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Elisa Tassinari,1 Veronica Mollica,1 Giacomo Nuvola,1 Andrea Marchetti,1 Matteo Rosellini,1 Francesco Massari1,2 1Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 2Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, ItalyCorrespondence: Francesco Massari, Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni-15, Bologna, Italy, Email francesco.massari@aosp.bo.itAbstract: Urothelial carcinoma (UC) is a frequently diagnosed tumor and an important cause of cancer deaths worldwide. Until a few years ago, despite the unquestioned role of platinum-based chemotherapy, therapeutic choices beyond the first line were limited and related to unsatisfactory outcomes. Metastatic UC has always been associated with a poor prognosis, with overall survival only slightly above a year. In the recent past, huge progress has been made in our understanding of the molecular and genomic disease characteristics, to enable stratification of patients in terms of prognosis and treatment responses. Unfortunately, we still do not have the perfect combination of clinical biomarkers to tailor the optimal treatment for each patient, despite making several efforts in this direction. The therapeutic arsenal has been augmented by immune checkpoint inhibitors (ICIs), which nowadays represent the backbone of the second-line setting. Equally revolutionary was the FDA’s approval of erdafitinib, a potent fibroblast growth factor receptor (FGFR) inhibitor, the use of which is reserved for patients whose tumor harbors specific FGF pathway alterations. Recently, the therapeutic landscape of metastatic UC has been enhanced by the introduction of novel compounds, consisting of antibody–drug conjugates (ADCs). Enfortumab vedotin is an antibody targeting nectin-4, a cell adhesion molecule highly expressed in UC, conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Sacituzumab govitecan is a humanized monoclonal antibody targeting Trop-2, a transmembrane glycoprotein, conjugated to the active metabolite of irinotecan. These two compounds have received accelerated approval by the FDA in patients pretreated with platinum-based chemotherapy and immunotherapy. Several ongoing trials are investigating the role of ICIs combined with chemotherapy, antiangiogenic drugs, or other ICIs, as well as the efficacy of PARP inhibitors and target therapies, hoping to provide information for some important unmet needs. In this review, we aim to evaluate the current potential treatment options after first-line chemotherapy.Keywords: urothelial carcinoma, immunotherapy, immune-checkpoint inhibitors, FGFR inhibitor, antibody–drug conjugates

A wearing action on a fabric first produces a fuzz of fibres, which then tangle together to form pills. In this paper, a theory is developed in which, by assuming the probability that a fibre becomes part of a pill to be constant, it is shown that the distribution of the number of fibres in pills is the sum of binomial distributions. Experimental data are shown to be consistent with theoretical predictions. In one sample, it was found that the pills developed in three phases, with a decreasing number of fibres entering the pills, whereas in another sample the pills developed in a single stage. [ABSTRACT FROM AUTHOR]

A simplified kinetic model describing the mechanism of pilling is proposed. This model involves only three parameters, which relate to the main stages of the process: the total number of pills, the rate of pill formation, and the rate of pill wear-off. These parameters can easily be calculated from the pill curve of the fabric. The published literature and the authors' own data are used to check the range of application of the proposed model. [ABSTRACT FROM AUTHOR]

Background: Total hip replacement in patients with Legg-Calvé-Perthes disease can be difficult because of the multiplanar deformities of the proximal part of the femur and previous surgery during childhood. The aim of the present study was to assess the long-term outcomes of total hip replacement in patients who had Legg-Calvé-Perthes disease during childhood.Methods: A retrospective study was carried out to assess the results of thirty-two total hip replacements that had been performed for twenty-seven patients from January 1989 to November 2004. The average age at the time of surgery was 37.8 years. The average duration of follow-up was 124 months (range, fifty-eight to 248 months). All but one of the implants were cementless.Results: There was only one failure in the present study; specifically, the one cemented stem in the study failed two years after surgery. The cumulative survival rate at fifteen years was 96.9% (95% confidence interval, 90.8% to 100.0%). The overall rate of complications was 12.5%, with two permanent sciatic nerve palsies. At the time of the latest follow-up, the average Harris hip score was 87.5 (range, 73 to 96), which was a marked improvement in comparison with the preoperative score (average, 50.1; range, 25 to 75).Conclusions: Despite the high rate of neurological complications, possibly related to excessive limb lengthening or inadequate soft-tissue release, total hip replacement can be considered a feasible option for patients with Legg-Calvé-Perthes disease. Careful preoperative planning is advisable in order to overcome the technical pitfalls related to the abnormal proximal femoral and acetabular anatomy of these patients. