Overexpression of H2AFX gene in neuroblastoma is associated with worse prognosis.

BACKGROUND: Neuroblastoma (NB) is the most common solid tumour in childhood, and rises in the sympathetic nervous system. Here, we addressed the in silico analysis of the association between the expression of H2AFX gene involved in DNA damage response, and the survival of a cohort of 786 NB patients. METHODS: In silico gene expression was retrieved from the publicly available dataset summarised by Cangelosi et al., including 13,696 gene expression profiles of 786 NB tumours at onset of disease. The prognostic value of H2AFX (H2A histone family member X) gene expression for event-free survival (EFS) and overall survival (OS) was evaluated by Kaplan-Meier and Cox regression analysis. The main results were validated on another openly accessible in silico database (NRC-283) containing 13,489 gene expressions in 283 NB patients. The expression of H2AFX protein was then tested by immunofluorescence on 48 primary NB samples of different tumour stages. H2AFX activity as an oncogene has been further validated in vitro by silencing the molecule in two NB cell lines, characterised by MYCN amplified or not, and performing cell growth and migration assays. RESULTS: A strong inverse association between H2AFX expression and patients' survival was observed and confirmed by immunofluorescence results on primary NB tissue sections. Cox regression analysis also disclosed H2AFX as an independent predictor of EFS and OS. The gene-silencing experiments strongly suggested an oncogenic role for H2AFX on NB cells, regardless of MYCN amplification. CONCLUSIONS: H2AFX is a prognostic marker for unfavourable NB and could be considered a target for therapeutic interventions.

Accuracy of Glucagon Testing Across Transition in Young Adults with Childhood-Onset Growth Hormone Deficiency.

CONTEXT: The 2019 AACE guidelines suggested peak GH-cutoffs to glucagon test (GST) of ≤3 µg/L and ≤1 µg/L in the diagnosis of permanent GH deficiency (GHD) during the transition phase. OBJECTIVE: Aim of the study was to evaluate the accuracy of GST compared to insulin tolerance test (ITT) in the definition of GHD at adult height achievement. PATIENTS AND METHODS: Ninety-seven subjects with childhood-onset GHD (median age, 17.39 years) underwent ITT, GST and IGF-1 testing; 44 subjects were idiopathic (isolated GHD), 35 moderate organic GHD (0-2 hormone deficiencies-HDs) and 18 severe organic GHD (≥3 HDs). RESULTS: Bland and Altman analysis showed a high consistency of GH peak measures after ITT and GST. Receiver operating characteristic analysis-ROC- identified 7.3 µg/L as the optimal GH peak cutoff to GST (95% CI 4.15-8.91; sensitivity 95.7%, specificity 88.2%, positive predictive value-PPV-88.0%, negative predictive value-NPV-95.7%), able to correctly classify 91.8% of the entire cohort while 5.8 µg/L was the best GH peak cutoff able to correctly classify 91.4% of moderate organic GHD patients (95% CI 3.16-7.39; sensitivity 96.0%, specificity 80.0%, PPV 92.3%, NPV 88.9%). Patients with ≥3HDs showed a GH peak <5µg/L at ITT and <5.8µg/L at GST but one. The optimal cutoff for IGF1 was -1.4 SDS (95% CI -1.94-0.77; sensitivity 75%, specificity 94%, PPV 91.7%, NPV 81.0%) that correctly classified 85.1% of the study population. CONCLUSIONS: A GH peak to GST <5.8 µg/L represents an accurate diagnostic cutoff for young adults with childhood-onset GHD and high pre-test probability of permanent GHD.

Evolving types of pudendal neuromodulation for lower urinary tract dysfunction.

