Circulating Tumor DNA Testing for Homology Recombination Repair Genes in Prostate Cancer: From the Lab to the Clinic.

Approximately 23% of metastatic castration-resistant prostate cancers (mCRPC) harbor deleterious aberrations in DNA repair genes. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) therapy has shown improvements in overall survival in patients with mCRPC who harbor somatic and/or germline alterations of homology recombination repair (HRR) genes. Peripheral blood samples are typically used for the germline mutation analysis test using the DNA extracted from peripheral blood leucocytes. Somatic alterations can be assessed by extracting DNA from a tumor tissue sample or using circulating tumor DNA (ctDNA) extracted from a plasma sample. Each of these genetic tests has its own benefits and limitations. The main advantages compared to the tissue test are that liquid biopsy is a non-invasive and easily repeatable test with the value of better representing tumor heterogeneity than primary biopsy and of capturing changes and/or resistance mutations in the genetic tumor profile during disease progression. Furthermore, ctDNA can inform about mutation status and guide treatment options in patients with mCRPC. Clinical validation and test implementation into routine clinical practice are currently very limited. In this review, we discuss the state of the art of the ctDNA test in prostate cancer compared to blood and tissue testing. We also illustrate the ctDNA testing workflow, the available techniques for ctDNA extraction, sequencing, and analysis, describing advantages and limits of each techniques.

Patients ask and pathologists answer: ten questions around prostate cancer grading.

Pathologists have closely collaborated with clinicians, mainly urologists, to update the Gleason grading system to reflect the current practice and approach in prostate cancer diagnosis, prognosis, and treatment. This has led to the development of what is called patient advocacy and patient information. Ten common questions asked by patients to pathologists concerning PCa grading and the answers given by the latter are reported.

Predictive and prognostic biomarkers in urological tumours.

Advancements in cutting-edge molecular profiling techniques, such as next-generation sequencing and bioinformatic analytic tools, have allowed researchers to examine tumour biology in detail and stratify patients based on factors linked with clinical outcome and response to therapy. This manuscript highlights the most relevant prognostic and predictive biomarkers in kidney, bladder, prostate and testicular cancers with recognised impact in clinical practice. In bladder and prostate cancer, new genetic acquisitions concerning the biology of tumours have modified the therapeutic scenario and led to the approval of target directed therapies, increasing the quality of patient care. Thus, it has become of paramount importance to choose adequate molecular tests, i.e., FGFR screening for urothelial cancer and BRCA1-2 alterations for prostate cancer, to guide the treatment plan for patients. While no tissue or blood-based biomarkers are currently used in routine clinical practice for renal cell carcinoma and testicular cancers, the field is quickly expanding. In kidney tumours, gene expression signatures might be the key to identify patients who will respond better to immunotherapy or anti-angiogenic drugs. In testicular germ cell tumours, the use of microRNA has outperformed conventional serum biomarkers in the diagnosis of primary tumours, prediction of chemoresistance, follow-up monitoring, and relapse prediction.

The Oncological and Functional Prognostic Value of Unconventional Histology of Prostate Cancer in Localized Disease Treated with Robotic Radical Prostatectomy: An International Multicenter 5-Year Cohort Study.

