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Purpose: The correct risk categorization and staging of upper tract urothelial cancer (UTUC) is key for disease management. Computerized tomography urography and urinary cytology have limited accuracy for risk stratification of UTUC. Ureteroscopy may increase the risk of bladder cancer recurrence. Recently, Bladder EpiCheckTM (EpiCheck) showed a high accuracy in the detection of bladder cancer. The aim of the study is to investigate the diagnostic accuracy of EpiCheck in the clinical management of UTUC and to compare it with urinary cytology. Materials and Methods: In this single-arm, blinded, prospective, single-center study (February 2019eDecember 2020), all patients who were candidates for ureteroscopy for suspicion of UTUC were included. Bladder and upper urinary tract (UUT) samples were collected before ureteroscopy to test for cytology and Epicheck. EpiCheck accuracy was calculated in bladder and UUT samples and compared to cytology. Results: EpiCheck resulted diagnostic in 83/86 (97%) and 73/75 (97%) of UUT and bladder samples. Histology was positive in 47/83 (57%) and 42/73 (58%) cases, respectively. In UUT samples, EpiCheck yielded a sensitivity/specificity/negative predictive value (NPV)/positive predictive value of 83%/79%/77%/84% vs 59%/88%/61%/87% of cytology. The sensitivity/NPV for high-grade tumors was 96%/97% for EpiCheck vs 71%/86% for cytology. EpiCheck indicated ureteroscopy in 45/80 (56%) patients, missing 17%/4% of all/high-grade UTUC with 9% of unnecessary ureteroscopy. In bladder samples, the sensitivity/NPV for high-grade tumors was 71%/88% for EpiCheck and 59%/87% for cytology. Conclusions: Epicheck may be an important tool to decrease the number of unnecessary ureteroscopy. The clinical implementation of EpiCheck in UTUC warrants further investigation in multicentric prospective randomized trials.

Resumen Introduccion y objetivo El carcinoma primario de uretra (CPU) es una enfermedad neoplasica poco frecuente que surge en la uretra, sin evidencia de carcinoma previo o sincronico en todo el tracto urinario. Dado que las enfermedades raras suelen diagnosticarse y tratarse de forma incorrecta, el objetivo de este estudio fue analizar la experiencia de un unico centro urologico en el tratamiento del CPU, centrandose en las neoplasias que surgen de la uretra anterior masculina. Materiales y metodos Se revisaron retrospectivamente las historias clinicas de los pacientes con neoplasias a nivel de la uretra peneana y bulbar que se presentaron en nuestro centro terciario de referencia entre enero de 1988 y diciembre de 2018. Se excluyeron los pacientes con carcinoma de la uretra prostatica. El diagnostico se obtuvo con la ayuda de una uretroscopia y biopsia de la lesion. El estadio patologico local se evaluo mediante resonancia magnetica nuclear (RMN) con contraste en pacientes seleccionados. El estadiaje se evaluo mediante examen clinico, ecografia y tomografia computarizada (TC). La cirugia radical (cistectomia radical + penectomia total + linfadenectomia inguinal bilateral) se propuso a los pacientes con tumores ≥ T2 o cN + con un buen estado funcional, tumor proximal y sin comorbilidades graves. En caso de afectacion ganglionar, se ofrecio adicionalmente quimioterapia neoadyuvante. Los pacientes con enfermedad localizada ( Resultados Se estudiaron retrospectivamente un total de 13 pacientes varones con CPU anterior. Se realizo penectomia total en siete casos, mientras que cinco casos recibieron uretrectomia parcial y un caso, penectomia parcial. De los siete pacientes que se sometieron a una penectomia total, cinco recibieron cistectomia radical junto con linfadenectomia inguinal bilateral. Tres pacientes fueron tratados con quimioterapia sistemica neoadyuvante, de los cuales dos eran cT3N + y 1 era cT3N0. El subtipo histologico predominante fue el carcinoma de celulas escamosas (CCE), encontrado en siete pacientes (53,8%), mientras que el carcinoma urotelial (CU) estaba presente en cinco pacientes (38,5%) y un fibrohistiocitoma maligno en un caso. La mayoria de los pacientes fueron diagnosticados en estadios avanzados de la enfermedad, con tumores T2 en el 15,4% y T3 en el 46,2%. La mediana de seguimiento fue de 24 meses (rango 1-294). Despues del tratamiento quirurgico, ocho pacientes (61,5%) presentaron recidiva de la enfermedad en una mediana de 6,3 meses, con una SLR a cinco anos del 58 ± 14%. La tasa de SG a cinco anos fue del 50 ± 14%, mientras que la tasa de SCE a cinco anos fue del 66 ± 13%. Conclusion Dada su poca frecuencia, el carcinoma uretral debe ser tratado en un centro de referencia. Las opciones de tratamiento incluyen enfoque radical o cirugia de preservacion del pene (uretrectomia o penectomia parcial) en casos de enfermedad localizada. Debido a la alta tasa de recurrencia, el seguimiento estricto es imprescindible.

