IRIS UniSR (’Università Vita-Salute San Raffaele)
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The sacrosanct canine: Considerations for the extraction of severely displaced, or impacted maxillary canine(s)
No full textObjective: The maxillary canines have long been considered critical for dental function and aesthetics, with traditional practice prioritizing their preservation and alignment. However, this view often stems from outdated teachings rather than evidence-based principles, since there is no scientific support for the concept of canine-protected occlusion. Therefore, this commentary paper provides justification for extraction of severely impacted maxillary canines with first premolar substitution.
Results: In cases of severely impacted maxillary canines, orthodontic alignment may be associated with higher morbidity, unpredictable outcomes, prolonged treatment times, and increased patient burden. As an alternative, extracting the impacted canines and substituting the first premolars offers a viable, efficient solution that can achieve functional and aesthetic outcomes with fewer complications.
Conclusion: This paper challenges traditional perspectives on the management of impacted canines, advocating for an evidence-based approach that prioritizes patient-centered care
Towards a biological view of multiple sclerosis from early subtle to clinical progression: an expert opinion
Full text linkThe classification of multiple sclerosis (MS) into the two distinct phases of relapsing–remitting and progressive, including primary progressive and secondary progressive phenotypes (PPMS and SPMS, respectively) has long been accepted; however, there are several unmet needs associated with this particular model. The observation that both inflammation and neurodegeneration are present from the onset of MS has resulted in a paradigm shift towards MS as a disease continuum driven by pathological mechanisms underlying clinical progression. Here we report the results from a meeting of Italian MS specialists, exploring the evolving perception of MS pathobiology and its implications for diagnosis and treatment. Insights garnered from the expert panel advocate for a redefined understanding of MS. This expert opinion paper reviews the disease continuum and the intertwined nature of inflammatory and neurodegenerative processes. Also, the need for changes in diagnostic criteria and treatment strategies, including the development of novel biomarkers and new therapies targeting smouldering disease, is discussed
Super- and absolute responders to anti-cgrp monoclonal antibodies in migraine: A one-year multicenter, prospective, observational study
Full text linkAim To assess the frequency of super-responders (>= 75% reduction in migraine frequency) and absolute responders (100% reduction) to monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) after one year of treatment in individuals with high frequency (HFEM) or chronic migraine (CM). Methods This multicenter (n = 16), prospective, real-life study, involved consecutive adults with HFEM or CM and >= 3 prior preventive failures, receiving subcutaneous anti-CGRP mAbs for >= 12 months. Co-primary endpoints were the 12-month rates of super- and absolute responders. Secondary endpoints included subgroup analyses by migraine type and timing of response, categorized as early (<= 3 months), late (> 3-6 month), or ultra-late (> 6-12 month). Results 572 patients completed 12 months of treatment: 70.0% achieved super-response (HFEM: 64.9%; CM: 71.8%) and 23.4% absolute response (HFEM: 29.9%; CM: 21.0%). Both outcomes exhibited a time-dependent progression. Among super-responders (n = 400), 29.4% were early, 22.6% late, and 18.0% ultra-late. Among absolute responders (n = 134), 3.1% responded early, 3.7% late, and 16.6% ultra-late. Conclusion One year of anti-CGRP mAbs therapy yields a >= 75% response in over two-thirds and a 100% response in nearly one-quarter of patients with HFEM or CM and prior treatment failures. Most super- and absolute responses emerge after six months, supporting long-term continuation treatment
Detection of clinically relevant variants in the TP53 gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL
Full text linkIn chronic lymphocytic leukemia, the reliability of next-generation sequencing (NGS) to detect TP53 variants ≤10% allelic frequency (low-VAF) is debated. We tested the ability to detect 23 such variants in 41 different laboratories using their NGS method of choice. The sensitivity was 85.6%, 94.5%, and 94.8% at 1%, 2%, and 3% VAF cut-off, respectively. While only one false positive (FP) result was reported at >2% VAF, it was more challenging to distinguish true variants <2% VAF from background noise (37 FPs reported by 9 laboratories). The impact of low-VAF variants on time-to-second-treatment (TTST) and overall survival (OS) was investigated in a series of 1092 patients. Among patients not treated with targeted agents, patients with low-VAF TP53 variants had shorter TTST and OS versus wt-TP53 patients, and the relative risk of second-line treatment or death increased continuously with increasing VAF. Targeted therapy in ≥2 line diminished the difference in OS between patients with low-VAF TP53 variants and wt-TP53 patients, while patients with high-VAF TP53 variants had inferior OS compared to wild type-TP53 cases. Altogether, NGS-based approaches are technically capable of detecting low-VAF variants. No strict threshold can be suggested from a technical standpoint, laboratories reporting TP53 mutations should participate in a standardized validation set-up. Finally, whereas low-VAF variants affected outcomes in patients receiving chemoimmunotherapy, their impact on those treated with novel therapies remains undetermined. Our results pave the way for the harmonized and accurate TP53 assessment, which is indispensable for elucidating the role of TP53 mutations in targeted treatment
Supplemental parenteral nutrition within an enhanced recovery program for open pancreatoduodenectomy for cancer: a pragmatic, multicenter, randomized controlled trial
Full text linkBackground: The role of supplemental parenteral nutrition (SPN) following pancreatoduodenectomy (PD) in the context of an enhanced recovery program is unexplored. This study aimed to determine whether SPN is superior to early oral feeding alone in reducing postoperative complications. Methods: This pragmatic, multicenter, randomized controlled, trial, across five centers in Italy, enrolled patients aged 18-89 years undergoing open PD for cancer. We excluded patients with an American Society of Anaesthesiology physical status >3 and a preoperative body weight loss of ≥15%. Patients were randomly assigned (1:1) postoperatively to either SPN from day 1 to 5 or no-SPN. All patients were free to begin oral feeding after the operation as desired in the context of a full enhanced recovery after surgery (ERAS) program. The primary outcome was morbidity burden, measured using the comprehensive complication index (CCI). Secondary outcomes included the overall rate of morbidity. Outcomes were assessed up to 90 days postoperatively. Overall, 120 patients per group were required to achieve 80% power and detect at least 30% reduction in the CCI in the SPN group, which was expected to be 23 (median) (interquartile range 21-31). The expected complication rate was 60%, and the type I error rate was set at 5%. Registration at ClinicalTrials.gov (#NCT04438447). Findings: From June 1, 2022, to December 20, 2023, 405 patients were screened for eligibility and 254 patients were randomly allocated to control (no-SPN; n = 129) or treatment (SPN; n = 125) group. All patients were included in the primary and secondary outcome analysis according to the intent-to-treat principle. The median CCI was 20.9 in both arms (median difference 0 [95% CI: -1.07 to 1.7]). The proportion of patients with at least one complication (CCI >0) was similar in both groups [(29.6% vs 29.2%; risk difference 0.4 (95% CI -11.1 to 7.0)]. The overall 90-day morbidity was 67.4% and 63.2% in the no-SPN arm and SPN arm groups, respectively [risk difference -4.2 (95% CI -16.7 to 8.2)]. In high nutritional risk patients (nutritional risk score ≥3), SPN was not protective against the primary outcome when compared with low-risk patients [OR 1.16 (95% CI 0.71-1.91)]. Interpretation: In an ERAS program emphasizing early postoperative oral feeding, SPN does not affect outcome measures, even in patients at high nutritional risk. However, these results do not apply to severely malnourished patients or with critical comorbidities. Funding: The Italian Society for Artificial Nutrition and Metabolism (SINPE) and Baxter Italia S.p.A (Rome, Italy)
Management of trastuzumab deruxtecan-related adverse events in breast cancer: Italian expert panel recommendations