Introduction: Sacral neuromodulation and posterior tibial nerve stimulation for lower urinary tract dysfunction (LUTD) and overactive bladder yield good and reliable results. However, neuromodulation research is continuously evolving because there is still need for more patient-friendly treatment options in the therapeutic management of LUTD. Pudendal neuromodulation (PNM) has been emerging as a promising alternative treatment option for the last few decades. The aim of this study is to review the current state of the art of PNM. Material and methods: A wide literature search was conducted in the field of PNM using Medline through the PubMed database and Elsevier using the Scopus database; a critical review of the results was then carried out. PNM has been studied in its various possible aspects: percutaneous PNM, transrectal/transvaginal PNM, and both percutaneous and transcutaneous dorsal genital nerve stimulation. Results: Each technique was found to result in promising improvements in different clinical outcomes, with some trials reporting even better results than sacral neuromodulation. Conclusions: As a result of a comparison between the various PNM techniques with both sacral neuromodulation and posterior tibial nerve stimulation, we think that PNM should be seen as seriously promising, and we believe it will expand the treatment options for overactive bladder. Even though several studies accordingly showed PNM to be safe and effective, a systematic review and meta-analysis were not feasible. PNM in its various techniques is a promising treatment for LUTD. Nevertheless, further research is needed to include it in treatment algorithms.

Overall Survival of Metastatic Prostate Cancer Patients According to Location of Visceral Metastatic Sites.

INTRODUCTION: It is unknown whether specific locations of visceral metastatic sites affect overall survival (OS) of metastatic prostate cancer (mPCa) patients. We tested the association between specific locations of visceral metastatic sites and OS in mPCa patients. MATERIALS AND METHODS: Within Surveillance, Epidemiology and End Results database (2010-2016), survival analyses relied on specific locations of visceral metastases: lung only vs. liver only vs. brain only vs. ≥2 visceral sites. Kaplan-Meier plots and Cox regression models were fitted. RESULTS: Of 1827 patients, 1044 (57%) harbored lung only visceral metastases vs. 457 (25%) liver only vs. 131 (7%) brain only vs. 195 (11%) ≥2 visceral sites. Median OS was 22 months in all patients vs. 33 months in lung only vs. 15 months in liver only vs. 16 months in brain only vs. 15 months in patients with ≥2 visceral sites. Highest OS was recorded in lung only visceral metastases patients, especially when concomitant nonvisceral metastases were located in lymph nodes only (median OS 57 months) vs. bone only (26 months) vs. lymph nodes and bone (28 months). Liver only, brain only or ≥2 visceral sites exhibited poor OS, regardless of concomitant nonvisceral metastases type (median OS from 13 to 19 months). CONCLUSION: In mPCa patients, lung only visceral metastases, especially when associated with lymph node only nonvisceral metastases, portend the best prognosis. Conversely, visceral metastatic sites other than lung portend poor prognosis, regardless of concomitant nonvisceral metastases type.

Survival of patients with clear cell renal carcinoma according to number and location of organ-specific metastatic sites.

BACKGROUND: The prognostic significance of number and location of organ-specific metastatic sites in treated metastatic clear cell renal carcinoma (ccmRCC) patients is object of debate. The current study aimed to test the association between number and location of organ-specific metastatic sites and overall survival (OS) in ccmRCC. MATERIALS AND METHODS: Within Surveillance, Epidemiology and End Results database (2010-2018), all ccmRCC patients treated with cytoreductive nephrectomy and/or systemic therapy were identified. Kaplan-Meier plots and Cox regression models focused on: A). number of organ-specific metastatic sites: solitary vs. 2 vs. 3 or more; B). solitary organ-specific metastatic sites (lung vs. bone vs. liver vs. brain); C). combinations of 2 and 3 or more different organ-specific metastatic sites. RESULTS: Of 4,527 patients (median OS: 19 months), 3,054 (67%) harbored solitary organ-specific metastatic sites (27 months) vs. 1,153 (25%) combinations of 2 different organ-specific metastatic sites (12 months) vs. 320 (8%) combinations of 3 or more different organ-specific metastatic sites (7 months). In patients with solitary organ-specific metastatic sites, bone metastases portended the longest median OS (median OS: 31 months) vs. liver metastases portended the shortest median OS (16 months). Both were independent predictors of OS (multivariable hazard ratio, bone: 0.87; liver: 1.21). Median OS was similarly poor in patients with combinations of 2 different organ-specific metastatic sites (9-13 months), regardless of their location. The same pattern applied to patients with combinations of 3 or more different organ-specific metastatic sites (6-7 months). CONCLUSIONS: Solitary organ-specific metastatic sites portend the most favorable OS (16-31 months). Solitary bone metastases yield the longest vs. liver metastases the shortest OS. Invariably poor OS applies to combinations of 2 (9-13 months), as well as 3 or more different organ-specific metastatic sites (6-7 months), regardless of their location.