BACKGROUND AND OBJECTIVE: The impact of prostate cancer of unconventional histology (UH) on oncological and functional outcomes after robot-assisted radical prostatectomy (RARP) and adjuvant radiotherapy (aRT) receipt is unclear. We compared the impact of cribriform pattern (CP), ductal adenocarcinoma (DAC), and intraductal carcinoma (IDC) in comparison to pure adenocarcinoma (AC) on short- to mid-term oncological and functional results and receipt of aRT after RARP. METHODS: We retrospectively collected data for a large international cohort of men with localized prostate cancer treated with RARP between 2016 and 2020. The primary outcomes were biochemical recurrence (BCR)-free survival, erectile and continence function. aRT receipt was a secondary outcome. Kaplan-Meier survival and Cox regression analyses were performed. KEY FINDINGS AND LIMITATIONS: A total of 3935 patients were included. At median follow-up of 2.8 yr, the rates for BCR incidence (AC 10.7% vs IDC 17%; p < 0.001) and aRT receipt (AC 4.5% vs DAC 6.3% [p = 0.003] vs IDC 11.2% [p < 0.001]) were higher with UH. The 5-yr BCR-free survival rate was significantly poorer for UH groups, with hazard ratios of 1.67 (95% confidence interval [CI] 1.16-2.40; p = 0.005) for DAC, 5.22 (95% CI 3.41-8.01; p < 0.001) for IDC, and 3.45 (95% CI 2.29-5.20; p < 0.001) for CP in comparison to AC. Logistic regression analysis revealed that the presence of UH doubled the risk of new-onset erectile dysfunction at 1 yr, in comparison to AC (grade group 1-3), with hazard ratios of 2.13 (p < 0.001) for DAC, 2.14 (p < 0.001) for IDC, and 2.01 (p = 0.011) for CP. Moreover, CP, but not IDC or DAC, was associated with a significantly higher risk of incontinence (odds ratio 1.97; p < 0.001). The study is limited by the lack of central histopathological review and relatively short follow-up. CONCLUSIONS AND CLINICAL IMPLICATIONS: In a large cohort, UH presence was associated with worse short- to mid-term oncological outcomes after RARP. IDC independently predicted a higher rate of aRT receipt. At 1-yr follow-up after RP, patients with UH had three times higher risk of erectile dysfunction post RARP; CP was associated with a twofold higher incontinence rate. PATIENT SUMMARY: Among patients with prostate cancer who undergo robot-assisted surgery to remove the prostate, those with less common types of prostate cancer have worse results for cancer control, erection, and urinary continence and a higher probability of receiving additional radiotherapy after surgery.

The pathway of isolated seminal vesicle invasion has a different impact on biochemical recurrence after radical prostatectomy and pelvic lymphadenectomy.

OBJECTIVE: Prostate cancer with seminal vesicle invasion (SVI) has been considered an aggressive cancer. To evaluate the prognostic significance of different patterns of isolated SVI in patients undergoing radical prostatectomy (RP) and pelvic lymphadenectomy. METHODS AND MATERIALS: We retrospectively analyzed all patients who underwent RP between 2007 and 2019. Inclusion criteria were localized prostate adenocarcinoma, SVI at RP, at least 24-months follow-up, and no adjuvant treatment. Patterns of SVI were following Ohori's classification: type 1: direct spread along the ejaculatory duct from inside; type 2: seminal vesicle invasion outside the prostate, through the capsule; type 3: the presence of cancer island(s) in the seminal vesicle with no continuity from the primary tumor (discontinuous metastases). Patients with type 3 SVI (isolated or in association) were included in the same group. Biochemical recurrence (BCR) was defined as any postoperative PSA ≥0.2 ng/ml. A logistic regression analysis was performed to assess predictors of BCR. Time to BCR was investigated using the Kaplan-Meier analysis with the log-rank test. RESULTS: Sixty-one out of 1,356 patients were included. Median age was 67(7.2) years. Median PSA was 9.4(8.92) ng/ml. Mean follow-up was 85.28 ± 45.27 months. BCR occurred in 28(45.9%) patients. Logistic regression showed that a positive surgical margin (OR 19.964, 95%CI:1.172-29.322, P = 0.038) was predictor of BCR. Kaplan-Meier analysis demonstrated that patients with pattern 3 had a significantly shorter time to BCR compared to other groups (log-rank, P = 0.016). The estimated time to BCR was 48.7 months in type 3, 60.9 months in pattern 1 + 2, 74.8, and 100.8 months in isolated patterns 1 and 2, respectively. In patients with negative surgical margins, pattern 3 confirmed a shorter time to BCR compared to other types of invasions, with an estimated time to BCR of 30.8 months. CONCLUSIONS: Patients with type 3 SVI demonstrated a shorter time to BCR compared to other patterns.

Which men with non-malignant pathology at magnetic resonance imaging-targeted prostate biopsy and persistent PI-RADS 3-5 lesions should repeat biopsy?

