Detection of disease-causing mutations in prostate cancer by NGS sequencing.

Gene mutations may affect the fate of many tumors including prostate cancer (PCa); therefore, the research of specific mutations associated with tumor outcomes might help the urologist to identify the best therapy for PCa patients such as surgical resection, adjuvant therapy or active surveillance. Genomic DNA (gDNA) was extracted from 48 paraffin-embedded PCa samples and normal paired tissues. Next, gDNA was amplified and analyzed by next-generation sequencing (NGS) using a specific gene panel for PCa. Raw data were refined to exclude false-positive mutations; thus, variants with coverage and frequency lower than 100× and 5%, respectively were removed. Mutation significance was processed by Genomic Evolutionary Rate Profiling, ClinVar, and Varsome tools. Most of 3000 mutations (80%) were single nucleotide variants and the remaining 20% indels. After raw data elaboration, 312 variants were selected. Most mutated genes were KMT2D (26.45%), FOXA1 (16.13%), ATM (15.81%), ZFHX3 (9.35%), TP53 (8.06%), and APC (5.48%). Hot spot mutations in FOXA1, ATM, ZFHX3, SPOP, and MED12 were also found. Truncating mutations of ATM, lesions lying in hot spot regions of SPOP and FOXA1 as well as mutations of TP53 correlated with poor prognosis. Importantly, we have also found some germline mutations associated with hereditary cancer-predisposing syndrome. gDNA sequencing of 48 cancer tissues by NGS allowed to detect new tumor variants as well as confirmed lesions in genes linked to prostate cancer. Overall, somatic and germline mutations linked to good/poor prognosis could represent new prognostic tools to improve the management of PCa patients.

Prostatic calculi detected in peripheral zone of the gland during a transrectal ultrasound biopsy can be significant predictors of prostate cancer.

PURPOSE: Prostatic calculi (PC) are usually associated with benign prostatic hyperplasia or chronic inflammation. However, in several studies prostatic inflammation and calcification have been implicated in the pathogenesis of prostate cancer (CaP). We evaluated the prevalence of PC during transrectal ultrasound (TRUS) and correlate the ultrasonographic patterns with histological findings. METHODS: A prospective study of 664 patients undergoing TRUS and prostate biopsy was planned. A standardized reproducible technique was used with using a GE Logiq 7 machine equipped with a 5-9MHz multi-frequency convex probe "end-fire". We defined marked presence of PC as multiple hyperechoic foci with significant area (≥ 3 mm in the largest diameter). PC were classified according to zone distribution into the gland: transitional zone (TZ), central zone (CZ), and peripheral zone (PZ). RESULTS: No significant difference was noted between the patients with PC and without PC, when comparing age, preoperative PSA level, prostate volume, and biopsy number, except for DRE findings. 168 patients (25.3%) had marked presence of PC on TRUS: 50.6% in TZ, 20.2% in CZ, and 29.2% in PZ. 31 patients (63.3%) with presence of PC in PZ had CaP on biopsy. The correlation observed between CaP and the presence of PC in PZ was statistically significant (p < 0.001). However, among patients in the CaP group there was no statistical association between PC and moderate or high Gleason grade. CONCLUSIONS: This study suggests that chronic prostatic inflammation and PC have a role in the biogenesis of cancer. CaP was more frequent in patients with PC in PZ of the gland, but was not associated with higher Gleason grade among these patients (p < 0.001).

18 F-Choline Versus 68 Ga-PSMA-11 PET/CT Imaging Comparison in Incidental Clear Cell Renal Cell Carcinoma.

ABSTRACT: Few articles in literature describe the potential usefulness of 18 F-choline PET/CT and particularly 68 Ga-PSMA-11 PET/CT in imaging of clear cell renal cell carcinoma (ccRCC). We report a unique comparison in literature between the 2 radiotracers in a patient who underwent left nephrectomy with diagnosis of ccRCC, grade 3. 68 Ga-PSMA-11 PET/CT confirmed its emerging role in imaging ccRCC, as the incidentally detected renal neoplasm showed a significant higher uptake in comparison to 18 F-choline PET/CT, inducing surgical indication.

