Developing a robust two-step machine learning multiclassification pipeline to predict primary site in head and neck carcinoma from lymph nodes.

This study aimed to develop a robust multiclassification pipeline to determine the primary tumor location in patients with head and neck carcinoma of unknown primary using radiomics and machine learning techniques. The dataset included 400 head and neck cancer patients with primary tumor in oropharynx, OPC (n = 162), nasopharynx, NPC (n = 137), oral cavity, OC (n = 63), larynx and hypopharynx, HL (n = 38). Two radiomic-based multiclassification pipelines (P1 and P2) were developed. P1 consisted in a direct identification of the primary sites, whereas P2 was based on a two-step approach: in the first step, the number of classes was reduced by merging the two minority classes which were reclassified in the second step. Diverse correlation thresholds (0.75, 0.80, 0.85), feature selection methods (sequential forwards/backwards selection, sequential floating forward selection, neighborhood component analysis and minimum redundancy maximum relevance), and classification models (neural network, decision tree, naïve Bayes, bagged trees and support vector machine) were assessed. P2 outperformed P1, with the best results obtained with the support vector machine classifier including radiomic and clinical features (accuracies of 75.3 % (HL), 75.4 % (OC), 71.3 % (OPC), 92.9 % (NPC)). These results indicate that the two-step multiclassification pipeline integrating radiomics and clinical information is a promising approach to predict the tumor site of unknown primary.

Prediction of diabetes insipidus occurrence after endoscopic endonasal removal of sellar lesions using MRI-based radiomics and machine learning.

BACKGROUND: Pituitary adenomas and craniopharyngiomas are the most common lesions of the sellar region. These tumors are responsible for invasion or compression of crucial neurovascular structures. The involvement of the pituitary stalk warrants high rates of both pre- and post- operative diabetes insipidus. The aim of our study was to assess the accuracy of machine learning analysis from preoperative MRI of pituitary adenomas and craniopharyngiomas for the prediction of DI occurrence. METHODS: All patients underwent MRI exams either on a 1.5- or 3-T MR scanner from two Institutions, including coronal T2-weighted (T2-w) and contrast-enhanced T1-weighted (CE T1-w) Turbo Spin Echo sequences. Feature selection was carried out as a multi-step process, with a threshold of 0.75 to identify robust features. Further feature selection steps included filtering based on feature variance (threshold >0.01) and pairwise correlation (threshold <0.80). A Bayesian Network model was trained with 10-fold cross validation employing SMOTE to balance classes exclusively within the training folds. RESULTS: Thirty patients were included in this study. In total 2394 features were extracted and 1791 (75%) resulted stable after ICC analysis. The number of variant features was 1351 and of non-colinear features was 125. Finally, 10 features were selected by oneR ranking. The Bayesian Network model showed an accuracy of 63% with a precision of 77% for DI prediction (0.68 area under the precision-recall curve). CONCLUSIONS: We assessed the accuracy of machine learning analysis of texture-derived parameters from preoperative MRI of pituitary adenomas and craniopharyngiomas for the prediction of DI occurrence.

Awareness of individual goals, preferences, and priorities of persons with severe congenital haemophilia A for a tailored shared decision-making approach to liver-directed gene therapy. A practical guideline.

In clinical medicine, shared decision making (SDM) is a well-recognized strategy to enhance engagement of both patients and clinicians in medical decisions. The success of liver-directed gene therapy (GT) to transform severe congenital haemophilia A (HA) from an incurable to a curable disease has launched a shift beyond current standards of treatment. However, GT acceptance remains low in the community of HA persons. We argue for both persons with haemophilia (PWH) and specialists in HA care including clinicians, as needing SDM-oriented educational programs devoted to GT. Here, we provide an ad hoc outline to implement education to SDM and tailor clinician information on GT to individual PWHs. Based on routine key components of SDM: patient priorities; recommendations based on individual risk reduction; adverse effects; drug-drug interactions; alternatives to GT; and ongoing re-assessment of the objectives as risk factors (and individual priorities) change, this approach is finalized to exploit efficacious communication.

Systematic review of the radiomics quality score applications: an EuSoMII Radiomics Auditing Group Initiative.

