The Role of Fast and Deep PSA Response in Castration-sensitive Prostate Cancer

Background: Outcomes of castration-sensitive prostate cancer (CSPC) have improved owing to new therapies and early treatment, previously reserved for castration-resistant disease (CRPC). Prostatic-specific antigen (PSA) remains the most used marker to follow-up patients under treatment, but only limited data are available about the prognostic role of its changes over time and the impact of response to subsequent therapies. This analysis aims to assess the prognostic role of the magnitude and velocity of PSA response in CSPC and describe how this may affect the outcome to subsequent treatment outcomes in CRPC. Patients and methods: A retrospective analysis was performed on patients with de novo CSPC referring to six oncology centers in Italy. Clinical and pathological features were recorded. PSA response (PSA50), defined as a decrease > 50% compared to baseline, PSA velocity (PSAv), defined as any decrease in PSA levels over time and the deep and fast PSA response (4mPSA50), defined as the PSA response reached within the threshold of 4 months from the beginning of androgen deprivation therapy (ADT) have been evaluated for their impact on survival. Survivals were estimated using the Kaplan-Meier method and compared across groups using the log-rank test. Cox proportional-hazard models, stratified according to baseline characteristics, were used to estimate hazard ratios for overall survival (OS). Results: A totals of 94.4% of patients had PSA50, which was correlated to longer OS compared to patients without PSA50 (56.0 vs. 14.8 months; p<0.001). The median PSAv was 6.9 (ng/dl)/month, which was predictive for longer OS: Each decrease of 1 (ng/dl)/month was able to improve OS by 0.2% (HR=0.998, 95%CI=0.997-1.000; p=0.008). A total of 47.9% of patients reached 4mPSA50, with a median OS and progression-free survival (PFS) to ADT-based therapy of 101.0 and 23.4 months compared to 41.9 and 11.0 months for those who did not (p<0.001), respectively. The independent prognostic role of 4mPSA50 was retained even when evaluated in multivariable analysis adjusted for other baseline characteristics and early docetaxel for CSPC. In CRPC, 4mPSA50 evaluated during CSPC retains its prognostic role even if it does not predict a different outcome between patients treated with abiraterone/enzalutamide or taxanes. Conclusion: Achieving a deep and fast PSA response correlates with a better outcome in patients with de novo mCSPC, also positively influencing the prognosis of the subsequent first-line therapy for CRPC disease

Pure stress urinary incontinence: analysis of prevalence, estimation of costs, and financial impact

BackgroundThe prevalence of pure stress urinary incontinence (P-SUI) and the role of urodynamic investigation (UDI) prior to surgery for stress urinary incontinence (SUI) is debated. Since the exact prevalence of P-SUI is not clear, its clinical and economic impact is not well defined. The aims of this study were to evaluate the prevalence of P-SUI in a population of women who underwent UDI for urinary incontinence (UI), also assessing: 1) the correspondence between clinical diagnosis of P-SUI and urodynamic findings; 2) the analysis of costs in terms of UDI and eventually post-UDI avoided surgical procedures.MethodsA single cohort of women who underwent UDI for UI between January 2012 and July 2016 was prospectively collected and retrospectively analyzed. Clinical P-SUI was defined by the strict criteria of the International Continence Society. For each patient, history, physical examination and UDI were collected. The correspondence between clinical and urodynamic findings of P-SUI was analyzed. The rate of clinical P-SUI changed after performing UDI and the number of unnecessary intervention after UDI were reported. A wide cost analysis of UDIs, and the amount of surgical procedures that were believed unnecessary after UDI was reported.ResultsStress urinary incontinence was present in 323/544 (59.4%) patients. The prevalence of clinical P-SUI was 20.7% (67/323), while the prevalence of complicated SUI (C-SUI) was 79.3% (256/323). After UDI, diagnosis of P-SUI decreased to 18.3% (59/232). In 10.2% of cases (6/59) the scheduled middle urethral sling (MUS) was suppressed after the UDI results because 3/6 cases had detrusor overactivity and urge incontinence, in 2/6 cases SUI was treated with a conservative management, in 1/6 case an important voiding dysfunction was detected. Considering the national reimbursement in our country, the cost of each UDI was 296.5 euros and the total amount was 17,493.5 euros. So far the surgery-related savings covered 61.7-105.0% of the costs of total number of UDIs performed in the uncomplicated patients.ConclusionsThe prevalence of clinical P-SUI is relevant, involving about 20% of women with clinical SUI. Although the correspondence between clinical and urodynamic diagnosis was high, we demonstrated that UDI may help in some cases to avoid an inappropriate surgical treatment. Therefore, UDI prior to SUI surgery should be considered to achieve a correct diagnosis and a proper therapeutic strategy