Somatic and Germline Variants Affect Prognosis and Susceptibility in Prostate Cancer.

BACKGROUND/AIM: Prostate cancer (PCa) is one of the most common tumors in men accounting for the 7.3% of all cancer-associated diseases in 2020. In advanced stage, this pathology is a lethal disease and is the fifth cause of cancer death in men worldwide. The diagnosis of PCa is performed by prostate-specific antigen (PSA) detection combined with direct rectal examination (DRE). However, high PSA levels can be detected in non-malignant conditions leading to overtreatment of non-oncological patients. Moreover, PSA levels are not associated with disease progression; therefore, the research of novel biomarkers could improve diagnosis and prognosis of this tumor. In this regard, genetic polymorphisms may affect PCa outcome as well as to be associated with cancer familiarity. In fact, germline variations detected in different genes including BRCA1, BRCA2, ATM and HOXB13 seem to be associated with PCa susceptibility and progression. MATERIALS AND METHODS: Somatic and germline polymorphisms were detected by next generation sequencing (NGS) in 48 PCa subjects and paired controls. Gene variants were matched with patient outcome and cancer familiarity to identify mutations linked to prognosis and tumor predisposition. RESULTS: NGS sequencing has allowed to identify different genetic polymorphisms that could be linked to cancer outcome and predisposition. In particular, somatic and germline mutations found in ATM, FOXA1 and SPOP genes correlate with poor prognosis and/or high Gleason score. Moreover, germline variants lying mainly in ATM, but also in ZFHX3, SPOP, CHD1, CDK12 and APC seem to be associated with hereditary-predisposing cancer syndrome. CONCLUSION: Variants correlating with poor prognosis and cancer susceptibility could be usable as possible tumor biomarkers in prostate cancer.

68Ga-PSMA-11 PET/CT in Bilateral Clear Cell Renal Cell Carcinoma: an Intra-patient Comparison Between High and Low Grade Tumors.

Recent studies have outlined the emerging role of 68Ga-PSMA-11 PET/CT in the diagnostic algorithm of clear cell renal cell carcinoma (ccRCC). We report a unique intra-patient comparison of bilateral primary ccRCC imaged with 68Ga-PSMA-11 PET/CT. Although both tumors resulted 68Ga-PSMA-11 avid, we found a remarkable discrepancy in uptake intensity between the high grade and the low grade ccRCC. This case confirms previous evidence reporting that SUVmax on 68Ga-PSMA-11 PET/CT could be used to discriminate aggressive high grade from more indolent low grade ccRCC, due to their different endothelial expression of PSMA.

[18F]FDG PET-TC radiomics and machine learning in the evaluation of prostate incidental uptake.

AIM: To evaluate the relevance of incidental prostate [18F]FDG uptake (IPU) and to explore the potential of radiomics and machine learning (ML) to predict prostate cancer (PCa). METHODS: We retrieved [18F]FDG PET/CT scans with evidence of IPU performed in two institutions between 2015 and 2021. Patients were divided into PCa and non-PCa, according to the biopsy. Clinical and PET/CT-derived information (comprehensive of radiomic analysis) were acquired. Five ML models were developed and their performance in discriminating PCa vs non-PCa IPU was evaluated. Radiomic analysis was investigated to predict ISUP Grade. RESULTS: Overall, 56 IPU were identified and 31 patients performed prostate biopsy. Eighteen of those were diagnosed as PCa. Only PSA and radiomic features (eight from CT and nine from PET images, respectively) showed statistically significant difference between PCa and non-PCa patients. Eight features were found to be robust between the two institutions. CT-based ML models showed good performance, especially in terms of negative predictive value (NPV 0.733-0.867). PET-derived ML models results were less accurate except the Random Forest model (NPV = 0.933). Radiomics could not accurately predict ISUP grade. CONCLUSIONS: Paired with PSA, radiomic analysis seems to be promising to discriminate PCa/non-PCa IPU. ML could be a useful tool to identify non-PCa IPU, avoiding further investigations.