OBJECTIVE: The main aim of the present systematic review was a comprehensive overview of the Radiomics Quality Score (RQS)-based systematic reviews to highlight common issues and challenges of radiomics research application and evaluate the relationship between RQS and review features. METHODS: The literature search was performed on multiple medical literature archives according to PRISMA guidelines for systematic reviews that reported radiomic quality assessment through the RQS. Reported scores were converted to a 0-100% scale. The Mann-Whitney and Kruskal-Wallis tests were used to compare RQS scores and review features. RESULTS: The literature research yielded 345 articles, from which 44 systematic reviews were finally included in the analysis. Overall, the median of RQS was 21.00% (IQR = 11.50). No significant differences of RQS were observed in subgroup analyses according to targets (oncological/not oncological target, neuroradiology/body imaging focus and one imaging technique/more than one imaging technique, characterization/prognosis/detection/other). CONCLUSIONS: Our review did not reveal a significant difference of quality of radiomic articles reported in systematic reviews, divided in different subgroups. Furthermore, low overall methodological quality of radiomics research was found independent of specific application domains. While the RQS can serve as a reference tool to improve future study designs, future research should also be aimed at improving its reliability and developing new tools to meet an ever-evolving research space. KEY POINTS: • Radiomics is a promising high-throughput method that may generate novel imaging biomarkers to improve clinical decision-making process, but it is an inherently complex analysis and often lacks reproducibility and generalizability. • The Radiomics Quality Score serves a necessary role as the de facto reference tool for assessing radiomics studies. • External auditing of radiomics studies, in addition to the standard peer-review process, is valuable to highlight common limitations and provide insights to improve future study designs and practical applicability of the radiomics models.

Ovarian imaging radiomics quality score assessment: an EuSoMII radiomics auditing group initiative.

OBJECTIVE: To evaluate the methodological rigor of radiomics-based studies using noninvasive imaging in ovarian setting. METHODS: Multiple medical literature archives (PubMed, Web of Science, and Scopus) were searched to retrieve original studies focused on computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), or positron emission tomography (PET) radiomics for ovarian disorders' assessment. Two researchers in consensus evaluated each investigation using the radiomics quality score (RQS). Subgroup analyses were performed to assess whether the total RQS varied according to first author category, study aim and topic, imaging modality, and journal quartile. RESULTS: From a total of 531 items, 63 investigations were finally included in the analysis. The studies were greatly focused (94%) on the field of oncology, with CT representing the most used imaging technique (41%). Overall, the papers achieved a median total RQS 6 (IQR, -0.5 to 11), corresponding to a percentage of 16.7% of the maximum score (IQR, 0-30.6%). The scoring was low especially due to the lack of prospective design and formal validation of the results. At subgroup analysis, the 4 studies not focused on oncological topic showed significantly lower quality scores than the others. CONCLUSIONS: The overall methodological rigor of radiomics studies in the ovarian field is still not ideal, limiting the reproducibility of results and potential translation to clinical setting. More efforts towards a standardized methodology in the workflow are needed to allow radiomics to become a viable tool for clinical decision-making. KEY POINTS: • The 63 included studies using noninvasive imaging for ovarian applications were mostly focused on oncologic topic (94%). • The included investigations achieved a median total RQS 6 (IQR, -0.5 to 11), indicating poor methodological rigor. • The RQS was low especially due to the lack of prospective design and formal validation of the results.

Meningioma Radiomics: At the Nexus of Imaging, Pathology and Biomolecular Characterization.

Meningiomas are the most common extra-axial tumors of the central nervous system (CNS). Even though recurrence is uncommon after surgery and most meningiomas are benign, an aggressive behavior may still be exhibited in some cases. Although the diagnosis can be made by radiologists, typically with magnetic resonance imaging, qualitative analysis has some limitations in regard to outcome prediction and risk stratification. The acquisition of this information could help the referring clinician in the decision-making process and selection of the appropriate treatment. Following the increased attention and potential of radiomics and artificial intelligence in the healthcare domain, including oncological imaging, researchers have investigated their use over the years to overcome the current limitations of imaging. The aim of these new tools is the replacement of subjective and, therefore, potentially variable medical image analysis by more objective quantitative data, using computational algorithms. Although radiomics has not yet fully entered clinical practice, its potential for the detection, diagnostic, and prognostic characterization of tumors is evident. In this review, we present a wide-ranging overview of radiomics and artificial intelligence applications in meningioma imaging.

The impact of radiomics for human papillomavirus status prediction in oropharyngeal cancer: systematic review and radiomics quality score assessment.