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to compare the use of cortisone (C), intra-articular injected at the end of hip arthroscopy in patients with femoroacetabular impingement (FAI), to a new Class III medical device based on hydrolyzed collagen peptides 'PEPTYS' (P) and, to investigate potential associations among preoperative symptoms and hip function, outcomes after arthroscopic surgery and presence of inflammatory biomarkers in synovial fluids (SFs) at basal condition., Methods: The two treatments were administrated to patients scheduled for arthroscopy with simple blind randomization sampling. Based on the sample size calculation, the number necessary to recruit was at least 20 patients for the C group and 20 for the P group. SFs, when available, were obtained by aspiration just prior to surgical intervention. At the baseline, osteoarthritis (OA) severity was assessed with a radiographic scoring system (Tönnis classification). Physical examination and clinical assessment using the Hip disability and Osteoarthritis Outcome Score (HOOS) and visual analogue scale (VAS) score for pain were performed at the time of surgery and at 1 and 6 months of follow-up. At the time of surgery, chondral (Outerbridge score) and labral pathology based on direct arthroscopic visualization were also evaluated., Results: Forty-seven FAI patients were enroled, with a median age of 35 years with a standard deviation (SD) of 10.6 and a body mass index of 24.3kg/m² with an SD of 4.5. 24 patients were treated with C and 23 with P. Both treatments did not show any statistically significant difference in hip function and pain. High expression of inflammatory molecules in SFs was correlated with the worst post-operative articular function., Conclusions: Our study showed that the use of P was completely comparable to cortisone. Therefore, PEPTYS might be a valuable candidate to improve early recovery, in terms of pain and function, from arthroscopic FAI treatment., Level of Evidence: Level III, comparative and randomized study., Competing Interests: The authors declare no conflicts of interest., (© 2025 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Purpose: The learning curve of a single surgeon performing hip arthroscopy is reported to be steep, but, to date, the inflection point after which procedures are more successful is still unknown. The aim of this study was to design a learning curve focused on clinical outcomes, complications and revision/conversion rates., Methods: Seventy-one hip arthroscopies performed for femoroacetabular impingement (FAI) by a single surgeon, with a minimum follow-up of 5 years, were considered. Demographics, intraarticular findings and operative and traction time were detailed. HOOS score, subjective outcomes, 30-day complication rates, complication rates, revision arthroscopies and conversions to hip arthroplasty were recorded., Results: The mean follow-up was 7.5 ± 1.8 years (range: 5-11). The progression of the learning curve implied a reduction in surgical time ( r : -0.847), traction time ( r : -0.806) and postoperative outcomes ( r  = 0.444). When the procedures were divided into three consecutive groups (25 vs. 25 vs. 21 procedures) or two consecutive groups (36 vs. 35 cases), the first group had a higher occurrence of 30-day complications ( p  = 0.002 and p  = 0.025, respectively) and the last group experienced a significant amelioration in terms of HOOS score between the preoperative and the postoperative condition ( p  < 0.001 and p  = 0.018)., Conclusions: The inflection point of the hip arthroscopy learning curve is between 25/36 procedures. The first arthroscopies were impacted by higher complications and lower clinical results but no higher rates of revision and conversion to arthroplasty., Level of Evidence: Level IV., Competing Interests: The authors declare no conflict of interest., (© 2025 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Immune checkpoint inhibitors (ICI) have become the cornerstone of treatment in renal cell carcinoma (RCC), for both metastatic disease and in an adjuvant setting. However, an adaptive resistance from cancer cells may arise during ICI treatment, therefore many studies are focusing on additional immune checkpoint inhibitor pathways. Promising targets of immunotherapeutic agents under investigation include T cell immunoglobulin and ITIM domain (TIGIT), immunoglobulin-like transcript 4 (ILT4), lymphocyte activation gene-3 (LAG-3), vaccines, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and chimeric antigen receptor (CAR) T cells. In this review of the literature, we recollect the current knowledge of the novel treatment strategies in the field of immunotherapy that are being investigated in RCC and analyze their mechanism of action, their activity and the clinical studies that are currently underway.

