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As the drive towards recycling electronic waste increases, demand for rapid and reliable analytical methodology to analyse the metal content of the waste is increasing, e.g. to assess the value of the waste and to decide the correct recycling routes. Here, we comprehensively assess the suitability of different x-ray fluorescence spectroscopy (XRF)-based techniques as rapid analytical tools for the determination of critical raw materials, such as Al, Ti, Mn, Fe, Co, Ni, Cu, Zn, Nb, Pd and Au, in three electronic waste matrices: printed circuit boards (PCB), light emitting diodes (LED), and lithium (Li)-ion batteries. As validated reference methods and materials to establish metrological traceability are lacking, several laboratories measured test samples of each matrix using XRF as well as other independent complementary techniques (instrumental neutron activation analysis (INAA), inductively coupled plasma mass spectrometry (ICP-MS) and ICP optical emission spectrometry (OES)) as an inter-laboratory comparison (ILC). Results highlighted key aspects of sample preparation, limits of detection, and spectral interferences that affect the reliability of XRF, while additionally highlighting that XRF can provide more reliable data for certain elements compared to digestion-based approaches followed by ICP-MS analysis (e.g. group 4 and 5 metals). A clear distinction was observed in data processing methodologies for wavelength dispersive XRF, highlighting that considering the metals present as elements (rather than oxides) induces overestimations of the mass fractions when compared to other techniques. Eventually, the effect of sample particle size was studied and indicated that smaller particle size (<200 µm) is essential for reliable determinations., Competing Interests: Declaration of competing interest The authors 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 © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Sporadic desmoid fibromatosis (DF) is a rare locally aggressive tumor characterized by mutation in exon 3 of CTNNB1 (T41A, S45F, and S45P). Standard of care is active surveillance (AS), but 30% require treatment. DF clinical course is unpredictable and identification of prognostic markers is needed to tailor strategy. In this prospective study, we investigated the consistency between mutation detected in tumor biopsies with that detected in plasma by digital droplet PCR (ddPCR) and the association between circulating tumor DNA (ctDNA) abundancy with clinical outcome., Patients and Methods: A total of 56 patients and 10 healthy donors were included. CTNNB1 mutation status of DF biopsies was determined by Sanger and in case of WT CTNNB1 with NGS. In matched plasma samples at enrollment and during AS at specific timepoints, we evaluated cfDNA quantity and ctDNA., Results: ctDNA levels were measured in 46 patients with CTNNB1 mutation. Detection rate for T41A, S45F and S45P was 68%, 42% and 100%, respectively. S45P variant has been detected in all patients with S45P mutation. Longitudinal assessment of ctDNA during AS in nine patients (four with regression and five with progression as first event according to RECIST) showed a concordance between the event and ctDNA level change in six out of nine patients tested (4/5 with progression and 2/4 with regression)., Conclusions: Results of ctDNA analysis support its potential clinical implementation as diagnostic tool in specific clinical scenarios where biopsy can be challenging. A prospective clinical trial needs to be performed to evaluate the potential role of ctDNA as predictive biomarker., (© 2024. Society of Surgical Oncology.)

Artificial intelligence (AI) has made a tremendous impact in the space of healthcare, and proton therapy is not an exception. Proton therapy has witnessed growing popularity in oncology over recent decades, and researchers are increasingly looking to develop AI and machine learning tools to aid in various steps of the treatment planning and delivery processes. This review delves into the emergent role of AI in proton therapy, evaluating its development, advantages, intended clinical contexts, and areas of application. Through the analysis of 76 studies, we aim to underscore the importance of AI applications in advancing proton therapy and to highlight their prospective influence on clinical practices., Competing Interests: Declaration of Competing Interest BAJF received speaker fees from Roche, Bayer, Janssen, Ipsen, Accuray, Astellas, Elekta, IBA and Astra Zeneca (all outside the current project). EGCT is member of the scientific advisory board of IBA and received speaker fees from Elekta (all outside the current manuscript). M.G.V received a research fellowship from the Associazione Italiana per la Ricerca sul Cancro (AIRC) entitled “Radioablation ± hormonotherapy for prostate cancer oligorecurrences (RADIOSA trial): potential of imaging and biology” registered at Clinical Trials.gov NCT03940235, approved by the Ethics Committee of IEO and Centro Cardiologico Monzino (IEO-997). GC reports speakers fee and advisory board from Roche, Novartis, Lilly, Pfizer, Astra Zeneca, Daichii Sankyo, Ellipsis, Veracyte, Exact Science, Celcuity, Merck, BMS, Gilead, Sanofi, Menarini. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The remaining authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: A substantial number of patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) experience adverse events after TAVI, with health care expenditure. We aimed to investigate cardiac remodeling and long-term outcomes in diabetic patients with severe AS, left ventricular ejection fraction (LVEF) < 50%, and extra-valvular cardiac damage (EVCD) undergoing TAVI treated with sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus other glucose-lowering strategies (no-SGLT2i users)., Methods: Multicenter international registry of consecutive diabetic patients with severe AS, LVEF < 50%, and EVCD undergoing TAVI. Based on glucose-lowering therapy at hospital discharge, patients were stratified in SGLT2i versus no-SGLT2i users. The primary endpoint was a composite of all-cause death and heart failure (HF)-hospitalization (major adverse cardiovascular events, MACE) at 2-year follow-up. Secondary outcomes included all-cause death, cardiovascular death, and HF hospitalization., Results: The study population included 311 patients, among which 24% were SGLT2i users. Within 1-year after TAVI, SGLT2i users experienced a higher rate of LV recovery (p = 0.032), especially those with baseline LVEF ≤ 30% (p = 0.026), despite the lower baseline LVEF. Patients not treated with SGLT2i were more likely to progress to a worse EVCD stage over time (p = 0.018). At 2-year follow-up, SGLT2i use was associated with a lower rate of MACE, all-cause death, and HF hospitalization (p < 0.01 for all). After adjusting for confounding factors, the use of SGLT2i emerged as an independent predictor of reduced MACE (HR = 0.45; 95% CI 0.17-0.75; p = 0.007), all-cause death (HR = 0.51; 95% CI 0.25-0.98; p = 0.042) and HF-hospitalization (HR = 0.40; 95% CI 0.27-0.62; p = 0.004)., Conclusions: In diabetic patients with severe AS, LVEF < 50%, and EVCD undergoing TAVI, the use of SGLT2i was associated with a more favorable cardiac remodeling and a reduced risk of MACE at 2-year follow-up., Competing Interests: Declarations. Ethics approval and consent to participate: Data were collected as part of an approved international multicenter observational study. The present study was conducted according to the principles of the Declaration of Helsinki; all patients were informed about their participation in the registry and provided informed consent for the anonymous publication of scientific data. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

We present a case of ventricular thrombosis occurring in myocarditis due to immune checkpoint inhibitors (ICIs), presenting as myocardial infarction and complicated by refractory cardiogenic shock. Although myocarditis is a well-known adverse event of ICIs, intraventricular thrombus formation in this context is extremely rare. Differential diagnosis between ventricular thrombosis and tumoral mass can be challenging, especially in oncologic patients. Careful clinical evaluation and multimodality imaging are essential for correct diagnosis. The incidence of ICI cardiovascular complications is relatively low, but associated mortality is alarmingly high. Therefore, we intend to discuss the difficulties in managing these life-threatening cardiovascular complications., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this article to disclose., (© 2024 The Authors.)