Elevated serum Neurofilament Light chain (NfL) as a potential biomarker of neurological involvement in Myotonic Dystrophy type 1 (DM1)

Background Cognitive and behavioural symptoms due to involvement of the central nervous system (CNS) are among the main clinical manifestations of Myotonic Dystrophy type 1 (DM1). Such symptoms affect patients' quality of life and disease awareness, impacting on disease prognosis by reducing compliance to medical treatments. Therefore, CNS is a key therapeutic target in DM1. Deeper knowledge of DM1 pathogenesis is prompting development of potential disease-modifying therapies: as DM1 is a rare, multisystem and slowly progressive disease, there is need of sensitive, tissue-specific prognostic and monitoring biomarkers in view of forthcoming clinical trials. Circulating Neurofilament light chain (NfL) levels have been recognized as a sensitive prognostic and monitoring biomarker of neuroaxonal damage in various CNS disorders. Methods We performed a cross-sectional study in a cohort of 40 adult DM1 patients, testing if serum NfL might be a potential biomarker of CNS involvement also in DM1. Moreover, we collected cognitive data, brain MRI, and other DM1-related diagnostic findings for correlation studies. Results Mean serum NfL levels resulted significantly higher in DM1 (25.32 +/- 28.12 pg/ml) vs 22 age-matched healthy controls (6.235 +/- 0.4809 pg/ml). Their levels positively correlated with age, and with one cognitive test (Rey's Auditory Verbal learning task). No correlations were found either with other cognitive data, or diagnostic parameters in the DM1 cohort. Conclusions Our findings support serum NfL as a potential biomarker of CNS damage in DM1, which deserves further evaluation on larger cross-sectional and longitudinal studies to test its ability in assessing brain disease severity and/or progression

The role of nutritional supplement on post-stroke fatigue: a pilot randomized controlled trial

Objectives: Post-stroke fatigue (PSF) is an experience characterized by an early feeling of exhaustion with fatigue, a lack of energy, and difficulty in exertion, both motor and cognitive. To counteract fatigue and limit its effects on activities of daily living, the use of vitamins and minerals is known in addition to the pharmacological approach. However, few studies have evaluated the effect of vitamin and mineral supplementation on fatigue management. SiderAL Med is a food for special medical purposes with a complete formulation containing vitamins, sucrosomal minerals, copper and algal calcium. The aim of the study is to evaluate whether nutritional supplementation with SiderAL Med improves the symptom of fatigue and motor and cognitive function in stroke patients. Design: This is a pilot, randomized study with a control group. Setting: Post-Acute Rehabilitation Unit of the Fondazione Policlinico “A. Gemelli” IRCCS. Participants: Twenty-four patients with stroke outcomes, admitted to rehabilitation, were recruited and randomized into the experimental group (Sid-G) and the control group (CG). Intervention: The Sid-G patients, in association with the pharmacological and rehabilitation therapy foreseen during hospitalization, took SiderAL1 Med, one sachet per day for 8 weeks, while the CG patients underwent only the pharmacological and rehabilitation therapy foreseen in the daily routine. Measurements: All patients were assessed at baseline (T0), after 4 weeks (T1), after 8 weeks (T2) and after 12 weeks (T3) for motor and cognitive fatigue, balance, walking, functional capacity, cognitive performance, autonomy, quality of life and body composition. Results: Both Sid-G and CG patients showed significant improvement on most rating scales between T0-T1-T2-T3 (p=0.0001). When comparing the two groups, a statistically significant difference emerged in favor of Sid-G with regard to motor fatigue (p=0.007), cognitive fatigue (p=0.009) and total fatigue (p=0.034); balance (p<0.001), functional capacity (p<0.001); cognitive performance (p=0.004); bone mineral content (p=0.005), lean mass (p=0.005), total mass (p<0.001) and percentage of fat mass (p=0.039). Conclusion: Nutritional supplementation with SiderAL Med, in concert with intensive rehabilitation treatment, appears to be effective in managing fatigue and improving motor and cognitive performance and body composition, representing a valuable tool to associate with rehabilitation treatment in stroke patients

Wide spetcrum mutational analysis of metastatic renal cell cancer : a retrospective next generation sequencing approach

