Development and validation of a clinical decision support system based on PSA, microRNAs, and MRI for the detection of prostate cancer.

OBJECTIVES: The aims of this study are to develop and validate a clinical decision support system based on demographics, prostate-specific antigen (PSA), microRNA (miRNA), and MRI for the detection of prostate cancer (PCa) and clinical significant (cs) PCa, and to assess if this system performs better compared to MRI alone. METHODS: This retrospective, multicenter, observational study included 222 patients (mean age 66, range 46-75 years) who underwent prostate MRI, miRNA (let-7a-5p and miR-103a-3p) assessment, and biopsy. Monoparametric and multiparametric models including age, PSA, miRNA, and MRI outcome were trained on 65% of the data and then validated on the remaining 35% to predict both PCa (any Gleason grade [GG]) and csPCa (GG ≥ 2 vs GG = 1/negative). Accuracy, sensitivity, specificity, positive and negative predictive value (NPV), and area under the receiver operating characteristic curve were calculated. RESULTS: MRI outcome was the best predictor in the monoparametric model for both detection of PCa, with sensitivity of 90% (95%CI 73-98%) and NPV of 93% (95%CI 82-98%), and for csPCa identification, with sensitivity of 91% (95%CI 72-99%) and NPV of 95% (95%CI 84-99%). Sensitivity and NPV of PSA + miRNA for the detection of csPCa were not statistically different from the other models including MRI alone. CONCLUSION: MRI stand-alone yielded the best prediction models for both PCa and csPCa detection in biopsy-naïve patients. The use of miRNAs let-7a-5p and miR-103a-3p did not improve classification performances compared to MRI stand-alone results. CLINICAL RELEVANCE STATEMENT: The use of miRNA (let-7a-5p and miR-103a-3p), PSA, and MRI in a clinical decision support system (CDSS) does not improve MRI stand-alone performance in the detection of PCa and csPCa. KEY POINTS: • Clinical decision support systems including MRI improve the detection of both prostate cancer and clinically significant prostate cancer with respect to PSA test and/or microRNA. • The use of miRNAs let-7a-5p and miR-103a-3p did not significantly improve MRI stand-alone performance. • Results of this study were in line with previous works on MRI and microRNA.

Patient and Context Factors in the Adoption of Active Surveillance for Low-Risk Prostate Cancer.

Importance: Although active surveillance for patients with low-risk prostate cancer (LRPC) has been recommended for years, its adoption at the population level is often limited. Objective: To make active surveillance available for patients with LRPC using a research framework and to compare patient characteristics and clinical outcomes between those who receive active surveillance vs radical treatments at diagnosis. Design, Setting, and Participants: This population-based, prospective cohort study was designed by a large multidisciplinary group of specialists and patients' representatives. The study was conducted within all 18 urology centers and 7 radiation oncology centers in the Piemonte and Valle d'Aosta Regional Oncology Network in Northwest Italy (approximate population, 4.5 million). Participants included patients with a new diagnosis of LRPC from June 2015 to December 2021. Data were analyzed from January to May 2023. Exposure: At diagnosis, all patients were informed of the available treatment options by the urologist and received an information leaflet describing the benefits and risks of active surveillance compared with active treatments, either radical prostatectomy (RP) or radiation treatment (RT). Patients choosing active surveillance were actively monitored with regular prostate-specific antigen testing, clinical examinations, and a rebiopsy at 12 months. Main Outcomes and Measures: Outcomes of interest were proportion of patients choosing active surveillance or radical treatments, overall survival, and, for patients in active surveillance, treatment-free survival. Comparisons were analyzed with multivariable logistic or Cox models, considering centers as clusters. Results: A total of 852 male patients (median [IQR] age, 70 [64-74] years) were included, and 706 patients (82.9%) chose active surveillance, with an increasing trend over time; 109 patients (12.8%) chose RP, and 37 patients (4.3%) chose RT. Median (IQR) follow-up was 57 (41-76) months. Worse prostate cancer prognostic factors were negatively associated with choosing active surveillance (eg, stage T2a vs T1c: odds ratio [OR], 0.51; 95% CI, 0.28-0.93), while patients who were older (eg, age ≥75 vs <65 years: OR, 4.27; 95% CI, 1.98-9.22), had higher comorbidity (Charlson Comorbidity Index ≥2 vs 0: OR, 1.98; 95% CI, 1.02-3.85), underwent an independent revision of the first prostate biopsy (OR, 2.35; 95% CI, 1.26-4.38) or underwent a multidisciplinary assessment (OR, 2.65; 95% CI, 1.38-5.11) were more likely to choose active surveillance vs active treatment. After adjustment, center at which a patient was treated continued to be an important factor in the choice of treatment (intraclass correlation coefficient, 18.6%). No differences were detected in overall survival between active treatment and active surveillance. Treatment-free survival in the active surveillance cohort was 59.0% (95% CI, 54.8%-62.9%) at 24 months, 54.5% (95% CI, 50.2%-58.6%) at 36 months, and 47.0% (95% CI, 42.2%-51.7%) at 48 months. Conclusions and Relevance: In this population-based cohort study of patients with LRPC, a research framework at system level as well as favorable prognostic factors, a multidisciplinary approach, and an independent review of the first prostate biopsy at patient-level were positively associated with high uptake of active surveillance, a practice largely underused before this study.