PURPOSE: Human papillomavirus (HPV) status assessment is crucial for decision making in oropharyngeal cancer patients. In last years, several articles have been published investigating the possible role of radiomics in distinguishing HPV-positive from HPV-negative neoplasms. Aim of this review was to perform a systematic quality assessment of radiomic studies published on this topic. METHODS: Radiomics studies on HPV status prediction in oropharyngeal cancer patients were selected. The Radiomic Quality Score (RQS) was assessed by three readers to evaluate their methodological quality. In addition, possible correlations between RQS% and journal type, year of publication, impact factor, and journal rank were investigated. RESULTS: After the literature search, 19 articles were selected whose RQS median was 33% (range 0-42%). Overall, 16/19 studies included a well-documented imaging protocol, 13/19 demonstrated phenotypic differences, and all were compared with the current gold standard. No study included a public protocol, phantom study, or imaging at multiple time points. More than half (13/19) included feature selection and only 2 were comprehensive of non-radiomic features. Mean RQS was significantly higher in clinical journals. CONCLUSION: Radiomics has been proposed for oropharyngeal cancer HPV status assessment, with promising results. However, these are supported by low methodological quality investigations. Further studies with higher methodological quality, appropriate standardization, and greater attention to validation are necessary prior to clinical adoption.

Spectral Photon-Counting Computed Tomography: A Review on Technical Principles and Clinical Applications.

Photon-counting computed tomography (CT) is a technology that has attracted increasing interest in recent years since, thanks to new-generation detectors, it holds the promise to radically change the clinical use of CT imaging. Photon-counting detectors overcome the major limitations of conventional CT detectors by providing very high spatial resolution without electronic noise, providing a higher contrast-to-noise ratio, and optimizing spectral images. Additionally, photon-counting CT can lead to reduced radiation exposure, reconstruction of higher spatial resolution images, reduction of image artifacts, optimization of the use of contrast agents, and create new opportunities for quantitative imaging. The aim of this review is to briefly explain the technical principles of photon-counting CT and, more extensively, the potential clinical applications of this technology.

A Combined Radiomics and Machine Learning Approach to Distinguish Clinically Significant Prostate Lesions on a Publicly Available MRI Dataset.

Although prostate cancer is one of the most common causes of mortality and morbidity in advancing-age males, early diagnosis improves prognosis and modifies the therapy of choice. The aim of this study was the evaluation of a combined radiomics and machine learning approach on a publicly available dataset in order to distinguish a clinically significant from a clinically non-significant prostate lesion. A total of 299 prostate lesions were included in the analysis. A univariate statistical analysis was performed to prove the goodness of the 60 extracted radiomic features in distinguishing prostate lesions. Then, a 10-fold cross-validation was used to train and test some models and the evaluation metrics were calculated; finally, a hold-out was performed and a wrapper feature selection was applied. The employed algorithms were Naïve bayes, K nearest neighbour and some tree-based ones. The tree-based algorithms achieved the highest evaluation metrics, with accuracies over 80%, and area-under-the-curve receiver-operating characteristics below 0.80. Combined machine learning algorithms and radiomics based on clinical, routine, multiparametric, magnetic-resonance imaging were demonstrated to be a useful tool in prostate cancer stratification.

Perspective - The case for zero bleeds and drug bioequivalence in the treatment of congenital hemophilia A in 2021.

Not all patients with severe hemophilia A (HA) respond optimally to a given dose of a given product. Within-individual variance in cross-over studies makes each patient unique in the response to each standard half-life (SHL) factor VIII (FVIII) product in pharmacokinetic (PK) terms. This hampers the prediction of efficacy when a SHL FVIII product is employed. PK data showing that half-lives of SHL rFVIII are unsatisfactory to achieve zero bleeding in individual HA patients provide the rationale for switching from SHL to extended half-life (EHL) products. However, not all subjects receiving prophylaxis with EHL products achieve zero bleeding, the most cogent objective of personalized prophylaxis. Known determinants of FVIII half-life (age, von Willebrand factor [VWF] levels, blood group) cumulatively account for one third of the total inter-individual variation in FVIII clearance in subjects with severe HA. Investigations into precision, and accuracy of laboratory measurement to be employed; newer pathways for the clearance of both free-FVIII and VWF-bound FVIII, and adequately powered studies on omics and phenotypic heterogeneity, are likely to provide additional information on the remaining two thirds of inter-individual variation in FVIII clearance in HA. Variability in the clinical response has also been documented in patients when FVIII activity is mimicked by fixed subcutaneous doses of the bispecific antibody emicizumab. National registries that collect PK data of available FVIII products and ad hoc information on the individual response to emicizumab should be encouraged, to establish newer standards of care and ease personalized clinical decisions to achieve zero bleeding.