Despite recent FDA approvals, Alzheimer's disease (AD) still represents an unmet medical need. Among the different available therapeutic approaches, the development of multitarget molecules represents one of the most widely pursued. In this work, we present a second generation of dual ligands directed toward highly networked targets that are deeply involved in the development of the disease, namely, Histone Deacetylases (HDACs) and Glycogen Synthase Kinase 3β (GSK-3β). The synthesized compounds are highly potent GSK-3β, HDAC2, and HDAC6 inhibitors with IC 50 values in the nanomolar range of concentrations. Among them, compound 4 inhibits histone H3 and tubulin acetylation at 0.1 μM concentration, blocks hyperphosphorylation of tau protein, and shows interesting immunomodulatory and neuroprotective properties. These features, together with its ability to cross the blood-brain barrier and its favorable physical-chemical properties, make compound 4 a promising hit for the development of innovative disease-modifying agents.

Alzheimer's disease (AD) and cancer are among the most devastating diseases of the 21st century. Although the clinical manifestations are different and the cellular mechanisms underlying the pathologies are opposite, there are different classes of molecules that are effective in both diseases, such as quinone-based compounds and histone deacetylase inhibitors (HDACIs). Herein, we investigate the biological effects of a series of compounds built to exploit the beneficial effects of quinones and histone deacetylase inhibition (compounds 1-8). Among the different compounds, compound 6 turned out to be a potent cytotoxic agent in SH-SY5Y cancer cell line, with a half maximal inhibitory concentration (IC 50 ) value lower than vorinostat and a pro-apoptotic activity. On the other hand, compound 8 was nontoxic up to the concentration of 100 μM and was highly effective in stimulating the proliferation of neural precursor cells (NPCs), as well as inducing differentiation into neurons, at low micromolar concentrations. In particular, it was able to induce NPC differentiation solely towards a neuronal-specific phenotype, without affecting glial cells commitment., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Introduction: Nausea and vomiting are frequent multifactorial symptoms in oncological patients. These manifestations, mainly affecting the advanced disease stages, may lead to existential, psychological, and physical suffering, with a negative impact on the quality of life (QoL) of the individual and his family. The medical approach makes use of a wide range of drugs, with different antiemetic potency and various mechanisms of action, taking into account the etiology and the patient's response to the different therapeutic strategies. In recent years, in addition to pharmacological treatments, some endoscopic procedures have been integrated into clinical practice as promising palliative approaches., Case Presentation: Herein, we describe and discuss a case of a 64-year-old female affected by advanced stage pancreatic adenocarcinoma, in which different techniques - both medical and endoscopic - have been used to approach a refractory symptomatology with a negative impact on the patient's QoL. In the context of a multidisciplinary approach in primary palliative care, a tailored intervention encompassing invasive methods for palliative purposes, may be considered adequate and appropriate when the prognostic expectation and the physical functionality indices allow it., Conclusion: Minimally invasive palliative interventions should be offered to patients with advanced cancer when symptoms become refractory to standard medical therapies, as part of the holistic approach in modern treatments. Therefore, the integration of an early palliative approach into the patient's therapeutic path becomes essential for the management of all the individual's needs., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Identifying biomarkers for metastatic renal cell carcinoma (mRCC) is an unmet need in actual immunotherapy era. Available data regarding chromosome 3p genes (i.e., VHL, PBRM1, SETD2) mutations as potential predictors for therapy response is conflicting. We describe the impact of these mutations on clinical outcomes in mRCC patients treated with immune checkpoint inhibitor (ICI)-doublet or ICI/tyrosine kinase inhibitor (TKI) combinations., Methods: We performed a single-center retrospective analysis on mRCC patients treated with first line ICI/ICI or ICI/TKI. A multi-gene panel was used, allowing the amplification of 841 amplicons (54.93 kb, human reference sequence hg19/GRCh37) in the coding sequences of the following genes: ATM, BAP1, KDM5C, MET, MTOR, NF2, PBRM1, PIK3CA, PTEN, SETD2, SMARCB1, TP53, TSC1, TSC2, VHL., Results: 18 patients undergoing ICI/ICI and ICI/TKI who had tumor tissue adequate for molecular analysis were included. Histology was 100% clear cell. IMDC risk was 50% intermediate, 33.4% good, 16.6% poor. First line therapy was 89% ICI/TKI, 11% ICI/ICI. 83.3% pts (n = 15) carried genomic alterations (GA). Most common GA included VHL in 44% (n = 8; 7 pathogenic - PAT and 1 variant of unknown significance - VUS), PBRM1 in 44% (n = 8; 5 PAT and 3 