Ki-67, topoisomerase IIα and miR-221 have a limited prostate cancer risk stratification ability on a medium-term follow-up: results of a high-risk radical prostatectomy cohort.

Background: Currently, no biomarkers are able to differentiate lethal from relatively indolent prostate cancer (PCa) within high-risk diseases. Nonetheless, several molecules are under investigation. Amongst them, topoisomerase-II-alpha (TOPIIA), Ki67 and miR-221 showed promising results. Our aim was to investigate their prognostic role in the context of biochemical recurrence (BCR), clinical recurrence (CR) and PCa-related death (PcD). Methods: We included 64 consecutive cM0 high-risk PCa [prostate specific antigen (PSA) >20 ng/mL or Gleason Score (GS) >7 or cT >2] undergoing radical prostatectomy (RP). Changes in miR-221 expression and alternative splicing were determined using microarrays. Immunohistochemical determination of Ki67 and TOPIIa were performed using monoclonal antibody MIB-1 and 3F6 respectively. Cox proportional-hazards regression models were used to predict BCR and CR as multivariate analysis. BCR and CR were defined as three consecutive rises in PSA and PSA >0.2 ng/mL and histologically-proven local recurrence or imaging positive for distant metastasis respectively. Results: We included 64 men. Mean pre-operative PSA was 26.53 (range, 1.3-135); all GSs were ≥7 and pT was ≥ T3 in 78.13%. Positive margins and lymph-nodes were present in 42.19% and 32.81% respectively. At a mean follow-up of 5.7 years (range, 1.8-12.5), 42.18% experienced BCR (n=27), 29.68% CR (n=19) and 7.81% PcD (n=5). On univariate analysis positive nodes (<0.01), seminal vesicle invasion (0.02) and miR-221 downregulation (P=0.03), but not Ki67 and TOPIIA (both P>0.5) were associated with BCR whereas only PSA (P<0.01), seminal vesicle invasion (P<0.01) and positive nodes (both P<0.01) were linked to CR. No parameters predicted PcD (all P>0.05) or BCR and CR on multivariate analysis (all P>0.05 - miR-221 HR 0.776; 95% CI: 0.503-1.196 for BCR and HR 0.673; 95% CI: 0.412-1.099 for CR). Limitation of the study include its small sample size and limited follow-up. Conclusions: TOPIIA, Ki-67 and miR-221 may not predict BCR, CR or PcD in high-risk PCa patients who underwent RP at a medium-term follow-up. Longer follow-up and larger cohorts are needed to confirm our findings.