What Is in the Pipeline on Investigational Neuromodulation Techniques for Lower Urinary Tract Dysfunction: A Narrative Review.

OBJECTIVES: Overactive bladder (OAB) affects millions of patients worldwide. Its treatment is challenging but improves the patient's quality of life. Besides standard techniques for neuromodulation (sacral and pudendal neuromodulation and posterior tibial nerve stimulation), several new techniques have been investigated to treat symptoms of refractory OAB. The purpose of the present review is to outline the state of the art of new neuromodulation techniques for lower urinary tract dysfunction (LUTD). MATERIALS AND METHODS: In March 2023, a comprehensive MEDLINE, EMBASE, and Scopus search was carried out (keywords: LUTD, new technologies, neuromodulation, LUTS, OAB, painful bladder syndromes, etc). Articles were included according to inclusion (randomized controlled trials, prospective trials, large retrospective studies) and exclusion (case reports, outcomes not clearly expressed in full text, animal studies) criteria. The reference lists of the included studies also were scanned. Both adult and pediatric populations were included, in addition to both neurogenic and nonneurogenic OAB. A narrative review was then performed. RESULTS: Peroneal neuromodulation, transcutaneous electrical nerve stimulation, magnetic nerve stimulation, and parasacral transcutaneous neuromodulation are the most studied investigative techniques and were shown to yield promising results in treating OAB symptoms. Most studies showed promising results even in the complex scenarios of patients with OAB refractory to standard treatments. Comparing investigational techniques with standard of care and their respective clinical outcomes and safety profiles, and confronting their pros and cons, we reasonably believe that once such treatment modalities are further developed, they could play a role in the OAB treatment algorithm. CONCLUSIONS: Although the described neuromodulation techniques are being intensely studied, the available results are not yet sufficient for any guidelines to recommend their use.

Neuroblastoma Patients' Outcome and Chromosomal Instability.

Chromosomal instability (CIN) induces a high rate of losses or gains of whole chromosomes or parts of chromosomes. It is a hallmark of most human cancers and one of the causes of aneuploidy and intra-tumor heterogeneity. The present study aimed to evaluate the potential prognostic role of CIN in NB patients at diagnosis. We performed array comparative genomic hybridization analyses on 451 primary NB patients at the onset of the disease. To assess global chromosomal instability with high precision, we focused on the total number of DNA breakpoints of gains or losses of chromosome arms. For each tumor, an array-CGH-based breakpoint instability index (BPI) was assigned which defined the total number of chromosomal breakpoints per genome. This approach allowed us to quantify CIN related to whole genome disruption in all NB cases analyzed. We found differences in chromosomal breakages among the NB clinical risk groups. High BPI values are negatively associated with survival of NB patients. This association remains significant when correcting for stage, age, and MYCN status in the Cox model. Stratified analysis confirms the prognostic effect of BPI index in low-risk NB patients with non-amplified MYCN and with segmental chromosome aberrations.

Advanced Hybrid Closed Loop users' satisfaction of telemedicine and telenursing in pediatric and young adult type 1 diabetes.

Background and aims: The aim of the study was to evaluate the satisfaction of the use of telemedicine and telenursing in children and young adults with Type 1 Diabetes (T1D) using Advanced Hybrid Closed Loop systems (AHCL) with a focus on the role of connectivity, data download and the ease of technical steps in the set and sensor change procedures. Methods: An online anonymous survey was administered to AHCL users. The questionnaire consisted of five Clusters: Cluster A-B-C included questions related to the general satisfaction in the use of telemedicine, Cluster D was focused on the role of data download and connectivity, Cluster E was related to satisfaction in telenursing and Cluster F to the perception of ease of execution of the technical steps like changing the infusion set and the sensor. Results: We collected 136 completed questionnaires. 83.8% of AHCL users were overall satisfied with the quality of the telemedicine service. 88.2% of patients downloaded AHCL data before visits and the overall quality of televisits (data sharing, connectivity, ease of use) was satisfactory for 85.3% of users. Telenursing support during set and sensor change procedures was considered effective by 98% of AHCL users. The sensor and insulin infusion set change procedure is perceived as different for the two systems: set change simpler for Medtronic (p = 0.011) users, while sensor change was simpler for Tandem users (p = 0.009). Conclusion: Telemedicine and telenursing have an essential role in diabetology and are highly appreciated in AHCL users. The nurse support in the education of the use of AHCL systems is effective and must be implemented. Unfortunately, not all patients have the technological tools needed for downloading data at home and using telemedicine services; this represents an important challenge for the future of diabetology and for the equity in accessibility to care.