Objectives: To identify correlates of survival and perioperative outcomes of upper tract urothelial carcinoma (UTUC) patients undergoing open (ORNU), laparoscopic (LRNU), and robotic (RRNU) radical nephroureterectomy (RNU). Methods: We conducted a retrospective, multicenter study that included non-metastatic UTUC patients who underwent RNU between 1990–2020. Multiple imputation by chained equations was used to impute missing data. Patients were divided into three groups based on their surgical treatment and were adjusted by 1:1:1 propensity score matching (PSM). Survival outcomes per group were estimated for recurrence-free survival (RFS), bladder recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS). Perioperative outcomes: Intraoperative blood loss, hospital length of stay (LOS), and overall (OPC) and major postoperative complications (MPCs; defined as Clavien–Dindo > 3) were assessed between groups. Results: Of the 2434 patients included, 756 remained after PSM with 252 in each group. The three groups had similar baseline clinicopathological characteristics. The median follow-up was 32 months. Kaplan–Meier and log-rank tests demonstrated similar RFS, CSS, and OS between groups. BRFS was found to be superior with ORNU. Using multivariable regression analyses, LRNU and RRNU were independently associated with worse BRFS (HR 1.66, 95% CI 1.22–2.28, p = 0.001 and HR 1.73, 95%CI 1.22–2.47, p = 0.002, respectively). LRNU and RRNU were associated with a significantly shorter LOS (beta −1.1, 95% CI −2.2–0.02, p = 0.047 and beta −6.1, 95% CI −7.2–5.0, p < 0.001, respectively) and fewer MPCs (OR 0.5, 95% CI 0.31–0.79, p = 0.003 and OR 0.27, 95% CI 0.16–0.46, p < 0.001, respectively). Conclusions: In this large international cohort, we demonstrated similar RFS, CSS, and OS among ORNU, LRNU, and RRNU. However, LRNU and RRNU were associated with significantly worse BRFS, but a shorter LOS and fewer MPCs.

The vast amount of data produced everyday (so-called digital traces) and available nowadays represent a gold mine for the social sciences, especially in a computational context, that allows to fully extract their informational and knowledge value. In the latest years, statistical offices have made efforts to profit from harnessing the potential offered by these new sources of data, with promising results. But how difficult is this integration process? What are the challenges that statistical offices would likely face to profit from new data sources and analytical methods? This chapter will start by setting the scene of the current official statistics system, with a focus on its fundamental principles and dimensions relevant to the use of non-traditional data. It will then present some experiments and proofs of concept in the context of data innovation for official statistics, followed by a discussion on prospective challenges related to sustainable data access, new technical and methodological approaches and effective use of new sources of data.

The advent of biologic therapies for severe asthma has profoundly changed the management of this pathology. The introduction of home administration is therefore an important innovation to optimize the patients' management, even if there are many aspects that need to be clarified and pointed out.This review summarizes the path that led to the possibility of self-administration of biologics, and what the pandemic has changed in the management of these patients.The growing understanding of asthma phenotypes and endotypes is enabling the careful selection of patients suitable for biologics. In this context, the availability of reliable and simple self-injection devices is important in implementing self-administration. The transition to self-injection is also possible thanks to the high safety profile of biologics. With attention, most patients may potentially be suitable for self-administration. The transition process from hospital to home administration can therefore be carried out correctly by clinicians with adequate expertise in the field of severe asthma and biologic therapies, with the support of other health professionals, pharmacists, and general practitioners. Home administration is probably the best way to guarantee high adherence and high-level satisfaction of patients, even in the long term.

Purpose Different energy sources are employed to perform en-bloc transurethral resection of bladder tumor (ERBT). No study compared different energy sources in ERBT. The aim is to compare the different ERBT sources in terms of pathological, surgical and postoperative outcomes. Methods This is a sub-analysis of a prospective randomized trial enrolling patients submitted to ERBT vs conventional TURBT from 03/2018 to 06/2021 (NCT04712201). 180 patients enrolled in ERBT group were randomized 1:1:1 to receive monopolar (m-ERBT), bipolar (b-ERBT) or thulium laser (l-ERBT). Endpoints were the comparison between energies in term of pathological analysis, intra, and post-operative outcomes. Results 49 (35%) m-ERBT, 45 (32.1%) b-ERBT, and 46 (32.9%) l-ERBT were included in final analysis. The rate of detrusor muscle (DM) presence was comparable between the energies used (p = 0.796) or the location of the lesion (p = 0.662). Five (10.2%), 10 (22.2%) and 0 cases of obturator nerve reflex (ONR) were recorded in m-ERBT, b-ERBT and I-ERBT groups, respectively (p = 0.001). Conversion to conventional TURBT was higher for lesions located in the anterior wall/dome/neck (p < 0.001), irrespective from the energy used. The presence of artifact in the pathological specimen was higher for lesions at the posterior wall (p = 0.03) and trigone (p = 0.03). Conclusions In our study, no difference in staging feasibility among energies was found. Laser energy might be beneficial in lateral wall lesions to avoid ONR. Since there is an increased risk of ERBT conversion to conventional TURBT for lesions of the anterior wall, electrocautery might be preferred over laser to avoid waste of material.