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

BACKGROUND: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation. METHODS: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls. RESULTS: In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q ≤ 0.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q = 8.4 × 10-4), methyl-CpG-binding protein 2 (MECP2; q = 2 × 10-3), and ZBTB4 (q = 0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q = 2.8 × 10-4), but not with nonseminomatous tumors (q = 0.22). CONCLUSIONS: Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk. IMPACT: This finding suggests that TGCT pathogenesis could be associated with the folate cycle status, and this relation could be partly due to hereditary factors.

Two Novel Ceramide-Like Molecules and miR-5100 Levels as Biomarkers Improve Prediction of Prostate Cancer in Gray-Zone PSA.

Reliable liquid biopsy-based tools able to accurately discriminate prostate cancer (PCa) from benign prostatic hyperplasia (BPH), when PSA is within the "gray zone" (PSA 4-10), are still urgent. We analyzed plasma samples from a cohort of 102 consecutively recruited patients with PSA levels between 4 and 16 ng/ml, using the SANIST-Cloud Ion Mobility Metabolomic Mass Spectrometry platform, combined with the analysis of a panel of circulating microRNAs (miR). By coupling CIMS ion mobility technology with SANIST, we were able to reveal three new structures among the most differentially expressed metabolites in PCa vs. BPH. In particular, two were classified as polyunsaturated ceramide ester-like and one as polysaturated glycerol ester-like. Penalized logistic regression was applied to build a model to predict PCa, using six circulating miR, seven circulating metabolites, and demographic/clinical variables, as covariates. Four circulating metabolites, miR-5100, and age were selected by the model, and the corresponding prediction score gave an AUC of 0.76 (C.I. = 0.66-0.85). At a specified cut-off, no high-risk tumor was misclassified, and 22 out of 53 BPH were correctly identified, reducing by 40% the false positives of PSA. We developed and applied a novel, minimally invasive, liquid biopsy-based powerful tool to characterize novel metabolites and identified new potential non-invasive biomarkers to better predict PCa, when PSA is uninformative as a tool for precision medicine in genitourinary cancers.

Low Levels of Urinary PSA Better Identify Prostate Cancer Patients.

Serum prostatic specific antigen (PSA) has proven to have limited accuracy in early diagnosis and in making clinical decisions about different therapies for prostate cancer (PCa). This is partially due to the fact that an increase in PSA in the blood is due to the compromised architecture of the prostate, which is only observed in advanced cancer. On the contrary, PSA observed in the urine (uPSA) reflects the quantity produced by the prostate, and therefore can give more information about the presence of disease. We enrolled 574 men scheduled for prostate biopsy at the urology clinic, and levels of uPSA were evaluated. uPSA levels resulted lower among subjects with PCa when compared to patients with negative biopsies. An indirect correlation was observed between uPSA amount and the stage of disease. Loss of expression of PSA appears as a characteristic of prostate cancer development and its evaluation in urine represents an interesting approach for the early detection of the disease and the stratification of patients.

68Ga-PSMA-11 PET/CT in recurrent hormone-sensitive prostate cancer (HSPC): a prospective single-centre study in patients eligible for salvage therapy.