Does the distal ureteral diameter ratio (UDR) matter in the surgical management of vesicoureteral reflux in children?

PURPOSE: To evaluate UDR reliability, sensitivity, specificity and to identify the best treatment basing on UDR among single or double endoscopic injections and ureteral reimplantation. METHODS: Data of patients affected by primary VUR and treated by endoscopic injection over a 10 years period were retrospectively analyzed. Two radiologist attributed reflux grade and UDR on voiding cystourethrogram twice and blinded. Follow-up focused on resolution after 1 or 2 endoscopic injections. Relation between UDR, reflux grade and outcomes were analyzed. RESULTS: Patient enrolled were 198. Low grade VUR was present in 24.8%, grade 3 in 41.6%, grade 4-5 in 33.6%. Resolution after one injection was obtained in 88 patients; among 110 not resolved 104 cases had a second injection. Success after 2 injections was reported in 138 cases. UDR showed a higher reliability compared with reflux grade both in intra than inter-reader measurement (ICC > 90%). Success after 1 or 2 injections was reported for UDR < 0.33 and UDR < 0.47 respectively. CONCLUSION: UDR shows to be a more reliable measurement that allows for an objective estimation of VUR severity and prognosis. It represents a quantitative parameter that might be useful to identify patients who may benefit endoscopic or surgical treatment, avoiding unnecessary under or over-treatment.

Radical cystectomy in bladder cancer patients previously treated for prostate cancer: Insights from a large European multicentric series.

INTRODUCTION: Previous radical prostatectomy (RP) for prostate cancer (PCa) might impair feasibility of radical cystectomy (RC) for bladder cancer (BCa). The current study addressed morbidity, operative time (OT), and length of stay (LOS) of RC, within the largest available series of patients with history of previous RP. MATERIALS AND METHODS: All patients previously submitted to RP for PCa and subsequently submitted to RC for BCa, at six high-volume European institutions between 2010 and 2019, were identified. Presence of either PCa or BCa metastases, RT as primary treatment for PCa, and palliative RC represented exclusion criteria. The quality criteria for accurate and comprehensive reporting of intra- and post-operative surgical outcomes, recommended by the European Association of Urology guidelines, were fulfilled. Multivariable logistic and Poisson regression analyses were performed. RESULTS: Overall, 140 RC patients with history of RP were identified. After RP, 69 (49%) patients received radiotherapy (RT) for PCa, either in adjuvant (n = 50, 36%) or salvage setting (n = 19, 13%). Median age-adjusted Charlson comorbidity index was 6 (IQR 5, 7). Median OT, estimated blood loss and LOS were, respectively, 300 min, 500 ml, and 16 days. Intra-operative transfusions rate was 47% (n = 65). One intra-operative complication occurred (EAUiaiC grade 2, perforation of the rectum managed with immediate repair). Eighty-two (59%) patients experienced a total of 107 post-operative complications during the hospital stay, and seven (5%) patients required hospital readmission. In multivariable regression analyses, RT for PCa was associated with higher risk of post-operative complications (odds ratio 1.82, p = 0.039), longer OT (incidence rate ratio 1.09, p < 0.001), and longer LOS (incidence rate ratio 1.24, p < 0.001). CONCLUSIONS: RC in patients with history of RP is feasible, albeit burdened by remarkable morbidity, even in centers of excellence. RT after RP for PCa portends worse surgical outcomes.

The definition of ideal training of a urology resident from two different perspectives: trainees vs professors. Is there agreement in their idea of good training?

