Search

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

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.

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.)

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.)

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.

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.)

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.)

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.)

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.)

Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs ( 2 - 7 ) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5 , characterized by a dianiline ( 4 ) or dianilide ( 5 ) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 μM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI 50 < 1 μM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity.

Background: Immunotherapy has determined unprecedented long-term responses in several hematological and solid tumors. In the MOUSEION-03 study, we conducted a meta-analysis to determine the possibility of achieving complete remissions (CR) with immunotherapy or immuno-oncology combinations in cancer patients., Methods: The primary endpoint was to assess the incidence of CR in cancer patients receiving immune checkpoint inhibitors (ICIs) alone or in combination with other agents versus control treatments. The pooled odds ratio (OR) and 95% confidence interval (CI) for CR rate were extracted., Results: A total of 12,130 potentially relevant trials were identified; 5 phase II and 80 phase III randomized studies (37 monotherapies and 48 combinations) and 49,425 cancer patients were included. The most frequent types of malignancies were non-small cell lung cancer (n = 14,249; 29%), urothelial cancer (n = 6536; 13%), renal cell carcinoma (n = 5743; 12%), and melanoma (n = 2904; 6%). In patients treated with immunotherapy (as monotherapy or in combination with other anticancer agents), the pooled OR was 1.67 (1.52-1.84). The highest OR was registered by immune-based combinations with two ICIs (3.56, 95% CI 1.28-9.90)., Conclusions: To the best of the authors' knowledge, no comprehensive meta-analysis on the use of ICIs and ICI-based combinations in solid tumors to systematically investigate the probability to achieve CR has been published so far. Although CR is not a common event in several cancer patients receiving immunotherapy, the MOUSEION-03 suggests that the use of ICIs may significantly increase the chance of achieving CR in comparison with control treatments., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Over the last decade, evidence has mounted for a prominent etiologic role of femoroacetabular impingement (FAI) in the development of early hip osteoarthritis (OA). The aim of this study was to compare the ultrastructure and tissue composition of the hip labrum in healthy and pathological conditions, as FAI and OA, to provide understanding of structural changes which might be helpful in the future to design targeted therapies and improve treatment indications. We analyzed labral tissue samples from five healthy multi-organ donors (MCDs) (median age, 38 years), five FAI patients (median age, 37 years) and five late-stage OA patients undergoing total hip replacement (median age, 56 years). We evaluated morpho-functional by histology and transmission electron microscopy. Extracellular matrix (ECM) structure changes were similar in specimens from FAI compared to those from patients with OA (more severe in the latter) showing disorganization of collagen fibers and increased proteoglycan content. In FAI and in OA nuclei the chromatin was condensed, organelle degenerated and cytoplasm vacuolized. Areas of calcification were mainly observed in FAI and OA labrum, as well as apoptotic-like features. We showed that labral tissue of patients with FAI had similar pathological alterations of tissue obtained from OA patients, suggesting that FAI patients might have high susceptibility to develop OA., (© 2023. The Author(s).)

Background: The antitumor efficacy of immune checkpoint inhibitors (ICIs) has increasingly emerged during the last few years. However, there is a need to identify the safety profile of these agents more comprehensively, including liver toxicity., Materials and Methods: Herein, we performed a meta-analysis to assess the risk of all-grade and grade 3-4 hypertransaminasemia in cancer patients receiving ICIs-as monotherapy or in combination with other anticancer agents. All the relevant trials were retrieved through EMBASE, Cochrane Library, and PubMed/Medline databases; eligible studies were selected according to PRISMA statement. The pooled relative risk (RR) and 95% confidence interval (CI) were extracted., Results: Fifty-nine studies were included. The pooled RRs for all-grade AST and ALT increase were 1.45 (95% CI 1.26-1.67) (Supplementary Fig. 3) and 1.51 (95% CI 1.29-1.77) in patients receiving ICIs monotherapy and immune-based combinations compared to control treatment, respectively. The pooled RRs for grade 3-4 AST and ALT increase were 2.16 (95% CI 1.77-2.64) and 2.3 (95% CI 1.91-2.77)., Conclusions: According to our results, ICIs monotherapy and immune-based combinations were associated with higher risk of all-grade and grade 3-4 hypertransaminasemia. Monitoring liver function should be recommended in cancer patients treated with ICIs monotherapy or immune-based combination, and in case of underlying liver disease, a careful risk-benefit assessment appears as a mandatory need., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Significant advances have been made in the first-line therapy of metastatic renal cell carcinoma (mRCC) since the approval of immune-based combinations, including nivolumab plus ipilimumab or cabozantinib, and pembrolizumab plus axitinib or lenvatinib., Areas Covered: The aim of this review is to compare the different safety profiles of first-line immune-based combinations versus sunitinib across the four respective pivotal trials (CheckMate 214, CheckMate 9ER, KEYNOTE-426, and CLEAR), with a particular attention to patients' health-related quality of life (HRQoL) assessment., Expert Opinion: The concurrent use of an immune-checkpoint inhibitor (ICI) with a tyrosine kinase inhibitor (TKI) as a first-line treatment strategy for mRCC has highlighted the unmet clinical need for prompt detection and consequently proper management of adverse events (AEs), both immune-related and TKI-induced. Overlapping AEs, such as hypertransaminasemia, are most challenging to manage, and evidence is still outlined from clinical practice. The specific patterns of toxicities of the approved first-line immune-based combinations, along with the impact of these interventions on patients' HRQoL, demand a deeper consideration by physicians while choosing the appropriate treatment for each individual mRCC patient. Both safety profile and HRQoL evaluation could be exploited to guide the first-line treatment selection in this setting.