OBJECTIVES: The primary objective is to assess the efficacy of 68Ga-PSMA-11-PET/CT to detect recurrent location(s) in hormone-sensitive prostate cancer (PCa). Secondary objectives are (1) to evaluate changes in clinical management; (2) to determine which covariates independently predict positive scan; (3) to assess 68Ga-PSMA-11-PET/CT performance in different settings of PSA relapse. MATERIALS AND METHODS: Inclusion criteria include (1) histologically diagnosed PCa; (2) previous radical therapy; (3) proven biochemical recurrence (BCR) or biochemical persistence (BCP); (4) hormone-sensitive PCa (HSPC); (5) androgen deprivation therapy (ADT)-free for at least 6 months; (6) PSA < 1.5 ng/mL or any PSA in case of negative choline-PET/CT (n = 38). Changes in clinical management were defined by multidisciplinary tumour-board. Clinical settings were BCP (group-1, n = 25); first-time BCR (group-2, n = 121); BCR after salvage therapy (group-3, n = 77). RESULTS: Two hundred twenty-three (223) consecutive patients were enrolled: median PSA = 0.65 ng/mL (0.2-8.9) and median PSAdt = 9.3 months (0.4-144.6). 96.9% received RP as primary therapy. 68Ga-PSMA-11-PET/CT positivity rate was 39.9% (CI95% 33.5-46.7%). Disease confined to pelvis was detected in 23.3% of cases. At least one distant lesion was observed in 16.6% of cases. Secondary objectives are as follows: (1) changes in clinical management were observed in 34.5% of patients; (2) PSA, PSAdt and T stage > 3a were independent predictors (all p < 0.03); (3) 68Ga-PSMA-11-PET/CT positivity rate was 56% (in group 1, 36.3% in group 2, 40.3% in group 3. CONCLUSION: This study attested the overall good performance of 68Ga-PSMA-11-PET/CT to detect PCa locations in HSPC patients eligible for salvage therapy, influencing the therapy management in 35.4% of cases. Furthermore, patient characteristics are influencing factors of 68Ga-PSMA-11-PET/CT positivity rate and should be considered to reduce false negative scan.

Transperineal Free-hand mpMRI Fusion-targeted Biopsies Under Local Anesthesia: Technique and Feasibility From a Single-center Prospective Study.

OBJECTIVE: To evaluate the feasibility of "in-office" TPFBx under local anesthesia (LA). MATERIALS AND METHODS: We prospectively screened for eligibility data of 724 consecutive men undergoing either TPFBx (target and systematic cores) or TPSBx (systematic cores only) from September 2016 to June 2018 due to suspicion of prostate cancer (CaP), according to predefined exclusion criteria. RESULTS: We included 459 men (TPFBx n = 279 including n = 338 mpMRI lesions, Pi-RADS 4 in 63.6%; TPSBx n = 180). Median procedural time and maximum pain were 19 minutes and 5 numeric rating scale (NRS) points; pain was highest at the time of LA. Only 1 major complication occurred (Clavien 3a). Hematuria and hematospermia were frequent (72.6% and 54.2%). Vaso-vagal reactions and AUR were rare (0.7% and 0.4%). No cases of UTI and 1 case of fever were recorded. No significant changes in erectile and urinary functions were noted from baseline compared to 40 days after TPFBx (P = .86 and P = .89). In comparison with TPSBx the sole differences were pain during prostatic sampling (P = .03), duration of hematospermia (P <.0001) and procedural time (P <.001) all higher for TPFBx. Clinically significant (cs) CaP was detected in n = 150 (53.8%) patients in the TPFBx group (34.9%, 51.7%, and 75% of Pirads 3, 4, and 5, respectively). Addition of systematic cores detected n = 25 csCaP that were missed by targeted cores (17.4% of all csCaP). CONCLUSION: TPFBx under LA are feasible, yielding high tolerability, low complications, no impact on erectile and urinary function and good csCaP detection. Addition of systematic to targeted cores remains recommended. Further studies are needed to confirm our findings.

Circulating microRNAs combined with PSA for accurate and non-invasive prostate cancer detection.

The dosage of prostate-specific antigen (PSA), an easily evaluable and non-invasive biomarker, has made early detection of prostate cancer (PCa) possible. However, it leads to high percentages of unnecessary biopsies and may miss aggressive tumors in men with PSA levels below 4 ng/ml. Therefore, we propose to combine circulating microRNAs (miRs) with PSA, to improve the diagnostic route for PCa. Plasma miR profiling identified candidate diagnostic miRs in a discovery cohort of 60 tumors and 60 controls (men with benign prostatic hyperplasia or healthy donors). Linear models with an empirical Bayesian approach and multivariate penalized logistic regression were applied to select tumor-associated miRs and/or clinical variables. A classifier was developed and tested on a validation cohort of 68 tumors and 174 controls consecutively collected, where miRs were evaluated by quantitative real-time polymerase chain reaction. A classifier based on miR-103a-3p, let-7a-5p and PSA could detect both overall and clinically significant tumors better than PSA alone, even in 50-69 years aged men with PSA ≤ 4 ng/ml. Even in the validation cohort, the classifier performed better than PSA alone in terms of specificity and positive predictive value, allowing to correctly identify eight out of nine tumors undetected by PSA, including three high-risk and three tumors in 50-69 years old men. Of carriers of non-malignant lesions with PSA in the 4-16 ng/ml interval, who may avoid unnecessary biopsies, 34% were correctly identified. Coupling two circulating miRs with PSA could be a useful strategy to diagnose clinically significant PCa and avoid an important fraction of unnecessary biopsies.