PURPOSE: To assess predictors of clinically significant (cs) prostate cancer (PCa) in men who had a non-malignant Multiparametric magnetic resonance imaging (mpMRI)-targeted biopsy and persistent Prostate Imaging-Reporting Data System (PI-RADS) 3 to 5 lesions in subsequent mpMRI. MATERIALS AND METHODS: We retrospectively analyzed MRI-targeted biopsy database in three centers. INCLUSION CRITERIA: persistence of at least one PI-RADS ≥3 lesion found negative for cancer in a previous MRI-targeted plus systemic biopsy (baseline biopsy). EXCLUSION CRITERIA: downgrading to PI-RADS 1-2. A logistic regression analysis was performed to estimate the predictors of csPCa. RESULTS: Fifty-seven patients were included. Median interval between biopsies was 12.9(2.43) months. Median age was 68.0(12) years. Median PSA was 7.0(5.45) ng/ml. At follow-up, 24.6%, 54.4%, and 21% of patients had a PI-RADS score 3, 4, and 5 index lesion (IL), respectively. At re-biopsy, 28/57(49.1%) men were found to harbor PCa. Among these, 22(78.6%) had csPCa. csPCa was found outside the IL in only 2 patients. Eleven, 13, and 5 patients with PI-RADS 3, 4, and 5, respectively, had no cancer. Three patients with a PI-RADS 3 lesion had cancer (2 with Gleason score 3+3, 1 with Gleason score 3+4). 14/43 men with a PI-RADS 4/5 lesion harbored Gleason score ≥3+4 PCa. Logistic regression analysis found that PSA (HR 1.281, 95% CI: 1.013-1.619, P = 0.039) and IL size (HR 1.146, 95% CI: 1.018-1.268, P = 0.041) were the predictors of csPCa at re-biopsy. CONCLUSIONS: Patients with non-malignant pathology from PI-RADS ≥3 lesions targeted biopsy should be follow-up with mpMRI, and those with persistent PI-RADS 4 to 5 lesions should repeat MRI-targeted and systematic biopsy.

Case report: A hybrid technique for a safe nephrectomy in a giant kidney angiomyolipoma.

Background: Giant angiomyolipoma is usually associated with genetic syndromes and complications (spontaneous rupture and bleeding, hematuria, hypertension) and mass-related symptoms (flank and abdominal pain). Case presentation: We present a case of a 20-year-old woman suffering from tuberous sclerosis who was referred to our hospital with a giant angiomyolipoma causing abdominal pain. A contrast-enhanced computed tomography showed a left angiomyolipoma, measuring 28 cm × 17 cm × 27 cm. After a multidisciplinary team discussion, the patient was submitted for a nephrectomy. Percutaneous temporary occlusion of the main renal artery was achieved through an endovascular balloon catheter. Through the balloon catheter guidewire, 2,500 IU of heparin was infused to reduce the risk of tumor vein thrombosis and venous embolism. This allowed a safe kidney manipulation through a left thoracoabdominal approach. The postoperative course was uneventful. Pathology showed a 40 cm × 30 cm × 9 cm and 10 kg AML. One year after surgery, the patient is on follow-up, and her estimated glomerular filtration is 120.5 ml/min/1.73 m2. Conclusion: The present case showed that the endovascular control of the main renal artery could be considered a useful approach to safely managing huge renal masses when renal hilar control is expected to be very difficult.

Hot topics in renal cancer pathology: implications for clinical management.

INTRODUCTION: The updated European Association of Urology (EAU) Guidelines issued a weak recommendation for adjuvant pembrolizumab for patients with high-risk operable clear cell Renal Cell Carcinoma (ccRCC). High risk of recurrence was defined, as per protocol-criteria, as T2 with nuclear grade 4 or sarcomatoid differentiation, T3 or higher, regional lymph node metastasis, or stage M1 with no evidence of disease. Considering the heterogeneous population included in the recommendation, it has been questioned if adjuvant pembrolizumab may lead to overtreatment of some patients as well as undertreatment of patients with worse prognosis. AREAS COVERED: In this review, we discuss the issues related to the assessment of pathological features required to identify those patients harboring a high-risk tumor, highlighting the issue related to interobserver variability and discuss the currently available prognostic scoring systems in ccRCC. EXPERT OPINION: PPathologist assessment of prognostic features suffers from interobserver variability which may depend on gross sampling and the pathologist's expertise. The presence of clear cell feature is not sufficient criteria by itself to define ccRCC since clear cell can be also found in other histotypes. Application of molecular biomarkers may be useful tools in the near future to help clinicians identify patients harboring tumors with worse prognosis.