilhas de CpG/genética , Epigenômica , Neoplasias Encefálicas/genética , Proteínas Nucleares/metabolismo , Proteínas Repressoras/genéticaRESUMO
Lymphovascular invasion, whereby tumour cells or cell clusters are identified in the lumen of lymphatic or blood vessels, is thought to be an essential step in disease dissemination. It has been established as an independent negative prognostic indicator in a range of cancers. We therefore aimed to assess the impact of lymphovascular invasion at the time of prostatectomy on oncological outcomes. We performed a multicentre, retrospective cohort study of 3495 men who underwent radical prostatectomy for localised prostate cancer. Only men with negative preoperative staging were included. We assessed the relationship between lymphovascular invasion and adverse pathological features using multivariable logistic regression models. Kaplan-Meier curves and Cox proportional hazard models were created to evaluate the impact of lymphovascular invasion on oncological outcomes. Lymphovascular invasion was identified in 19% (n = 653) of men undergoing prostatectomy. There was an increased incidence of lymphovascular invasion-positive disease in men with high International Society of Urological Pathology (ISUP) grade and non-organ-confined disease (p < 0.01). The presence of lymphovascular invasion significantly increased the likelihood of pathological node-positive disease on multivariable logistic regression analysis (OR 15, 95%CI 9.7-23.6). The presence of lymphovascular invasion at radical prostatectomy significantly increased the risk of biochemical recurrence (HR 2.0, 95%CI 1.6-2.4). Furthermore, lymphovascular invasion significantly increased the risk of metastasis in the whole cohort (HR 2.2, 95%CI 1.6-3.0). The same relationship was seen across D'Amico risk groups. The presence of lymphovascular invasion at the time of radical prostatectomy is associated with aggressive prostate cancer disease features and is an indicator of poor oncological prognosis.
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Background: Molecular detection of lymph node (LN) micrometastases by analyzing mRNA expression of epithelial markers in prostate cancer (PC) patients provides higher sensitivity than histopathological examination. Objective: To investigate which type of marker to use and whether molecular detection of micrometastases in LNs was predictive of biochemical recurrence. Design setting and participants: LN samples from PC patients undergoing radical prostatectomy with extended LN dissection between 2009 and 2011 were examined for the presence of micrometastases by both routine histopathology and molecular analyses. Outcome measurements and statistical analysis: The mRNA expression of a panel of markers of prostate epithelial cells, prostate stem cell-like cells, epithelial-to-mesenchymal transition, and stromal activation, was performed by quantitative real-time polymerase chain reaction. The expression levels of these markers in LN metastases from three PC patients were compared with the expression levels in LN from five control patients without PC in order to identify the panel of markers best suited for the molecular detection of LN metastases. The predictive value of the molecular detection of micrometastases for biochemical recurrence was assessed after a follow-up of 10 yr. Results and limitations: Prostate epithelial markers are better suited for the detection of occult LN metastases than molecular markers of stemness, epithelial-to-mesenchymal transition, or reactive stroma. An analysis of 1023 LNs from 60 PC patients for the expression of prostate epithelial cell markers has revealed different expression levels and patterns between patients and between LNs of the same patient. The positive predictive value of molecular detection of occult LN metastasis for biochemical recurrence is 66.7% and the negative predictive value is 62.5%. Limitations are sample size and the hypothesis-driven selection of markers. Conclusions: Molecular detection of epithelial cell markers increases the number of positive LNs and predicts tumor recurrence already at surgery. Patient summary: We show that a panel of epithelial prostate markers rather than single genes is preferred for the molecular detection of lymph node micrometastases not visible at histopathological examination.