MRI based radiomics in nasopharyngeal cancer: Systematic review and perspectives using radiomic quality score (RQS) assessment.

BACKGROUND: MRI based radiomics has the potential to better define tumor biology compared to qualitative MRI assessment and support decisions in patients affected by nasopharyngeal carcinoma. Aim of this review was to systematically evaluate the methodological quality of studies using MRI- radiomics for nasopharyngeal cancer patient evaluation. METHODS: A systematic search was performed in PUBMED, WEB OF SCIENCE and SCOPUS using "MRI, magnetic resonance imaging, radiomic, texture analysis, nasopharyngeal carcinoma, nasopharyngeal cancer" in all possible combinations. The methodological quality of study included ( = 24) was evaluated according to the RQS (Radiomic quality score). Subgroup, for journal type (imaging/clinical) and biomarker (prognostic/predictive), and correlation, between RQS and journal Impact Factor, analyses were performed. Mann-Whitney U test and Spearman's correlation were performed. P value < .05 were defined as statistically significant. RESULTS: Overall, no studies reported a phantom study or a test re-test for assessing stability in image, biological correlation or open science data. Only 8% of them included external validation. Almost half of articles (45 %) performed multivariable analysis with non-radiomics features. Only 1 study was prospective (4%). The mean RQS was 7.5 ± 5.4. No significant differences were detected between articles published in clinical/imaging journal and between studies with a predictive or prognostic biomarker. No significant correlation was found between total RQS and Impact Factor of the year of publication (p always > 0.05). CONCLUSIONS: Radiomic articles in nasopharyngeal cancer are mostly of low methodological quality. The greatest limitations are the lack of external validation, biological correlates, prospective design and open science.

The evolving landscape of gene therapy for congenital haemophilia: An unprecedented, problematic but promising opportunity for worldwide clinical studies.

With liver-directed gene therapy, congenital haemophilia has the potential to progress from an incurable to a phenotypically curable condition. However, the proportion of haemophilia population likely to benefit from gene therapy remains to be established. Achieving a phenotypic curative goal is presently hampered by: 1) availability of effective treatments (e.g. extended half-life products, non-factor therapies) that address major unmet needs in haemophilia; 2) key differences between hope and reality that patients undergoing gene therapy face (e.g. unknown risks and long-term follow-up, durability of the therapeutic effect, possibility of re-administering the vector), 3) lack of expertise of health care professionals (HCP) in managing/monitoring unexpected side effects in patients, and 4) lack of expertise of HCP in advising payers on key issues for cost-effectiveness analyses of gene therapy (e.g., eligibility criteria, predictability of response, unknown risks, long-term complications). There is also uncertainty about the possibility to absorb the cost of the "one-time, one-dose cure" by payers that are used to different payment models. An active partnership between regulators, payers, patients and health care professionals is key to identify patient sub-populations that might benefit the most from gene therapy, and to align the interests of patients (needing effective disease correction and improved quality of life) and pharma companies (reluctant to lose the profitability of lifelong repeated treatments). Educational programs will provide the healthcare chain with information on the strategy that is expected to transform morbidity and mortality patterns and how it should be regarded as part of the future therapeutic options in haemophilia.

Sarcoidosis-like disease mimicking metastases during adjuvant ipilimumab therapy in advanced melanoma patient: CT scan and MRI help in managing difficult clinical decision.

The onset of an autoimmune, sarcoidosis-like reaction during or after treatment with immunomodulatory drugs as Ipilimumab is an atypical but renowned eventuality. Awareness of this scenario and its radiological features helps the Radiologist to avoid misdiagnosis of disease progression. In this case report, we present a patient operated for advanced cutaneous melanoma of the left forearm who developed hilar adenopathies with lung and splenic nodules during therapy with Ipilimumab in adjuvant setting. These findings were at first referred to as disease recurrences. Based on discrepancies between imaging, clinic and blood test findings we decided to put the patient on strict follow-up which showed a spontaneous complete regression on the visceral lesions few months after Ipilimumab withheld.

Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background Bempedoic acid (BA) is a novel lipid-lowering drug. We performed a systematic review and meta-analysis on efficacy and safety of BA compared with standard treatment in patients with hypercholesterolemia. Methods and Results Studies were systematically searched in the PubMed, Web of Science, Scopus, and EMBASE databases. Efficacy outcome was represented by percentage changes (mean difference [MD] with pertinent 95% CIs) in total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol, and hs-CRP (high-sensitivity C-reactive protein) in BA patients and controls. Seven studies were included (2767 BA-treated patients and 1469 controls), showing a more significant reduction in low-density lipoprotein cholesterol (MD, -17.5%; 95% CI, -22.9% to -12.0%), total cholesterol (MD, -10.9%; 95% CI, -13.3% to -8.5%), non-high-density lipoprotein cholesterol (MD, -12.3%; 95% CI, -15.3% to -9.20%), apolipoprotein B (MD, -10.6%; 95% CI, -13.2% to -8.02%), and hs-CRP (MD, -13.2%; 95% CI, -16.7% to -9.79%) in BA-treated patients compared with controls. Results were confirmed when separately analyzing studies on patients with high cardiovascular risk, studies on statin-intolerant patients, and studies on patients with hypercholesterolemia on maximally tolerated lipid-lowering therapy. BA-treated subjects reported a higher rate of treatment discontinuation caused by adverse effects, of gout flare, and of increase in uric acid compared with controls. On the other hand, BA-treated patients showed a lower incidence of new-onset diabetes mellitus than controls. Conclusions BA is associated with a significant reduction in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and hs-CRP compared with standard treatment. Documented efficacy is accompanied by an acceptable safety profile.

Spontaneous bronchobiliary fistula: Case report.

Bronchobiliary fistula (BBF) is a rare condition that results from the communication between the bile ducts and the bronchial tree. It is characterized by the presence of bile in the sputum as pathognomonic symptom, and it is often associated with suspicious pneumonia. The most common causes include infections (e.g. echinococcosis), hepatobiliary surgery, blunt torso traumas, tumors and percutaneous transhepatic procedures. Opinions about BBF treatment are still controversial as it can be treated by both conservative and surgical procedures, while pharmacological treatments are only rarely used. This case report presents a patient who had been diagnosed with chronic BBF of unknown cause, underwent several ineffective conservative procedures and was at last surgically treated.

From unfractionated heparin to pentasaccharide: Paradigm of rigorous science growing in the understanding of the in vivo thrombin generation.

Following a chance discovery made by a medical student who was searching for a clot-promoting activity in tissue extracts, it took 15-20 years to attain the therapeutic use of standard unfractionated heparin (UFH), due to problems with the purification and extraction of the active material. Soon it was found that: 1) thrombin inactivation by UFH was associated with the formation of molecular complexes between antithrombin and the activated forms of factor X (FXa) and thrombin, 2) low-molecular-weight fractions of UFH lose their antithrombin activity while still interacting with FXa, 3) a pentasaccharide sequence of UHF increases FXa (but not thrombin) inactivation by antithrombin. Low-molecular-weight heparins (LMWHs) with little effect on thrombin and strongly active versus FXa were then developed. In patients, LMWHs (and the pentasaccharide sequence) came up as a useful class of drugs to prevent and treat thrombosis, their greatest advantage over UFH being the convenience of the once/twice daily subcutaneous injections at a fixed dose without any laboratory monitoring. In addition to providing major information on in vivo modulation of thrombin generation, the heparin saga served as a paradigm to support an alternative coagulation scheme that includes platelets and tissue factor as integral parts of the model. Forthcoming work with this scheme - also supported by studies in hemophilia and rare bleeding disorders - is expected to provide major hints for understanding why some patients benefit more than others from the small amount of thrombin they form and directions to tailor prevention and treatment of thromboembolic disorders.

Paradigm shift for the treatment of hereditary haemophilia: Towards precision medicine.

Patients with haemophilia A (HA) or B (HB) experience spontaneous limb- or life-threatening bleedings which are prevented by regular prophylactic intravenous infusions of the deficient coagulation factor (FVIII or FIX). Prophylaxis with subcutaneous long-acting non-factor products that improve in vivo thrombin generation is now under intensive investigation (concizumab, fitusiran) or successfully employed (emicizumab) in haemophilia patients. Both haemophilia patients with/without inhibitors take advantage of non-factor products employed alone. In those who also need bypassing agents (or FVIII concentrates) for breakthrough bleeds, thromboembolic events and/or thrombotic microangiopathy may occur. By enhancing thrombin generation, prothrombotic mutations co-segregating with FVIII/FIX gene mutations may trigger thrombotic episodes in HA patients carrying acquired thrombogenic factors (e.g. venous catheters). A thorough knowledge of individual needs increasingly contributed to improve comprehensive care and personalize treatments in haemophilia. Integrating genomics, lifestyle and environmental data is expected to be key to: 1) identify which haemophilia patients are less likely to benefit from a given intervention; 2) define optimal dosing and scheduling of bypassing agents (or FVIII) to employ in combination with non-factor products; 3) establish tests to monitor in vivo thrombin generation; 4) improve communication and deliver results to individuals. As individual outcomes will be improved and the risk of adverse events minimized, non-factor products will come into wider use within the haemophilia community, and patients will hopefully have no more risks of breakthrough bleeds. The risks of a normal life for a "former haemophilia patient" is likely to change the treatment landscape and the structure of haemophilia Centers.