New insights on occupational exposure and bladder cancer risk: a pooled analysis of two Italian case-control studies.

PURPOSE: The main risk factor for bladder cancer (BC) is cigarette smoking, but also occupational exposure to carcinogens is relevant, causing about 4-10% of BC. We aimed at investigating the association between BC risk, occupations held in the past and exposure to occupational carcinogens, also assessing whether these associations were influenced by tumour grade. METHODS: We pooled data from two Italian case-control studies on male BC, analyzing 893 cases and 978 controls. Occupations were classified using the International Standard Classification of Occupations and exposure to carcinogens was assigned using a validated Job Exposure Matrix. Logistic regression approach was used as well as a semi-Bayesian model, based on a priori information on exposure. RESULTS: A significantly increased BC risk was found for chemical engineering technicians, postmen, and lathe operators, but only, for the latter, the association remained significant after Bayesian control for type I error. Among carcinogens, cadmium and trichloroethylene were associated with BC. When analyzing data by grade, exposure to these carcinogens was associated with low-grade BC only. CONCLUSIONS: Our results suggest that monitoring workplaces to prevent exposure to carcinogenic agents is still an important task, which should be still given adequate importance in public health.

MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression.

Mutations and deletions in components of ubiquitin ligase complexes that lead to alterations in protein turnover are important mechanisms in driving tumorigenesis. Here we describe an alternative mechanism involving upregulation of the microRNA miR-424 that leads to impaired ubiquitination and degradation of oncogenic transcription factors in prostate cancers. We found that miR-424 targets the E3 ubiquitin ligase COP1 and identified STAT3 as a key substrate of COP1 in promoting tumorigenic and cancer stem-like properties in prostate epithelial cells. Altered protein turnover due to impaired COP1 function led to accumulation and enhanced basal and cytokine-induced activity of STAT3. We further determined that loss of the ETS factor ESE3/EHF is the initial event that triggers the deregulation of the miR-424/COP1/STAT3 axis. COP1 silencing and STAT3 activation were effectively reverted by blocking of miR-424, suggesting a possible strategy to attack this key node of tumorigenesis in ESE3/EHF-deficient tumors. These results establish miR-424 as an oncogenic effector linked to noncanonical activation of STAT3 and as a potential therapeutic target.

Prostate Cancer Detection Rate with Koelis Fusion Biopsies versus Cognitive Biopsies: A Comparative Study.

OBJECTIVE: Targeted fusion biopsies have led to an improved prostate cancer (PCa) detection rate (CDR). Our aim was to assess if device-assisted fusion biopsies are superior to cognitive ones in terms of CDR. The association between multiparametric MRI parameters and PCa was also evaluated. METHODS: We retrospectively enrolled 50 patients who underwent transrectal biopsy with elastic fusion (Koelis; group KB, n = 25) or cognitive approach (group CB, n = 25). Targeted biopsies were done on targets, while a variable number of random biopsies were performed depending on the clinical case. RESULTS: The groups did not significantly differ in terms of age, prostate-specific antigen, prostate volume and previous biopsies. Mean number of random cores was significantly inferior in KB group (8.4 vs. 12.1) and mean number of targeted biopsies was significantly higher (3.6 vs. 2.6). CDR was higher in fusion biopsies (64 vs. 40%), with the gap becoming significant when considering CDR of MRI targets only (59 vs. 27%). The difference was marked for lesions ≤10 mm, where CDR was 52% in KB against 21% in CB group. CONCLUSIONS: According to our study, elastic fusion biopsies performed with Koelis achieve an increased per-patient and per-lesion CDR as compared to cognitive biopsies, especially in the case of lesions ≤10 mm.