It has been proposed that en bloc resection of bladder tumor (ERBT) improves the quality of tumor resection. A recent international collaborative consensus statement on ERBT underlined the lack of high-quality prospective studies precluding the achievement of solid conclusion on ERBT.To compare conventional transurethral resection of bladder tumor (cTURBT) and ERBT.This study (NCT04712201) was a prospective, randomized, noninferiority trial enrolling patients diagnosed with bladder cancer (BC) undergoing endoscopic intervention. Inclusion criteria were: tumor size ≤3 cm, three or fewer lesions, and no sign of muscle invasion and/or ureteral involvement. For a noninferiority rate in BC staging of 5% (α risk 2.5%; β risk 20%), a total of 300 subjects were randomized to ERBT treatment at a 1:1.5 allocation ratio.TURBT and ERBT.The primary outcome was the presence of detrusor muscle at final histology. Secondary outcomes include BC staging, T1 substaging, artifacts, complications, the rate of adjuvant treatment, and oncological outcomes.From April 2018 to June 2021, 300 patients met the inclusion criteria. Of these, 248 (83%) underwent the assigned intervention: 108 patients (44%) underwent cTURBT and 140 (57%) underwent ERBT. The rate of detrusor muscle presence for ERBT was noninferior to that for TURBT (94% vs 95%; p = 0.8). T1 substaging was feasible in 80% of cTURBT cases versus 100% of ERBT cases (p = 0.02). Complication rates, rates of postoperative adjuvant treatment, catheterization time, and hospital stay were comparable between the two groups (p 0.05). The recurrence rate at median follow-up of 15 mo (interquartile range 7-28) was 18% for cTURBT versus 13% for ERBT (p = 0.16). Limitations include the single high-volume institution and the short-term follow-up.Our study has the highest level of evidence for comparison of ERBT versus TURBT. ERBT was noninferior to TURBT for BC staging. The rate of T1 substaging feasibility was significantly higher with ERBT.We compared two techniques for removing tumors from the bladder. The en bloc technique removes the tumor in one piece and is not inferior to the conventional method in terms of the quality of the surgical resection and cancer staging assessment.

Purpose Bladder perforation (BP) is the most important intraoperative adverse event of transurethral resection of bladder tumor (TURBT). It is frequently underreported despite its impact on the postoperative course. There is no standardized classification of BP. The study aims to develop a classification of the depth of endoscopic bladder perforation during TURBT. Methods This is a sub-analysis of a prospective randomized trial enrolling 248 patients submitted to en-bloc vs conventional TURBT from 03/2018 to 06/2021. The DEpth of Endoscopic Perforation (DEEP) scale is as follows: "0" visible muscular layer with no perivesical fat; "1" visible muscle fibers with spotted perivesical fat; "2" exposition of perivesical fat; "3" intraperitoneal perforation. Logistic and linear regression models were used to investigate predictors of high-grade perforations (DEEP 2-3) and to assess whether the DEEP scale independently predicted patients' postoperative outcomes. Results A total of 146/248 (58.9%), 56/248 (22.6%), 41/248 (16.5%), 5/248 (2.0%) patients presented DEEP grade 0, 1, 2, and 3, respectively. Female gender [B coeff. 0.255 (95% CI 0.001-0.513); p = 0.05], tumor location [B coeff. 0.188 (0.026-0.339); p = 0.015], and obturator-nerve reflex [B coeff. 0.503 (0.148-0.857); p = 0.006] were independent predictors of DEEP. The scale predicted independently major complications [Odd Ratio (OR) 2.221 (1.098-4.495); p = 0.026], no post-operative chemotherapy intravesical instillation [OR 9.387 (2.434-36.200); p = 0.001], longer irrigation time [B coeff. 0.299 (0.166-0.441); p < 0.001] and hospital stay [B coeff. 0.315 (0.111-0.519); p = 0.003]. Conclusion The DEEP scale provides a visual tool for grading bladder perforation during TURBT, which can help physicians standardize complication reporting and plan postoperative management accordingly.