Introduction: At the end of their residency program, urology trainees should reach the minimum skills required to be able to work by themselves and within a team. To achieve this objective, it is fundamental that the training involves not only surgical activities, but also theoretical, academic, and relational ones. What is the perfect balance between these activities within the ideal urological training? This study aims to evaluate the concordance in different concepts of good urological training between different perspectives (trainees vs professors). Material and methods: Between January and December 2020 the same survey was distributed via email to 967 urology trainees and urology tutors. The survey investigated 5 educational fields: theoretical, clinical, surgical, relational, and simulation. For each field, specific questions investigated the importance of different activities and the training outcomes considered fundamental to be reached by a resident. The questions were evaluated by responders through a Likert 10-point scale. Results: The survey was completed by 155 trainees (58.9%, Group A) and 108 tutors (41.1%, Group B) from 26 different countries. Relative to the tutors, residents assigned statistically significantly lower scores to prostate biopsy (median score 9.11 vs 9.24), robotic simulator training (5.66 vs 5.93), on-call duties with consultants (6.85 vs 7.99), as well as all aspects of relational training (e.g., proper dialogue with colleagues: 7.95 vs 8.88). Conversely, residents assigned statistically significantly higher scores, albeit below sufficiency, to the performance of robotic prostatectomy as a first operator (4.45 vs 4.26). Finally, no discrepancies between residents' and tutors' scores were recorded regarding the remaining items of clinical training (e.g., urodynamics, outpatient clinic, ward duties) and surgical training (e.g., major open, laparoscopic and endoscopic surgical training; all p values >0.05). Conclusions: There was partial concordance between trainees and tutors regarding the activities that should be implemented and the skills that should be achieved during a urological residency. The residents aimed for more surgical involvement, while the tutors and professors, although giving importance to surgical and theoretical training, considered clinical practice as the fundamental basis on which to train future urologists.

A survey on preferences, attitudes, and perspectives of Italian urology trainees: implications of the novel national residency matching program.

BACKGROUND: Since 2014, a new residency program selection process has been established with a national examination. The aim of this study was to assess characteristics, career goals, and practice preferences of current Italian urology residents. METHODS: A web-based survey of 25 items performed from May 2021 to September 2021 was sent to 585 Italian urology residents. Descriptive analyses were conducted to describe the surveys' domains: demographics characteristics, studies, plans for fellowship training, interest in the urology field, and career expectations. RESULTS: Four hundred and one residents completed the online survey (response rate 68.5%). Most residents were male (70.3%), with a median of 29 (IQR 28-31) years. Urology was the first chosen School in 325 (81.0%) cases, and 174 (43.4%) trainees have chosen to remain in the same University. Uro-oncology was the main field, and endourology the main subspeciality of interest, respectively. More than 40.0% of residents expressed a good level of satisfaction for the training urological course. 232 (57.2%) residents were strongly interested in seeking a hospital career, followed by private career (43.4%) and academic career (20%). CONCLUSIONS: After the introduction of the novel national residency matching program the Italian Urology trainees showed a good satisfaction level. Further improvements of the Italian residency programs should be focused on the training network within and outside the main School of Urology.

Multiple Genes with Potential Tumor Suppressive Activity Are Present on Chromosome 10q Loss in Neuroblastoma and Are Associated with Poor Prognosis.

Neuroblastoma (NB) is a tumor affecting the peripheral sympathetic nervous system that substantially contributes to childhood cancer mortality. Despite recent advances in understanding the complexity of NB, the mechanisms determining its progression are still largely unknown. Some recurrent segmental chromosome aberrations (SCA) have been associated with poor survival. However, the prognostic role of most SCA has not yet been investigated. We examined a cohort of 260 NB primary tumors at disease onset for the loss of chromosome 10q, by array-comparative genomic hybridization (a-CGH) and Single Nucleotide Polymorphism (SNP) array and we found that 26 showed 10q loss, while the others 234 displayed different SCA. We observed a lower event-free survival for NB patients displaying 10q loss compared to patients with tumors carrying other SCA. Furthermore, analyzing the region of 10q loss, we identified a cluster of 75 deleted genes associated with poorer outcome. Low expression of six of these genes, above all CCSER2, was significantly correlated to worse survival using in silico data from 786 NB patients. These potential tumor suppressor genes can be partly responsible for the poor prognosis of NB patients with 10q loss.

The Association Between Cytoreductive Nephrectomy and Overall Survival in Metastatic Renal Cell Carcinoma with Primary Tumor Size ≤4 cm.