Cardiovascular morbidity and mortality in patients with aortic valve calcification: A systematic review and meta-analysis.

BACKGROUND: Aortic valve calcification (AVC) is an active process that involves inflammation, disorganization of matrix disposition, lipid accumulation and lamellar bone formation. AVC without hemodynamic changes has been associated with cardiovascular (CV) risk factors and increased risk of coronary and CV events. Nowadays, echocardiography is the standard imaging technique to evaluate aortic valve pathologies. However, cardiac computed tomography (CT) allows high accuracy and reproducible measurement of AVC, without exposing the patients to excessive radiation or contrast administration. AIMS: To better understand if AVC assessment may improve CV risk-prediction, we performed a systematic search and meta-analysis of literature studies, evaluating the relationship among AVC, coronary artery disease (CAD), and overall mortality. METHODS AND RESULTS: A detailed search, according to PRISMA guidelines, was performed to identify all available studies investigating AVC, measured by CT scan, and CV events. Thirteen studies on 3,782 AVC patients and 32,890 controls were included in the final analysis. Patients with AVC have a higher risk of CAD (OR 1.7, 95%CI: 1.04-2.87; p = 0.04) when compared to controls. We also found an association between AVC and coronary artery calcification (OR 3.8; 95%CI: 2.4-6.0; p < 0.001.) Finally, AVC had 93.2% specificity for overall mortality (95%CI: 92.8-93.6) with a negative predictive value of 98.8% (95%CI: 98.7-98.8). CONCLUSION: AVC is associated with coronary artery calcification and overall mortality. The present data cannot support the use of cardiac CT over echocardiography for AVC assessment in all patients, but when cardiac CT is performed for suspected CAD, AVC evaluation may contribute to risk stratification and patient management. Ad hoc designed studies should address this issue in the next future.

Petroclival meningiomas: radiological features essential for surgeons.

Petroclival meningiomas (PCMs) have always been a challenge for surgeons because of their difficult anatomical location. The role of radiology in providing precise indications regarding the tumour site and aggressiveness plays a major part in guiding the subsequent therapeutic process. The purpose of this review is to provide a set of the main radiological features helpful in the management of PCMs towards the most correct therapeutic approach. We aim to offer a radiological overview to allow the patient to be directed to surgery with the least possible risk of complications.

Attempting to remedy sub-optimal medication adherence in haemophilia: The rationale for repeated ultrasound visualisations of the patient's joint status.

Haemophilia is marked by joint bleeding (haemarthrosis) leading to cartilage damage (arthropathy). Lifelong prophylaxis-initiated after the first bleeding episode-leads to a dramatic decrease in arthropathy in haemophilia patients. However, adherence to continuous intravenous administrations of factor VIII (FVIII) or FIX products is challenging, and patients potentially suffer from breakthrough bleedings while on prophylaxis. Newer FVIII/FIX products with enhanced convenience attributes and/or easier infusion procedures are intended to improve adherence. However, pharmacokinetic data should be harmonised with information from individual attitudes and treatment needs, to tailor intravenous dosing and scheduling in patients who receive extended half-life products. Nor is there sound evidence as to how subcutaneous non-FVIII/FIX replacement approaches (concizumab; emicizumab; fitusiran) or single intravenous injections of adeno-associated viral vectors (when employing gene therapy) will revolutionize adherence in haemophilia. In rheumatoid arthritis, repeated ultrasound examination of a patient's major joints is a valuable tool to educate patients and parents to understand the disease and provide an objective framework for clinicians to acknowledge patient's adherence. Joint ultrasound examination in haemophilia significantly correlates with cartilage damage, effusion, and synovial hypertrophy evaluated by magnetic resonance imaging. Furthermore, in patients with haemophilia undergoing prophylaxis with an extended half-life product for a ≈ 2.8 year period, a significant continued improvement in joint health is detected at the physical examination. This provides the rationale for studies on repeated ultrasound examinations of joint status to attempt to remedy sub-optimal medication adherence and help identify which approach is most suited on which occasion and for which patient.