The prevalence of coronary microvascular dysfunction (CMD) beyond the spectrum of chronic coronary syndromes (CCS) is non-negligible, pertaining to pathophysiological and therapeutical implications. Thanks to the availability of accurate and safe non-invasive technique, CMD can be identified as a key player in heart failure, cardiomyopathies, Takotsubo syndrome, aortic stenosis. While CMD is widely recognized as a cause of myocardial ischemia leading to a worse prognosis even in the absence of obstructive coronary artery disease, the characterization of CMD patterns beyond CCS might provide valuable insights on the underlying disease progression, being potentially a "red flag" of adverse cardiac remodeling and a major determinant of response to therapy and outcomes. In this review, we aimed to provide an overview of the latest evidence on the prevalence, mechanistic and prognostic implications of CMD beyond the spectrum of CCS (i.e. heart failure, cardiomyopathies, Takotsubo syndrome, aortic stenosis)., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Background: In patients with atrial fibrillation (AF), the association between cancer and cardioembolic or bleeding risk during oral anticoagulant therapy still remains unclear., Purpose: We aimed to assess the impact of cancer present at baseline (CB) or diagnosed during follow-up (CFU) on bleeding events in patients treated with direct oral anticoagulants (DOACs) for non-valvular AF (NVAF) compared with patients without CB or CFU, respectively., Methods: All consecutive patients with NVAF treated with DOACs for stroke prevention were enrolled between January 2017 and March 2019. Primary outcomes were bleeding events or cardiovascular death, non-fatal stroke and non-fatal myocardial infarction, and the composite endpoint between patients with and without CB and between patients with and without CB., Results: The study population comprised 1170 patients who were followed for a mean time of 21.6 ± 9.5 months. Overall, 81 patients (6.9%) were affected by CB, while 81 (6.9%) were diagnosed with CFU. Patients with CFU were associated with a higher risk of bleeding events and major bleeding compared with patients without CFU. Such an association was not observed between the CB and no CB populations. In multivariate analysis adjusted for anemia, age, creatinine, CB and CFU, CFU but not CB remained an independent predictor of overall and major bleeding (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.8-3.89, p < 0.001; HR 3.02, 95% CI 1.6-3.81, p = 0.001, respectively)., Conclusion: During follow-up, newly diagnosed primitive or metastatic cancer in patients with NVAF taking DOACs is a strong predictor of major bleeding regardless of baseline hemorrhagic risk assessment. In contrast, such an association is not observed with malignancy at baseline. Appropriate diagnosis and treatment could therefore reduce the risk of cancer-related bleeding., (© 2024. The Author(s).)

In the era of big data, young patients may be overwhelmed by artificial intelligence-based tools, like chatbots. Five clinical experts were asked to evaluate the performance of the most currently used chatbots in providing information on a rare cancer affecting young people, like rhabdomyosarcoma. Generally speaking, despite their high performance in giving general information about the disease, these chatbots were considered by the experts to be inadequate in providing suggestions on cancer treatments and specialized centers, and also lacking in "sensitivity." Efforts are planned by the pediatric oncology community to improve the quality of data used to train these tools., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

This paper describes the complexity of the clinical management of foreign minors suffering from cancer, through the clinical experience of an Italian referral center. The study includes 50 patients less than 18 years (22% of the patients admitted to the unit in 2023), 32 foreigners who were Italian resident and 18 who had come to Italy specifically to receive cancer treatment. Patients who migrate for healthcare reasons often arrive at the referral center with advanced disease or relapse. Numerous socio-cultural issues were reported. To address them, specific strategies were implemented to ensure equal and high-quality care for all patients, respecting their needs., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: The hepatic response after ST-elevation myocardial infarction (STEMI) may be associated with mortality and morbidity. We aimed to assess the cardio-hepatic axis post-STEMI using cardiovascular magnetic resonance (CMR)., Methods: This prospective, observational, single-centre study included consecutive STEMI patients who underwent CMR after primary angioplasty from January 2015 to January 2019. Standard infarct characteristics were analysed, and hepatic T1 and hepatic extracellular volume (ECV) were assessed using pre- and post-contrast T1-mapping sequences. The primary endpoint was the relationship between native hepatic T1-values and ischemic right ventricular (RV) involvement, determined by RV ejection fraction (EF) dysfunction and/or the presence of RV acute myocardial infarction (AMI). The diagnostic performance of hepatic T1 values for detecting RV involvement was assessed using the area under the receiver operating characteristic curve (AUC)., Results: Of 177 consecutive STEMI patients undergoing CMR, 142 were included. Patients with RV ischemic involvement, compared to those without, had significantly higher native hepatic T1 (p < 0.001) and hepatic ECV (p = 0.016). Hepatic T1 values demonstrated a good diagnostic performance in detecting RV involvement (AUC 0.826, p < 0.001) and correlated positively with NT-proBNP values (r = 0.754, p < 0.001). Patients with high hepatic T1 values (>605 ms) had significantly higher NT-proBNP levels (<0.001), larger RV end-diastolic volume (p < 0.001), lower RV-EF (p < 0.001), and a higher prevalence of RV AMI (p = 0.022) compared to those with hepatic T1 ≤ 605 ms, while left ventricular EF and infarct size were similar. Multivariable logistic regression analysis identified RV-EF (p = 0.010) and NT-proBNP values (p < 0.001) as independent predictors of increased hepatic T1 values. Patients with increased hepatic T1 values had a higher rate of re-hospitalization for heart failure at 17-month follow-up (12.1% vs 2.0%, p = 0.046)., Conclusions: Hepatic T1 mapping has emerged as a possible novel imaging biomarker of the cardio-hepatic axis in STEMI, being associated with RV involvement and increased NT-proBNP values., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Takotsubo syndrome (TTS) is a clinical syndrome characterized by a transient left ventricular dysfunction whose diagnosis can be challenging due to its resemblance to acute myocardial infarction (AMI). Despite the growing recognition of TTS, acute complications and long-term mortality rates are comparable to those observed in AMI patients. In this context, a systematic diagnostic approach is imperative for an accurate patient assessment, with due consideration of the distinctive characteristics and optimal timing of each imaging modality. Coronary angiography with ventriculography may be reserved for cases presenting with ST-segment elevation, whereas in all other cases, the use of multimodality noninvasive imaging allows for a comprehensive evaluation of typical diagnostic features and detection of acute complications while also providing prognostic insights. The aim of this review is to evaluate the current research on non-invasive modalities and to propose a diagnostic algorithm that will facilitate the identification and management of TTS., (© 2024 Wiley Periodicals LLC.)