BACKGROUND: It is unknown whether the survival benefit of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) applies to patients with primary tumor size ≤4 cm. OBJECTIVE: To test the association between CN on overall survival (OS) of mRCC patients with primary tumor size ≤4 cm. DESIGN, SETTING, AND PARTICIPANTS: Within the Surveillance, Epidemiology, and End Results (SEER) database (2006-2018), all mRCC patients with primary tumor size ≤4 cm were identified. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Propensity score matching (PSM), Kaplan-Meier plots, multivariable Cox regression analyses, and 6-mo landmark analyses addressed OS according to CN status. Sensitivity analyses examined specific populations of special interest: systemic therapy exposed versus naïve, clear-cell (ccmRCC) versus non-clear-cell (non-ccmRCC) mRCC histology, historical (2006-2012) versus contemporary (2013-2018), and young (≤65 yr) versus old (>65 yr) patients. RESULTS AND LIMITATIONS: Of 814 patients, 387 (48%) underwent CN. After PSM, the median OS was 44 versus 7 mo (Δ = 37 mo; p < 0.001) in CN versus no-CN patients. CN was associated with higher OS in overall population (multivariable hazard ratio [HR]: 0.30; p < 0.001) as well as in landmark analyses (HR: 0.39; p < 0.001). In all sensitivity analyses, CN was independently associated with higher OS: systemic therapy exposed, HR: 0.38; systemic therapy naïve, HR: 0.31; ccmRCC, HR: 0.29; non-ccmRCC, HR: 0.37; historical, HR: 0.31; contemporary, HR: 0.30; young, HR: 0.23; and old, HR: 0.39 (all p < 0.001). CONCLUSIONS: The current study validates the association between CN and higher OS in patients with primary tumor size ≤4 cm. This association is robust, controlled for immortal time bias, and valid across systemic treatment exposure, histologic subtypes, years of surgery, and patient age. PATIENT SUMMARY: In the current study, we tested the association between cytoreductive nephrectomy (CN) and overall survival in patients with metastatic renal cell carcinoma and small primary tumor size. We found a strong association between CN and survival, which persists even after several significant variations in patient and tumor characteristics.

Adenocarcinoma of the Bladder: Assessment of Survival Advantage Associated With Radical Cystectomy and Comparison With Urothelial Bladder Cancer.

PURPOSE: To evaluate the association between radical cystectomy (RC) and cancer-specific mortality (CSM) in patients diagnosed with adenocarcinoma of the bladder (ACB). Moreover, to directly compare the survival advantage of RC between ACB vs. urothelial bladder cancer (UBC). MATERIALS AND METHODS: Non-metastatic muscle-invasive ACB and UBC patients were identified within Surveillance, Epidemiology, and End Results database (SEER 2000-2018). All analyses were stratified between RC vs. no-RC, in either organ-confined (OC: T2N0M0) or non-organ-confined (NOC: T3-4N0M0 or TanyN1-3M0) stages. Propensity score matching (PSM), cumulative incidence plots, competing risks regression (CRR) analyses, and 3 months' landmark analyses were performed. RESULTS: Overall, 1,005 ACB and 47,741 UBC patients were identified, of whom 475 (47%) and 19,499 (41%) were treated with RC, respectively. After PSM, comparison between RC vs. no-RC applied to 127 vs. 127 OC-ACB, 7,611 vs. 7,611 OC-UBC, 143 vs. 143 NOC-ACB, and 4,664 vs. 4,664 NOC-UBC patients. 36-month CSM rates in RC vs. no-RC patients were 14 vs. 44% in OC-ACB, 18 vs. 39% in OC-UBC, 49 vs. 66% in NOC-ACB, and 44 vs. 56% in NOC-UBC patients. In CRR analyses, the effect of RC on CSM yielded a hazard ratio of 0.37 in OC-ACB, of 0.45 in OC-UBC, of 0.65 in NOC-ACB and of 0.68 in NOC-UBC patients (all P values<0.001). Landmark analyses virtually perfectly replicated the results. CONCLUSIONS: In ACB, regardless of stage, RC is associated with lower CSM. The magnitude of this survival advantage was greater in ACB than in UBC, even after control for immortal time bias.