A randomized double-blind placebo controlled phase I-II study on clinical and molecular effects of dietary supplements in men with precancerous prostatic lesions. Chemoprevention or "chemopromotion"?

BACKGROUND: Antioxidants effectiveness in prostate cancer (PCa) chemoprevention has been severely questioned, especially after the recent results of the Selenium and Vitamin E Cancer Prevention Trial. We present the results of a double-blind randomized controlled trial (dbRCT) on the pharmacokinetic, clinical, and molecular activity of dietary supplements containing lycopene, selenium, and green tea catechins (GTCs) in men with multifocal high grade prostatic intraepithelial neoplasia (mHGPIN) and/or atypical small acinar proliferation (ASAP). METHODS: From 2009 to 2014, we conducted a dbRCT including 60 patients with primary mHGPIN and/or ASAP receiving daily lycopene 35 mg, selenium 55 µg, and GTCs 600 mg, or placebo for 6 months. Pharmacokinetic analysis were performed with UV-Visible spectrophotometric assay under standard (SC) and accelerated (AC) conditions. Upon plasma lycopene concentrations falling within the expected range (1.2-90 mcg/l) and no side-effects of grade >1, study proceeded to phase II (n = 50). After unblinding of results, eight men (4 per arm, 2 without and 2 with PCa, respectively) were randomly selected and totRNA extracted from "non-pathological" tissues. MicroRNA profiling was performed with the Agilent platform. Raw data processing used R-statistical language and linear models for microarray analysis. RESULTS: Samples were stable except for lycopene, showing significant degradation (SC = 56%, AC = 59%) and consequently stabilized under vacuum in a dark packaging. Mean plasmatic lycopene concentration was 1,45 ± 0,4 µM. At 6 months, 53 men underwent re-biopsy and 13 (24.5%) were diagnosed with PCa (supplementation n = 10, placebo n = 3 [P = 0.053]). At a mean 37 months follow-up, 3 additional PCa were found in the placebo group. No significant variations in PSA, IPSS, and PR25 questionnaires were observed. Stronger modulation of miRNAs was present on re-biopsy in the supplementation group compared to the placebo, including: (i) overexpression of miRNAs present in PCa versus non-cancer tissue; (ii) underexpression of miRNAs suppressing PCa proliferation; (iii) detection of 35 miRNAs in PCa patients versus disease-free men, including androgen-regulated miR-125b-5p and PTEN-targeting miR-92a-3p (both upregulated). CONCLUSION: Administration of high doses of lycopene, GTCs, and selenium in men harboring HGPIN and/or ASAP was associated with a higher incidence of PCa at re-biopsy and expression of microRNAs implicated in PCa progression at molecular analysis. The use of these supplements should be avoided.

Shorter leukocyte telomere length is independently associated with poor survival in patients with bladder cancer.

BACKGROUND: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, which may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival. METHODS: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 patients with bladder cancer from a total 726 cases who were followed for up to 18 years. RESULTS: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non-muscle-invasive tumor/high-grade and with non-muscle-invasive tumor/non-high-grade (TL reference 0.7 ± 0.2; vs. respectively, 0.8 ± 0.2, P = 3.4 × 10(-2) and 0.8 ± 0.2, P = 3.6 × 10(-2)). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P = 3.9 × 10(-4)). A Cox regression adjusted by age, cancer aggressiveness, Bacillus Calmette-Guérin, radical cystectomy, radiotherapy, and chemotherapy showed an independent effect of TL on bladder cancer survival (HR, 3.9; 95% confidence interval, 1.7-9.1; P = 1.2 × 10(-3)). CONCLUSIONS: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in patients with bladder cancer. TL information may allow to better select therapeutic approaches in patients with the same stage and grade. IMPACT: Blood leukocyte TL levels could provide an additional noninvasive prognostic marker to better predict survival and personalize therapies in patients with bladder cancer.