The Role of [18F]F-Choline PET/CT in the Initial Management and Outcome Prediction of Prostate Cancer: A Real-World Experience from a Multidisciplinary Approach.

Initial staging of prostate cancer (PCa) is usually performed with conventional imaging (CI), involving computed tomography (CT) and bone scanning (BS). The aim of this study was to analyze the role of [18F]F-choline positron emission tomography (PET)/CT in the initial management and outcome prediction of PCa patients by analyzing data from a multidisciplinary approach. We retrospectively analyzed 82 patients who were discussed by the uro-oncology board of the University Hospital of Ferrara for primary staging newly diagnosed PCa (median age 72 (56-86) years; median baseline prostate specific antigen (PSA) equal to 8.73 ng/mL). Patients were divided into three groups based on the imaging performed: group A = only CI; group B = CI + [18F]F-choline PET/CT; group C = only [18F]F-choline PET/CT. All data on imaging findings, therapy decisions and patient outcomes were retrieved from hospital information systems. Moreover, we performed a sub-analysis of semiquantitative parameters extracted from [18F]F-choline PET/CT to search any correlation with patient outcomes. The number of patients included in each group was 35, 35 and 12, respectively. Patients with higher values of initial PSA were subjected to CI + PET/CT (p = 0.005). Moreover, the use of [18F]F-choline PET/CT was more frequent in patients with higher Gleason score (GS) or ISUP grade (p = 0.013). The type of treatment performed (surgery n = 33; radiation therapy n = 22; surveillance n = 6; multimodality therapy n = 6; systemic therapy n = 13; not available n = 2) did not show any relationship with the modality adopted to stage the disease. [18F]F-choline PET/CT induced a change of planned therapy in 5/35 patients in group B (14.3%). Moreover, patients investigated with [18F]F-choline PET/CT alone demonstrated longer biochemical recurrence (BCR)-free survival (30.8 months) in comparison to patients of groups A and B (15.5 and 23.5 months, respectively, p = 0.006), probably due to a more accurate selection of primary treatment. Finally, total lesion choline kinase activity (TLCKA) of the primary lesion, calculated by multiplying metabolic tumor volume and mean standardized uptake value (SUVmean), was able to more effectively discriminate patients who had recurrence after therapy compared to those without (p = 0.03). In our real-world experience [18F]F-choline PET/CT as a tool for the initial management of PCa had a relevant impact in terms of therapy selection and was associated with longer BCR-free survival. Moreover, TLCKA of the primary lesion looks a promising parameter for predicting recurrence after curative therapy.

Role of PSMA-ligands imaging in Renal Cell Carcinoma management: current status and future perspectives.

BACKGROUND: Renal masses detection is continually increasing worldwide, with Renal Cell Carcinoma (RCC) accounting for approximately 90% of all renal cancers and remaining one of the most aggressive urological malignancies. Despite improvements in cancer management, accurate diagnosis and treatment strategy of RCC by computed tomography (CT) and magnetic resonance imaging (MRI) are still challenging. Prostate-Specific Membrane Antigen (PSMA) is known to be highly expressed on the endothelial cells of the neovasculature of several solid tumors other than prostate cancer, including RCC. In this context, recent preliminary studies reported a promising role for positron emission tomography (PET)/CT with radiolabeled molecules targeting PSMA, in alternative to fluorodeoxyglucose (FDG) in RCC patients. PURPOSE: The aim of our review is to provide an updated overview of current evidences and major limitations regarding the use of PSMA PET/CT in RCC. METHODS: A literature search, up to 31 December 2021, was performed using the following electronic databases: PubMed, SCOPUS, Web of Science, and Google Scholar. RESULTS: The findings of this review suggest that PSMA PET/CT could represent a valid imaging option for diagnosis, staging, and therapy response evaluation in RCC, particularly in clear cell RCC. CONCLUSIONS: Further studies are needed for this "relatively" new imaging modality to consolidate its indications, timing, and practical procedures.

The impact of orthotopic reconstruction on female sexuality and quality of life after radical cystectomy for non-malignant bladder conditions.