A Simple, Test-Based Method to Control the Overestimation Bias in the Analysis of Potential Prognostic Tumour Markers.

The early evaluation of prognostic tumour markers is commonly performed by comparing the survival of two groups of patients identified on the basis of a cut-off value. The corresponding hazard ratio (HR) is usually estimated, representing a measure of the relative risk between patients with marker values above and below the cut-off. A posteriori methods identifying an optimal cut-off are appropriate when the functional form of the relation between the marker distribution and patient survival is unknown, but they are prone to an overestimation bias. In the presence of a small sample size, which is typical of rare diseases, the external validation sets are hardly available and internal cross-validation could be unfeasible. We describe a new method to obtain an unbiased estimate of the HR at an optimal cut-off, exploiting the simple relation between the HR and the associated p-value estimated by a random permutation analysis. We validate the method on both simulated data and set of gene expression profiles from two large, publicly available data sets. Furthermore, a reanalysis of a previously published study, which included 134 Stage 4S neuroblastoma patients, allowed for the identification of E2F1 as a new gene with potential oncogenic activity. This finding was confirmed by an immunofluorescence analysis on an independent cohort.

The effect of chemotherapy in sarcomatoid bladder cancer patients treated with radical cystectomy.

INTRODUCTION: Data about the role of chemotherapy in sarcomatoid bladder cancer (SBC) are limited. We addressed the effect of chemotherapy in non-metastatic SBC patients treated with radical cystectomy (RC). METHODS: Using the Surveillance, Epidemiology, and End Results database (2001-2018), we identified 331 patients with non-metastatic muscle-invasive or higher SBC (T2-4N0-3M0). Kaplan-Meier plots and Cox regression models tested cancer-specific mortality (CSM ). Sample size and power analyses tested for power limitations. RESULTS: Of 331 SBC patients, 129 (38.9%) were exposed to chemotherapy. The rate of organ-confined stage (T2N0M0) was 33% in both chemotherapy-exposed and chemotherapy-naive patients. In the overall cohort, median CSM-free survival was 84 months (interquartile range [IQR] 21-NA) vs. 26 months (IQR 17-84) in chemotherapy exposed vs. chemotherapy-naive patients, respectively. In multivariable Cox regression models, chemotherapy was associated with lower CSM, without reaching statistical significance (hazard ratio [HR ] 0.72, confidence interval [CI] 0.51-1.01, p=0.054). In subgroup analyses, chemotherapy exposure in organ-confined (n=110) vs. non-organ-confined (n=221) patients resulted in a HR of 0.51 (p=0.12) vs. 0.77 (p=0.17), respectively. Power analyses, based on two-sided α=0.05, revealed values of 52%, 14%, and 43% in the entire population, organ-confined, and nonorgan-confined subgroups, respectively. CONCLUSIONS: In non-metastatic SBC treated with RC, the association between chemotherapy and lower CSM is particularly strong in organ-confined stage. A substantially larger cohort would be required to confirm the statistical significance of the recorded protective effect of chemotherapy.

Radical cystectomy in non-metastatic sarcomatoid bladder cancer: A direct comparison vs urothelial bladder cancer.

INTRODUCTION: The effect of radical cystectomy (RC) on cancer-specific mortality (CSM) is unclear in non-metastatic sarcomatoid bladder cancer (SBC) patients. We aimed to test the benefit of RC in SBC, and to perform a direct comparison vs urothelial bladder cancer (UCB). MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results database (SEER 2001-2018) all non-metastatic SBC and UBC patients were identified. Endpoint of interest was CSM. Propensity score matching (PSM), cumulative incidence plots, competing risks regression (CRR) analyses, three-months landmark analyses, and sensitivity analyses were performed. All results were stratified according to organ-confined (OC: T2N0M0) vs non-organ-confined (NOC: T3-4N0M0 or TanyN1-3M0) stages. RESULTS: Of 554 SBC patients, 49 vs 51% harbored OC vs NOC stages. Of 47,741 UBC patients, 62 vs 38% harbored OC vs NOC stages. RC rates were 33 vs 67% in OC vs NOC-SBC patients, and 40 vs 60% in OC vs NOC-UBC patients. After 1:1 PSM, comparison between RC vs no-RC was performed in OC-SBC (67 patients per group), OC-UBC (7611 patients per group), NOC-SBC (63 patients per group), and NOC-UBC patients (4644 patients per group). CRR hazard ratios associated with RC vs no-RC were 0.37 (p < 0.001) in OC-SBC vs 0.45 (p < 0.001) in OC-UBC, and 0.56 (p = 0.01) in NOC-SBC vs 0.68 (p < 0.001) in NOC-UBC. These results were replicated in sensitivity and landmark analyses. CONCLUSIONS: The protective effect of RC vs no-RC is stronger in SBC than UBC patients, regardless of OC vs NOC stages.

