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Testicular sex cord-stromal tumors (TSCSTs) are relatively rare, representing ~5% of testicular neoplasms overall. Historically, TSCSTs have been classified into 3 major entities: Leydig cell tumor, Sertoli cell tumor, and granulosa cell tumor. In recent years, immunophenotypic and molecular analyses have led to a more detailed understanding of the biological and genomic features of these neoplasms, resulting in the description of new entities, some of which have been included in the latest WHO classification. This review summarizes novel histopathologic, clinical, and molecular findings that may lead to a reappraisal of established concepts and help improve the diagnosis and clinical management of TSCSTs in the coming years., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Adult-onset vitelliform macular dystrophy (AVMD) is an inherited maculopathy characterized by metamorphopsias and decrease in visual acuity occurring between the fourth and the sixth decade. It is characterized by an 'egg yolk' macular lesion eventually evolving towards foveal atrophy and fibrosis. It is usually an autosomal dominant inherited disorder with variable penetrance, mainly related to variants in BEST1 , PRPH2 , IMPG1 , and IMPG2 genes., Case Description: A 47-year-old woman complaining of "wavy" vision was referred to our clinic. Her past medical history and reported family history did not reveal any ocular disease. Complete ophthalmological evaluation was performed. Funduscopic examination and multimodal imaging revealed a round vitelliform lesion in both eyes, leading to a diagnosis of AVMD. Genetic analysis revealed a novel, likely pathogenetic, heterozygous c.478G > T (p.Glu160Ter), (NM_016247) variant in the IMPG2 gene., Discussion: Our patient exhibits a novel pathogenetic variant in a gene associated with AVMD. Heterozygous variants in the IMPG2 gene have been reported in multiple individuals with vitelliform macular dystrophy, with an autosomal dominant mode of inheritance. Genetic screening is essential to characterize patients, to predict vision loss in patients with a positive family history and to characterize eligible patients for new potential emerging therapies. Genotype-phenotype correlation studies are needed to have a clearer picture of pathogenetic mechanisms. Our study characterizes the phenotype related to a novel IMPG2 pathogenic variant through multimodal imaging., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Giuseppe Querques is GQ is a consultant for Alimera Sciences (Alpharetta, Georgia, USA), Allergan Inc. (Irvine, California, USA), Bayer Schering Pharma (Berlin, Germany), Heidelberg Engineering (Heidelberg, Germany), Novartis (Basel, Switzerland), Sandoz (Berlin, Germany), Zeiss (Dublin, California, USA). Riccardo Sacconi is a consultant for Allergan Inc, Bayer Shering-Pharma, Medivis, Novartis, and Zeiss. Nicolò Ribarich and Maria Chiara Rivolta have no financial interest to disclose. Nicolò Ribarich, Maria Chiara Rivolta, Riccardo Sacconi and Giuseppe Querques report no conflicting interest regarding this manuscript.

Background and Aims: The Pharmacovigilance Risk Assessment Committee (PRAC) proposed measures to address severe side effects linked to Janus kinase inhibitors (JAKi) in immune-mediated inflammatory diseases (IMID). Use of these medications in individuals aged 65 and older, those at high cardiovascular risk, active or former long-term smokers, and those with increased cancer risk should be considered only if no alternatives exist. Caution is advised when administering JAKi to patients at risk of venous thromboembolism. We aim to implement recommendations from regulatory guidelines based on areas of uncertainty identified., Methods: A two-round modified Research and Development/University of California Los Angeles appropriateness methodology study was conducted. A panel of 21 gastroenterologists, dermatologists and rheumatologists used a 9-point Likert scale to rate the appropriateness of administering a JAKi for each proposed clinical scenario. Scores for appropriateness were categorized as appropriate, uncertain, or inappropriate. Two rounds were performed, each with online surveys and a virtual meeting to enable discussion and rating of each best practice., Results: Round 1 involved participants rating JAKi appropriateness and suggesting descriptors to reduce uncertainty. Survey results were discussed in a virtual meeting, identifying areas of disagreement. In round 2, participants rated their agreement with descriptors from round 1, and the level of uncertainty and disagreement reduced. Age flexibility is recommended in the absence of other risk factors. Active counseling on modifiable risks (e.g., overweight, mild hyperlipidemia and hypertension) and smoking cessation is advised. Uncertainty persists regarding cancer risk due to various factors., Conclusions: We outlined regulatory guidance without a personalized evaluation of the patient's risk profile might lead to uncertainty and become an arid technicality. Therefore, we identified gaps and implemented PRAC recommendations to help health professionals in clinical practice., Competing Interests: Declaration of Competing Interest Virginia Solitano and Magnus Petersen declare no conflict of interest. Paola Facheris has served as consultant for Eli Lilly. Ferdinando D'Amico has served as a speaker for Sandoz, Janssen, Galapagos, and Omega Pharma. He has also served as advisory board member for Abbvie, Ferring, Galapagos, and Nestlè. Michela Ortoncelli has declared no conflicts of interest. Daniel Aletaha received grants from AbbVie, Amgen, Galapagos, Eli Lilly and Sanofi, and honoraria (speaker's bureau, consultancy) from AbbVie, Amgen, Galapagos, Eli Lilly, Janssen, Merck, Novartis, Pfizer and Sandoz and is a member of the ARD Editorial Board. Pablo A. Olivera received consulting fees from Abbvie, Takeda, and Janssen and lecture fees from Takeda and Janssen. Thomas Bieber was speaker or consultant or Investigator for AbbVie, Affibody, Allmiral, AnaptysBio, Arena, Asana Biosciences, ASLAN pharma, Bayer Health, BioVerSys, Böhringer-Ingelheim, Bristol-Myers Squibb, Connect Pharma, Dermavant, Domain Therapeutics, EQRx, Eli Lilly and Company, Galderma, Glenmark, GSK, Incyte, Innovaderm, IQVIA, Janssen, Kirin, Kymab, LEO, LG Chem, L'Oréal, MSD, Novartis, Numab, OM-Pharma, Pfizer, Pierre Fabre, Q32bio, RAPT, Sanofi/Regeneron, UCB. He is founder and chairman of the board of the non-profit biotech “Davos Biosciences”. Sofia Ramiro research grants and/or consultancy fees: AbbVie, Eli Lilly, Janseen, Galapagos, MSD, Novartis, Pfizer, UCB, Sanofi. Subrata Ghosh declares receiving consulting fees from Pfizer, Janssen, AbbVie, Takeda, Bristol Myers Squibb, Receptos, Celgene, Gilead, Eli Lilly, and Boehringer Ingelheim, and speaker fees from AbbVie, Janssen, Takeda, Ferring, Pfizer, Shield, and Falk Pharma outside of the submitted work. Maria Antonietta D'Agostino reports speaker or consultant fees from Novartis, BMS, Janssen,Pfizer, Amgen, Galapagos, AbbVie, UCB, and Eli Lilly. PC reports research grants from UCB, MSD and Pfizer; speaker fees or consultant fees from Pfizer, MSD, Novartis, Bristol Myers Squibb, AbbVie, UCB, Eli Lilly, Gilead and Celgene Corporation. Britta Siegmund has served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité). Isabelle Chary-Valckenaere received consulting fees from Abbvie, BMS, Galapagos, Lilly, Novartis, Pfizer, UCB. Ailsa Hart has served as consultant, advisory board member or speaker for AbbVie, Arena, Atlantic, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Galapogos, Lilly, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda. She also serves on the Global Steering Committee for Genentech. Lorenzo Dagna Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Galapagos, GlaxoSmithKline, Janssen, Kiniksa Pharmaceuticals, Novartis, Pfizer, Sanofi-Genzyme, SOBI, and Vifor outside of the current work. Fernando Magro has served as a speaker and received honoraria from Merck Sharp & Dohme, Abbvie, Vifor, Falk, Laboratorios Vitoria, Ferring, Hospira, and Biogen. Renaud Felten has been a consultant for Amgen, BMS, Galapagos, GSK, Janssen-Cilag, Lilly, Medac, MSD, Nordic, Novartis, Pfizer, Sanofi, UCB. Paulo Kotze has received honoraria from AbbVie, Ferring, Janssen, Pfizer, and Takeda as a speaker and member of advisory boards. He also received scientific research grants from Pfizer and Takeda. Vipul Jairath has received consultancy/advisory board fees from AbbVie, Alimentiv Inc., Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Topivert, Ventyx, and Vividion; and speaker's fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi. Antonio Costanzo has served as an advisory board member, consultant and has received fees and speaker's honoraria or has participated in clinical trials for Abbvie, Almirall, Biogen, LEO Pharma, Lilly, Janssen, Novartis, Pfizer, Sanofi Genzyme and UCB-Pharma. Lars Erik Kristensen has received fees for participation in speakers bureaus, research grants and consultancy fees from Pfizer, AbbVie, Amgen, Galapagos, UCB, Celgene, BMS, MSD, Novartis, Eli Lilly and Janssen Pharmaceuticals. Laurent Peyrin Biroulet has served as a speaker, consultant, and advisory board member for Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boerhinger Ingelheim, Lilly, HAC Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera, Samsung Bioepis, and Theravance. Silvio Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma, and Vifor., (Copyright © 2023. Published by Elsevier B.V.)

Background: In adoptive T cell therapy, the long term therapeutic benefits in patients treated with engineered tumor specific T cells are limited by the lack of long term persistence of the infused cellular products and by the immunosuppressive mechanisms active in the tumor microenvironment. Exhausted T cells infiltrating the tumor are characterized by loss of effector functions triggered by multiple inhibitory receptors (IRs). In patients, IR blockade reverts T cell exhaustion but has low selectivity, potentially unleashing autoreactive clones and resulting in clinical autoimmune side effects. Furthermore, loss of long term protective immunity in cell therapy has been ascribed to the effector memory phenotype of the infused cells., Methods: We simultaneously redirected T cell specificity towards the NY-ESO-1 antigen via TCR gene editing (TCR ED ) and permanently disrupted LAG3 , TIM-3 or 2B4 genes (IR KO ) via CRISPR/Cas9 in a protocol to expand early differentiated long-living memory stem T cells. The effector functions of the TCR ED -IR KO and IR competent (TCR ED -IR COMP ) cells were tested in short-term co-culture assays and under a chronic stimulation setting in vitro . Finally, the therapeutic efficacy of the developed cellular products were evaluated in multiple myeloma xenograft models., Results: We show that upon chronic stimulation, TCR ED -IR KO cells are superior to TCR ED -IR COMP cells in resisting functional exhaustion through different mechanisms and efficiently eliminate cancer cells upon tumor re-challenge in vivo . Our data indicate that TIM-3 and 2B4-disruption preserve T-cell degranulation capacity, while LAG-3 disruption prevents the upregulation of additional inhibitory receptors in T cells., Conclusion: These results highlight that TIM-3, LAG-3, and 2B4 disruptions increase the therapeutic benefit of tumor specific cellular products and suggest distinct, non-redundant roles for IRs in anti-tumor responses., Competing Interests: CB, ER, ZM, BC, AP, LV, FC, PG, LN and BCC are inventors on different patents on cancer immunotherapy and genetic engineering. CB has been member of Advisory Board and Consultant for Molmed, Intellia, TxCell, Novartis, GSK, Allogene, Kite/Gilead, Miltenyi, Kiadis, Evir, Janssen and received research support from Molmed s.p.a and Intellia Therapeutics. LV received royalties and research support from GEN-DX and research support from Moderna Therapeutics. The remaining 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cianciotti, Magnani, Ugolini, Camisa, Merelli, Vavassori, Potenza, Imparato, Manfredi, Abbati, Perani, Spinelli, Shifrut, Ciceri, Vago, Di Micco, Naldini, Genovese, Ruggiero and Bonini.)