Background: We applied the strategy for M+ medulloblastoma across all high-risk subgroups, including LC/A histology, TP53 mutations, MYC/MYCN amplification., Methods: Patients over 3-years-old received,after surgery,staging and histo-biological analysis,sequential high-dose-methotrexate(HD-MTX),high-dose-etoposide(HD-VP16),high-dose-cyclophosphamide(HD-Cyclo),high-dose-carboplatin(HD-Carbo).Hyperfractionated-accelerated-radiotherapy-craniospinal(HART-CSI),administered in twice daily 1.3 Gy-fractions reached a total dose tailored to the patients' age and pre-radiation response to chemotherapy(CT): 31.2 Gy if under 10-years-old and complete response(CR) or partial response(PR) obtained or absence of metastatic disease,39 Gy in other/older patients.Boosts to posterior fossa/residual metastatic(M+) deposits were given up to a total dose of 60 Gy/9 Gy,respectively,but avoided if metastatic nodules were very big or patients very young.Two courses of high-dose-thiotepa were delivered in case of not CR/PR after pre-radiotherapy(RT) phase and in all M0 patients either - pre/post HART.Subgrouping was performed where tissue was available., Results: Eighy-nine patients were enrolled,median age 8.8 years,median follow up 136 months.Overall-survival(OS) and event-free-survival(EFS) at 5/15 years were 75.9/66.5% and 68.2/65.3%, respectively;5/28 fatal events were not related to relapse(three developed secondary malignancies).Sex,age less than 10 years,histological subtype,presence of MYC/MYCN amplification,reduction in CSI dose,omission of RT-boosts,implementation of myeloablative therapy,presence/absence of metastases did not impact prognosis.Patients progressing after pre-HART CT(14/89) and stable-disease(SD)+PD after HART(10/89) negatively affected outcome(P<0.001).Subgrouping in 66/89 patients' samples demonstrated a significantly worse EFS for patients with Sonic Hedgehog(SHH)-tumors(#15, 2 with constitutional TP53-mutations) vs. group 3 and 4(15 and 29 patients, respectively, group3/4 in 7).Patients younger than 10 received lower CSI doses if stratified according to CT response., Conclusions: This strategy, partly adopted in the ongoing SIOPE protocol,confirmed improved EFS and OS over previously reported outcomes in all high-risk categories;SHH tumors appeared the most aggressive., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Anthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis., Methods: The ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS)., Findings: Tumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI., Interpretation: The different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS., Funding: Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5 × 1000 Funds-2016, Italian Ministry of Health; AIRC Grant [ID#28546]., Competing Interests: Declaration of interests Sandro Pasquali reports institutional research funds from Pharmamar, Ikena Oncology, and ASTX Pharmaceutical. Cleofe Romagosa reports institutional research funds from Pharmamar. Angelo Paolo Dei Tos reports institutional research funds from Pharmamar. Javier Martin-Broto reports institutional research funds from Pharmamar, Adaptimmune, Amgen, AROG, Bayer, Blueprint, BMS, Celgene, Daiichi Sankyo, Deciphera, Eisai, Forma, GSK, IMMIX Biopharma, Karyopharm, Lilly, LIXTE, Nektar, Novartis, Pfizer, Roche, and PharmaMar and compensations for advisory board or consulting relationship from Tecnofarma. Jean-Yves Blay reports compensations for advisory board or consulting relationship with Merck Sharp & Dohme, Merck Serono, Daiichi-Sankyo, Astellas, Alexo Oncology, Samyang Biopharm, Hanmi, Daewoong and Amgen and has received institutional research funds from Genentech/Roche, Merck Sharp & Dohme, Merck Serono, Daiichi-Sankyo, Astellas and Amgen. Giovanni Grignani reports institutional research funds from Eli Lilly and Company, GlaxoSmithKline, Merk, Novartis, and Pharmamar. Emanuela Palmerini reports compensations for advisory boards from Daiichi Sankyo Company, Daiichi Sankyo Europe GmbH, Deciphera Pharmaceuticals Inc., EUSA Pharma (US) LLC, and SynOx Therapeutics. Paolo Casali received honoraria for speaker, consultancy, or advisory roles from: Bayer, Deciphera, Eisai, Eli Lilly, and Pfizer; his unit received funds from: Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Glaxo, Karyopharm Pharmaceuticals, Novartis, Pfizer, and PharmaMar. Silvia Stacchiotti reports institutional research funds from: Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Glaxo Smith Kline, Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, and SpringWorks; honoraria, consultancy, or advisory role from: Bayer, Bavarian Nordic, Boehringer, Deciphera, Daiichi Sankyo Pharma, Gentili, Glaxo Smith Kline, Inhibrix, Maxivax, PharmaMar, and Servier; travel, accommodations, expenses from: PharmaMar. Alessandro Gronchi reports compensations for advisory boards from Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks, and Deciphera and institutional research grants from PharmaMar and Nanobiotix. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Since the beginning of the war in Ukraine on February 24, 2022, many pediatric oncology centers welcomed evacuated patients. To better understanding the needs of patients and families arriving at two Lombardy hospitals in the period March to November 2022, an anonymous questionnaire investigated the families' backgrounds, feelings, and impressions about hospitality and care., Methods: Twenty questions investigated how patients had reached Italy, from whom they had received help (logistically/financially); the emotions regarding their status as war refugees; the knowledge, expectations, and opinions about Italy and Italians; the quality of medical care received and the relationships with the healthcare staff; lastly, suggestions to improve assistance., Results: The questionnaires were completed by 19/32 patients/parents in November 2022 in two different pediatric-oncology centers. Most families had reached Italy (58%) and received medical care (95%) with the help of charities and the Italian Public Health Care System. A significant majority (69%) expressed satisfaction with the assistance provided. The Italian population demonstrated remarkable warmth, for 95% exhibiting friendliness and for 58% generosity. An improvement in their stay could be linked with the positive outcome of their children's cancer (15%), achieving complete family reunification (15%), the cessation of the conflict (10%), and the overcoming of language barriers (10%)., Conclusions: Providing care for children from another country, not only grappling with the trauma of fleeing their homeland but also battling cancer, is an immense undertaking. It demands a diverse range of efforts and resources to ensure a positive and fulfilling outcome for this experience., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Coronary artery disease (CAD) is a prevalent cause of left ventricular dysfunction. Nevertheless, effective elective revascularization, particularly surgical revascularization, can enhance long-term outcomes and, in selected cases, global left ventricular contractility. The assessment of myocardial viability and scars is still relevant in guiding treatment decisions and selecting patients who are likely to benefit most from blood flow restoration. Although the most recent randomized studies challenge the notion of "hibernating myocardium" and the clinical usefulness of assessing myocardial viability, the advancement of imaging techniques still renders this assessment valuable in specific situations. According to the guidelines of the European Society of Cardiology, non-invasive stress imaging may be employed to define myocardial ischemia and viability in patients with CAD and heart failure before revascularization. Currently, several non-invasive imaging techniques are available to evaluate the presence and extent of viable myocardium. The selection of the most suitable technique should be based on the patient, clinical context, and resource availability. This narrative review evaluates the characteristics of available imaging modalities for assessing myocardial viability to determine the most appropriate therapeutic strategy., (© 2024 Wiley Periodicals LLC.)