Introduction: Androgen deprivation therapy (ADT) plus Androgen Receptor Target Agents (ARTAs) or docetaxel are the actual standard of care in prostate cancer (PC). Several therapeutic options are available for pretreated patients: cabazitaxel, olaparib, and rucaparib for BRCA mutations, Radium-223 for selected patients with symptomatic bone metastasis, sipuleucel T, and 177 LuPSMA-617., Areas Covered: This review the new potential therapeutic approaches and the most impacting recent published trials to provide an overview on the future management of PC., Expert Opinion: Currently, there is a growing interest in the potential role of triplet therapies encompassing ADT, chemotherapy, and ARTAs. These strategies, explored in different settings, appeared to be particularly promising in metastatic hormone-sensitive PC. Recent trials investigating ARTAs plus poly(adenosine diphosphate-ribose) polymerase (PARPi) inhibitor provided helpful insights for patients with metastatic castration resistant disease, regardless of homologous recombination genes status. Otherwise, the publication of the complete data is awaited, and more evidence is required. In advanced settings, several combination approaches are under investigation, to date with contradictory results, such as immunotherapy plus PARPi or chemotherapy. The radionuclide 177 Lu-PSMA-617 proved successful outcomes in pretreated mCRPC patients. Additional studies will better clarify the appropriate candidates to each strategy and the correct treatments' sequence.

Purpose: Computer-assisted arthroplasty supports the surgeons in planning, simulating, and performing the replacement procedure, using robotic or navigation technologies. However, the safety of the technology has not been widely ascertained. Food and Drug Administration (FDA) database was interrogated about software-related recalls in computer-assisted arthroplasty, aiming to assess: (1) the incidence, (2) the root causes, and (3) the actions taken due to recalls., Methods: The Medical Device Recalls database was investigated about software-related recalls in computer-assisted hip and knee arthroplasty surgery, between 2017 and 2022. The incidence of the software-related recalls, the root causes according to FDA and manufacturers, and the corrective actions taken by firms were determined., Results: Eighteen recall numbers could be identified (1.6%), corresponding to 11 recall events. A total of 4634 units were involved. The FDA determined root causes were: software design (66.6%), design change (22.2%), manufacturing deployment (1, 5.6%), and design manufacturing process (5.6%). Among the manufacturers' reasons for recalls, a specific error was declared in 16 cases (88.9%). In seven cases (43.8%), a coding error about lower limb alignment assessment was identified. Seventeen software-related recalls (94.4%) were classified as class 2; only one case was class 3 (5.6%). Return of the device was the main action taken by firms (8, 44.4%), followed by software update (7, 38.9%)., Conclusion: Software-related recalls in computer-assisted hip and knee arthroplasty were quite uncommon among all the recalls, deemed non-life threatening and usually due to software design errors. The main actions taken by manufacturers were the return of the device or the software update., (© 2023. The Author(s) under exclusive licence to SICOT aisbl.)