No full textTrastuzumab deruxtecan (T-DXd)–antibody–drug conjugate targeting the human epidermal growth factor receptor 2 (HER2)–has demonstrated high efficacy in clinical studies, with high rates of durable responses and improved outcomes in HER2-positive and HER2-low metastatic breast cancer (mBC) patients. T-DXd has demonstrated a generally manageable safety profile across the DESTINY trials, but there is an emerging unmet need for additional real-world clinical practice information. Italian experts conducted a Delphi panel and several roundtables to develop recommendations for the prevention and practical management of T-DXd-related AEs and toxicities, including nausea and vomiting (N/V), neutropenia, anemia, cardiovascular events, interstitial lung disease/pneumonitis (ILD/P), and treatment safety. ILD/P and N/V are the most challenging AEs associated with T-DXd. Being T-DXd now classified as a Highly Emetogenic Chemotherapy, Italian experts recommend pre-treatment with the triplet (NK1 RA + 5-HT3 RA + dexamethasone) in all patients to prevent acute N/V. Patients must be monitored early on treatment for signs/symptoms of ILD/P and any clinical suspicion should be promptly investigated and managed according to guidelines. These recommendations and proactive surveillance may substantially improve the management of T-DXd-related AEs, maximizing the benefit of this treatment for HER2-positive and HER2-low mBC, and potentially increasing treatment acceptance
ASO Visual Abstract: Perioperative Changes in Serum Transaminases Levels Predicts Long-Term Survival Following Liver Resection of Hepatocellular Carcinoma
No full textUnderstanding the Chemical Characteristics of Payloads and the Expression of Tumor-Associated Antigens of ADCs in Clinical Development
No full textAntibody–drug conjugates (ADCs) have become one of the most promising therapeutic strategies for the treatment of cancer. This family of agents is composed of an antibody, a cytotoxic drug, and a linker that conjugates the drug to the antibody. The optimization of each component can potentially improve clinical activity and reduce the toxicity profile. In this article, we collected data from public sources regarding all ADCs that are currently in clinical development and extracted information for payload chemical characteristics, antibody, and linker type. In addition, we also evaluated data from genomic data sets to explore the expression of the tumor-associated antigen (TAA) in nontransformed tissue compared with the tumor. We evaluated 121 ADCs in clinical development. The most frequent targets included ERBB2, followed by FOLR1 and EGFR. 73% of ADCs used cleavable linkers, and only 14% were noncleavable, with 13% considered as undisclosed. While analyzing the physicochemical characteristics using established rules, we observed that 86% of the payloads violated the Lipinski rules, 11% violated Ghose rules, and 42% violated Brenk rules. Only three payloads did not violate any rule: deruxtecan, exatecan, and SN38, all from the camptothecin family. Regarding the conjugation type, only trastuzumab deruxtecan, labetuzumab govitecan, sacituzumab govitecan, BYON3521, and SYD1875 used homogeneous conjugation. An interesting observation was that for some ADCs, TAA expression was higher in normal tissue than in the tumor. In summary, our analysis highlights that only a limited number of ADCs incorporate payloads with favorable physicochemical properties and that several ADCs currently under development target TAAs with higher expression in normal tissues than in the corresponding tumors
EULAR recommendations for the treatment of systemic sclerosis: 2023 update
Full text linkObjectives: To update the 2017 European Alliance of Associations for Rheumatology (EULAR) recommendations for treatment of systemic sclerosis (SSc), incorporating new evidence and therapies. Methods: An international task force was convened in line with EULAR standard operating procedures. A nominal group technique exercise was performed in two rounds to define questions underpinning a subsequent systematic literature review. The evidence derived was discussed and overarching principles, recommendations and future research agenda were iteratively developed with voting rounds. Results: The task force agreed on 22 recommendations covering 8 clinical/organ domains including Raynaud's phenomenon, digital ulcers, pulmonary arterial hypertension, scleroderma renal crisis, skin fibrosis, interstitial lung disease (ILD), gastrointestinal manifestations and arthritis. Most new recommendations are related to skin fibrosis and ILD. These included novel recommendations for the use of mycophenolate mofetil, nintedanib, rituximab and tocilizumab for the treatment of these crucial disease manifestations. The recommendations also included first-line and second-line interventions, providing increased utility for rheumatology practitioners. Important additions to the future research agenda included consideration of novel interventions for the management of vascular, musculoskeletal and gastrointestinal manifestations and calcinosis, as well as for the local management of digital ulcers. Conclusion: These updated recommendations include the first set of synthetic and biological targeted therapies recommended for key fibrotic manifestations of SSc as well as first-line combination treatment for newly diagnosed pulmonary artery hypertension and prioritise a new research agenda for the coming years