Effect of inguinal lymph node dissection in lymph node negative patients with squamous cell carcinoma of the penis.

INTRODUCTION: The survival benefit of inguinal lymph node dissection (ILND) vs no ILND in patients with squamous cell carcinoma of the penis (SCCP) and the absence of lymph node invasion is unclear. We addressed this uncertainty within the Surveillance, Epidemiology and End Results (SEER 2000-2018) database. MATERIAL AND METHODS: We identified lymph node negative SCCP patients who either underwent ILND (pN0) or clinical examination only (cN0). We tested for the effect of ILND vs no ILND on cancer-specific mortality (CSM) in Kaplan-Meier plots, univariable and multivariable Cox regression analyses, in a pT stage-specific fashion, before and after 1:3 propensity score matching (PSM). Sensitivity analyses were conducted according to historical and contemporary treatment periods as well as geographic regions. RESULTS: Of 2520 SCCP patients, 369 (15%) underwent ILND (pN0) vs 2151 (85%) did not (cN0). The pN0 vs cN0 distribution according to pT stages was as follows: 80 (7%) vs 1092 (93%) in pT1b, and 289 (21%) vs 1059 (79%) in pT2-3. At 36 months, CSM-free survival in pT2-3 stage was 89% in ILND vs 74% in no ILND patients (multivariable hazard ratio: 0.42, CI 0.30-0.60, p < 0.001). This result was confirmed in sensitivity analyses, and after 1:3 PSM. The same analyses could not be completed in pT1b stage due to insufficient number of observations and events. CONCLUSIONS: In pT2-3 stage SCCP, a significantly lower CSM was recorded in lymph node negative patients treated with ILND than in their clinical lymph node negative counterparts who did not undergo ILND.

Management of Type 1 Diabetes in a school setting: effectiveness of an online training program for school staff.

Background and aims: Since Type 1 Diabetes (T1D) onset usually occurs at a young age, a relevant number of affected people attend school for most of their time; it is necessary that school personnel receive appropriate education and training. We aimed to evaluate the effectiveness of the online training program offered by IRCCS Istituto Giannina Gaslini during and after COVID-19 pandemic. Methods: The Institute's Diabetes team offered an online training program to school staff of the Region during COVID-19 pandemic. A validated questionnaire was proposed to all the schools in which training meetings were held in the previous 2 years (2020-2021 and 2021-2022). The questionnaire consisted of four sections: Section 1 (Socio-demographical data), Section 2 (Theoretical knowledge on T1D), Section 3 (Confidence in handling T1D), and Section 4 (Practical skills and Glucagon Administration). To evaluate the effectiveness of the online training program, the answers between participants (Group A) and non-participants (Group B) were then compared. Results: 225 subjects from 19 schools participated in the survey. People who participated to the training (Group A, n = 53) demonstrated better T1D theoretical knowledge compared to non-participants (Group B, n = 154; p < 0.001). Group A revealed to feel more confident in the management of children with T1D during scholastic (p = 0.006) and extra-scholastic activities (p = 0.01), in supporting the children in the administration of insulin (p < 0.001) and in recognizing hypoglycaemia (p = 0.006). Moreover, results confirmed good levels of confidence among scholastic personnel who participated in the training of administration of glucagon in case of severe hypoglycaemia. Conclusion: School staff who took part in the online training program on management of T1D showed better theoretical knowledge and better confidence in the management of daily needs and possible emergencies of students with T1D. It appears essential to offer educational programs on T1D for school staff by implementing the use of technological tools to reach a wider population. Moreover, it is advisable to offer a more practical approach, involving educational nurses.