DKK-1 in prostate cancer diagnosis and follow up.

BACKGROUND: Dickoppf-1 (DKK-1) is a negative regulator of bone formation with tumorigenic potential. The up-regulation of DKK-1 is an early event in prostate cancer (PCa) development, thus we investigated its role as a marker in the diagnosis and prognosis of PCa. METHODS: We retrospectively enrolled 159 patients who underwent prostate biopsy, either for elevated PSA or suspect digital rectal examination, between 2003 and 2010. During the biopsy, one serum sample was collected from all patients; PSA and DKK-1 were measured by ELISA technique. Amongst the biopsy of 159 patients 75 were affected by PCa and 84 were not the mean period of follow-up for these patients was 5 years; a new biopsy was performed in case of PCa suspicion. RESULTS: PSA performed better than DKK-1 in detecting PCa (0.63 vs 0.51 respectively). Differently from PSA DKK-1 was significantly higher in patients who developed PCa during follow-up than in cancer-free ones, thus DKK-1 performed better than PSA in detecting these patients (0.67 vs 0.55). DKK-1 was significantly lower in patients with bone metastases, whereas PSA was not significantly different in patients with different outcomes. CONCLUSIONS: DKK-1 might be predictive for patients negative at first biopsy who will develop PCa and in the prognosis of bone metastases. It performed worse than PSA in the early diagnosis of Pca.

Prognostic factors of 'high-grade' Ta bladder cancers according to the WHO 2004 classification: are these equivalent to 'high-risk' non-muscle-invasive bladder cancer?

OBJECTIVE: To determine the impact of prognostic factors of a series of high-grade Ta non-muscle-invasive bladder cancers (NMIBCs) according to the new International Society of Urological Pathology (ISUP) 1998/WHO 2004 grading system (previously classified as either TaG2 or TaG3). METHODS: One hundred and thirty-one high-grade Ta (105 G2 and 26 G3) cases were identified after independent review by two pathologists. Univariable and multivariable Cox regression models addressed recurrence and progression-free survival. Progression was defined as appearance of any T ≥1 recurrence after complete TUR (type 1) or occurrence of T ≥2 (type 2). RESULTS: Ten-year recurrence, type-1 and type-2 progression-free survival were 60, 75 and 95%, respectively. The previous grading system (G3 vs. G2) significantly predicted type 1 progression in the univariate model only. In the multivariate model, Ki67 was the only independent predictor of progression according to both definitions (HR = 5.25, p = 0.002 and HR = 6.16, p = 0.03, respectively). CONCLUSIONS: High-grade Ta NMIBC as defined by the WHO 2004 grading system cannot be equated with high-risk NMIBC. The risk of progression to muscle-invasive disease (type 2) is low, more in keeping with an intermediate-risk category of NMIBC. The previous WHO 1973 subcategorization into G2 and G3 is of little help in the prediction of outcome. Ki67 is a strong independent predictor of progression worthy of consideration for a clinical setting.

Polymorphisms in the XRCC1 gene modify survival of bladder cancer patients treated with chemotherapy.

Survival of bladder cancer patients depends on several factors including disease stage and grade at diagnosis, age, health status of the patient and the applied treatment. Several studies investigated the role of DNA repair genetic variants in cancer susceptibility, but only few studies investigated their role in survival and response to chemotherapy for bladder cancer. We genotyped 28 single nucleotide polymorphisms (SNP) in DNA repair genes in 456 bladder cancer patients, reconstructed haplotypes and calculated a score for combinations of the SNPs. We estimated Hazard Ratios (adjHR) for time to death. Among patients treated with chemotherapy, variant alleles of five SNPs in the XRCC1 gene conferred better survival (rs915927 adjHR 0.55 (95%CI 0.32-0.94); rs76507 adjHR 0.48 (95%CI 0.27-0.84); rs2854501 adjHR 0.25 (95%CI 0.12-0.52); rs2854509 adjHR 0.21 (95%CI 0.09-0.46); rs3213255 adjHR 0.46 (95%CI 0.26-0.80). In this group of patients, an increasing number of variant alleles in a XRCC1 gene score were associated with a better survival (26% decrease of risk of death for each additional variant allele in XRCC1). By functional analyses we demonstrated that the previous XRCC1 SNPs confer lower DNA repair capacity. This may support the hypothesis that survival in these patients may be modulated by the different DNA repair capacity determined by genetic variants. Chemotherapy treated cancer patients bearing an increasing number of "risky" alleles in XRCC1 gene had a better survival, suggesting that a proficient DNA repair may result in resistance to therapy and shorter survival. This finding may have clinical implications for the choice of therapy.