Purpose: Though the prognosis for pediatric patients with localised synovial sarcoma (SS) is generally good, the chances of being cured after relapse are limited. This study describes a retrospective multi-institutional series of relapsing SS patients treated at six selected European referral centers for pediatric sarcoma., Patients and Methods: The study included 41 patients <21 years with relapsing SS, treated between 2002 and 2022. The analysis included patient's characteristics at first diagnosis, first-line treatments, clinical findings at relapse, and second-line treatment modalities., Results: The first relapse occurred within 3-132 months (median 18 months) after first diagnosis and was local in 34%, metastatic in 54%, and both in 12%. Treatment at first relapse included surgery in 56% of cases, radiotherapy in 34%, and systemic therapy in 88%. In all, 36 patients received second-line medical treatment, that was chemotherapy in 32 cases (with 10 different regimens) and targeted therapy in four. No patient was included in an early-phase clinical trial as second-line therapy-line therapy. Overall response rate was 42%. Median event-free survival (EFS) was 12 months, postrelapse 5-year EFS was 15.8%. Median overall survival (OS) was 30 months, postrelapse 5-year OS was 22.2%. At the Cox's multivariable regression analysis, OS was significantly associated with time and type of relapse., Conclusion: Pediatric patients with relapsed SS have a poor prognosis and generally receive an individualized approach, due to the lack of a uniform standardized approach. New comprehensive strategies are needed to improve the knowledge on the biologic landscape of SS and develop tailored prospective clinical trials., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Cardiac masses represent a heterogeneous clinical scenario. Potential electrocardiographic (ECG) red flags of malignancy remain to be investigated., Objectives: The purpose of this study was to describe the spectrum of ECG abnormalities in a large cohort of cardiac masses and to evaluate potential red flags suggestive of malignancy., Methods: This was an observational cohort study of 322 consecutive patients with a cardiac mass and available ECG at Bologna University Hospital. All masses were diagnosed by histologic examination or, in the case of cardiac thrombi, by radiologic resolution after proper anticoagulant therapy. Multivariable regression analysis was used to assess potential predictors of malignancy among ECG abnormalities. All-cause mortality at follow-up was evaluated., Results: Of 322 patients, 98 (30.4%) had malignant tumors. Compared with patients with benign masses, those with malignant tumors exhibited a higher heart rate, right-axis deviation, greater depolarization, repolarization abnormalities, and bradyarrhythmia at presentation. Regarding specific ECG features, a higher heart rate on admission (P = .014), bradyarrhythmias (P = .009), ischemic-like repolarization abnormalities (ST-segment deviation, both depression and elevation, and negative T-wave; P <.001), low voltages (P = .001), and right-axis deviation (P = .025) were identified as independent predictors of malignancy. Considering these specific ECG alterations, a malignancy-oriented ECG was associated with higher mortality at follow-up (median 20.7 months)., Conclusion: ECG frequently is abnormal in cases of malignant cardiac tumors. Some specific ECG changes are strongly suggestive for malignancy and type of infiltration., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) is a global health concern, and the incidence of early onset (EO) CRC, has an upward trend. This study delves into the genomic landscape of EO-CRC, specifically focusing on pediatric (PED) and young adult (YA) patients, comparing them with adult (AD) CRC. In this retrospective monocentric investigation, we performed targeted next-generation sequencing to compare the mutational profile of 38 EO-CRCs patients (eight PED and 30 YA) to those of a 'control group' consisting of 56 AD-CRCs. Our findings reveal distinct molecular profiles in EO-CRC, notably in the WNT and PI3K-AKT pathways. In pediatrics, we observed a significantly higher frequency of RNF43 mutations, whereas APC mutations were more prevalent in adult cases. These observations suggest age-related differences in the activation of the WNT pathway. Pathway and copy number variation analysis reveal that AD-CRC and YA-CRC have more similarities than the pediatric patients. PED shows a peculiar profile with CDK6 amplification and the enrichment of lysine degradation pathway. These findings may open doors for personalized therapies, such as PI3K-AKT pathway inhibitors or CDK6 inhibitors for pediatric patients. Additionally, the distinct molecular signatures of EO-CRC underscore the need for age-specific treatment strategies and precision medicine. This study emphasizes the importance of comprehensive molecular investigations in EO-CRCs, which can potentially improve diagnostic accuracy, prognosis, and therapeutic decisions for these patients. Collaboration between the pediatric and adult oncology community is fundamental to improve oncological outcomes for this rare and challenging pediatric tumor., (© 2024. The Author(s).)

Biomarkers for monitoring COVID-19 disease course are lacking. Study aim was to identify biomarkers associated with disease severity, survival, long-term outcome, and Long COVID. As excessive macrophages activation is a hallmark of COVID-19 and complement activation is key in this, we selected the following proteins involved in these processes: PTX3, C1q, C1-INH, C1s/C1-INH, and sMR. EDTA-plasma concentrations were measured in 215 patients and 47 controls using ELISA. PTX3, sMR, C1-INH, and C1s/C1-INH levels were associated with disease severity. PTX3 and sMR were also associated with survival and long-term immune recovery. Lastly, sMR levels associate with ICU admittance. sMR (AUC 0.85) and PTX3 (AUC 0.78) are good markers for disease severity, especially when used in combination (AUC 0.88). No association between biomarker levels and Long COVID was observed. sMR has not previously been associated with COVID-19 disease severity, ICU admittance or survival and may serve as marker for disease course., Competing Interests: E.T. is an employee of Hycult Biotechnology b.v., (© 2024 The Author(s).)

Dyslipidaemia and hyperhomocysteinemia are known risk factors for cardiovascular disease. While it is evident that optimization of plasma lipid is associated with low risk of cardiovascular disease in the general population, it is not yet fully clear whether reduction of homocysteinemia is associated with an improvement in risk in all subjects. The aim of our narrative review is to highlight eventual effects of folate supplementation on LDL-C levels, LDL-C oxidation and atherosclerosis-related complications. A comprehensive literature search was done in electronic database, including PubMed, Web of Science, Cochrane, and Scopus from inception up to January 2024. Based on the available evidence, epidemiological data, pathophysiological observations and meta-analyses of randomized clinical trials suggest that folic acid supplementation may modestly but significantly improve plasma lipid levels, lipid atherogenicity, and atherosclerosis-related early vascular damage, and that folic acid supplementation may significantly reduce the risk of cerebrovascular disease. Considering the low-cost and high safety profile of folic acid, its long-term supplementation could be considered for dyslypidaemic patients in secondary prevention for cardiovascular disease., Competing Interests: Declaration of competing interest The authors 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: High-level evidence on hypofractionated proton therapy (PT) for localized and locally advanced prostate cancer (PCa) patients is currently missing. The aim of this study is to provide a systematic literature review to compare the toxicity and effectiveness of curative radiotherapy with photon therapy (XRT) or PT in PCa., Methods: PubMed, Embase, and the Cochrane Library databases were systematically searched up to April 2022. Men with a diagnosis of PCa who underwent curative hypofractionated RT treatment (PT or XRT) were included. Risk of grade (G) ≥ 2 acute and late genitourinary (GU) OR gastrointestinal (GI) toxicity were the primary outcomes of interest. Secondary outcomes were five-year biochemical relapse-free survival (b-RFS), clinical relapse-free, distant metastasis-free, and prostate cancer-specific survival. Heterogeneity between study-specific estimates was assessed using Chi-square statistics and measured with the I2 index (heterogeneity measure across studies)., Results: A total of 230 studies matched inclusion criteria and, due to overlapped populations, 160 were included in the present analysis. Significant lower rates of G ≥ 2 acute GI incidence (2 % vs 7 %) and improved 5-year biochemical relapse-free survival (95 % vs 91 %) were observed in the PT arm compared to XRT. PT benefits in 5-year biochemical relapse-free survival were maintained for the moderate hypofractionated arm (p-value 0.0122) and among patients in intermediate and low-risk classes (p-values < 0.0001 and 0.0368, respectively). No statistically relevant differences were found for the other considered outcomes., Conclusion: The present study supports that PT is safe and effective for localized PCa treatment, however, more data from RCTs are needed to draw solid evidence in this setting and further effort must be made to identify the patient subgroups that could benefit the most from PT., Competing Interests: Declaration of competing interest The authors 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 © 2024 Elsevier B.V. All rights reserved.)