Renal cell cancer (RCC) is characterized by histological and molecular heterogeneity that may account for variable response to targeted therapies. We evaluated retrospectively with a next generation sequencing (NGS) approach using a pre-designed cancer panel the mutation burden of 32 lesions from 22 metastatic RCC patients treated with at least one tyrosine kinase or mTOR inhibitor. We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes. Somatic alterations were correlated with response to therapy. Most mutations hit VHL1 (31,8%) followed by PTEN (13,6%), JAK3, FGFR and TP53 (9% each). Eight (36%) patients were wild-type at least for the genes included in the panel. A genotype concordance between primary RCC and its secondary lesion was found in 3/6 cases. Patients were treated with Sorafenib, Sunitinib and Temsirolimus with partial responses in 4 (18,2%) and disease stabilization in 7 (31,8%). Among the 4 partial responders, 1 (25%) was wild-type and 3 (75%) harbored different VHL1 variants. Among the 7 patients with disease stabilization 2 (29%) were wild-type, 2 (29%) PTEN mutated, and single patients (14% each) displayed mutations in VHL1, JAK3 and APC/CDKN2A. Among the 11 non-responders 7 (64%) were wild-type, 2 (18%) were p53 mutated and 2 (18%) VHL1 mutated. No significant associations were found among RCC histotype, mutation variants and response to therapies. In the absence of predictive biomarkers for metastatic RCC treatment, a NGS approach may address single patients to basket clinical trials according to actionable molecular specific alterations.Peer reviewe

Transperineal Laser Ablation for Focal Therapy of Localized Prostate Cancer: 12-Month Follow-up Outcomes from a Single Prospective Cohort Study

Introduction and objectives: to evaluate the oncological and functional outcomes of transperineal laser ablation (TPLA) as the focal therapy for localized prostate cancer (PCa) after a 12-month follow-up. Materials and methods: patients with low- and intermediate-risk localized PCa were prospectively treated with focal TPLA between July 2021 and December 2022. The inclusion criteria were the following: clinical stage < T2b; PSA < 20 ng/mL; International Society of Urological Pathology (ISUP) grade ≤ 2; MRI-fusion biopsy-confirmed lesion classified as PI-RADS v2.1 ≥ 3. Intra-, peri-, and post-operative data were collected. Variables including age, PSA, prostate volume (PVol), Charlson’s Comorbidity Index (CCI), International Prostate Symptom Score (IPSS) with QoL score, International Index of Erectile Function (IIEF-5), International Consultation on Incontinence Questionnaire—Short Form (ICIQ-SF), and Male Sexual Health Questionnaire—Ejaculatory Dysfunction Short Form (MSHQ-EjD) were collected at baseline and at 3, 6 and 12 months after TPLA. Post-operative mpMRI was performed at 3 and 12 months. Finally, all patients underwent prostatic re-biopsy under fusion guidance at 12 months. The success of this technique was defined as no recurrence in the target treated lesion at the 12-month follow up. Results: Twenty-four patients underwent focal TPLA. Baseline features were age [median 67 years (IQR 12)], PSA [5.7 ng/mL (3.9)], PVol [49 mL (27)], CCI [0 (0)], IPSS [11 (9)], IPSS-QoL [2 (2)], IIEF-5 [21 (6)], ICIQ-SF [0 (7)], MSHQ-EjD ejaculation domain [14 (4)] and bother score [0 (2)]. Median operative time was 34 min (IQR 12). Median visual analogue scale (VAS) 6 h after TPLA was 0 (IQR 1). The post-operative course was regular for all patients, who were discharged on the second post-operative day and underwent catheter removal on the seventh post-operative day. No patient had incontinence at catheter removal. A significant reduction in PSA (p = 0.01) and an improvement in IPSS (p = 0.009), IPSS-QoL (p = 0.02) and ICIQ-SF scores (p = 0.04) compared to baseline were observed at the 3-month follow-up. Erectile and ejaculatory functions did not show any significant variation during the follow-up. No intra- and peri-operative complications were recorded. Three Clavien–Dindo post-operative complications were recorded (12%): grade 1 (two cases of urinary retention) and grade 2 (one case of urinary tract infection). At the 12-month follow-up, eight patients showed mpMRI images referable to suspicious recurrent disease (PIRADS v2.1 ≥ 3). After re-biopsy, 7/24 patients’ (29%) results were histologically confirmed as PCa, 3 of which were recurrences in the treated lesion (12.5%). The success rate was 87.5%. Conclusions: the focal TPLA oncological and functional results seemed to be encouraging. TPLA is a safe, painless, and effective technique with a good preservation of continence and sexual outcomes. Recurrence rate at 12 months was about 12.5%