Abstract: Large B-cell lymphoma (LBCL) carrying MYC rearrangement, alone or together with BCL2 and/or BCL6 translocations, have shown a poor prognosis when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the HIV population. Scanty data are available on the prevalence and prognostic impact of MYC rearrangements in HIV-associated LBCL. We conducted a retrospective study to evaluate the clinical effect of MYC rearrangement in HIV-associated LBCL. We evaluated clinical characteristics, treatment received, and outcome of LBCL in patients with HIV with MYC rearrangement (MYC+) and without MYC rearrangement (MYC-). A total of 155 patients with HIV who had received fluorescence in situ hybridization analysis for MYC were enrolled in 11 European centers: 43 with MYC+ and 112 MYC-. Among patients with MYC, 10 had double-/triple-hit lymphomas, and 33 had isolated MYC rearrangement (single-hit lymphoma). Patients with MYC+ had more frequently advanced stage, >2 extranodal site at presentation, and higher proliferative index. There were no significant differences in overall survival and progression-free survival (PFS) between the 2 groups. However, patients with MYC+ received more frequently intensive chemotherapy (iCT) (44%) than (R)CHOP alone (35%) or infusional treatment (DA-EPOCH-R and R-CDE) (19%). Among patients with MYC+, those who received iCT achieved a better outcome than patients who received nonintensive treatment (complete remission, 84% vs 52%; P = .028; 5-year PFS, 66% vs 36%; P = .021). Our retrospective results suggest that HIV-associated LBCL with MYC+ could be considered for an intensive therapeutic approach whenever possible, whereas (R)CHOP seems to give inferior results in this subset of patients in terms of complete remission and PFS., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Transcatheter mitral edge-to-edge repair (TEER) is an established procedure for managing mitral regurgitation (MR) in high-risk patients. It is effective in treating both primary and secondary MR, as reported in the surgical and interventional literature. Over time, TEER has gained popularity and achieved procedural success in various anatomies. The less invasive nature of TEER, along with its high safety profile and immediate haemodynamic improvement suggest potential benefits in high-risk populations who are not normally included in major trials. These patients, often deemed unsuitable for surgical intervention, are typically managed conservatively, despite accumulating evidence suggesting the potential of clinical improvement by reducing MR through TEER. Examples include post-myocardial infarction MR, patients with hypertrophic obstructive cardiomyopathy and patients experiencing recurrent MR after surgical intervention. This review discusses the utilisation of TEER beyond recognised indications, examining outcomes and limitations in diverse patient populations. Further studies are warranted to evaluate the benefits of TEER in clinical scenarios beyond the current indications.

Abstract: DNA-damaging agents have represented the first effective treatment for the blood cancer multiple myeloma, and after 65 years since their introduction to the clinic, they remain one of the mainstay therapies for this disease. Myeloma is a cancer of plasma cells. Despite exceedingly slow proliferation, myeloma cells present extended genomic rearrangements and intense genomic instability, starting at the premalignant stage of the disease. Where does such DNA damage stem from? A reliable model argues that the powerful oncogenes activated in myeloma as well the phenotypic peculiarities of cancer plasma cells, including the dependency on the proteasome for survival and the constant presence of oxidative stress, all converge on modulating DNA damage and repair. Beleaguered by these contraposing forces, myeloma cells survive in a precarious balance, in which the robust engagement of DNA repair mechanisms to guarantee cell survival is continuously challenged by rampant genomic instability, essential for cancer cells to withstand hostile selective pressures. Shattering this delicate equilibrium has been the goal of the extensive use of DNA-damaging agents since their introduction in the clinic, now enriched by novel approaches that leverage upon synthetic lethality paradigms. Exploiting the impairment of homologous recombination caused by myeloma genetic lesions or treatments, it is now possible to design therapeutic combinations that could target myeloma cells more effectively. Furthermore, DNA-damaging agents, as demonstrated in solid tumors, may sensitize cells to immune therapies. In all, targeting DNA damage and repair remains as central as ever in myeloma, even for the foreseeable future., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Several systematic reviews (SRs) assessing the use of telemedicine for musculoskeletal conditions have been published in recent years. However, the landscape of evidence on multiple clinical outcomes remains unclear., Objective: We aimed to summarize the available evidence from SRs on telemedicine for musculoskeletal disorders., Methods: We conducted an umbrella review of SRs with and without meta-analysis by searching PubMed and EMBASE up to July 25, 2022, for SRs of randomized controlled trials assessing telemedicine. We collected any kind of patient-reported outcome measures (PROMs), patient-reported experience measures (PREMs), and objective measures, including direct and indirect costs. We assessed the methodological quality with the AMSTAR 2 tool (A Measurement Tool to Assess systematic Reviews 2). Findings were reported qualitatively., Results: Overall, 35 SRs published between 2015 and 2022 were included. Most reviews (n=24, 69%) were rated as critically low quality by AMSTAR 2. The majority of reviews assessed "telerehabilitation" (n=29) in patients with osteoarthritis (n=13) using PROMs (n=142 outcomes mapped with n=60 meta-analyses). A substantive body of evidence from meta-analyses found telemedicine to be beneficial or equal in terms of PROMs compared to conventional care (n=57 meta-analyses). Meta-analyses showed no differences between groups in PREMs (n=4), while objectives measures (ie, "physical function") were mainly in favor of telemedicine or showed no difference (9/13). All SRs showed notably lower costs for telemedicine compared to in-person visits., Conclusions: Telemedicine can provide more accessible health care with noninferior results for various clinical outcomes in comparison with conventional care. The assessment of telemedicine is largely represented by PROMs, with some gaps for PREMs, objective measures, and costs., Trial Registration: PROSPERO CRD42022347366; https://osf.io/pxedm/., (©Silvia Bargeri, Greta Castellini, Jacopo Antonino Vitale, Stefania Guida, Giuseppe Banfi, Silvia Gianola, Federico Pennestrì. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 02.02.2024.)

Upper blepharoplasty is a common aesthetic surgery procedure which is frequently performed wide awake, under local anesthesia. However, advancements concerning the patients' perception during and after the procedure are still needed. This study aimed to evaluate the efficacy of a new method for local anesthetic infiltration in the upper eyelid comparing it to the traditional needle injections.A prospective, randomized, and clinical trial was conducted on 20 patients who underwent upper eyelid blepharoplasty in local anesthesia. After randomization, one eyelid was infiltrated using a Nanosoft technology needle, while on the contralateral side traditional needle injections were performed. Preoperative demographics, Fitzpatrick, and SNAP test were recorded. Postoperative patients visual analog scale (VAS) scores for both infiltration methods and ecchymosis and edema were recorded.Our results showed that the mean VAS scores for perceived pain were significantly lower on the eye infiltrated with Nanosoft technology ( p  < 0.05). Furthermore, the rate of postoperative ecchymosis and edema were also significantly lower with Nanosoft technology ( p  = 0.0012 and 0 = 0.0197, respectively). All 20 patients were satisfied with outcomes, and there were no major complications or need for a revision.Our case series study suggests that Nanosoft technology may be a more effective and efficient method for the local anesthetic infiltration in upper eyelid blepharoplasty in reducing discomfort and downtime for the patient., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Malignant ovarian germ cell tumors usually occur in young women. The standard of care is fertility sparing surgery and comprehensive surgical staging followed by adjuvant chemotherapy with BEP (bleomycin, etoposide, cisplatin) if needed. The aim of this study was to analyze the reproductive outcomes after conservative treatment in patients diagnosed, treated and followed up in MITO (Multicenter Italian Trials in Ovarian Cancer) centers., Methods: A questionnaire concerning gynecological symptoms, reproductive outcomes and fertility treatment was administered to 164 MOGCTs survivors. Data regarding patients deceased were collected from MITO-9 database. There were 114 patients diagnosed at reproductive age between 1983 and 2019 included., Results: 109 patients answered the questionnaire and 5 patients decesased were included (median age 24.9 years). 78.1% were stage I,4.4% stage II, 14.9% stage III and 2.6% stage IV. 57.9% received chemotherapy, the mean number of cycles was 4.1. Median time to menstrual recovery after BEP was of 5.6 months range, only 1 case of premature ovarian failure was reported. Among the 114 patients 38 (33.3%) attempted to become pregnant, 29/38 (76.3%) got pregnant with a total of 44 conceptions. 40.9% received chemotherapy and 22.9% did not (p 0.048). Pregnancy desire was the only predictive factor associated with live births among women who attempted pregnancy after treatment., Conclusions: As MOGCTs affect women of child-bearing age, fertility preservation represents a major treatment issue. Our results are consistent with the available evidence, confirming that adjuvant chemotherapy for MOGCT does not impact the reproductive function and fertility., Competing Interests: Conflicts of interest Alice Bergamini, Giorgia Mangili and Gabriella Ferrandina declare honoraria and research funding from MSD, GSK, Clovis and Astrazeneca. Sandro Pignata declares honoraria from Roche, MSD, Astrazeneca, GSK and research funding from Pfizer, Roche, Astrazeneca, MSD and GSK., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Obesity is characterized by the accumulation of T cells in insulin-sensitive tissues, including the visceral adipose tissue (VAT), that can interfere with the insulin signaling pathway eventually leading to insulin resistance (IR) and type 2 diabetes. Here, we found that PD-1 + CD4 conventional T (Tconv) cells, endowed with a transcriptomic and functional profile of partially dysfunctional cells, are diminished in VAT of obese patients with dysglycemia (OB-Dys), without a concomitant increase in apoptosis. These cells showed enhanced capacity to recirculate into the bloodstream and had a non-restricted TCRβ repertoire divergent from that of normoglycemic obese and lean individuals. PD-1 + CD4 Tconv were reduced in the circulation of OB-Dys, exhibited an altered migration potential, and were detected in the liver of patients with non-alcoholic steatohepatitis. The findings suggest a potential role for partially dysfunctional PD-1 + CD4 Tconv cells as inter-organ mediators of IR in obese patients with dysglycemic., Competing Interests: The authors have declared that no conflict of interest exists., (© 2024 The Author(s).)