VUS) and SETD2 in 33% (n = 6; 4 PAT and 2 VUS). With the limit of a small sample that did not allow proper statistical analyses, SETD2-mutated patients had lower median progression free (mPFS) and overall survival (mOS) than non-SETD2 mutated patients. Higher mPFS and mOS were shown with VHL or PBRM1 GA, especially in PBRM1 +VHL mutated pts., Conclusions: Our data shows a possible negative predictive role of SETD2 GA for ICI-based therapy in RCC. Concomitant VHL and PBRM1 GA could act as a predictor for ICI/TKI efficacy. Our hypothesis-generating analysis highlights the need of an integrated evaluation of these genes as promising biomarkers in RCC. Further larger studies are required., Competing Interests: Declaration of Competing Interest Francesco Massari has received research support and/or honoraria from Astellas, BMS, Janssen, Ipsen, MSD and Pfizer outside the submitted work.The other Authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: TERT promoter mutation is one of the most common genomic alterations in urothelial carcinoma (UC). Its prognostic role on patients' outcomes is still not clear., Methods: We performed a single-center retrospective analysis on patients with advanced UC treated with platinum-based chemotherapy or immunotherapy to assess the presence of somatic TERT -124[C>T] and TERT -146[C>T] mutations and their association with clinicopathologic factors and survival outcomes. Patients were assessed for Overall Survival (OS), Progression-Free Survival (PFS), and Overall Response Rate (ORR)., Results: We analyzed 45 UC tumors; 38 of them received first-line chemotherapy and 21 second-line pembrolizumab; 6 patients (13%) harbored -146 C > T TERTp mutation and 25 patients (56%)-124 C > T. The presence of TERT promoter mutations was associated with a higher rate of lower tract UC and a lower rate of synchronous or lymph node metastases. TERT wild-type patients showed higher 12- and 24-months OS-rates in the chemotherapy subgroup and 6-, 12- and 24-months OS rates in the pembrolizumab subgroup. The presence of TERT promoter mutations was also associated with a lower 6 months-PFS rate in patients receiving chemotherapy and in all the three time points in those treated by pembrolizumab. The ORRs of pembrolizumab were 21% and 71% in patients with or without TERT promoter mutations, respectively (p < 0.001)., Conclusions: Our analysis suggests that the presence of TERT promoter mutations could negatively affect the outcome of UC patients treated by chemotherapy or pembrolizumab. This hypothesis should be further evaluated in wider cohorts., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Despite the significant improvements in the field of oncological treatments in recent decades, and the advent of targeted therapies and immunotherapy, urothelial carcinoma of the bladder remains a highly heterogeneous and difficult-to-treat neoplasm with a poor prognosis. In this context, owing to the new methods of genomic sequencing, numerous studies have analyzed the genetic features of muscle-invasive bladder cancer, providing a consensus set of molecular classes, to identify malignancies that may respond better to specific treatments (standard chemotherapy, immunotherapy, target therapy, local-regional treatment, or combinations) and improve the survival. The aim of the current review is to provide an overview of the current status of the molecular landscape of muscle-invasive bladder cancer, focusing our attention on therapeutic and prognostic implications in order to select the most effective and tailored therapeutic regimen for the individual patient., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Positron emission tomography (PET) with 18-fluorodeoxyglucose ( 18 FDG) has proven to be highly sensitive in the early assessment of tumor response in gastrointestinal stromal tumors (GIST), especially in cases where there is doubt or when the early prediction of the response could be clinically useful for patient management. As widely known, kinase mutations have an undoubtful predictive value for sensitivity to imatinib, and the inclusion of KIT and PDGFRa mutational analysis in the diagnostic workup of all GIST is now considered standard practice., Case Presentation: Herein, we described in detail a case of an exon 11 KIT mutated-metastatic GIST patient, who presented an unexpected metabolic progression at the early 18 FDG-PET evaluation after 1 month of first-line imatinib, unconfirmed at the liver biopsy performed near after, which has conversely shown a complete pathological response., Conclusions: This report aims to highlight the existence of this metabolic pseudoprogression in GIST at the beginning of imatinib therapy in order to avoid early treatment discontinuation. Therefore, an early metabolic progression during a molecular targeted therapy always deserves to be evaluated in the context of the disease molecular profiling, and in case of a discordant finding between functional imaging and molecular background, a short-term longitudinal control should be suggested., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tassinari, Conci, Battisti, Porta, Di Scioscio, Pirini, de Biase, Nigro, Iezza, Castagnetti, Lovato, Fanti, Pantaleo and Nannini.)