Background: In total hip arthroplasty (THA), the outcomes of single taper (ST) and dual taper (DT) versions of the same stem design have been scarcely studied. A registry study comparing ST and DT versions of the same stem design was designed, aiming to assess: (1) the survival rates and the hazard ratios for failure; (2) the survival rates and the hazard ratios for failure using stem-focused endpoints., Material and Methods: A regional arthroplasty registry was interrogated about stem designs with ST and DT versions in cementless THAs performed for primary osteoarthritis. Only the same cup and ceramic-on-ceramic bearings were included: the DT stems had a titanium-on-titanium modularity. Demographic and implant features were recorded. Survival rates and hazard ratios were evaluated and compared. Stem-focused endpoints were also investigated., Results: A total of 5359 THAs were included, with three stem designs. The two versions of every stem showed different demographics and implant-related features: ST versions were preferentially implanted in heavier young men. For each stem, the two versions had similar survival rates at 5 years (p = 0.076; p = 0.319; p = 0.616) and similar adjusted hazard ratios for failures (p = 0.084; p = 0.308; p = 0.729). When stem-focused endpoints were adopted, the ST and DT versions of the three stems achieved similar survival rates (p = 0.710; p = 0.784; p = 0.983) and similar adjusted hazard ratios (p = 0.647; p = 0.858; p = 0.787). Three neck breakages occurred (0.0007% of all the modular implants)., Conclusions: ST and DT versions of the same stem design did not show any differences in terms of survival rates and hazard ratios for failures at 5 years., Level of Evidence: IV., (© 2023. The Author(s).)

Aims: We performed a meta-analysis to assess the relative risk (RR) of all-grade and grade 3-4 hypertransaminasemia in studies comparing immune-based combinations with sunitinib in treatment-naive patients with advanced renal cell carcinoma. Materials & methods: Outcomes of interest included all-grade and grade 3-4 hypertransaminasemia measured as RRs and 95% confidence intervals (CIs). Results: RRs for all-grade hypertransaminasemia were 1.73 (95% CI: 1.25-2.4) and 1.63 (95% CI: 1.25-2.12) in patients receiving immunocombinations and sunitinib, respectively. The pooled RRs for grade 3-4 hypertransaminasemia were 3.24 and 3.04 in patients treated with immunocombinations or sunitinib. Conclusion: Immune-based combinations were associated with higher hypertransaminasemia risk. Physicians should pay attention to these common but overlooked events. Careful monitoring of tolerability remains a crucial need.

Cup overhanging in total hip arthroplasty is a predisposing factor to iliopsoas impingement. In dysplastic hips, cup implantation was simulated in an anatomic hip center of rotation (AHCR) and in high hip center (HHCR). We sought to assess: (1) the percentage of prominent cups; (2) quantify the cup protrusion at different sites on frontal, axial and sagittal views. In 40 Crowe III-IV hips, using a 3D CT-based planning software, cup planning in AHCR and HHCR (CR height ≥ 20 mm) was performed for every hip. Cup prominence was assessed on every plane. HHCR cups were less anteverted (p < 0.01), less medialized (p < 0.001) and less caudal (p = 0.01) than AHCR sockets. AHCR cups were more frequently prominent on at least one plane (92.5% vs. 77.5%), with minimal agreement between the two configurations (k = 0.31, p = 0.07). AHCR cups protruded more than HHCR sockets in the sagittal (p = 0.02) and axial planes (p < 0.001). Axially, at the center of the cup, prominence 6−11 mm occurred in nine (22.5%) AHCR and one (2.5%) HHCR socket. In conclusion, while a routine high hip center should not be recommended, cup placement at a center of rotation height < 20 mm is associated with higher rates and magnitudes of anterior cup protrusion in severe dysplasia.

Background: An acceptable risk-benefit ratio may encourage the prescription of immune checkpoint inhibitors (ICI) near the late stage of life. The lung immune prognostic index (LIPI) was validated in advanced non-small cell lung cancer (NSCLC) patients treated with ICIs. The palliative prognostic (PaP) score without clinical prediction of survival (PaPwCPS) predicts early mortality probability in terminal cancer patients. Methods: We performed a retrospective study including 182 deceased advanced NSCLC patients, treated with single-agent ICI at our Institution. Two prognostic categories of high and low mortality risk were identified through ROC curve analysis for PaPwCPS and LIPI scores. Results: Most were >65 years of age (68.3%) and received second-line ICI (61.2%). A total of 29 (15.9%) and 131 (72.0%) patients died within 30 and 90 days from treatment start, respectively. A total of 81 patients (44.5%) received ICI during the last month of life. Baseline PaPwCPS and LIPI scores were assessable for 78 patients. The AUC of ROC curves was significantly increased for PaPwCPS as compared with LIPI score for both 30-day and 90-day mortality. A high PaPwCPS score was associated in multivariate analysis with increased 30-day (HR 2.69, p = 0.037) and 90-day (HR 4.01, p < 0.001) mortality risk. A high LIPI score was associated with increased 90-day mortality risk (p < 0.001). Conclusion: We found a tendency towards ICI prescription near the late stage of life. The PaPwCPS score was a reliable predictor of 30- and 90-day mortality.