Objective: To investigate the association between immune-related adverse events (irAEs) and oncological outcomes in patients with advanced urothelial cancer receiving immune checkpoint inhibitors (ICIs), and whether the administration of systemic corticosteroids diminishes therapeutic impact., Patients and Methods: The association between irAEs occurrence and clinical progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS) was tested by means of multivariable Cox or competing-risks regression, when appropriate. Patients experiencing irAEs were further stratified based on systemic corticosteroids administration. A sensitivity analysis was conducted by repeating all the analyses with median time to irAE as landmark point., Results: We relied on individual participant data from two prospective trials for advanced urothelial cancer: IMvigor210 and IMvigor211. A total of 896 patients who received atezolizumab for locally advanced or metastatic urothelial cancer were considered. Overall, irAEs were recorded in 195 patients and the median time to irAEs was 64 days. On multivariable analysis, irAEs were inversely associated with the risk of disease progression (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.40-0.61; P < 0.001), overall mortality (HR 0.51, 95% CI 0.41-0.64; P < 0.001), and cancer-specific mortality (subdistributional HR [sHR] 0.55, 95% CI 0.45-0.72; P < 0.001). Moreover, our results did not refute the supposition that the administration of systemic corticosteroids does not impact oncological outcomes (PFS: HR 0.92, 95% CI 0.62-1.34, P = 0.629; OS: HR 0.86, 95% CI 0.51-1.64, P = 0.613; CSS: sHR 0.90, 95% CI 0.60-1.36, P = 0.630). The sensitivity analysis confirmed our findings., Conclusions: The development of irAEs while receiving atezolizumab treatment was associated with improved oncological outcomes, namely overall and cancer-specific mortality, and PFS. These findings seem to not be substantially affected by administration of systemic corticosteroids., (© 2023 BJU International.)

Sleep abnormalities may represent an independent risk factor for neurodegeneration. An international expert group convened in 2021 to discuss the state-of-the-science in this domain. The present article summarizes the presentations and discussions concerning the importance of a strategy for studying sleep- and circadian-related interventions for early detection and prevention of neurodegenerative diseases. An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years; discussed the current challenges in the field of relationships among sleep, sleep disorders, and neurodegeneration; and identified future priorities. Sleep efficiency and slow wave activity during non-rapid eye movement (NREM) sleep are decreased in cognitively normal middle-aged and older adults with Alzheimer's disease (AD) pathology. Sleep deprivation increases amyloid-β (Aβ) concentrations in the interstitial fluid of experimental animal models and in cerebrospinal fluid in humans, while increased sleep decreases Aβ. Obstructive sleep apnea (OSA) is a risk factor for dementia. Studies indicate that positive airway pressure (PAP) treatment should be started in patients with mild cognitive impairment or AD and comorbid OSA. Identification of other measures of nocturnal hypoxia and sleep fragmentation could better clarify the role of OSA as a risk factor for neurodegeneration. Concerning REM sleep behavior disorder (RBD), it will be crucial to identify the subset of RBD patients who will convert to a specific neurodegenerative disorder. Circadian sleep-wake rhythm disorders (CSWRD) are strong predictors of caregiver stress and institutionalization, but the absence of recommendations or consensus statements must be considered. Future priorities include to develop and validate existing and novel comprehensive assessments of CSWRD in patients with/at risk for dementia. Strategies for studying sleep-circadian-related interventions for early detection/prevention of neurodegenerative diseases are required. CSWRD evaluation may help to identify additional biomarkers for phenotyping and personalizing treatment of neurodegeneration., (© 2023. Fondazione Società Italiana di Neurologia.)

Purpose: This study aims to assess the efficacy of two aprepitant formulations (X1 and X2), in a preclinical model of dry eye disease (DED) induced by benzalkonium chloride (BAK)., Methods: Two aprepitant formulations were tested on 7 to 8-week-old male mice for their efficacy. In vivo corneal fluorescein staining assessed epithelial damage as the primary end point on days 0, 3, 5, 7, 9, 12, and 14 using slit-lamp microscopy. The DED model was induced with 0.2% BAK twice daily for the first week and once daily for the next week. Mice were randomly assigned to 5 treatment groups: Aprepitant X1 (n = 10) and X2 (n = 10) formulation, 2 mg/mL dexamethasone (n = 10), control vehicle X (n = 10), 0.2% hyaluronic acid (n = 10), or no treatment (n = 10). Eye wiping, phenol red, and Cochet Bonnet tests assessed ocular pain, tear fluid secretion, and nerve function. After 7 days, the mice were euthanized to quantify leukocyte infiltration and corneal nerve density., Results: Topical aprepitant X1 reduced BAK-induced corneal damage and pain compared to gel vehicle X (P = 0.007) and dexamethasone (P = 0.021). Aprepitant X1 and X2 improved corneal sensitivity versus gel vehicle X and dexamethasone (P < 0.001). Aprepitant X1 reduced leukocyte infiltration (P < 0.05) and enhanced corneal nerve density (P < 0.001). Tear fluid secretion remained statistically unchanged in both the X1 and X2 groups., Conclusions: Aprepitant formulation X1 reduced pain, improved corneal sensitivity and nerve density, ameliorated epitheliopathy, and reduced leukocyte infiltration in male mouse corneas., Translational Relevance: Aprepitant emerges as a safe, promising therapeutic prospect for the amelioration of DED's associated symptoms.

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34 + cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34 + cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34 + cells infused and younger age at GT affected positively the plateau of CD3 + transduced cells, lymphocytes and CD4 + CD45RA + naive T cells, whereas the cell dose positively influenced the final plateau of CD15 + transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

A range of drugs have a direct role in triggering ischaemic priapism. We aimed at identifying: a) which medications are associated with most priapism-reports; and, b) within these medications, comparing their potential to elicit priapism through a disproportionality analysis. The FDA Adverse Event Reporting System (FAERS) database was queried to identify those drugs associated the most with priapism reports over the last 5 years. Only those drugs being associated with a minimum of 30 priapism reports were considered. The Proportional Reporting Ratios (PRRs), and their 95% confidence intervals were computed. Out of the whole 2015-2020 database, 1233 priapism reports were identified, 933 of which (75.7%) were associated with 11 medications with a minimum of 30 priapism-reports each. Trazodone, olanzapine and tadalafil showed levels of disproportionate reporting, with a PRR of 9.04 (CI95%: 7.73-10.58), 1.55 (CI95%: 1.27-1.89), and 1.42 (CI95%: 1.10-1.43), respectively. Most (57.5%) of the reports associated with the phosphodiesterase type 5 inhibitors (PDE5Is) were related with concomitant priapism-eliciting drugs taken at the same time and/or inappropriate intake/excessive dosage. Patients taking trazodone and/or antipsychotics need to be aware of the priapism-risk; awareness among prescribers would help in reducing priapism-related detrimental sequelae; PDE5I-intake is not responsible for priapism by itself, when appropriate medical supervision is provided., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Despite effective antiretroviral therapies (ARTs), a subset of people living with HIV (PLWH) still experience low-level viremia (LLV, i.e., 50-1,000 copies/mL). The present study compared PLWH experiencing LLV with those maintaining virological suppression (VS) and explored the potential impact of preexisting drug resistance and other factors on LLV. We conducted a retrospective, 1:1 matched case-control study within a cohort of drug-experienced VS subjects from the Italian Antiviral Response Cohort Analysis database, followed in the period 2009-2019. Cases were individuals experiencing LLV, while controls were those who maintained VS. Matching was for calendar year of first ART regimen. Preexisting drug resistance was calculated as cumulative genotypic susceptibility score (GSS) according to regimen administered at the observational period start. To explore the effect of cumulative GSS, treated as a binary variable (≥2 and <2) and other factors on LLV, we performed a logistic regression analysis. Within a main population of 3,455 PLWH, 337 cases were selected. Cases were comparable to the controls for both gender and age. However, cases showed that they had experienced a longer time since HIV diagnosis, a higher number of drugs previously administered, lower baseline CD4 + T cell count and a higher zenith viral load (VL). By multivariate analysis, we found that higher zenith VL [adjusted odds ratio (aOR) (95% confidence interval [CI]) 1.30 (1.14-1.48)], a cumulative usage of both PI [aOR (95% CI): 2.03 (1.19-3.48)] and InSTI [aOR (95% CI): 2.23 (1.47-3.38)] and a cumulative GSS <2 [aOR (95% CI) 0.67 (0.46-0.98)], were associated with a higher risk in developing LLV. In current high-efficacy ART era, in drug-experienced PLWH, the predictors of increased risk of LLV were the presence of preexisting drug resistance, higher zenith VL, and previous PI, and InSTI exposure.

In our society interaction with robots is becoming more and more frequent since robots are not only used in the industry, but increasingly often in assistance and in health system. Perception of robots and their movements is crucial for their acceptance. Here we shortly review basic mechanisms of perception of actions, and then of perception of robotic and human movements. The literature demonstrates that there are commonalities, but also differences in the perception of human and robotic movements. Especially interesting are biologic gender differences in the perception of robotic movements. The results show that males seem to be more sensitive to the differences between robotic and anthropomorphic movements, whereas females seem not to perceive such differences. However, females transfer more anthropomorphic features to robotic movements. While looking at the brain activation during perception of humanoid and robotic movements in different genders one can conclude that different strategies are used; female seem to analyse robotic movements online, while male seem to use previous knowledge from interaction with robots. Further research is needed to specify more such gender differences., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Abel, Buccino and Binkofski.)

Aminopeptidase N/CD13, a membrane-bound enzyme upregulated in tumor vasculature and involved in angiogenesis, can be used as a receptor for the targeted delivery of drugs to tumors through ligand-directed targeting approaches. We describe a novel peptide ligand (VGCARRYCS, called "G4") that recognizes CD13 with high affinity and selectivity. Enzymological and computational studies showed that G4 is a competitive inhibitor that binds to the catalytic pocket of CD13 through its N-terminal region. Fusing the peptide C-terminus to tumor necrosis factor-alpha (TNF) or coupling it to a biotin/avidin complex causes loss of binding and inhibitory activity against different forms of CD13, including natural or recombinant ectoenzyme and a membrane form expressed by HL60 promyelocytic leukemia cells (likely due to steric hindrance), but not binding to a membrane form of CD13 expressed by endothelial cells (ECs). Furthermore, G4-TNF systemically administered to tumor-bearing mice exerted anticancer effects through a CD13-targeting mechanism, indicating the presence of a CD13 form in tumor vessels with an accessible binding site. Biochemical studies showed that most CD13 molecules expressed on the surface of ECs are catalytically inactive. Other functional assays showed that these molecules can promote endothelial cell adhesion to plates coated with G4-avidin complexes, suggesting that the endothelial form of CD13 can exert catalytically independent biological functions. In conclusion, ECs express a catalytically inactive form of CD13 characterized by an accessible conformation that can be selectively targeted by G4-protein conjugates. This form of CD13 may represent a specific target receptor for ligand-directed targeted delivery of therapeutics to tumors., (© 2024. The Author(s).)