Actigraphic Sensors Describe Stroke Severity in the Acute Phase: Implementing Multi-Parametric Monitoring in Stroke Unit

: Actigraphy is a tool used to describe limb motor activity. Some actigraphic parameters, namely Motor Activity (MA) and Asymmetry Index (AR), correlate with stroke severity. However, a long-lasting actigraphic monitoring was never performed previously. We hypothesized that MA and AR can describe different clinical conditions during the evolution of the acute phase of stroke. We conducted a multicenter study and enrolled 69 stroke patients. NIHSS was assessed every hour and upper limbs' motor activity was continuously recorded. We calculated MA and AR in the first hour after admission, after a significant clinical change (NIHSS ± 4) or at discharge. In a control group of 17 subjects, we calculated MA and AR normative values. We defined the best model to predict clinical status with multiple linear regression and identified actigraphic cut-off values to discriminate minor from major stroke (NIHSS ≥ 5) and NIHSS 5-9 from NIHSS ≥ 10. The AR cut-off value to discriminate between minor and major stroke (namely NIHSS ≥ 5) is 27% (sensitivity = 83%, specificity = 76% (AUC 0.86 p < 0.001), PPV = 89%, NPV = 42%). However, the combination of AR and MA of the non-paretic arm is the best model to predict NIHSS score (R2: 0.482, F: 54.13), discriminating minor from major stroke (sensitivity = 89%, specificity = 82%, PPV = 92%, NPV = 75%). The AR cut-off value of 53% identifies very severe stroke patients (NIHSS ≥ 10) (sensitivity = 82%, specificity = 74% (AUC 0.86 p < 0.001), PPV = 73%, NPV = 82%). Actigraphic parameters can reliably describe the overall severity of stroke patients with motor symptoms, supporting the addition of a wearable actigraphic system to the multi-parametric monitoring in stroke units

First line avelumab in PD-L1+ve metastatic or locally advanced urothelial cancer (aUC) patients unfit for cisplatin (cis): The ARIES trial

Background: Avelumab (ave) was approved as maintenance therapy after platinum-based first line (1L) therapy for patients (pts) with aUC based on ph. 3 Javelin Bladder 100 study (NCT02603432), showing significant overall survival (OS) improvement. Here we tested the activity of ave as 1L of therapy in cis-unfit pts with aUC and PD-L1+ve expression. Methods: ARIES is a single-arm, multi-site, open-label phase II trial. Enrolled pts had aUC, were cis-unfit (at least one of: ECOG-PS = 2, CrCl < 60 mL/min, grade ≥2 peripheral neuropathy/hearing loss, progression within 6-mos before the end of neo/adj chemo), had not previously received chemo for aUC and PD-L1≥5% (SP263) centrally assessed. Pts received ave 10 mg/Kg IV Q2W until progression, unacceptable toxicity and withdrawal, whichever occurred first. The primary endpoint was the 1-year OS. Key secondary endpoints were median-OS, -PFS, ORR and safety. Results: A total of 198 eligible cis-unfit pts have been tested for PD-L1 and 71 (35.6%) have been found positive. Among enrolled patients (N = 71), median age was 75 y, 35 (49.3%) had visceral disease, and 22 (31.0%) had ECOG-PS = 2; 50 (70.4%) had CrCl < 60 mL/min and 9 (12.7%) progressed within 6-mos from the end of neo/adj chemo. At the cut-off data (Oct 7, 2021), median follow up was 9.0 mo and 13 patients are still on treatment. The median OS was 10.0 mos (95% CI, 5.7-14.3), and 40.8% of patients were alive at 1-year. The ORR for all patients was 22.5%; complete response, 1.4% (n = 1); partial response, 21.1% (n = 15). Clinical benefit was 43.6% (n = 31). Median PFS was 2.0 mos (95% CI, 1.4-2.6). Among the 56 pts who received at least 3 cycles (29 days) of therapy the median OS was 16.0 vs 1.0 mos. Five (7.0%) grade 3 ave-related adverse events, and no treatment-related death were reported. Conclusions: Ave is active and safe in pts with cis-unfit, PD-L1+ve aUC and poor baseline characteristics