Background: ST-segment elevation myocardial infarction (STEMI) is associated with a systemic and local inflammatory response with edema. However, their role at the tissue level is poorly characterized., Objectives: This study aims to characterize T2 values of the noninfarcted myocardium (NIM) and surrounding tissue and to investigate prognostic relevance of higher NIM T2 values after STEMI., Methods: A total of 171 consecutive patients with STEMI without prior cardiovascular events who underwent cardiac magnetic resonance after primary percutaneous coronary intervention were analyzed in terms of standard infarct characteristics. Edema of the NIM, liver, spleen, and pectoralis muscle was assessed based on T2 mapping. Follow-up was available for 130 patients. The primary endpoint was major adverse cardiac events (MACE), defined as cardiovascular death, myocardial infarction, unplanned coronary revascularization or rehospitalization for heart failure. The median time from primary percutaneous coronary intervention to cardiac magnetic resonance was 3 days (IQR: 2-5 days)., Results: Higher (above the median value of 45 ms) T2 values in the NIM area were associated with larger infarct size, microvascular obstruction, and left ventricular dysfunction and did not correlate with C-reactive protein, white blood cells, or T2 values of the pectoralis muscle, liver, and spleen. At a median follow-up of 17 months, patients with higher (>45 ms) NIM T2 values had increased risk of MACE (P < 0.001) compared with subjects with NIM T2 values ≤45 ms, mainly caused by a higher rate of myocardial reinfarction (26.3% vs 1.4%; P < 0.001). At multivariable analysis, higher NIM T2 values independently predicted MACE (HR: 2.824 [95% CI: 1.254-6.361]; P = 0.012)., Conclusions: Higher NIM T2 values after STEMI are independently associated with worse cardiovascular outcomes, mainly because of higher risk of myocardial infarction., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Takotsubo syndrome (TTS) is an acute cause of heart failure characterized by a reversible left ventricular (LV) impairment usually induced by a physical or emotional trigger. TTS is not always a benign disease since it is associated with a relatively higher risk of life-threatening complications, such as cardiogenic shock, ventricular arrhythmias, respiratory failure, cardiopulmonary resuscitation and death. Despite notable advancements in the management of patients with TTS, physiopathological mechanisms underlying transient LV dysfunction remain largely unknown. Since TTS carries similar prognostic implications than acute myocardial infarction, the identification of mechanisms and predictors of worse prognosis remain key to establish appropriate treatments. The greater prevalence of TTS among post-menopausal women and the activation of the neuro-cardiac axis triggered by physical or emotional stressors paved the way forward to several studies focused on coronary microcirculation and impaired blood flow as the main physiopathological mechanisms of TTS. However, whether microvascular dysfunction is the cause or a consequence of transient LV impairment remains still unsettled. This review provides an up-to-date summary of available evidence supporting the role of microvascular dysfunction in TTS pathogenesis, summarizing contemporary invasive and non-invasive diagnostic techniques for its assessment. We will also discuss novel techniques focused on microvascular dysfunction in TTS which may support clinicians for the implementation of tailored treatments., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Atrial fibrillation (AF) could impact on left ventricular function leading to a sublinical myocardial dysfunction, as identified by myocardial work parameters in a population-based cohort of AF patients compared with healthy individuals; factors associated with these parameters are also shown. SBP: systolic blood pressure; LAVI: left atrial volume index., (© 2024 Wiley Periodicals LLC.)

Background: Pediatric non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) are a heterogeneous group of aggressive tumors. Patients with locally advanced/initially unresected disease represent a subset of patients with unsatisfactory outcome: limited data are available on the best treatment approach, in particular regarding local therapy., Methods: This retrospective analysis concerned 71 patients < 21 years old with nonmetastatic, initially unresected adult-type NRSTS, treated at a referral center for pediatric sarcomas from 1990 to 2021. Patients were treated using a multimodal approach, based on the protocols adopted at the time of their diagnosis., Results: The series included a selected group of patients with unfavorable clinical characteristics, i.e., most cases had high-grade and large tumors, arising from axial sites in 61% of cases. All patients received neoadjuvant chemotherapy, 58 (82%) had delayed surgery (R0 in 45 cases), and 50 (70%) had radiotherapy. Partial response to chemotherapy was observed in 46% of cases. With a median follow-up of 152 months (range, 18-233), 5-year event-free survival (EFS) and overall survival (OS) were 39.9% and 56.5%, respectively. Survival was significantly better for patients who responded to chemotherapy, and those who had a delayed R0 resection. Local relapse at 5 years was 7.7% for patients who did not undergo delayed surgery., Conclusions: Our series underscores the unsatisfactory outcome of initially unresected NRSTS patients. Improving the outcome of this patient category requires therapeutic strategies able to combine novel effective systemic therapies with a better-defined local treatment approach to offer patients the best chances to have R0 surgery., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

The term "MINOCA" refers to myocardial infarction with non-obstructed coronary arteries and has been used to define acute myocardial infarction with no angiographic evidence of significant epicardial coronary artery stenosis. Patients with MINOCA represent a rather heterogeneous group of acute coronary syndrome, and this may account for the wide variation in the incidence of MINOCA in different studies. Several pathogenic mechanisms have been suggested to underlie MINOCA, but the condition continues to represent a diagnostic and therapeutic challenge for the cardiologist. Therefore, an adequate diagnostic assessment, carefully characterizing the pathogenic mechanisms, and a selection of more targeted treatments are needed to improve clinical outcomes. In this focused review, we will try to provide answers to the most common questions on the causes, diagnosis, treatment, and outcomes of MINOCA.

SOD1 gene is associated with progressive motor neuron degeneration in the familiar forms of amyotrophic lateral sclerosis. Although studies on mutant human SOD1 transgenic rodent models have provided important insights into disease pathogenesis, they have not led to the discovery of early biomarkers or effective therapies in human disease. The recent generation of a transgenic swine model expressing the human pathological hSOD1 G93A gene, which recapitulates the course of human disease, represents an interesting tool for the identification of early disease mechanisms and diagnostic biomarkers. Here, we analyze the activation state of CNS cells in transgenic pigs during the disease course and investigate whether changes in neuronal and glial cell activation state can be reflected by the amount of extracellular vesicles they release in biological fluids. To assess the activation state of neural cells, we performed a biochemical characterization of neurons and glial cells in the spinal cords of hSOD1 G93A pigs during the disease course. Quantification of EVs of CNS cell origin was performed in cerebrospinal fluid and plasma of transgenic pigs at different disease stages by Western blot and peptide microarray analyses. We report an early activation of oligodendrocytes in hSOD1 G93A transgenic tissue followed by astrocyte and microglia activation, especially in animals with motor symptoms. At late asymptomatic stage, EV production from astrocytes and microglia is increased in the cerebrospinal fluid, but not in the plasma, of transgenic pigs reflecting donor cell activation in the spinal cord. Estimation of EV production by biochemical analyses is corroborated by direct quantification of neuron- and microglia-derived EVs in the cerebrospinal fluid by a Membrane Sensing Peptide enabled on-chip analysis that provides fast results and low sample consumption. Collectively, our data indicate that alteration in astrocytic EV production precedes the onset of disease symptoms in the hSOD G93A swine model, mirroring donor cell activation in the spinal cord, and suggest that EV measurements from the cells first activated in the ALS pig model, i.e. OPCs, may further improve early disease detection., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