Introduction: The development of several effective biological drugs for moderate-to-severe plaque psoriasis has dramatically changed the lives of patients. Despite the wide use of interleukin (IL) inhibitors, limited data are available to date regarding long-term treatment persistence., Method: This multicenter retrospective real-world study evaluated 5932 treatment courses across 5300 patients, all treated with interleukin inhibitors. Drug survival was expressed by using the Kaplan-Meier estimator for each biological drug at 6, 12, 24, 36 and 48 months. We also stratified by discontinuation associated with primary or secondary ineffectiveness., Results: In our study, the most prescribed drugs were secukinumab (1412), ixekizumab (1183), and risankizumab (977). After four years of follow-up, risankizumab emerged as the treatment with the highest drug survival overall, as 91.6% of patients were still on treatment. The overall probability of drug survival at four years was comparable for tildrakizumab (83.5%), ixekizumab (82.6%), guselkumab (82.4%) and brodalumab (81.8%). When evaluating only patients who discontinued the treatment because of ineffectiveness, once again risankizumab was the molecule with the highest drug survival at 4 years (93.4%), this time followed by ixekizumab (87%). Our study, in which all IL inhibitors were adequately represented, confirmed a slightly better treatment persistence for IL-23 inhibitors, consistent with other real-world studies., Conclusion: Our experience showed that IL-23 inhibitors, and risankizumab in particular, had a higher probability of drug survival overall during a 4-year follow-up. Risankizumab and ixekizumab were less likely to be discontinued because of ineffectiveness after four years., Competing Interests: LG has been a consultant for Almirall. LI has been a consultant for Almirall. PM has been a speaker for AbbVie, Lilly, Novartis, Janssen-Cilag, Celgene, Leopharma and Almirall. AB has received honoraria for participation in advisory boards, meetings or as speaker for AbbVie, Celgene, Janssen-Cilag, Eli Lilly, Novartis Pharma, Pfizer, Sanofi-Genzyme and UCB Pharma. FB has been a consultant advisor and clinical study investigator for Eli Lilly, Abbvie, Novartis, Leo Pharma, Sandoz, Bristol Myers, Abiogen-Pharma, Celgene and Janssen. MB has acted as a speaker and consultant for AbbVie, Janssen, Amgen, Novartis, Eli Lilly and UCB Pharma. CC has served as a board participant or speaker for Abbvie, Lilly, Janssen, Novartis, Celgene, Almirall and Leopharma. GD served as consultant and/or speaker for AbbVie, Almirall, Bristol-Meyers Squibb, LeoPharma, Novartis, Pfizer, Sanofi and UCB and received unrestricted grants from Pfizer and Almirall. PD has been a speaker for Novartis, Abbvie, Sanofi, UCB, Janssen, Lilly and LeoPharma. FG acted as a speaker or consultant for Novartis, Abbvie, Eli Lilly, Celgene, LeoPharma and Almirall. GG served as consultant and/or speaker for AbbVie, Almirall, Amgen, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Eli-Lilly, LeoPharma, Novartis, Pfizer, Samsung, Sanofi and UCB. CG has been a scientific consultant/speaker/clinical study investigator for Abbvie, Celgene, Janssen, Eli Lilly, Novartis, Pfizer, Sanofi, Almirall and LEO Pharma. CL declares a conflict of interest with Abbvie, Novartis, Lilly and Almirall. FL served on advisory boards and/or received honoraria for lectures from Abbvie, Janssen-Cilag, Novartis, Lilly and Sanofi. AM reports consultancy/advisory boards disease-relevant honoraria from AbbVie, Boehringer-Ingelheim, Novartis, Pfizer, Sanofi and UCB. MM acted as a speaker or consultant for Abbvie, Eli Lilly, Janssen, Leo-Pharma, UCB and Novartis. AC has served as an advisory board member, consultant and has received fees and speaker’s honoraria or has participated in clinical trials for Abbvie, Almirall, Biogen, LEO Pharma, Lilly, Janssen, Novartis, Pfizer, Sanofi Genzyme and UCB-Pharma. AN has served on advisory boards, received honoraria for lectures and research grants from Almirall, Abbvie, Leo Pharma, Celgene, Eli Lilly, Janssen, Novartis, Sanofi-Genzyme, Amgen and Boehringer Ingelheim. The remaining 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 © 2024 Gargiulo, Ibba, Malagoli, Balato, Bardazzi, Burlando, Carrera, Damiani, Dapavo, Dini, Gaiani, Girolomoni, Guarneri, Lasagni, Loconsole, Marzano, Megna, Mercuri, Travaglini, Costanzo and Narcisi.)

Hematopoiesis is a complex process that takes place inside the bone marrow, where a specialized structure, the bone marrow niche, participates in the maintenance of hematopoietic stem cell functionality. Inflammatory conditions, such as autoimmune diseases, could alter this equilibrium leading to pathologic consequences. Immune cells, which also reside in the bone marrow, directly participate in sustaining the inflammatory state in autoimmune diseases. In particular, memory lymphocytes are key players in the long-term maintenance of the immune response against self-antigens, causing tissue damage and bone marrow alterations., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Chronic lymphocytic leukemia (CLL) therapies differ in efficacy, side effects, route, frequency, and duration of administration. We assessed patient preferences for treatment attributes and evaluated associations with disease stage, treatment line, and socio-demographic characteristics in a cross sectional, observational study conducted at 16 Italian hematology centers. Study visits occurred between February and July 2020; 401 adult patients with CLL (201 Watch and Wait (W&W), 200 treated) participated in a discrete choice experiment (DCE), composed of 8 choices between pairs of treatment profiles with different levels of 5 attributes of currently available CLL treatments (length of response, route and duration of administration, risk of side effects including diarrhea, infections, or organ damage). Health-related quality of life was assessed with the EQ-5D-5L, EORTC QLQ-C30 and QLQ CLL-16. Previously treated patients had longer disease duration (7 vs. 5 years), higher prevalence of serious comorbidities (45.5% vs. 36.2%) and high-risk molecular markers (unmutated IGHV 55.6% vs. 17.1%; TP53 mutation 15.2% vs. 4.0%). Health-related quality of life scores were similar between groups. In the DCE, W&W patients rated "possible occurrence of infections" highest (relative importance [RI] = 36.2%), followed by "treatment and relevant duration" (RI = 28.0%) and "progression-free survival (PFS)" (RI = 16.9%). Previously treated patients rated "treatment and relevant duration" highest (RI = 33.3%), followed by "possible occurrence of infections" (RI = 28.8%), "possible occurrence of organ damage" (RI = 19.4%), and "PFS" (RI = 9.8%). Concern over infection was rated highest overall; unexpectedly PFS was not among the most important criteria in either group, suggesting that the first COVID-19 pandemic wave may have influenced patient preferences and concerns about CLL therapy options., (© 2023 Abbvie SRL and The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Background: Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed., Methods: We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints., Findings: 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n = 87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p = 0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p = 0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA: (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p = 0.01)., Interpretation: Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure., Funding: There was no external funding source for this study., Competing Interests: R.dlC. Has received honoraria from Pfizer and MSD; J.S. reports personal fees from Gilead, outside the submitted work. EDK reports grants from Gilead sciences, personal fees from Pfizer, outside the submitted work. L.Y. reports grants and personal fees from Janssen, personal fees from Abbvie, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Beigene, personal fees and non-financial support from Kite/Gilead, personal fees and non-financial support from Pfizer, outside the submitted work; S.M reports other from Celgene/BMS, other from Novartis, other from Kite/Gilead, other from Pfizer, other from Miltenyi, other from Mendes, other from SWECARNET, other from Scientify Research, outside the submitted work; J.M. reports personal fees and non-financial support from Gilead Sciences, personal fees and non-financial support from Mundipharma, personal fees and non-financial support from F2G, personal fees and non-financial support from Takeda, personal fees and non-financial support from Basilea, outside the submitted work; M.M. reports grants and personal fees from Gilead, personal fees from Mundipharma, personal fees from Pfizer, from null, outside the submitted work; H.P. reports non-financial support from Neovii, during the conduct of the study; OP has no COIs directly related to this work. HP reports non-financial support from Neovii during the conduct of the study; OP has received honoraria or travel support from Gilead, Jazz, MSD, Neovii, Novartis, Pfizer and Therakos. He has received research support from Incyte and Priothera. He is member of advisory boards to Equillium Bio, Jazz, Gilead, Novartis, MSD, Omeros, Orca Bio, Priothera, Sanofi, Shionogi and SOBI. T.Z. reports personal fees from AbbVie, personal fees from Orgenesis Inc, personal fees from BioSight Ltd, personal fees from Cellect Biotechnology, personal fees from Janssen, personal fees from Novartis, personal fees from Gilead Sciences, outside the submitted work. The remaining authors declare no conflict of interests., (© 2023 The Authors.)

This review aims to critically analyze the pathways of interaction and the pathogenic mechanisms linking periodontitis and oral bacteria with the initiation/progression of cancer at different body compartments. A higher risk of head and neck cancer has been consistently associated with periodontitis. This relationship has been explained by the local promotion of dysbiosis, chronic inflammation, immune evasion, and direct (epi)genetic damage to epithelial cells by periodontal pathobionts and their toxins. Epidemiological reports have also studied a possible link between periodontitis and the incidence of other malignancies at distant sites, such as lung, breast, prostate, and digestive tract cancers. Mechanistically, different pathways have been involved, including the induction of a chronic systemic inflammatory state and the spreading of oral pathobionts with carcinogenic potential. Indeed, periodontitis may promote low-grade systemic inflammation and phenotypic changes in the mononuclear cells, leading to the release of free radicals and cytokines, as well as extracellular matrix degradation, which are all mechanisms involved in carcinogenic and metastatic processes. Moreover, the transient hematogenous spill out or micro-aspiration/swallowing of periodontal bacteria and their virulence factors (i.e., lipopolysaccharides, fimbriae), may lead to non-indigenous bacterial colonization of multiple microenvironments. These events may in turn replenish the tumor-associated microbiome and thus influence the molecular hallmarks of cancer. Particularly, specific strains of oral pathobionts (e.g., Porphyromonas gingivalis and Fusobacterium nucleatum) may translocate through the hematogenous and enteral routes, being implicated in esophageal, gastric, pancreatic, and colorectal tumorigenesis through the modulation of the gastrointestinal antitumor immune system (i.e., tumor-infiltrating T cells) and the increased expression of pro-inflammatory/oncogenic genes. Ultimately, the potential influence of common risk factors, relevant comorbidities, and upstream drivers, such as gerovulnerability to multiple diseases, in explaining the relationship cannot be disregarded. The evidence analyzed here emphasizes the possible relevance of periodontitis in cancer initiation/progression and stimulates future research endeavors., (© 2023 The Authors. Periodontology 2000 published by John Wiley & Sons Ltd.)

