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Introduction: The observational multicenter prospective FLOWER study (NCT04965701) confirmed effectiveness and safety of osimertinib in the real-world (RW) management of untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) patients., Methods: Herein, we report updated survival data, post-progression management, cost/effectiveness and budget impact (BI) of osimertinib compared with a RW population receiving gefitinib or erlotinib., Results: Overall, 189 Caucasian patients receiving first-line osimertinib were included. After a follow-up of 20.7 months, 74(39.2%) patients discontinued osimertinib, median time-to-treatment discontinuation (mTTD) was 27.9 months, overall survival 36.8 months. At progression, tissue biopsy was performed in 29 (56.9%), liquid biopsy in 15 (29.4%) and both in 7 (13.7%) cases. The most frequent resistant mechanism was MET amplification (N = 14, 29.8%). At data cutoff, 13 (6.9%) patients were continuing osimertinib beyond progression; 52 (67.5%) received second-line treatment; no further treatments were administered in 25 (32.5%) cases. Thirty-three (63.4%) patients received chemotherapy, 12(23.1%) TKIs combination. Cost-effectiveness analysis showed a total cost per patient based on RW mTTD of 98,957.34€, 21,726.28€ and 19,637.83€ for osimertinib, erlotinib and gefitinib, respectively. The incremental cost-effectiveness ratio (ICER)/month for osimertinib was 359,806.0€/life-year-gained (LYG) and 197,789.77€/LYG compared to erlotinib and gefitinib. For osimertinib, the BI-gap between RW-TTD and theoretical-TTD was 16,501.0€ per patient., Conclusions: This updated analysis confirms the effectiveness of osimertinib in RW. Although the ICER of osimertinib seems not cost-effective, additional costs for the management of disease progression to old generation TKIs were not considered in this study. The BI-gap suggests RW mTTD as a more reliable measure for expense estimation., (© The Author(s) 2024. Published by Oxford University Press.)

Aim: To determine (i) prevalence and the risk factors for acute kidney injury (AKI) in children hospitalised for febrile urinary tract infection (fUTI) and (ii) role of AKI as indicator of an underlying VUR. AKI, in fact, is favoured by a reduced nephron mass, often associated to VUR., Methods: This retrospective Italian multicentre study enrolled children aged 18 years or younger (median age = 0.5 years) discharged with a primary diagnosis of fUTI. AKI was defined using Kidney Disease/Improving Global Outcomes serum creatinine criteria., Results: Of 849 children hospitalised for fUTI (44.2% females, median age 0.5 years; IQR = 1.8), 124 (14.6%) developed AKI. AKI prevalence rose to 30% in the presence of underlying congenital anomalies of the kidney and urinary tract (CAKUT). The strongest AKI predictors were presence of CAKUT (OR = 7.5; 95%CI: 3.8-15.2; p = 9.4e-09) and neutrophils levels (OR = 1.13; 95%CI: 1.08-1.2; p = 6.8e-07). At multiple logistic regression analysis, AKI during fUTI episode was a significant indicator of VUR (OR = 3.4; 95%CI: 1.7-6.9; p = 0.001) despite correction for the diagnostic covariates usually used to assess the risk of VUR after the first fUTI episode. Moreover, AKI showed the best positive likelihood ratio, positive predictive value, negative predictive value and specificity for VUR., Conclusion: AKI occurs in 14.6% of children hospitalised for fUTI and is a significant indicator of VUR., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Purpose: Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only in a patient subgroup. Thus, the identification of predictive biomarkers is an urgent unmet medical need., Experimental Design: Tumor samples from naive extensive-stage (ES) SCLC patients receiving atezolizumab plus carboplatin-etoposide were analyzed by gene expression profiling and two 9-color multiplex immunofluorescence panels, to characterize the immune infiltrate and SCLC subtypes. Associations of tissue biomarkers with time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS), were assessed., Results: 42 patients were included. Higher expression of exhausted CD8-related genes was independently associated with a longer TTF and PFS while increased density of B lymphocytes correlated with longer TTF and OS. Higher percentage of M2-like macrophages close to tumor cells and of CD8+T cells close to CD4+T lymphocytes correlated with increased risk of TF and longer survival, respectively. A lower risk of TF, disease progression and death was associated with a higher density of ASCL1+tumor cells while the expression of POU2F3 correlated with a shorter survival. A composite score combining the expression of exhausted CD8-related genes, B lymphocyte density, ASCL1 tumor expression and quantification of CD163+macrophages close to tumor cells, was able to stratify patients into high-risk and low-risk groups., Conclusions: In conclusion, we identified tissue biomarkers and a combined score that can predict a higher benefit from chemoimmunotherapy in ES-SCLC patients., Competing Interests: Competing interests: GP reports Advisory Boards/Honoraria/Speakers’ fee/Consultant by Amgen, AstraZeneca, BMS, Eli Lilly, Jansenn, MSD, Novartis, Pfizer, Roche, and unconditioned research support by AstraZeneca, Roche, MSD. VG reports personal fees for advisory board membership for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, Merck Serono, MSD, Novartis, Pfizer, Olema Oncology, Pierre Fabre; personal fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK, Novartis, Roche and Zentiva; personal fees for expert testimony for Eli Lilly., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs-selective estrogen receptor modulators-or SERDs-selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors ( HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR + /HER2 - BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination.