ECOG performance status (PS) is a pivotal prognostic factor in a wide number of solid tumors. We performed a meta-analysis to assess the role of ECOG PS in terms of survival in patients with ECOG PS 0 or ECOG PS 1 treated with immunotherapy alone or combined with other anticancer treatments. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses, all phase II and III randomized clinical trials that compared immunotherapy or immune-based combinations in patients with solid tumors were retrieved. The outcomes of interest were overall survival (OS) and progression-free survival (PFS). We also performed subgroup analyses focused on type of therapy (ICI monotherapy or combinations), primary tumor type, setting (first line of treatment, subsequent lines). Overall, 60 studies were included in the analysis for a total of 35.020 patients. The pooled results showed that immunotherapy, either alone or in combination, reduces the risk of death or progression in both ECOG PS 0 and 1 populations. The survival benefit was consistent in all subgroups. Immune checkpoint inhibitors monotherapy or immune-based combinations are associated with improved survival irrespective of ECOG PS 0 or 1. Clinical trials should include more frail patients to assess the value of immunotherapy in these patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: The purpose of this systematic review is to assess clinical and radiographic outcomes, complications rates, rates and reasons of re-revision of isolated femoral or tibial component revisions, comparing them with total knee revisions., Methods: A review of the published literature was performed using Medline, Embase and Cochrane libraries. The terms "isolate" and "revision" and "knee arthroplasty" or "knee replacement" were together used as MESH terms. Partial knee replacement, non-English literature, case reports and papers published before 2000 were excluded., Results: Out of 911 papers, six papers met the inclusion criteria. Mean MINORS scores achieved quite low values (13.33 and 13.67). No study encompassed revisions for septic loosening or infection. Total revisions performed for instability and wear achieved better clinical outcomes: in the other cases, partial and total revisions showed no differences in clinical outcomes. Both the cohorts showed similar radiographic features. Lesser bleeding and shorter operative times were observed in partial revisions compared to total revisions. The re-revision rates were similar in most of comparative studies: only one study noticed a significant difference in the failure rate between partial (25% at 3 years) and full (7% at 3.5 years) revisions., Conclusions: The poor quality of the studies precluded sound conclusions. Isolated tibial or femoral component revision is an option when the other component is well-fixed and positioned and in absence of chronic periprosthetic infection; nevertheless, it should be carefully evaluated when the reasons for revision are wear or instability., (The Author(s). Published by S. Karger AG, Basel.)

Introduction: The current strategy for modular neck failures in total hip arthroplasty (THA) is calibrated on CrCo neck failures. Stem revision is usually required, but the procedure is challenging and achieves modest outcomes (up to 20% of re-revisions at short-term). No study reports revision strategies and outcomes after Ti neck failures. Aims of the study were to evaluate: (1) demographic and implant features of the cohort to be revised, (2) intra-operative findings and surgical revision strategies and (3) clinical and radiological post-revision outcomes., Materials and Methods: Hospital database was enquired about revisions due to Ti neck failures in primary THAs. Sixty-five revisions were enrolled (all with the same modular system). Neck exchange was attempted as the first-line treatment. Patients were clinically and radiographically evaluated after revision., Results: The revision cohort encompassed fatigue neck fractures occurred 4.4 ± 2.6 years after THA: patients < 65 years and/or > 80 kg (98.5%) were predominant. Fifty-three neck exchanges were performed (81.5%). Eleven failures required stem revisions (16.9%), generally due to demanding neck extraction. Six complications occurred after neck exchange (11.3%), among them 2 acute infections requiring surgery (3.8%). Among stem revisions, one aseptic loosening and one neck re-fracture (18.5%) required re-revisions. At a mean follow-up of 7.1 ± 4 years, the neck exchange cohort achieved a mean HHS of 89.1 ± 6.3 (stem revisions: 84.1 ± 10.9)., Conclusions: Revisions for Ti neck failures were predominantly performed due to fatigue fractures. In case of failures, neck exchange is a feasible procedure in most of the cases, with good outcomes at 7 years., Level of Evidence: Level IV, retrospective case series., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)