Introduction: The effectiveness of canakinumab may change according to the different times it is used after Still's disease onset. This study aimed to investigate whether canakinumab (CAN) shows differences in short- and long-term therapeutic outcomes, according to its use as different lines of biologic treatment., Methods: Patients included in this study were retrospectively enrolled from the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to Still's disease. Seventy-seven (51 females and 26 males) patients with Still's disease were included in the present study. In total, 39 (50.6%) patients underwent CAN as a first-line biologic agent, and the remaining 38 (49.4%) patients were treated with CAN as a second-line biologic agent or subsequent biologic agent., Results: No statistically significant differences were found between patients treated with CAN as a first-line biologic agent and those previously treated with other biologic agents in terms of the frequency of complete response ( p  =0.62), partial response ( p  =0.61), treatment failure ( p  >0.99), and frequency of patients discontinuing CAN due to lack or loss of efficacy ( p  =0.2). Of all the patients, 18 (23.4%) patients experienced disease relapse during canakinumab treatment, 9 patients were treated with canakinumab as a first-line biologic agent, and nine patients were treated with a second-line or subsequent biologic agent. No differences were found in the frequency of glucocorticoid use ( p  =0.34), daily glucocorticoid dosage ( p  =0.47), or concomitant methotrexate dosage ( p  =0.43) at the last assessment during CAN treatment., Conclusion: Canakinumab has proved to be effective in patients with Still's disease, regardless of its line of biologic treatment., 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 Vitale, Caggiano, Sfikakis, Dagna, Lopalco, Ragab, La Torre, Almaghlouth, Maggio, Sota, Tufan, Hinojosa-Azaola, Iannone, Loconte, Laskari, Direskeneli, Ruscitti, Morrone, Mayrink Giardini, Panagiotopoulos, Di Cola, Martín-Nares, Monti, De Stefano, Kardas, Duran, Campochiaro, Tomelleri, Alabdulkareem, Gaggiano, Tarsia, Bartoloni, Romeo, Hussein, Laymouna, Parente de Brito Antonelli, Dagostin, Fotis, Bindoli, Navarini, Alibaz-Oner, Sevik, Frassi, Ciccia, Iacono, Crisafulli, Portincasa, Jaber, Kawakami-Campos, Wiesik-Szewczyk, Iagnocco, Simonini, Sfriso, Balistreri, Giacomelli, Conti, Frediani, Fabiani and Cantarini.)