(1) Background: Systemic inflammation stands as a well-established risk factor for ischemic cardiovascular disease, as well as a contributing factor in the development of cardiac arrhythmias, notably atrial fibrillation. Furthermore, scientific studies have brought to light the pivotal role of localized vascular inflammation in the initiation, progression, and destabilization of coronary atherosclerotic disease. (2) Methods: We comprehensively review recent, yet robust, scientific evidence elucidating the use of perivascular adipose tissue attenuation measurement on computed tomography applied to key anatomical sites. Specifically, the investigation extends to the internal carotid artery, aorta, left atrium, and coronary arteries. (3) Conclusions: The examination of perivascular adipose tissue attenuation emerges as a non-invasive and indirect means of estimating localized perivascular inflammation. This measure is quantified in Hounsfield units, indicative of the inflammatory response elicited by dense adipose tissue near the vessel or the atrium. Particularly noteworthy is its potential utility in assessing inflammatory processes within the coronary arteries, evaluating coronary microvascular dysfunction, appraising conditions within the aorta and carotid arteries, and discerning inflammatory states within the atria, especially in patients with atrial fibrillation. The widespread applicability of perivascular adipose tissue attenuation measurement underscores its significance as a diagnostic tool with considerable potential for enhancing our understanding and management of cardiovascular diseases.

Background: Paucity and low evidence-level data on proton therapy (PT) represent one of the main issues for the establishment of solid indications in the PT setting. Aim of the present registry, the POWER registry, is to provide a tool for systematic, prospective, harmonized, and multidimensional high-quality data collection to promote knowledge in the field of PT with a particular focus on the use of hypofractionation., Methods: All patients with any type of oncologic disease (benign and malignant disease) eligible for PT at the European Institute of Oncology (IEO), Milan, Italy, will be included in the present registry. Three levels of data collection will be implemented: Level (1) clinical research (patients outcome and toxicity, quality of life, and cost/effectiveness analysis); Level (2) radiological and radiobiological research (radiomic and dosiomic analysis, as well as biological modeling); Level (3) biological and translational research (biological biomarkers and genomic data analysis). Endpoints and outcome measures of hypofractionation schedules will be evaluated in terms of either Treatment Efficacy (tumor response rate, time to progression/percentages of survivors/median survival, clinical, biological, and radiological biomarkers changes, identified as surrogate endpoints of cancer survival/response to treatment) and Toxicity. The study protocol has been approved by the IEO Ethical Committee (IEO 1885). Other than patients treated at IEO, additional PT facilities (equipped with Proteus®ONE or Proteus®PLUS technologies by IBA, Ion Beam Applications, Louvain-la-Neuve, Belgium) are planned to join the registry data collection. Moreover, the registry will be also fully integrated into international PT data collection networks., (© 2024. The Author(s).)

Background: Vaginal dryness (VD) represents a significant concern affecting women across diverse life stages, encompassing both pre- and postmenopausal women at any age. Dyspareunia, defined by genital pain that can be experienced before, during, or after intercourse, is often associated with vaginal dryness., Aim: This study aimed to evaluate the effectiveness and safety of a water-based vaginal lubricant with hyaluronic acid to reduce sexual discomfort associated with vaginal dryness., Methods: A prospective, multicenter, uncontrolled clinical investigation was conducted over a three-month period in women aged 18 years or older experiencing pain or difficulty during sexual intercourse for whom the use of a vaginal lubricant was recommended., Results: Significant improvements were observed in the FSFI scores, indicating enhanced sexual function ( p  < .001). Vaginal dryness symptoms, including irritation, dryness, itching, and dyspareunia, significantly decreased after product use ( p  < .001)., Clinical Implications: This study contributes to the limited scientific knowledge on the application of lubricants in the context of symptoms associated with VD., Strengths & Limitations: In addition to the short study period, inherent limitations of the study design, and lack of placebo control, it is pertinent to acknowledge that some of the pros used in this study were not based on validated questionnaires. However, as far as we know, this study is the only one that analyzes well-being and sexual pleasure as results using a lubricant formulated with hyaluronic acid., Conclusion: This tested vaginal lubricant with hyaluronic acid has demonstrated efficacy in improving vaginal dryness and female sexual function, particularly in reducing pain and improving lubrication during sexual intercourse, and showed a favorable safety profile, with minimal and transient adverse events.

Background: Multimodality imaging is currently suggested for the noninvasive diagnosis of cardiac masses. The identification of cardiac masses' malignant nature is essential to guide proper treatment. We aimed to develop a cardiac magnetic resonance (CMR)-derived model including mass localization, morphology, and tissue characterization to predict malignancy (with histology as gold standard), to compare its accuracy versus the diagnostic echocardiographic mass score, and to evaluate its prognostic ability., Methods: Observational cohort study of 167 consecutive patients undergoing comprehensive echocardiogram and CMR within 1-month time interval for suspected cardiac mass. A definitive diagnosis was achieved by histological examination or, in the case of cardiac thrombi, by histology or radiological resolution after adequate anticoagulation treatment. Logistic regression was performed to assess CMR-derived independent predictors of malignancy, which were included in a predictive model to derive the CMR mass score. Kaplan-Meier curves and Cox regression were used to investigate the prognostic ability of predictors., Results: In CMR, mass morphological features (non-left localization, sessile, polylobate, inhomogeneity, infiltration, and pericardial effusion) and mass tissue characterization features (first-pass perfusion and heterogeneity enhancement) were independent predictors of malignancy. The CMR mass score (range, 0-8 and cutoff, ≥5), including sessile appearance, polylobate shape, infiltration, pericardial effusion, first-pass contrast perfusion, and heterogeneity enhancement, showed excellent accuracy in predicting malignancy (areas under the curve, 0.976 [95% CI, 0.96-0.99]), significantly higher than diagnostic echocardiographic mass score (areas under the curve, 0.932; P =0.040). The agreement between the diagnostic echocardiographic mass and CMR mass scores was good (κ=0.66). A CMR mass score of ≥5 predicted a higher risk of all-cause death ( P <0.001; hazard ratio, 5.70) at follow-up., Conclusions: A CMR-derived model, including mass morphology and tissue characterization, showed excellent accuracy, superior to echocardiography, in predicting cardiac masses malignancy, with prognostic implications., Competing Interests: None.

Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC. A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1-3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable., (© 2024. The Author(s).)