Motivated by the pressing request of methods able to create prediction sets in a general regression framework for a multivariate functional response and pushed by new methodological advancements in non-parametric prediction for functional data, we propose a set of conformal predictors that produce finite-sample either valid or exact multivariate simultaneous prediction bands under the mild assumption of exchangeable regression pairs. The fact that the prediction bands can be built around any regression estimator and that can be easily found in closed form yields a very widely usable method, which is fairly straightforward to implement. In addition, we first introduce and then describe a specific conformal predictor that guarantees an asymptotic result in terms of efficiency and inducing prediction bands able to modulate their width based on the local behavior and magnitude of the functional data. The method is investigated and analyzed through a simulation study and a real-world application in the field of urban mobility.

Francesco Menzella,1 Matteo Fontana,1 Marco Contoli,2 Patrizia Ruggiero,1 Carla Galeone,1 Silvia Capobelli,1 Anna Simonazzi,1 Chiara Catellani,1 Chiara Scelfo,1 Claudia Castagnetti,1 Francesco Livrieri,1 Nicola Facciolongo1 1Pulmonology Unit, Arcispedale Santa Maria Nuova, Azienda USL – IRCCS di Reggio Emilia, Reggio Emilia, Italy; 2Respiratory Section, Department of Translational Medicine, University of Ferrara, Ferrara, ItalyCorrespondence: Francesco Menzella, Pulmonology Unit, Arcispedale Santa Maria Nuova, Azienda USL – IRCCS di Reggio Emilia, Reggio Emilia, Italy, Tel +39 0522 296073, Email fmenzella@gmail.comPurpose: Treatment of severe asthma has made great strides thanks to rapid progress in understanding immune response and inflammatory pathways. This led to the advent of the first biologic for severe allergic asthma (SAA), omalizumab. Although the long-term efficacy and safety of omalizumab has been confirmed, increasingly longer follow-up data can further reinforce this evidence and potentially provide new ones, for example on any loss of efficacy or the appearance of unexpected side effects. This study reports omalizumab treatment-related outcomes after 16 years of follow-up.Patients and Methods: In this real-life retrospective study, an extension of a previous 9-year follow-up study on patients initially recruited in a clinical trial, we enrolled 8 adult patients with SAA followed-up from November 2005 to December 2021. Study subjects were selected based on omalizumab eligibility criteria.Results: Exacerbation rate significantly decreased from 3.6 ± 2.1 events in year before index date to 0.1 ± 0.4 after 32 weeks of treatment (p < 0.0001). Mean annual number of mild-to-moderate exacerbations at 16 years was 0.88 compared with 1.8 in the year before the index date and 1.1 at 32 weeks. No hospitalizations were documented during the 16-year follow-up compared to 0.3 hospitalizations/patient in the year before the index date. Respiratory function also progressively and significantly improved. Regarding patient-reported outcomes (PROs), The AQLQ and ACT significantly improved from baseline throughout the follow-up, particularly up to 9 years of follow-up. During the study, an overall reduction in doses of asthma medications was observed, with a significant OCS-sparing effect.Conclusion: Our study, the longest clinical follow-up on patients treated with anti-IgE, confirms and amplifies the results of the studies carried out so far, as they are maintained over a very long interval of time without drops in efficacy without any type of side effect.Keywords: severe allergic asthma, biologics, omalizumab, exacerbations, side effects, oral corticosteroids

Background According to the guidelines, endobronchial ultrasound guided transbronchial needle aspiration (EBUS‐TBNA) is the technique of choice for the diagnosis of mediastinal involvement in lung cancer; it is also useful for other mediastinal malignancies and benign pathology. Nevertheless, there is still discussion about whether to perform it under general anesthesia or under conscious sedation. Methods We retrospectively analyzed the data of all patients who underwent EBUS‐TBNA under conscious sedation with up to 1 mg/kg of meperidine and up to 0.15 mg/kg of midazolam in the Interventional Pulmonology Unit of the Azienda USL‐IRCCS Santa Maria Nuova of Reggio Emilia during 2 consecutive years. Demographic data, indication for the procedure, duration, number of lymph node sampled, number of passes per station, diagnostic yield, drugs dosage, questionnaire score, and complications were collected. Results A total of 302 patients underwent EBUS‐TBNA, and 68% of the patients were males and the mean age was 65 ± 13 years old. The average duration of procedures was 24.4 minutes and the mean dosage of drugs was 4.32 ± 1.52 mg for midazolam and 50.86 ± 13.71 mg for meperidine. The mean number of lymph nodes sampled per patient was 1.75 ± 0.82, and each patient received an average of 4.71 ± 1.78 passes. A total of 90.7% of patients completed the procedures, 85% had adequate samples, and 94.4% of patients declared with Likert's questionnaire that they strongly agree to repeat the test if necessary. Conclusion EBUS‐TBNA performed under conscious sedation with meperidine and midazolam is feasible and well‐tolerated and has a similar diagnostic yield of that reported in literature.