Background: Bone-targeted agents (BTA), such as denosumab (DN) and zoledronic acid (ZA), have historically reduced the risk of skeletal related events in cancer patients with bone metastases (BM), with no improvement in survival outcomes. In the immunotherapy era, BM have been associated with poor prognosis upon immune-checkpoint inhibitors (ICI). Currently, the impact of bone tumor burden on survival upon BTAs in advanced non-small cell lung cancer (aNSCLC) patients treated with ICI remains unknown., Methods: Data from ICI-treated aNSCLC patients with BM (4/2013-5/2022) in one institution were retrospectively collected. BTA-ICI concurrent treatment was defined as BTA administration at any time before or within 90 days from ICI start. High bone tumor burden (HBTB) was defined as ≥ 3 sites of BM. Median OS (mOS) was estimated with Kaplan-Meier. Aikaike's information criterion (AIC) was used to select the best model for data analysis adjusted for clinical variables., Results: Of 134 patients included, 51 (38 %) received BTA. At a mFU of 39.6 months (m), BTA-ICIs concurrent treatment did not significantly impact on mOS [8.3 m (95% CI 3.9-12.8) versus (vs) 6.8 m (95% CI 4.0-9.6) p = 0.36]; these results were confirmed after adjustment for clinical variables selected by AIC. A multivariate model showed a significant interaction between BTA use and HBTB or radiation therapy to BM. In subgroup analyses, only HBTB confirmed to be associated with significantly longer mOS [8.3 m (95% CI 2.4-14.2) vs 3.5 m (95% CI 2.9-4.1), p = 0.003] and mPFS [3.0 m (95% CI 1.6-4.4) vs 1.8 m (95% CI 1.6-2.0) p = 0.001] upon BTA-ICI concurrent treatment, with the most pronounced OS benefit observed for DN-ICI concurrent regimen [15.2 m (95% CI 0.1-30.7) vs 3.5 m (95% CI 2.9-4.1) p = 0.002]., Conclusions: In the immunotherapy era, HBTB can identify patients experiencing survival benefit with BTA, especially with DN-ICI combination. HBTB should be included as a stratification factor in the upcoming trials assessing BTA and ICI combinations in patients with aNSCLC and BM., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SM declares personal fees from Italfarmaco, Sanofi and MSD outside the submitted work. EZ declares personal fees from AMGEN, outside the submitted work CP declares personal fees from BMS and MSD, outside the submitted work. AP declares personal fees from Astrazeneca, Roche, BMS. GG declares travel accommodation from Roche and personal fees from Italfarmaco, Astra Zeneca, BMS, MSD outside the submitted work. MCG declares personal financial interests with the following organizations: AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda; she also declares Institutional financial interests with the following organizations: Eli Lilly, MSD, Pfizer (MISP), AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine; at the end, she has received research funding from the following organizations: AIRC, AIFA, Italian Moh, TRANSCAN. FdB provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Eli Lilly, F. Hoffmann-La Roche, Ignyta, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer. GLR declares personal fees from MSD, TAKEDA; GSK; AMGEN; PFIZER; SANOFI; JANSEN; Eli Lilly, BMS, Roche, Italfarmaco, Novartis and AstraZeneca, outside the submitted work. DS declares personal fees from AstraZeneca, MSD, Boehringer Ingelheim and BMS, outside the submitted work. RF declares personal fees from MSD and Beigene outside the submitted work. The other authors report no conflict of interest. ., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hyper IgM1 is an X-linked combined immunodeficiency caused by CD40LG mutations, potentially treatable with CD4 + T-cell gene editing with Cas9 and a "one-size-fits-most" corrective template. Contrary to established gene therapies, there is limited data on the genomic alterations following long-range gene editing, and no consensus on the relevant assays. We developed drop-off digital PCR assays for unbiased detection of large on-target deletions and found them at high frequency upon editing. Large deletions were also common upon editing different loci and cell types and using alternative Cas9 and template delivery methods. In CD40LG edited T cells, on-target deletions were counter-selected in culture and further purged by enrichment for edited cells using a selector coupled to gene correction. We then validated the sensitivity of optical genome mapping for unbiased detection of genome wide rearrangements and uncovered on-target trapping of one or more vector copies, which do not compromise functionality, upon editing using an integrase defective lentiviral donor template. No other recurring events were detected. Edited patient cells showed faithful reconstitution of CD40LG regulated expression and function with a satisfactory safety profile. Large deletions and donor template integrations should be anticipated and accounted for when designing and testing similar gene editing strategies., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Objective: Still's disease is more frequently observed in the paediatric context, but a delayed onset is not exceptional both in the adulthood and in the elderly. However, whether paediatric-onset, adult-onset and elderly-onset Still's disease represent expressions of the same disease continuum or different clinical entities is still a matter of controversy. The aim of this study is to search for any differences in demographic, clinical features and response to treatment between pediatric-onset, adult-onset and elderly-onset Still's disease., Methods: Subjects included in this study were drawn from the International AutoInflammatory Disease Alliance Network registry for patients with Still's disease., Results: A total of 411 patients suffering from Still's disease were enrolled; the disease occurred in the childhood in 65 (15.8%) patients, in the adult 314 (76.4%) patients and in the elderly in 32 (7.8%) patients. No statistically significant differences at post-hoc analysis were observed in demographic features of the disease between pediatric-onset, adult-onset and elderly-onset Still's disease. The salmon-coloured skin rash (p=0.004), arthritis (p=0.009) and abdominal pain (p=0.007) resulted significantly more frequent among paediatric patients than in adult cases, while pleuritis (p=0.015) and arthralgia (p<0.0001) were significantly more frequent among elderly-onset patients compared with paediatric-onset subjects. Regarding laboratory data, thrombocytosis was significantly more frequent among paediatric patients onset compared with adult-onset subjects (p<0.0001), while thrombocytopenia was more frequent among elderly-onset patients although statistical significance was only bordered. No substantial differences were observed in the response to treatments., Conclusions: Despite some minor difference between groups, overall, demographic, clinical, laboratory and treatments aspects of Still's disease were similarly observed in patients at all ages. This supports that pediatric-onset, adult-onset and elderly-onset Still's disease is the same clinical condition arising in different ages., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: To date, the management of critical-sized bone defects lacks a universally accepted approach among orthopedic surgeons. Currently, the main options to treat severe bone loss include autologous grafting, free vascularized bone transfer, bone transport and induced-membrane technique. The purpose of this study is to critically compare the outcomes of Masquelet technique and bone transport to provide a higher level of evidence regarding the indexed techniques., Material and Methods: The authors conducted a systematic search on several databases according to the PRISMA guidelines. English-written reports comparing outcomes of the Masquelet technique versus the bone transport technique in patients with critical-sized defects in lower extremities were included., Results: Six observational studies involving 364 patients were included. The systematic review and meta-analysis of pooled data showed no significant difference in most outcomes, except for ASAMI bone outcomes and residual deformity, which showed better results in the bone transport group. The 64% of patients treated with Masquelet technique obtained excellent/good bone ASAMI results compared to 82.8% with bone transport (p = 0.01). Post-operative residual deformity was 1.9% with the bone transport method versus 9.7% with the Masquelet technique (p = 0.02)., Conclusions: Both the Masquelet technique and bone transport showed comparable results for the management of critical-sized bone defects of the lower limb. However, these findings must be carefully interpreted due to the high risk of bias. Further prospective randomized controlled trials are necessary to better clarify the strengths and limitations of these two techniques and to identify the variables affecting the outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is considered the prodromal stage of alpha-synucleinopathies. Thus, iRBD patients are the ideal target for disease-modifying therapy. The risk FActoRs PREdictive of phenoconversion in iRBD Italian STudy (FARPRESTO) is an ongoing Italian database aimed at identifying risk factors of phenoconversion, and eventually to ease clinical trial enrollment of well-characterized subjects., Methods: Polysomnography-confirmed iRBD patients were retrospectively and prospectively enrolled. Baseline harmonized clinical and nigrostriatal functioning data were collected at baseline. Nigrostriatal functioning was evaluated by dopamine transporter-single-photon emission computed tomography (DaT-SPECT) and categorized with visual semi-quantification. Longitudinal data were evaluated to assess phenoconversion. Cox regressions were applied to calculate hazard ratios., Results: 365 patients were enrolled, and 289 patients with follow-up (age 67.7 ± 7.3 years, 237 males, mean follow-up 40 ± 37 months) were included in this study. At follow-up, 97 iRBD patients (33.6%) phenoconverted to an overt synucleinopathy. Older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression, and visual semi-quantification of nigrostriatal functioning predicted phenoconversion. The remaining 268 patients are in follow-up within the FARPRESTO project., Conclusions: Clinical data (older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression) predicted phenoconversion in this multicenter, longitudinal, observational study. A standardized visual approach for semi-quantification of DaT-SPECT is proposed as a practical risk factor for phenoconversion in iRBD patients. Of note, non-converted and newly diagnosed iRBD patients, who represent a trial-ready cohort for upcoming disease-modification trials, are currently being enrolled and followed in the FARPRESTO study. New data are expected to allow better risk characterization., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Antibody-drug conjugates (ADCs) are a rapidly expanding class of compounds in oncology. Our goal was to assess the expression of ADC targets and potential downstream determining factors of activity across pan-cancer and normal tissues., Materials and Methods: ADCs in clinical trials (n = 121) were identified through ClinicalTrials.gov, corresponding to 54 targets. Genes potentially implicated in treatment response were identified in the literature. Gene expression from The Cancer Genome Atlas (9000+ cancers of 31 cancer types), the Genotype-Tissue Expression database (n = 19,000 samples from 31 normal tissue types), and the TNMplot.com (n = 12,494 unmatched primary and metastatic samples) were used in this analysis. To compare relative expression across and within tumour types we used pooled normal tissues as reference., Results: For most ADC targets, mRNA levels correlated with protein expression. Pan-cancer target expression distributions identified appealing cancer types for each ADC development. Co-expression of multiple targets was common and suggested opportunities for ADC combinations. Expression levels of genes potentially implicated in ADC response downstream of the target might provide additional information (e.g. TOP1 was highly expressed in many tumour types, including breast and lung cancers). Metastatic compared to primary tissues overexpressed some ADCs targets. Single sample "targetgram" plots were generated to visualise the expression of potentially competing ADC targets and resistance/sensitivity markers highlighting high inter-patient heterogeneity. Off-cancer target expression only partially explains adverse events, while expression of determinants of payload activity explained more of the observed toxicities., Conclusion: Our findings draw attention to new therapeutic opportunities for ADCs that can be tested in the clinic and our web platform (https://tnmplot.com) can assist in prioritising upcoming ADC targets for clinical development., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.B.: Financial interests: personal consulting fees from Kardo srl (personal); travel support for attending meetings from Daiichi-Sankyo and Lilly. G.N.: Travel support for attending meetings from Lilly and Sanofi. M.M.: Travel support for attending meetings from Lilly. L.L.: Financial interests: Consulting fees from Exact Sciences, Helsinn, EISAI; honoraria for speakers’ bureaus from Gilead, Exact Sciences, Helsinn; support for attending meetings from Lilly and Gilead; advisory board for Lilly, Exact Sciences, AstraZeneca, Italfarmaco, Accord, Seagen and Daiichi Sankyo (all personal and financial). G.V.: Financial interests: Advisory board for Gilead; speakers’ bureaus: Novartis, Lilly; support for attending meetings: Pfizer, Lilly (all personal and financial). B.P.: Financial interests: Consulting fees from AstraZeneca (institutional), Seagen (institutional), Gilead (institutional), Novartis (institutional), Lilly (institutional), MSD (institutional), Pierre Fabre (personal), Daiichi-Sankyo (institutional/personal); research funding (to the institution): Astra Zeneca, Daiichi-Sankyo, Gilead, Seagen, MSD; travel support: Astra Zeneca; Pierre Fabre; MSD; Daiichi-Sankyo, Pfizer. F.A.: Financial interests: grants or speaker/Advisory compensated to hospital: AstraZeneca, Daiichi Sankyo, Pfizer, Lilly, Relay; honorarium: Lilly. M.P.: Financial interests: Travel support for attending meetings from Gilead and Novartis. C.C.: Financial interests: Personal fees for consulting, advisory role, and speakers’ bureau from Lilly, Roche, Novartis, MSD, Seagen, Gilead, Daiichi Sankyo, AstraZeneca, and Pfizer. L.P.: Financial interests: Consulting fees and honoraria for advisory board participation from Pfizer, Astra Zeneca, Merck, Novartis, Bristol-Myers Squibb, Stemline-Menarini, GlaxoSmithKline, Genentech/Roche, Personalis, Daiichi, Natera, Exact Sciences (personal), and institutional research funding from Seagen, GlaxoSmithKline, AstraZeneca, Merck, Pfizer and Bristol Myers Squibb. G.C.: Financial Interests: AstraZeneca, Invited Speaker, Personal; AstraZeneca, Advisory Board, Personal, BMS, Advisory Board, Personal; Celcuity, Advisory Board, Personal; Daiichi Sankyo, Invited Speaker, personal; Daiichi Sankyo, Advisory Board, Personal; Exact Sciences, Advisory Board, Personal; Gilead, Advisory Board, Personal, Advisory Board; Lilly, Advisory Board, Personal; Menarini, Advisory Board, Personal, Advisory Board; Merck, Advisory Board, Personal; Novartis, Invited Speaker, Personal; Pfizer, Writing Engagement, Personal; Pfizer, Advisory Board, Personal; Pfizer, Invited Speaker, Personal; Roche, Advisory Board, Personal; Roche, Invited Speaker, Personal; Veracyte, Advisory Board, Personal; Ellipsis, Other, Personal, Advisory Board; Astellas, Funding, Institutional, Financial interest, Phase I studies; AstraZeneca, Funding, Institutional, Financial interest, Phase I studies; Blueprint Medicine, Funding, Institutional, Financial interest, Phase I studies; BMS, Funding, Institutional, Financial interest, Phase I studies; Daiichi Sankyo, Funding, Institutional, Financial interest, Phase I studies; Kymab, Funding, Institutional, Financial interest, Phase I studies; Merck, Research Grant, Institutional, Financial interest, Investigator Initiated Trial; Novartis, Funding, Institutional, Financial interest, Phase I studies; Philogen, Funding, Institutional, Financial interest, Phase I studies; Relay Therapeutics, Coordinating PI, Institutional, Financial interest, Phase I clinical basket trial; Roche, Funding, Institutional, Financial interest, Phase I studies; Sanofi, Funding, Institutional, Financial interest, Phase I studies. Non-financial interests: Consiglio Superiore di Sanità, Officer, Italian National Health Council as Advisor for Ministry of Health; ESMO, Officer, ESMO Clinical Practice Guidelines Chair; ESMO, Member of Board of Directors, Chair of Clinical Practice Guidelines Committee; Europa Donna, Advisory Role, Member of the Scientific Council. Patient advocacy association; EUSOMA, Officer, Member of the Advisory Council; Fondazione Beretta, Advisory Role, Cancer Research Foundation; Lega Italiana Lotta ai Tumori, Member of Board of Directors, No compensation for this role. This a public national company for cancer prevention. G.B.: Financial Interests: AstraZeneca, Advisory Board, Personal; AstraZeneca, Other, Personal, Consultancy; Daiichi Sankyo, Advisory Board, Personal; Daiichi Sankyo, Other, Personal, Consultancy; Lilly, Advisory Board, Personal; Lilly, Invited Speaker, Personal; Novartis, Advisory Board, Personal; Pfizer, Advisory Board, Personal; Roche, Other, Personal, Consultancy; MSD, Other, Personal, Consultancy; Gilead, Other, Personal, Consultancy; Sanofi, Other, Personal, Consultancy; Roche, Invited Speaker, Personal; AstraZeneca, Invited Speaker, Personal; Daiichi Sankyo, Invited Speaker, Personal; MSD, Invited Speaker, Personal; Chugai, Invited Speaker, Personal; EISAI, Invited Speaker, Personal; Gilead, Invited Speaker, Personal; Seagen, Invited Speaker, Personal; Neopharm Israel, Invited Speaker, Personal; Roche, Other, Personal, Support for attending meetings and/or travel; Pfizer, Other, Personal, Support for attending meetings and/or travel; MSD, Other, Personal, Support for attending meetings and/or travel; Chugai, Other, Personal, Support for attending meetings and/or travel; Novartis, Other, Personal, Support for attending meetings and/or travel; Roche, Advisory Board, Personal; Amgen, Advisory Board, Personal; MSD, Advisory Board, Personal; Chugai, Advisory Board, Personal; EISAI, Advisory Board, Personal; Gilead, Advisory Board, Personal; Seagen, Advisory Board, Personal; Exact Science, Advisory Board, Personal; Roche, Advisory Board, Personal; MSD, Advisory Board, Personal; Gilead, Advisory Board, Personal; Gilead, Other, Personal, Support for attending meetings and/or travel; Daiichi Sankyo, Other, Personal, Support for attending meetings and/or travel; Roche, Steering Committee Member, Financial interest, Personal and Institutional; Novartis, Steering Committee Member, Financial interest, Personal and Institutional; Lilly, Steering Committee Member, Financial interest, Personal and Institutional; AstraZeneca, Steering Committee Member, Financial interest, Personal and Institutional; Gilead, Local PI, Financial interest, Institutional; Pfizer, Local PI, Financial interest, Institutional; Daiichi Sankyo, Local PI, Financial interest, Institutional; Lilly, Local PI, Financial interest, Institutional; MSD, Local PI, Financial interest, Institutional; Novartis, Local PI, Financial interest, Institutional; Non-Financial Interests: Fondazione Michelangelo, Leadership Role, Head of Traslational Research. A.B., B.Ga, H.R.A., M.C., M.B., A.L., L.V., M.D., M.M.N., and B.G. declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In non-small cell lung cancer (NSCLC), the immune checkpoint inhibitors (ICI) revolution is rapidly moving from metastatic to early-stage, however, the impact of clinicopathological variables and optimal treatment sequencing remain unclear., Methods: Randomized controlled trials (RCTs) in patients with early-stage NSCLC treated with ICI as single agent or in combination with platinum-based chemotherapy (PCT) were included. Primary outcomes were pathological complete response (pCR), event free survival (EFS) (neoadjuvant/perioperative), and disease-free survival (DFS) (adjuvant). Secondary outcomes were major pathological response (MPR), overall survival (OS), toxicity, surgical outcomes (neoadjuvant/perioperative); OS and toxicity (adjuvant). An additional secondary endpoint was to compare EFS and OS between neoadjuvant and perioperative strategies., Results: 8 RCTs (2 neoadjuvant, 4 perioperative, 2 adjuvant) (4661 participants) were included. Neoadjuvant/perioperative ICI+PCT significantly improved pCR, EFS, OS, MPR and R0 resection compared to PCT. Adjuvant ICI significantly improved DFS compared to placebo. There was a significant subgroup interaction by PD-L1 status (χ 2 = 10.72, P = 0.005), pCR (χ 2 = 17.80, P < 0.0001), and stage (χ 2 = 4.46, P = 0.003) for EFS. No difference according to PD-L1 status was found for pCR, with 14% of patients having PD-L1 negative tumors still experiencing a pCR. No interaction by PD-L1 status was found for DFS upon adjuvant ICI. Indirect comparison showed no difference in EFS and OS between neoadjuvant and perioperative ICI+PCT., Conclusions: PD-L1 status, pCR and stage impact on survival upon neoadjuvant/perioperative ICI. The restriction of neoadjuvant/perioperative ICI to PD-L1 + patients could preclude pCR and long-term benefit in the PD-L1- subgroup. Neoadjuvant and perioperative could be equivalent strategies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T.C. reports (over the past 36 months) speaker fees/honoraria from the Society for Immunotherapy of Cancer (SITC), Mark Foundation for Cancer Research, Bristol Myers Squibb, Roche, Medscape, IDEOlogy Health, Physicians' Education Resource® LLC (PER®), OncLive, PeerView and Clinical Care Options (CCO); advisory role/consulting fees from MedImmune/AstraZeneca, Bristol Myers Squibb, Merck & Co., Genentech, Arrowhead Pharmaceuticals, Pfizer Inc. and Regeneron; institutional research funding from MedImmune/AstraZeneca and Bristol Myers Squibb; and travel, food and/or beverage expenses from Physicians' Education Resource® LLC (PER®), Dava Oncology, SITC, International Association for the Study of Lung Cancer, Parker Institute for Cancer Immunotherapy, IDEOlogy Health, OncLive, AstraZeneca and Bristol Myers Squibb.M.C.G. reports AstraZeneca, Abion, MSD International GmbH, Bayer, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Incyte, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Blueprint, Jansenn, Sanofi, AbbVie, BeiGenius, Oncohost, Medscape G.V. is consultant for Ab Medica, Roche, AstraZeneca, MSD, outside the submitted work R.F. reports advisory board for MSD and advisory board for BeiGene M.R. declares grants or contracts from AstraZeneca and participation on a Data Safety Monitoring Board or Advisory Board for Eli Lilly, PANAVANCE, Celgene, AstraZeneca, Viatris, Merck Sharp & Dohme, Servier, SOTIO, and Baxter. All remaining authors have declared no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to produce evidence on quality of life (QoL) among Italian growth hormone deficiency (GHD) children and adolescents treated with growth hormone (GH) and their parents., Methods: A survey was conducted among Italian children and adolescents aged 4-18 with a confirmed diagnosis of GHD and treated with GH therapy and their parents. The European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L) and the Quality of Life in Short Stature Youth (QoLISSY) questionnaires were administered between May and October 2021 through the Computer-Assisted Personal Interview (CAPI) method. Results were compared with national and international reference values., Results: The survey included 142 GHD children/adolescents and their parents. The mean EQ-5D-3L score was 0.95 [standard deviation (SD) 0.09], while the mean visual analogue scale (VAS) score was 86.2 (SD 14.2); the scores are similar to those of a reference Italian population aged 18-24 of healthy subjects. As for the QoLISSY child-version, compared to the international reference values for GHD/ idiopathic short stature (ISS) patients, we found a significantly higher score for the physical domain, and lower scores for coping and treatment; compared to the specific reference values for GHD patients, our mean scores were significantly lower for all domains except the physical one. As for the parents, we found a significantly higher score for the physical domain, and a lower score for treatment; compared to reference values GHD-specific, we found lower score in the social, emotional, treatment, parental effects, and total score domains., Conclusions: Our results suggest that the generic health-related quality of life (HRQoL) in treated GHD patients is high, comparable to that of healthy people. The QoL elicited by a disease specific questionnaire is also good, and comparable with that of international reference values of GHD/ISS patients., (© 2023. The Author(s).)