Epilepsies have numerous specific mechanisms. The understanding of neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing therapeutic approaches. We investigated electrographic activities and neural dynamics leading to convulsive seizures in patients and mouse models of Dravet syndrome (DS), a developmental and epileptic encephalopathy in which hypoexcitability of GABAergic neurons is considered to be the main dysfunction. We analyzed EEGs from DS patients carrying a SCN1A pathogenic variant, as well as epidural electrocorticograms, hippocampal local field potentials, and hippocampal single-unit neuronal activities in Scn1a +/- and Scn1a RH/+ DS mice. Strikingly, most seizures had low-voltage-fast onset in both patients and mice, which is thought to be generated by hyperactivity of GABAergic interneurons, the opposite of the main pathological mechanism of DS. Analyzing single-unit recordings, we observed that temporal disorganization of the firing of putative interneurons in the period immediately before the seizure (preictal) precedes the increase of their activity at seizure onset, together with the entire neuronal network. Moreover, we found early signatures of the preictal period in the spectral features of hippocampal and cortical field potential of Scn1a mice and of patients' EEG, which are consistent with the dysfunctions that we observed in single neurons and that allowed seizure prediction. Therefore, the perturbed preictal activity of interneurons leads to their hyperactivity at the onset of generalized seizures, which have low-voltage-fast features that are similar to those observed in other epilepsies and are triggered by hyperactivity of GABAergic neurons. Preictal spectral features may be used as predictive seizure biomarkers., Competing Interests: Competing interests statement:The authors declare no competing interest.

Artificial intelligence (AI) is the branch of science aiming at creating algorithms able to carry out tasks that typically require human intelligence. In medicine, there has been a tremendous increase in AI applications thanks to increasingly powerful computers and the emergence of big data repositories. Multiple sclerosis (MS) is a chronic autoimmune condition affecting the central nervous system with a complex pathogenesis, a challenging diagnostic process strongly relying on magnetic resonance imaging (MRI) and a high and largely unexplained variability across patients. Therefore, AI applications in MS have the great potential of helping us better support the diagnosis, find markers for prognosis to eventually design more powerful randomised clinical trials and improve patient management in clinical practice and eventually understand the mechanisms of the disease. This topical review aims to summarise the recent advances in AI applied to MRI data in MS to illustrate its achievements, limitations and future directions., 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.

Osteosarcoma is the most common malignant primary bone cancer, but it is infrequently reported in cats. Feline appendicular osteosarcoma typically exhibits good prognosis when treated with surgery alone. A retrospective multi-institutional study was conducted to identify possible prognostic factors. Cats diagnosed with appendicular osteosarcoma were included if initial staging and follow-up information were available. Data including signalment, tumour characteristics, treatment modalities, and survival outcomes were collected and analysed. Fifty-six cats were included; the femur was the most frequently affected bone. Eight cats had distant metastasis at admission and an additional 9 developed metastatic disease during follow-up, resulting in an overall metastatic rate of 30%. Forty-nine (87.5%) cats underwent surgery, and 4 also received adjuvant chemotherapy. Among operated cats, median time to local progression (TTLP), time to distant progression and tumour-specific survival (TSS) were not reached. One- and 2-year survival rates were 66% and 55%, respectively. Seven (12.5%) cats received no treatment; 1- and 2-year survival rates were 25% and 0%, respectively. Operated cats had significantly longer TTLP (P < .001) and TSS (P = .001) compared with non-operated cats. Among operated cats, young age negatively impacted local tumour progression, while the presence of distant metastasis at diagnosis was associated with a higher risk of tumour-related death. This study reaffirms the good prognosis for cats with appendicular osteosarcoma undergoing surgery, but sheds light on some additional factors to consider. Accurate initial staging is recommended, as the metastatic rate may exceed many previous estimations. Surgery substantially extends survival time, whereas the role of chemotherapy remains uncertain., (© 2024 John Wiley & Sons Ltd.)

This retrospective study aimed at evaluating the clinical outcomes of lithium disilicate prostheses onto teeth and implants. A total of 860 restorations were delivered to 312 patients, including crowns, veneers and onlays. Patients with uncontrolled gingival inflammation and/or periodontitis were excluded, whilst subjects with occlusal parafunctions were included. The retrospective observational period ranged between 13 to 17 years. The mechanical and esthetic performances of the restorations were rated according to the modified CDA criteria. The recorded data were analyzed statistically. In total, 26 mechanical complications were noticed: 17 ceramic chippings, 5 core fractures and 4 losses of retention. Mechanical complications occurred predominantly in posterior areas; monolithic prostheses showed the lowest percentage of structural problems. The clinical scores of layered and monolithic restorations were fully satisfactory according to the modified CDA rating. The cumulative survival and success rates ranged between 95.46-100% and 93.75-100% respectively up to 17 years of follow-up. Although patient selection and the rigorous application of validated clinical protocols were considered paramount, the use of lithium disilicate prostheses onto teeth and implants was reported to be a viable and reliable treatment option in the long-term.