Prognostic factors including Ki-67 and p53 in Bacillus Calmette-Guérin-treated non-muscle-invasive bladder cancer: a prospective study.

OBJECTIVES: To prospectively evaluate the prognostic utility of the traditional prognostic factors and molecular markers p53 and Ki-67 in a homogeneous series of patients with non-muscle-invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: 192 intermediate- and high-risk NMIBC cases were enrolled. The variables in study were age, stage, grade, focality, tumour size, presence of associated carcinoma in situ, recurrence rate before BCG, maintenance for BCG, Ki-67 and p53. The endpoints considered were recurrence-free survival, progression-free survival, cancer-specific survival (CSS) and overall survival (OS). RESULTS: T stage resulted in being associated with CSS, whereas age with OS. BCG maintenance was a significantly favourable independent predictor of OS, CSS, recurrence and progression. In univariate analysis, the labelling index of Ki-67 was significantly associated with OS, CSS and progression. Multivariate analysis, however, confirmed this association only for OS. On the contrary, the labelling index of p53 was a significant predictor of recurrence, both in uni- and multivariate analyses, but with a HR inferior to 1. CONCLUSIONS: Ki-67 was an independent predictor of survival. p53 overexpression showed a significant yet inverse correlation with recurrence, thus showing little clinical utility. Age, stage and maintenance were confirmed as independent predictors of BCG response.

[Alternative tests to PSA for prostate cancer diagnosis]. / Nuovi test in competizione con il PSA per la diagnosidel carcinoma prostatico.

Prostate specific antigen (PSA) is still the most useful tool to select the population requiring prostatebiopsy. The main downsides of PSA are an inadequate sensitivity to be used in screening and a low specificity for cancer detection. So far, a limited value for PSA derivates (velocity, density, free, proisoforms and doubling time) has been recognised. We present a short review of the literature describing a selection of the most promising alternatives to PSA being studied currently: PCA3, serum kallikreins, serum detectable prostate specific membrane antigen, the nuclear matrix protein EPCA, EPCA-2, prostatic acid phosphatase, urine detectable GSTP1, anti-AMACR antibodies, sarcosine, plasminogen activating urokinase, IGFBP, TGF beta 1,PSP94, IL6, plasmatic DNA, serum autoantibodies, neuroendocrine markers, proteomic analysis.

Adrenal ganglioneuroma with multifocal retroperitoneal extension: a challenging diagnosis.

A ganglioneuroma (GN) is the rarest and most benign of the neuroblastic tumors and originates from neural crest cells wherever sympathetic nervous tissue exists, such as in the retroperitoneum and adrenal gland. The diagnosis can be very challenging, given the rarity and asymptomatic presentation of this neoplasia, and can be achieved only by means of histological evaluation. Although benign, a few cases of metastatic GNs have been reported in the literature. The prognosis, however, seems to be excellent after surgical resection. We describe a rare case of multifocal retroperitoneal GN, diagnosed incidentally in a 46-year-old woman, with para-aortic and adrenal localizations. After intraoperative pathological diagnosis was made, complete excision of all the visible masses was performed. The postoperative period was uneventful and she was recurrence free 3 months after surgery. To our knowledge, this is the first case report of a multifocal retroperitoneal GN. Among the broad differential diagnoses of adrenal incidentalomas, an adrenal location of neuroblastic tumors should not be forgotten.