Introduction: The reactivation of telomerase represents a key moment in the carcinogenesis process. Mutations in the central promoter region of the telomerase reverse transcriptase (TERT) gene cause telomerase reactivation in approximately 90% of solid tumors. In some of these, its prognostic and predictive role in response to treatments has already been demonstrated, in others (such as tumors of the genitourinary tract like urothelial carcinoma) data are controversial and the research is still ongoing. In the future, TERT promoter mutations and telomerase activity could have diagnostic, prognostic, and therapeutic applications in many types of cancer., Areas Covered: We performed a review the literature with the aim of describing the current evidence on the prognostic and predictive role of TERT promoter mutations. In some tumor types, TERT promoter mutations have been associated with a worse prognosis and could have a potential value as biomarkers to guide therapeutic decisions. Mutations in TERT promoter seems to make the tumor particularly immunogenic and more responsive to immunotherapy, although data is controversial., Expert Opinion: We described the role of TERT promoter mutations in solid tumors with a particular focus in genitourinary cancers, considering their frequency in this tract.

Salmonella enterica serovar Typhimurium ( S . Typhimurium) comprises a group of closely related human and animal pathogens that account for a large proportion of all Salmonella infections globally. The epidemiological record of S . Typhimurium in Europe is characterized by successive waves of dominant clones, each prevailing for approximately 10-15 years before replacement. Succession of epidemic clones may represent a moving target for interventions aimed at controlling the spread and impact of this pathogen on human and animal health. Here, we investigate the relationship of phage sensitivity and population structure of S . Typhimurium using data from the Anderson phage typing scheme. We observed greater resistance to phage predation of epidemic clones circulating in livestock over the past decades compared to variants with a restricted host range implicating increased resistance to phage in the emergence of epidemic clones of particular importance to human health. Emergence of monophasic S . Typhimurium ST34, the most recent dominant multidrug-resistant clone, was accompanied by increased resistance to phage predation during clonal expansion, in part by the acquisition of the mTmII prophage that may have contributed to the fitness of the strains that replaced ancestors lacking this prophage.

Background: The purpose of this paper is to study the dependence of Co levels in hair on Co levels in blood after metal-on-metal (MoM) hip replacement and prove the suitability of hair analysis coupled to blood analysis in the decision process regarding implant revision evaluation., Methods: Hair samples of 19 MoM patients having both well-functioning and malfunctioning implants and Co mass concentration levels in blood between 0.2 μg L -1 and 221.0 μg L -1 were included. A method based on inductively coupled plasma mass spectrometry was validated and used to measure the Co level in hair., Results: The Co mass fraction in the hair of patients ranged between 0.011 mg kg -1 and 0.712 mg kg -1 . A correlation analysis showed a statistically significant positive correlation ( r  = 0.932, P < .001) between Co in the hair and that in the blood in the full-level range and a statistically nonsignificant positive correlation ( r  = 0.595, P  = .091) in the low-level range., Conclusions: A correlation between the Co level in the hair and that in the blood exists when the latter is clearly above the 7 μg L -1 mass concentration threshold suggested for implant revision evaluation. The correlation disappears when the Co level in blood approaches or falls down the mass concentration threshold and that in the hair approaches or falls within the normal population range of 0.004-0.14 mg kg -1 . Accordingly, clinicians could consider a hair analysis coupled to a blood analysis to assess the revision of malfunctioning MoM implants that release metals in patient's body., (© 2022 The Authors.)