Background: Cardiac magnetic resonance (CMR) plays a pivotal diagnostic role in myocardial infarction with nonobstructive coronary arteries (MINOCA). To date, a prognostic stratification of these patients is still lacking., Objectives: This study aims to assess the prognostic role of CMR in MINOCA., Methods: The authors assessed 437 MINOCA from January 2017 to October 2021. They excluded acute myocarditis, takotsubo syndromes, cardiomyopathies, and other nonischemic etiologies. Patients were classified into 3 subgroups according to the CMR phenotype: 1) presence of late gadolinium enhancement (LGE) and abnormal mapping (M) values (LGE+/M+); 2) regional ischemic injury with abnormal mapping and no LGE (LGE-/M+); and 3) nonpathological CMRs (LGE-/M-). The primary outcome was the presence of major adverse cardiovascular events (MACE). The mean follow-up was 33.7 ± 12.0 months and CMR was performed on average at 4.8 ± 1.5 days from the acute presentation., Results: The final cohort included 198 MINOCA; 116 (58.6%) comprised the LGE+/M+ group. During follow-up, MACE occurred significantly more frequently in MINOCA LGE+/M+ than in the LGE+/M- and normal-CMR (LGE-/M-) subgroups (20.7% vs 6.7% and 2.7%; P = 0.006). The extension of myocardial damage at CMR was significantly greater in patients who developed MACE. In multivariable Cox regression, %LGE was an independent predictor of MACE (HR: 1.123 [95% CI: 1.064-1.185]; P < 0.001) together with T2 mapping values (HR: 1.190 [95% CI: 1.145-1.237]; P = 0.001)., Conclusions: In MINOCA with early CMR execution, the %LGE and abnormal T2 mapping values were identified as independent predictors of adverse cardiac events at ∼3.0 years of follow-up. These parameters can be considered as high-risk markers in MINOCA., Competing Interests: Funding Support and Author Disclosures Dr Bucciarelli-Ducci has received speaker fees from Circle Cardiovascular Imaging, Bayer, Siemens Healthineers; and is the Chief Executive Officer (part-time) for the Society for Cardiovascular Magnetic Resonance. Dr Paolisso is supported by a research grant from the CardioPaTh PhD Program. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Hippocampal sparing whole-brain radiotherapy (HS-WBRT) showed significantly lower long-term side effects compared to standard WBRT. Aim of this study is to describe a HS-WBRT real-world monoinstitutional experience within a retrospective cohort., Methods: Patients who completed HS-WBRT course, with Karnofsky Performance Status ⩾ 60 and radiological diagnosis of brain metastases (BMs) were enrolled. Treatment was performed using helical Tomotherapy scheduled in 30 Gy in 10 or 12 fractions or 25 Gy in 10 fractions. Oncological outcomes were clinically and radiologically assessed every three months. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events 4.3., Results: One hundred and nineteen patients from 2016 to 2020 met inclusion criteria; after a median follow-up of 18 months, 29 patients were alive; 6- and 12-months overall survival rates were 66% and 41%, respectively. HS-WBRT response was assessed for 72 patients. Median time to any progression and intracranial failure (IF) was 4.5 and 13.7 months, respectively. The 6- and 12-month IF rates were 85% and 57%. Among 40 patients (34%) who experienced IF, 17 (42%) were oligometastatic, 23 (58%) polymetastatic and 15/40 developed IF within the hippocampi avoidance zone. No grade (G) ⩾ 2 acute toxicities were reported and one G2 (dizziness) late toxicity was described., Conclusions: HS-WBRT is well tolerated, and despite the hippocampal sparing region, the oncological control is satisfying. Further investigation is warranted to find patients who could most benefit from a HS-WBRT approach., 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.

Objectives: Cancer remains the leading cause of mortality by disease in childhood in high-income countries. For terminally ill children, care focuses on quality of life, and patient management fundamentally affects grieving families. This paper describes our experience of palliative sedation (PS) for children with refractory symptoms caused by solid tumours, focusing on the drugs involved., Methods: We retrospectively collected data on all children treated for cancer who died at the pediatric oncology unit of the Fondazione IRCCS Istituto Nazionale dei Tumori between January 2016 and December 2020., Results: Of the 29 patients eligible for the study, all but 4 received PS. Midazolam was always used, combined in 16 cases with other drugs (mainly classic neuroleptics, alpha-2 agonists and antihistamines). Throughout the period of PS and on the day of death, patients with sarcoma were given higher doses of midazolam and morphine, and more often received combinations of drugs than patients with brain tumours. Sarcoma causes significant symptoms, while brain tumours require less intensive analgesic-sedative therapies because they already impair a patient's state of consciousness., Conclusions: Optimising pharmacological treatments demands a medical team that knows how drugs (often developed for other indications) work. Emotional and relational aspects are important too, and any action to lower a patient's consciousness should be explained to the family and justified. Parents should not feel like helpless witnesses. Guidelines on PS in paediatrics could help, providing they acknowledge that a child's death is always a unique case., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Durable remissions are observed in 10%-20% of treated patients with advanced metastatic melanoma but the factors associated with long-term complete clinical responses are largely unknown. Here, we report the molecular characteristics of tumor evolution during disease progression along a 9-year clinical course in a patient with advanced disseminated melanoma who received different treatments, including trametinib, ipilimumab, radiation, vemurafenib, surgical tumor debulking and a second ipilimumab course, ultimately achieving complete long-term disease remission.Longitudinal analyses of therapies-resistant metastatic tumors revealed the effects of different treatments on tumor's microenvironment and immunogenicity, ultimately creating a milieu favorable to immunotherapy response. Monitoring of the temporal dynamics of T cells by analysis of the T cell receptor (TCR) repertoire in the tumor and peripheral blood during disease evolution indicated that T-cell clones with common TCR rearrangements, present at low levels at baseline, were maintained and expanded after immunotherapy, and that TCR diversity increased. Analysis of genetic, molecular, and cellular components of the tumor depicted a multistep process in which treatment with kinase inhibitors strongly conditioned the immune microenvironment creating an inflamed milieu converting cold into hot tumors, while ipilimumab impacted and increased the TCR repertoire, a requirement for tumor rejection.Since the optimal sequencing of treatment with antibodies targeting immune checkpoints and kinase inhibitors for advanced melanoma is still clinically debated, this case indicates that immunotherapy success is possible even after progression on targeted therapy., Competing Interests: Competing interests: None declared., (© 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.)

Speckle tracking echocardiography (STE) is a reliable imaging technique of recognized clinical value in several settings. This method uses the motion of ultrasound backscatter speckles within echocardiographic images to derive myocardial velocities and deformation parameters, providing crucial insights on several cardiac pathological and physiological processes. Its feasibility, reproducibility, and accuracy have been widely demonstrated, being myocardial strain of the various chambers inserted in diagnostic algorithms and guidelines for various pathologies. The most important parameters are Global longitudinal strain (GLS), Left atrium (LA) reservoir strain, and Global Work Index (GWI): based on large studies the average of the lower limit of normality are -16%, 23%, and 1442 mmHg%, respectively. For GWI, it should be pointed out that myocardial work relies primarily on non-invasive measurements of blood pressure and segmental strain, both of which exhibit high variability, and thus, this variability constitutes a significant limitation of this parameter. In this review, we describe the principal aspects of the theory behind the use of myocardial strain, from cardiac mechanics to image acquisition techniques, outlining its limitation, and its principal clinical applications: in particular, GLS have a role in determine subclinical myocardial dysfunction (in cardiomyopathies, cardiotoxicity, target organ damage in ambulatory patients with arterial hypertension) and LA strain in determine the risk of AF, specifically in ambulatory patients with arterial hypertension., (© 2024 Wiley Periodicals LLC.)