In the immunoncology era, growing evidence has shown a clear sex dimorphism in antitumor immune response with a potential impact on outcomes upon immunecheckpoint blockade (ICI) in patients with cancer. Sex dimorphism could affect tumor microenvironment composition and systemic anticancer immunity; however, the modifications induced by sex are heterogeneous. From a clinical perspective, six metanalyses have explored the role of sex in cancer patients receiving ICI with conflicting results. Environmental and reproductive factors may further jeopardize the sex-related heterogeneity in anticancer immune response. In particular, pregnancy is characterized by orchestrated changes in the immune system, some of which could be long lasting. A persistence of memory T-cells with a potential fetal-antigen specificity has been reported both in human and mice, suggesting that a previous pregnancy may positively impact cancer development or response to ICI, in case of fetal-antigen sharing from tumor cells. On the other hand, a previous pregnancy may also be associated with a regulatory memory characterized by increased tolerance and anergy towards cancer-fetal common antigens. Finally, fetal-maternal microchimerism could represent an additional source of chronic exposure to fetal antigens and may have important immunological implications on cancer development and ICI activity. So far, the role of pregnancy dimorphism (nulliparous vs parous) in women and the impact of pregnancy-related variables remain largely underexplored in cancer patients. In this review, we summarize the evidence regarding sex and pregnancy dimorphism in the context of immune response and anticancer immunotherapy and advocate the importance of analyzing pregnancy variables on ICIs clinical trials., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Francesco Maria Venanzi: no conflict of interest to this manuscript. Marta Bini no conflict of interest to this manuscript. Antonio Nuccio no conflict of interest to this manuscript. Alessandro De Toma: no conflict of interest to this manuscript. Matteo Lambertini: advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo and Takeda, Travel Grants from Gilead and research support (to the Institution) from Gilead outside the submitted work. Francesca Rita Ogliari: no conflict of interest to this manuscript. Sara Oresti: no conflict of interest to this manuscript. Maria Grazia Viganò: no conflict of interest to this manuscript. Elena Brioschi: no conflict of interest to this manuscript. Maggie Polignano: no conflict of interest to this manuscript. Matteo Maria Naldini: no conflict of interest to this manuscript. Silvia Riva: no conflict of interest to this manuscript. Michele Ferrara: no conflict of interest to this manuscript. Nicola Fogale: no conflict of interest to this manuscript. Giuseppe Damiano: no conflict of interest to this manuscript. Vincenzo Russo: no conflict of interest to this manuscript. Michele Reni: no conflict of interest to this manuscript. Giulia Veronesi: no conflict of interest to this manuscript. Giorgia Foggetti: no conflict of interest to this manuscript. Fabio Conforti: no conflict of interest to this manuscript. Alessandra Bulotta: no conflict of interest to this manuscript. Roberto Ferrara: advisory board MSD and Beigene., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Aims: Standardising health outcome measurements supports delivery of care, enables data-driven learning systems, and secondary data use for research. As part of the Health Outcomes Observatory initiative and building on existing knowledge, a core outcome set (COS) for inflammatory bowel diseases (IBD) was defined through an international modified Delphi method., Methods: Stakeholders rated 90 variables on a 9-point importance scale twice, allowing score modification based on feedback displayed per stakeholder group. Two consecutive consensus meetings were held to discuss results and formulate recommendations for measurement in clinical practice. Variables scoring 7 or higher by ≥80% of the participants, or based on consensus meeting agreement, were included in the final set., Results: In total, 136 stakeholders (45 IBD patients (advocates), 74 healthcare professionals/researchers, 13 industry representatives and 4 regulators), from 20 different countries participated. The final set includes 18 case-mix variables, 3 biomarkers (haemoglobin to detect anaemia, C-reactive protein and faecal calprotectin to detect inflammation) for completeness and 28 outcomes (including 16 patient-reported outcomes (PROs) and 1 patient-reported experience). The PRO-2 and IBD-Control questionnaires were recommended to collect disease-specific PROs at every contact with an IBD practitioner, and the Subjective Health Experience model questionnaire, PROMIS Global Health and Self-Efficacy short form to collect generic PROs annually., Conclusions: A COS for IBD, including a recommendation for use in clinical practice, was defined. Implementation of this set will start in Vienna, Berlin, Barcelona, Leuven and Rotterdam, empowering patients to better manage their care. Additional centres will follow worldwide., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Type 1 diabetes (T1D) presents a persistent medical challenge, demanding innovative strategies for sustained glycemic control and enhanced patient well-being. Beta cells are specialized cells in the pancreas that produce insulin, a hormone that regulates blood sugar levels. When beta cells are damaged or destroyed, insulin production decreases, which leads to T1D. Allo Beta Cell Transplantation has emerged as a promising therapeutic avenue, with the goal of reinstating glucose regulation and insulin production in T1D patients. However, the path to success in this approach is fraught with complex immunological hurdles that demand rigorous exploration and resolution for enduring therapeutic efficacy. This exploration focuses on the distinct immunological characteristics inherent to Allo Beta Cell Transplantation. An understanding of these unique challenges is pivotal for the development of effective therapeutic interventions. The critical role of glucose regulation and insulin in immune activation is emphasized, with an emphasis on the intricate interplay between beta cells and immune cells. The transplantation site, particularly the liver, is examined in depth, highlighting its relevance in the context of complex immunological issues. Scrutiny extends to recipient and donor matching, including the utilization of multiple islet donors, while also considering the potential risk of autoimmune recurrence. Moreover, unanswered questions and persistent gaps in knowledge within the field are identified. These include the absence of robust evidence supporting immunosuppression treatments, the need for reliable methods to assess rejection and treatment protocols, the lack of validated biomarkers for monitoring beta cell loss, and the imperative need for improved beta cell imaging techniques. In addition, attention is drawn to emerging directions and transformative strategies in the field. This encompasses alternative immunosuppressive regimens and calcineurin-free immunoprotocols, as well as a reevaluation of induction therapy and recipient preconditioning methods. Innovative approaches targeting autoimmune recurrence, such as CAR Tregs and TCR Tregs, are explored, along with the potential of stem stealth cells, tissue engineering, and encapsulation to overcome the risk of graft rejection. In summary, this review provides a comprehensive overview of the inherent immunological obstacles associated with Allo Beta Cell Transplantation. It offers valuable insights into emerging strategies and directions that hold great promise for advancing the field and ultimately improving outcomes for individuals living with diabetes., 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 Caldara, Tomajer, Monti, Sordi, Citro, Chimienti, Gremizzi, Catarinella, Tentori, Paloschi, Melzi, Mercalli, Nano, Magistretti, Partelli and Piemonti.)

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disease mostly affecting people around 50-60 years of age. TDP-43, an RNA-binding protein involved in pre-mRNA splicing and controlling mRNA stability and translation, forms neuronal cytoplasmic inclusions in an overwhelming majority of ALS patients, a phenomenon referred to as TDP-43 proteinopathy. These cytoplasmic aggregates disrupt mRNA transport and localization. The axon, like dendrites, is a site of mRNA translation, permitting the local synthesis of selected proteins. This is especially relevant in upper and lower motor neurons, whose axon spans long distances, likely accentuating their susceptibility to ALS-related noxae. In this work we have generated and characterized two cellular models, consisting of virtually pure populations of primary mouse cortical neurons expressing a human TDP-43 fusion protein, wt or carrying an ALS mutation. Both forms facilitate cytoplasmic aggregate formation, unlike the corresponding native proteins, giving rise to bona fide primary culture models of TDP-43 proteinopathy. Neurons expressing TDP-43 fusion proteins exhibit a global impairment in axonal protein synthesis, an increase in oxidative stress, and defects in presynaptic function and electrical activity. These changes correlate with deregulation of axonal levels of polysome-engaged mRNAs playing relevant roles in the same processes. Our data support the emerging notion that deregulation of mRNA metabolism and of axonal mRNA transport may trigger the dying-back neuropathy that initiates motor neuron degeneration in ALS., 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 Pisciottani, Croci, Lauria, Marullo, Savino, Ambrosi, Podini, Marchioretto, Casoni, Cremona, Taverna, Quattrini, Cioni, Viero, Codazzi and Consalez.)

Circulating senescent CD8 + T (T 8 sen) cells are characterized by a lack of proliferative capacities but retain cytotoxic activity and have been associated to resistance to immunotherapy in patients with advanced non-small cell lung cancer (aNSCLC). We aimed to better characterize T 8 sen and to determine which factors were associated with their accumulation in patients with aNSCLC. Circulating T 8 sen cells were characterized by a higher expression of SA-βgal and the transcription factor T-bet, confirming their senescent status. Using whole virome profiling, cytomegalovirus (CMV) was the only virus associated with T 8 sen. CMV was necessary but not sufficient to explain high accumulation of T 8 sen (T 8 sen high status). In CMV + patients, the proportion of T 8 sen cells increased with cancer progression. Last, CMV-induced T 8 sen high phenotype but not CMV seropositivity itself was associated with worse progression-free and overall survival in patients treated with anti-PD-(L)1 therapy but not with chemotherapy. Overall, CMV is the unique viral driver of T 8 sen-driven resistance to anti-PD-(L)1 antibodies in patients with aNSCLC.