Background: Adjuvant treatment has always been a cornerstone in the therapeutic approach of many cancers, considering its role in reducing the risk of relapse and, in some cases, increasing overall survival. Adjuvant immune checkpoint inhibitors have been tested in different malignancies., Methods: We performed a meta-analysis aimed to explore the impact of adjuvant PD-1 and PD-L1 inhibitors on relapse-free survival (RFS) in cancer patients enrolled in randomized controlled clinical trials. We retrieved all phase III trials published from 15 June 2008 to 15 May 2022, evaluating PD-1/PD-L1 inhibitors monotherapy as an adjuvant treatment by searching on EMBASE, Cochrane Library, and PubMed/ Medline, and international oncological meetings' abstracts. The outcome of interest was RFS. We also performed subgroup analyses focused on age and gender., Results: Overall, 8 studies, involving more than 6000 patients, were included in the analysis. The pooled results highlighted that the use of adjuvant PD-1/PD-L1 inhibitors may reduce the risk of relapse compared to control treatments (hazard ratio, 0.72; 95% confidence intervals, 0.67-0.78). In addition, the subgroup analyses observed that this benefit was consistent in different patient populations, including male, female, younger, and older patients., Conclusions: Adjuvant anti-PD-1/PD-L1 treatment is associated with an increased RFS in the overall population and in subgroups divided according to age and gender.

Background: High-grade neuroendocrine carcinoma (NEC) is a rare and aggressive variant of bladder cancer. Considering its rarity, its therapeutic management is challenging and not standardized. Methods: We analyzed data extracted from the Surveillance, Epidemiology, and End Results (SEER) registry to evaluate prognostic factors for high-grade NEC of the bladder. Results: We extracted data on 1134 patients: 77.6% were small cell NEC, 14.6% were NEC, 5.5% were mixed neuro-endocrine non-neuroendocrine neoplasia, and 2.3% were large cell NEC. The stage at diagnosis was localized for 45% of patients, lymph nodal disease (N+M0) for 9.2% of patients, and metastatic disease for 26.1% of patients. The median overall survival (OS) was 12 months. Multivariate analysis detected that factors associated with worse OS were age being >72 years old (HR 1.94), lymph nodal involvement (HR 2.01), metastatic disease (HR 2.04), and the size of the primary tumor being >44.5 mm (HR 1.80). In the N0M0 populations, the size of the primary tumor being <44.5 mm, age being <72 years old, and major surgery were independently associated with a lower risk of death. In the N+M0 group, the size of the primary lesion was the only factor to retain an association with OS. Conclusions: Our SEER database analysis evidenced prognostic factors for high-grade NEC of the bladder that are of pivotal relevance to guide treatment and the decision-making process.

Background: The therapeutic scenario of urothelial carcinoma is constantly expanding with the widening of the knowledge on molecular characteristics, thus claiming for the need of prognostic and predictive factors to guide treatment strategy. TERT promoter mutation is one of the most frequent genomic alterations in urothelial carcinoma and could present several implications, from diagnostic to prognostic or potentially even predictive., Methods: We performed a single-center retrospective analysis on patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor as second line of therapy to assess the status of the TERT promoter and the potential implication of its mutation on survival outcomes., Results: We analyzed tissue samples from 11 patients with a next-generation sequencing multi-gene panel. The most frequently altered genes were TP53 (54.5%, n = 6) and TERT promoter (36.3%, n = 4). Other mutations found were BRAF, SMAD4, PIK3CA / PDGRFA. The only type of detected TERT promoter mutation was the c 0.124 C>T (n = 4/4, 100%). Of the 4 TERT mutated patients, 2 presented a co-mutation of TP53. Patients with TERT promoter mutation treated with immunotherapy presented a low median overall survival (16.5 months) and progression-free survival (3.8 months)., Conclusions: Our hypothesis-generating analysis suggests that the presence of TERT promoter mutation could have a negative prognostic value and should be further evaluated in wider cohorts., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Introduction: Bone metastases are the most frequent site of secondary localization of prostate cancer (PCa) and are present in about 90% of cases of advanced disease. Consequently, an adequate management of bone involvement is of pivotal importance in the therapeutic approach and skeletal-related events (SREs) need to be closely monitored and promptly assessed and treated. Bone targeting agents (BTAs), consisting in bisphosphonates and denosumab, are an essential part of the treatment of metastatic prostate cancer that accompanies systemic treatments throughout the most part of the history of the disease. Activity and safety of bone targeting agents: These treatments are correlated to better outcomes in terms of reduction of SREs and, in metastatic castration resistant setting, of increased overall survival (OS), but several important adverse events have to be managed and prevented. Of these, osteonecrosis of the jaw (ONJ) is extremely invalidating and should be managed with a special attention., Discussion: The role of BTAs in prostate cancer is pivotal throughout many stages of the disease, but several toxicities should be quickly recognized and treated. We aim at recollecting evidence on clinical benefit of BTAs, common and specific toxicities, and explore the pathophysiology and clinical aspects of osteonecrosis of the jaw. We present a review of the literature to report the role of the different types of bone targeting agents in the management of prostate cancer with bone metastases with a particular focus on common toxicities and ONJ to recollect current evidences on the activity of these compounds and the correct management of their adverse events.