Image registration is a key task in medical imaging applications, allowing to represent medical images in a common spatial reference frame. Current approaches to image registration are generally based on the assumption that the content of the images is usually accessible in clear form, from which the spatial transformation is subsequently estimated. This common assumption may not be met in practical applications, since the sensitive nature of medical images may ultimately require their analysis under privacy constraints, preventing to openly share the image content. In this work, we formulate the problem of image registration under a privacy preserving regime, where images are assumed to be confidential and cannot be disclosed in clear. We derive our privacy preserving image registration framework by extending classical registration paradigms to account for advanced cryptographic tools, such as secure multi-party computation and homomorphic encryption, that enable the execution of operations without leaking the underlying data. To overcome the problem of performance and scalability of cryptographic tools in high dimensions, we propose several techniques to optimize the image registration operations by using gradient approximations, and by revisiting the use of homomorphic encryption trough packing, to allow the efficient encryption and multiplication of large matrices. We focus on registration methods of increasing complexity, including rigid, affine, and non-linear registration based on cubic splines or diffeomorphisms parameterized by time-varying velocity fields. In all these settings, we demonstrate how the registration problem can be naturally adapted for accounting to privacy-preserving operations, and illustrate the effectiveness of PPIR on a variety of registration tasks., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Riccardo Taiello reports financial support was provided by University of Côte d’ Azur., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Extensive stage-Small-Cell Lung Cancer (ES-SCLC) is an aggressive cancer with dismal prognosis. The addition of immune-checkpoint inhibitors (ICIs) to platinum-based chemotherapy have been consistently demonstrated to improve outcomes and survival, becoming the new standard in first - line treatment of ES-SCLC patients. However, despite positive results reported in the pivotal trials, longer benefit appears evident only for a selected group of patients. Several predictive biomarkers have been studied so far but the prospective identification of patients more likely to experience better outcome seems to be challenging in SCLC. Indeed, classical immune predictive biomarkers as PD-L1 and tumor mutational burden (TMB) seem not to correlate with outcomes. Recently, a new molecular classification of SCLC based on differential expression of genes associated with specific clinical behaviors and therapeutic vulnerability have been presented suggesting a new field to be investigated. Despite the achievements, these studies focused mainly on inter-tumoral heterogeneity, limiting the exploration of intra-tumoral heterogeneity and cell to cell interactions. New analysis methods are ongoing in order to explore subtypes plasticity. Analysis on single biopsies cannot catch the whole genomic profile and dynamic change of disease over time and during treatment. Moreover, the availability of tissue for translational research is limited due to the low proportion of patients undergoing surgery. In this context, liquid biopsy is a promising tool to detect reliable predictive biomarkers. Here, we reviewed the current available data on predictive role of tissue and liquid biomarkers in ES-SCLC patients receiving ICIs. We assessed latest results in terms of predictive and prognostic value of gene expression profiling in SCLC. Finally, we explored the role of liquid biopsy as a tool to monitor SCLC patients over time., 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 Lorenzi, Resi, Bonanno, Frega, Dal Maso, Ferro, Guarneri and Pasello.)

Introduction: Immune-related adverse events (irAEs) constitute a challenge in the clinical management of solid tumors. This study aims to collect real-world data on the occurrence of immune-mediated diarrhea and colitis (IMDC) in advanced non-small cell lung cancer (aNSCLC) treated with immune checkpoint inhibitors (ICIs) and to assess the clinical impact of a multidisciplinary approach (MDA) on IMDC management., Methods: We retrospectively collected data on patients with aNSCLC consecutively treated with ICIs, either as single agent or in combination with chemotherapy, between September 2013 and July 2022. Among patients developing IMDC, we conducted blinded revision of colonic biopsies and evaluated the clinical impact of the introduction of MDA through predefined indicators., Results: Among the 607 patients included, 84 (13.8%) experienced IMDC. Pathological review highlighted a high prevalence of microscopic colitis (28%), with a collagenous pattern linked to longer symptoms duration (P = .01). IMDC occurred more frequently in females (P = .05) and PD-L1 expressors (P = .014) and was correlated with longer progression-free survival (17.0 vs 5.8, P < .001) and overall survival (28.3 vs 9.5, P < .001). The introduction of MDA was associated with increased employment of diagnostical tools such as fecal calprotectin test (P < .001), colonoscopy (P < .001), and gastroenterological evaluation (P = .017) and a significant decrease in both grade 3 conversion rate (P = .046) and recurrence after rechallenge (P = .016). Hospitalization rate dropped from 17.2% to 3.8% (P: ns)., Conclusion: These findings highlight the clinical relevance of IMDC and support the incorporation of a MDA to optimize the clinical management of this irAE to improve patient care. Prospective validation has been planned., (© The Author(s) 2023. Published by Oxford University Press.)