Since the beginning of the pandemic, SARS-CoV-2 has shown a great genomic variability, resulting in the continuous emergence of new variants that has made their global monitoring and study a priority. This work aimed to study the genomic heterogeneity, the temporal origin, the rate of viral evolution and the population dynamics of the main circulating variants (20E.EU1, Alpha and Delta) in Italy, in August 2020-January 2022 period. For phylogenetic analyses, three datasets were set up, each for a different main lineage/variant circulating in Italy in that time including other Italian and International sequences of the same lineage/variant, available in GISAID sampled in the same times. The international dataset showed 26 (23% Italians, 23% singleton, 54% mixed), 40 (60% mixed, 37.5% Italians, 1 singleton) and 42 (85.7% mixed, 9.5% singleton, 4.8% Italians) clusters with at least one Italian sequence, in 20E.EU1  clade, Alpha and Delta variants, respectively. The estimation of tMRCAs in the Italian clusters (including >70% of genomes from Italy) showed that in all the lineage/variant, the earliest clusters were the largest in size and the most persistent in time and frequently mixed. Isolates from the major Italian Islands tended to segregate in clusters more frequently than those from other part of Italy. The study of infection dynamics showed a positive correlation between the trend in the effective number of infections estimated by BSP model and the R e curves estimated by birth-death skyline plot. The present work highlighted different evolutionary dynamics of studied lineages with high concordance between epidemiological parameters estimation and phylodynamic trends suggesting that the mechanism of replacement of the SARS-CoV-2 variants must be related to a complex of factors involving the transmissibility, as well as the implementation of control measures, and the level of cross-immunization within the population., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Purpose: To evaluate the persistence of symptoms after radiotherapy (RT) for localised prostate cancer (PCa) and the association with quality of life (QOL)., Materials and Methods: Prospective patient-reported outcome (PRO) from a multi-institutional study on PCa treated with radical RT (2010-2014) was analysed. Data was collected at baseline (BL) and follow-ups (FUPs) up to 5 years. Patients with BL and ≥3 late FUPs (≥6 months) were analysed. PRO was scored by means of the IPSS and ICIQ-SF (urinary), LENT-SOMA (gastrointestinal [GI]), and EORTC-C30 (pain, insomnia, fatigue, and QOL) questionnaires. Symptoms were defined 'persistent' if the median score over FUPs was ≥3 (urinary) or ≥2 (GI, pain, insomnia, and fatigue), and worse than BL. Different thresholds were chosen to have enough events for each symptom. QOL was linearly transformed on a continuous scale (0-100). Linear-mixed models were used to identify significant differences between groups with and without persistent symptoms including age, smoking status, previous abdominal surgery, and diabetes as confounders. Mean QOL differences between groups were evaluated longitudinally over FUPs., Results: The analysis included 293 patients. Persistent urinary symptoms ranged from 2% (straining) to 12% (weak stream, and nocturia). Gastrointestinal symptoms ranged from 7% (rectal pain, and incontinence) to 30% (urgency). Proportions of pain, insomnia, and fatigue were 6, 13, and 18%. Significant QOL differences of small-to-medium clinical relevance were found for urinary incontinence, frequency, urgency, and nocturia. Among GI symptoms, rectal pain and incontinence showed small-to-medium differences. Fatigue was associated with the largest differences., Conclusions: The analysis showed that symptoms after RT for PCa occur with different persistence and their association with QOL varies in magnitude. A number of persistent urinary and GI symptoms showed differences in a comparable range. Urinary incontinence and frequency, rectal pain, and faecal incontinence more often had significant associations. Fatigue was also prevalent and associated with largely deteriorated QOL.

Healthcare institutions face the pressure generated by modern medicine and society, in terms of increasing expectations and financial constraints. Chronic patients need multidisciplinary care pathways to preserve their wellbeing across the entire journey.The orthopaedic community has been particularly receptive in testing solutions to align good clinical outcomes and financial sustainability, given the increase in elective procedures provided among aging populations to alleviate pain and reduce disability. Fast-track (FT) total joint arthroplasty (TJA) and bundled payments (BPs) offer relevant examples both from the clinical and the financial perspective; however, they have not been evaluated in combination yet.The aim of this manuscript is to provide a road map to improve the value of high-volume, multidisciplinary elective procedures, with potential applications in a vast number of surgical specialties, (1) based on an integrated financial budget per episode of care (the BP), (2) building on lessons from a review of the literature on FT TJA.Although clinical outcomes vary from procedure to procedure, the coordination between the single treatments and providers involved across the patient journey; the commitment of patients and relatives; and the systematic adoption of patient-reported outcomes; can add further value for the benefit of patients, healthcare funders and providers, once essential clinical, financial and administrative conditions are guaranteed., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Immunotherapy (IO) single agent or combined with chemotherapy (CT-IO) is the standard treatment for advanced non-small-cell lung cancer (aNSCLC) without driver alterations. IO efficacy in patients with novel driver alterations is not well reported., Materials and Methods: Data of aNSCLC patients treated with IO or CT-IO in any line from January 2016 to September 2022 were retrospectively collected. Patients harboring novel driver alterations (m-cohort), including MET exon 14 skipping, BRAF (V600E or atypical), RET rearrangements, HER2 point mutations/exon 20 insertions or uncommon EGFR mutations/EGFR exon 20 insertions, and wild type patients (wt-cohort) were eligible. Clinico-pathological data were extracted from Institutional databases and compared through chi square or Fisher's exact test. Survivals were estimated through Kaplan-Meier method and compared by log-rank test., Results: m-cohort and wt-cohort included 84 and 444 patients, respectively. Progression free survival (PFS) was 5.53 vs. 4.57 months (P= .846) and overall survival (OS) was 25.1 vs. 9.37 months, (P < .0001) for m-cohort compared to wt-cohort. Within the m-cohort, BRAF atypical mutations had the better outcomes (Overall Response Rate [ORR], PFS), targeted agents timing did not affect response to IO and CT-IO had better ORR and disease control rate (DCR) compared to IO single agent (P = .0160 and P = .0152). In the PD-L1≥50% group, first line IO single agent resulted in inferior ORR (P = .027) and PFS (P = .022) in m-cohort compared to wt-cohort., Conclusion: IO based treatments seem not detrimental for patients harboring novel driver alteration. Adding CT could improve modest responses to IO alone. Confirmation on larger datasets is required., Competing Interests: Disclosure Diego Signorelli declares personal fees from AstraZeneca, Merck Sharp and Dohme, Boehringer Ingelheim, BMS, Roche and Sanofy. Arsela Prelaj declares personal fees from AstraZeneca, Italfarmaco, F. Hoffmann-La Roche, BMS. Roberto Ferrara declares advisory role from Merck Sharp and Dohme. Claudia Proto declares personal fees from Italfarmaco, AstraZeneca, BMS and Merck Sharp and Dohme. Giuseppe Lo Russo provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: Merck Sharp and Dohme, Takeda, Amgen, Eli Lilly, B.M.S., F. Hoffmann-La Roche, Italfarmaco, Novartis, Sanofi, Pfizer, G.S.K. and AstraZeneca. Marina Chiara Garassino declares personal financial interests with the following organizations: AstraZeneca, Merck Sharp and Dohm, International GmbH, BMS, Boehringer Ingelheim Italia S.P.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, F. Hoffmann-La Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Ose Immuno Therapeutics, Blueprint, Jansenn, Sanofi; she also declares Institutional financial interests with the following organizations: Eli Lilly, Merck Sharp and Dohm, Pfizer (MISP); AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.P.A, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, Glaxo Smith Kline GSK, Spectrum pharmaceuticals. Paolo Marchetti provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: F. Hoffmann-La Roche, Merck Sharp and Dohme, BMS, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novartis and Pfizer. Filippo de Braud provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Eli Lilly, F. Hoffmann-La Roche, Ignyta, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer. Sara Manglaviti: advisory board for Italpharma; travel accommodation by MSD and Sanofi outside the submitted work. Mario Occhipinti: advosry board for BMS and personal fee by MSD. Laura Mazzeo: travel accomodation by Sanofi. Marta Brambilla: travel accomodation by Lilli and Leo Pharma, Teresa Beninato: travel accomodation by Lilli, MSD, BMS and Sanofi. The other authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Here we evaluated the epigenomic and transcriptomic profile of XPO1 mutant chronic lymphocytic leukaemia (CLL) and their clinical phenotype. By ATAC-seq, chromatin regions that were more accessible in XPO1 mutated CLL were enriched of binding sites for transcription factors regulated by pathways emanating from the B-cell receptor (BCR), including NF-κB signalling, p38-JNK and RAS-RAF-MEK-ERK. XPO1 mutant CLL, consistent with the chromatin accessibility changes, were enriched with transcriptomic features associated with BCR and cytokine signalling. By combining epigenomic and transcriptomic data, MIR155HG, the host gene of miR-155, and MYB, the transcription factor that positively regulates MIR155HG, were upregulated by RNA-seq and their promoters were more accessible by ATAC-seq. To evaluate the clinical impact of XPO1 mutations, we investigated a total of 957 early-stage CLL subdivided into 3 independent cohorts (N = 276, N = 286 and N = 395). Next-generation sequencing analysis identified XPO1 mutations as a novel predictor of shorter time to first treatment (TTFT) in all cohorts. Notably, XPO1 mutations maintained their prognostic value independent of the immunoglobulin heavy chain variable status and early-stage prognostic models. These data suggest that XPO1 mutations, conceivably through increased miR-155 levels, may enhance BCR signalling leading to higher proliferation and shorter TTFT in early-stage CLL., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: To highlight and compare experts' laser settings during endoscopic laser treatment of upper tract urothelial carcinoma (UTUC), to identify measures to reduce complications, and to propose guidance for endourologists., Methods: Following a focused literature search to identify relevant questions, a survey was sent to laser experts. We asked participants for typical settings during specific scenarios (ureteroscopy (URS), retrograde intrarenal surgery (RIRS), and percutaneous treatment). These settings were compared among the reported laser types to find common settings and limits. Additionally, we identified preventive measures commonly applied during surgery., Results: Twenty experts completed the survey, needing a mean time of 12.7 min. Overall, most common laser type was Holmium-Yttrium-Aluminum-Garnet (Ho:YAG) (70%, 14/20) followed by Thulium fiber laser (TFL) (45%, 9/20), pulsed Thulium-Yttrium-Aluminum-Garnet (Tm:YAG) (3/20, 15%), and continuous wave (cw)Tm:YAG (1/20, 5%). Pulse energy for the treatment of distal ureteral tumors was significantly different with median settings of 0.9 J, 1 J and 0.45 J for Ho:YAG, TFL and pulsed Tm:YAG, respectively (p = 0.048). During URS and RIRS, pulse shapes were significantly different, with Ho:YAG being used in long pulse and TFL in short pulse mode (all p < 0.05). We did not find further disparities., Conclusion: Ho:YAG is used by most experts, while TFL is the most promising alternative. Laser settings largely do not vary significantly. However, further research with novel lasers is necessary to define the optimal approach. With the recent introduction of small caliber and more flexible scopes, minimal-invasive UTUC treatment is further undergoing an extension of applicability in appropriately selected patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)