OBJECTIVE: To review the literature on the impact on female quality of life and sexual function of orthotopic reconstruction after radical cystectomy for non-malignant bladder conditions. Radical cystectomy is commonly required to treat malignant conditions but may also be considered for the treatment of non-malignant diseases. These heterogeneous group of disorders includes interstitial cystitis, painful bladder syndrome, neurogenic bladder, haemorrhagic/ radiation cystitis, endometriosis and refractory genitourinary fistula. Treatment begins with non-invasive medical therapies but, in non-responder cases, a surgical solution should be considered. Such invasive techniques include urinary diversion and reconstructive procedures that have an impact on healthrelated quality of life, physical, social, and mental status. MATERIALS AND METHODS: This narrative review research was done using the PubMed database up until 2020, July. All papers referring to cystectomy for benign indication were considered. RESULTS: In comparison to other reconstructive options, orthotopic neobladder allows the restoration of a normal self-image and consequently it is the most suitable procedure when a surgical reconstruction is necessary for non-malignant conditions. However, women can face many disorders that impact on everyday life, such as voiding dysfunction or sexual activity problems. CONCLUSIONS: Scant data is available about quality of life, sexual life and self-perception in women treated by cystectomy for benign conditions and most literature is dedicated to those indicators in cancer patients. More research is needed to understand the tolerability and the quality of life results of the female population affected by benign conditions undergoing this kind of surgical approach.

The impact of core length on prostate cancer diagnosis during a standard 14-core prostate biopsy scheme.

INTRODUCTION: Even if many studies in the literature purposed to evaluate the improvement of the prostate biopsy (PBx), few studies assessed the diagnostic value of core length in PBx. In this study, we evaluated the length of needle cores sampled during transrectal PBx (TRUSBx) and its impact on cancer diagnosis in a standard 14-core scheme. METHODS: Medical records of 573 patients who underwent an initial TRUSBx with 14-cores scheme for suspicious prostate cancer (PCa) at our Department were reviewed. The PBx procedure and pathological evaluation were standardized. Cores lengths were compared in patients with versus without cancer, and were divided into group A and B, respectively. Statistical analysis was done to define an acceptable cut-off for biopsy length. RESULTS: The mean age of the entire cohort was 62.1 ± 7.2 years, while median total prostate-specific antigen (PSA) and prostate volume were 4.2 ng/ml and 44.7 ml, respectively. PCa was showed in 33.3% of patients. Mean core length in group A versus B was 11.9 ± 3.9 versus 11.1 ± 3.2 mm (p = 0.016). Thus, core lengths were significantly longer in patients with cancer. There were no statistically significant differences when we considered the whole length of cores sampled from the right lobe (p = 0.58) and left lobe (p = 0.34). CONCLUSIONS: The cancer detection rates in cores may be increased by core length in PCa patients during a TRUSBx. Our results suggest a core length of greater than 11.8 mm as a cut-off for quality warranty.

[Role of transrectal ultrasonography in prostatic brachytherapy]. / Ruolo dell'ecografia transrettale nella brachiterapia prostatica.

UNLABELLED: The rationale for interstitial brachytherapy (seed implant) is based on the principle that dissipation of radiation energy in tissues decreases exponentially as the square of source would receive maximal doses of radiation, there will be a rapid fall-off the dose in surrounding normal tissues. Over the years, a range of isotopes have been tested, and the technique have evolved from free-hand implantation to ultrasound guided template system. MATERIALS AND METHODS: From September 2001 to March 2002 we treated 17 patients with clinically localized prostatic cancer. For seed implantation we used the transrectal ultrasound guided implantation of 125I source. Isodose distributions are provided at each 5 mm increment throughout the treatment volume to determine the precise localization of seed placement. RESULTS: 23.5% of patients developed acute urinary retention, 11.8% incidence of transurethral resection after 6 months and 0% incidence of urinary incontinence. Longer follow-up will be necessary for biochemical failure. CONCLUSIONS: Permanent interstitial implantation should be limited to patients with early stage disease with favourable prognostic features. The use of transrectal ultrasound as diagnostic system as guided implantation is the most popular approach even in experienced hands.