In recent years, the advances in the knowledge on the molecular characteristics of prostate cancer is allowing to explore novel treatment scenarios. Furthermore, technological discoveries are widening diagnostic and treatment weapons at the clinician disposal. Among these, great relevance is being gained by PARP inhibitors and radiometabolic approaches. The result is that DNA repair genes need to be altered in a high percentage of patients with metastatic prostate cancer, making these patients optimal candidates for PARP inhibitors. These compounds have already been proved to be active in pretreated patients and are currently being investigated in other settings. Radiometabolic approaches combine specific prostate cancer cell ligands to radioactive particles, thus allowing to deliver cytotoxic radiations in cancer cells. Among these, radium-223 and lutetium-177 have shown promising activity in metastatic pretreated prostate cancer patients and further studies are ongoing to expand the applications of this therapeutic approach. In addition, nuclear medicine techniques also have an important diagnostic role in prostate cancer. Herein, we report the state of the art on the knowledge on PARP inhibitors and radiometabolic approaches in advanced prostate cancer and present ongoing clinical trials that will hopefully expand these two treatment fields.

Purpose: The aim is to compare the results of isolated hip arthroscopy in patients with borderline dysplasia with Lateral center edge angle (LCEA) between 18° and 25° with a control group of patients with normal LCEA (> 25°)., Methods: Fifty hip arthroscopies performed in 45 patients were retrospectively evaluated. Exclusion criteria were: age > 40, hip arthritis > grade 2 according to Tonnis classification, femoral head avascular necrosis, pediatric's orthopaedics conditions and true dysplasia with LCEA < 18°.Two groups were identified: group A with 15 hips with LCEA between 25° and 18° and Group control B made of 35 hips with LCEA > 25°., Results: The groups were homogeneous for demography and pre-operative WOMAC and HOOS. Osteoplasty for CAM were performed in 100% of patients in both groups, only in 12 hips (34.4%) in group B we had both femoral and acetabular osteoplasty. Labral repair was performed in 86% of patients in group A, in 60% of patients in group B, capsular plication in 93% of group A, in 5% of case of group B. WOMAC and HOOS statically significant improved in both groups at final follow-up (24 months). No cases in both groups required conversion to total hip arthroplasty. Clinical outcomes of study group were comparable to the control group., Conclusion: Even if the present small series is not conclusive, we suggest isolated arthroscopic management of patients with FAI and LCEA between 18° and 25°, but capsular plication and careful labral management are strongly recommended., Level of Evidence: Level IV., (© 2021. The Author(s).)

Objective: Stem anteversion in total hip arthroplasty (THA) has been measured using two different distal references, the posterior condyle (PC) or the transepicondylar axis (TEA). The reliability, the difference in value between these two techniques, and the possible confounding factors are scarcely known. Aims of this work were to assess (1) the intraclass correlation and the difference between the two measurement techniques and (2) the possible influence of condylar dysmorphisms on the anteversion value discrepancy., Materials and Methods: A consecutive series of post-THA CT scans were selected, excluding hip dysplasia, end-stage knee osteoarthritis, and replaced knees. Using a surgical planning software, stem anteversion was measured using the PC or the TEA reference. The intraclass reliability was assessed. The anteroposterior femoral condyle diameters were measured: the difference and the ratio were measured and correlated with the stem anteversion values., Results: 91 CT scans were included. Inter/intra-observer TEA measurements were more reliable than PC. The intraclass correlation between PC and TEA anteversion measurements was good, 0.954 (CI 95% 0.922-0965). The mean difference between PC and TEA anteversion was 5.27 ± 2.41°. The difference and the ratio between the two anteroposterior condyle diameters did not influence the anteversion difference (respectively, p 0.797 and p 0.901)., Conclusions: TEA and PC demonstrated to achieve a good correlation, not dependent from the condyle morphology. However, the difference between the two measurements (5°) can severely influence the combined anteversion (10-20%): due to clinical applicability and better inter/intra-observer agreement, TEA should be preferred for measuring stem anteversion., (© 2021. ISS.)

Copyright of Revista Foco (Interdisciplinary Studies Journal) is the property of Revista Foco and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)