B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27 + memory B cells of patients with active AAV was performed, revealing an upregulated NF-κB-associated gene signature. NF-κB signaling pathways act downstream of various B cell surface receptors, including the BCR, CD40, BAFFR and TLRs, and are essential for B cell responses. Here we demonstrate that novel pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signaling) and inhibitor-of-κB-kinase-β (IKKβ, canonical NF-κB signaling) can effectively inhibit NF-κB signaling in B cells, whereas T cell responses were largely unaffected. Moreover, both inhibitors significantly reduced B cell proliferation, differentiation and production of antibodies, including proteinase-3 (PR3) autoantibodies, in B lineage cells of AAV patients. These findings indicate that targeting NF-κB, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement., Competing Interests: Declaration of competing interest “The authors have declared that no conflict of interest exists”., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: Radiation-induced oral mucositis (RIOM) is the most frequent side effect in head and neck cancer (HNC) patients treated with curative radiotherapy (RT). A standardized strategy for preventing and treating RIOM has not been defined. Aim of this study was to perform a real-life survey on RIOM management among Italian RT centers., Methods: A 40-question survey was administered to 25 radiation oncologists working in 25 different RT centers across Italy., Results: A total of 1554 HNC patients have been treated in the participating centers in 2021, the majority (median across the centers 91%) with curative intent. Median treatment time was 41 days, with a mean percentage of interruption due to toxicity of 14.5%. Eighty percent of responders provide written oral cavity hygiene recommendations. Regarding RIOM prevention, sodium bicarbonate mouthwashes, oral mucosa barrier agents, and hyaluronic acid-based mouthwashes were the most frequent topic agents used. Regarding RIOM treatment, 14 (56%) centers relied on literature evidence, while internal guidelines were available in 13 centers (44%). Grade (G)1 mucositis is mostly treated with sodium bicarbonate mouthwashes, oral mucosa barrier agents, and steroids, while hyaluronic acid-based agents, local anesthetics, and benzydamine were the most used in mucositis G2/G3. Steroids, painkillers, and anti-inflammatory drugs were the most frequent systemic agents used independently from the RIOM severity., Conclusion: Great variety of strategies exist among Italian centers in RIOM management for HNC patients. Whether different strategies could impact patients' compliance and overall treatment time of the radiation course is still unclear and needs further investigation., (© 2023. The Author(s).)

Osteoradionecrosis (ORN) is a serious long-term complication of head and neck radiotherapy (RT), which is often triggered by dental extractions. It results from avascular aseptic necrosis due to irradiated bone damage. ORN is challenging to treat and can lead to severe complications. Furthermore, ORN causes pain and distress, significantly reducing the patient's quality of life. There is currently no established preventive strategy. This narrative review aims to provide an update for the clinicians on the risk of ORN associated with oral surgery in head and neck RT patients, with a focus on the timing suitable for the oral surgery and possible ORN preventive treatments. An electronic search of articles was performed by consulting the PubMed database. Intervention and observational studies were included. A multidisciplinary approach to the patient is highly recommended to mitigate the risk of RT complications. A dental visit before commencing RT is highly advised to minimize the need for future dental extractions after irradiation, and thus the risk of ORN. Post-RT preventive strategies, in case of dento-alveolar surgery, have been proposed and include antibiotics, hyperbaric oxygen (HBO), and the combined use of pentoxifylline and tocopherol ("PENTO protocol"), but currently there is a lack of established standards of care. Some limitations in the use of HBO involve the low availability of HBO facilities, its high costs, and specific clinical contraindications; the PENTO protocol, on the other hand, although promising, lacks clinical trials to support its efficacy. Due to the enduring risk of ORN, removable prostheses are preferable to dental implants in these patients, as there is no consensus on the appropriate timing for their safe placement. Overall, established standards of care and high-quality evidence are lacking concerning both preventive strategies for ORN as well as the timing of the dental surgery. There is an urgent need to improve research for more efficacious clinical decision making.

Objectives: Although transfusion support is commonly used in oncological palliative care, there is still a paucity of literature. We examined the transfusion support provided in the terminal stage of the disease and compared the approach at a pediatric oncology unit and a pediatric hospice., Case Description: This case series analyzed patients treated at the Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT)'s pediatric oncology unit who died between January 2018 and April 2022. We compared these with those who died at the VIDAS hospice and analyzed the number of complete blood counts taken in a patient's last 14 days of life, and the number of transfusions performed in the same period.We analyzed 44 patients (22 in pediatric oncology unit; 22 in hospice) in total. Twenty-eight complete blood counts were performed (7/22 patients at the hospice; 21/22 patients at the pediatric oncology unit). Nine patients were given transfusions, three at the hospice, six at our pediatric oncology unit (24 transfusions in total): 20 transfusions at the pediatric oncology unit, four at the hospice. In total 17/44 patients were given active therapies in the last 14 days of life: 13 at the pediatric oncology unit, four at the pediatric hospice. Ongoing cancer treatments did not correlate with a greater likelihood of receiving a transfusion (p=0.91)., Conclusions: The hospice's approach was more conservative than the pediatric oncology one. In the in-hospital setting, the need for a transfusion cannot always be decided on by a combination of numerical values and parameters alone. The family's emotional-relational response must be considered too., 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: The therapeutic potential of proton therapy (PT) was first recognized in 1946 by Robert Wilson, and nowadays, over 100 proton centers are in operation worldwide, and more than 60 are under construction or planned. Bibliometric data can be used to perform a structured analysis of large amounts of scientific data to provide new insights, e.g., to assess the growth and development of the field and to identify research trends and hot topics. The aim of this study is to provide a comprehensive bibliometric analysis of the current status and trends in scientific literature in the PT field., Methods: The literature on PT until the 31st December 2022 in the Scopus database was searched, including the following keywords: proton AND radiotherapy AND cancer / tumor in title, abstract, and/or keywords. The open-source R Studio's Bibliometrix package and Biblioshiny software (version 2.0) were used to perform the analysis., Results: A total of 7335 documents, mainly articles (n = 4794, 65%) and reviews (n = 1527, 21%), were collected from 1946 to 2022 from 1054 sources and 21,696 authors. Of these, roughly 84% (n = 6167) were produced in the last 15 years (2008-2022), in which the mean annual growth rate was 13%. Considering the corresponding author's country, 79 countries contributed to the literature; the USA was the top contributor, with 2765 (38%) documents, of whom 84% were single-country publications (SCP), followed by Germany and Japan, with 535 and 531 documents of whom 66% and 93% were SCP. Considering the themes subanalysis (2002-2022), a total of 7192 documents were analyzed; among all keywords used by authors, the top three were radiotherapy (n = 1394, 21% of documents), intensity-modulated radiotherapy (n = 301, 5%), and prostate cancer (n = 301, 5%). Among disease types, prostate cancer is followed by chordoma, head and neck, and breast cancer. The change in trend themes demonstrated the fast evolution of hotspots in PT; among the most recent trends, the appearance of flash, radiomics, relative biological effectiveness (RBE) , and linear energy transfer (LET) deserve to be highlighted., Conclusions: The results of the present bibliometric analysis showed that PT is an active and rapidly increasing field of research. Themes of the published works encompass the main aspects of its application in clinical practice, such as the comparison with the actual photon-based standard of care technique and the continuing technological advances. This analysis gives an overview of past scientific production and, most importantly, provides a useful point of view on the future directions of the research activities.