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Somatic activating Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations have been reported in patients with arteriovenous malformations. By producing LSL-Kras (G12D); Cdh5 (PAC)-CreERT2 [iEC-Kras (G12D∗)] mice, we hoped to activate KRAS within vascular endothelial cells (ECs) to generate an arteriovenous malformation mouse model. Neonatal mice were treated daily with tamoxifen from postnatal (PN) days 1–3. Mortality and phenotypes varied amongst iEC-Kras (G12D∗) pups, with only 31.5% surviving at PN14. Phenotypes (focal lesions, vessel dilations) developed in a consistent manner, although with unpredictable severity within multiple soft tissues (such as the brain, liver, heart and brain). Overall, iEC-Kras (G12D∗) pups developed significantly larger vascular lumen areas compared with control littermates, beginning at PN8. We subsequently tested whether the MEK inhibitor trametinib could effectively alleviate lesion progression. At PN16, iEC-Kras (G12D∗) pup survival improved to 76.9%, and average vessel sizes were closer to controls than in untreated and vehicle-treated mutants. In addition, trametinib treatment helped normalize iEC-Kras (G12D∗) vessel morphology in PN14 brains. Thus, trametinib could act as an effective therapy for KRAS-induced vascular malformations in patients.

INTRODUCTION: Ankle arthropathy is highly prevalent among people with haemophilia (PwH), even with prophylaxis, and leads to pain and disability. Mechanisms and consequences of painful symptoms related to ankle arthropathy have not been extensively studied. METHODS: A consecutive sample of 30 adult PwH was included (60 ankles). Ankle structure was assessed with magnetic resonance imaging (IPSG-MRI) and ultrasound (HEAD-US). The HJHS 2.1 assessed function of ankles and knees. Physical functioning was assessed with the Timed Up and Go test, the 2-Minute Walking Test and activity limitations with the HAL questionnaire. Health-related quality of life was evaluated using the EQ-5D-5L questionnaire. Overall pain severity was examined using the Brief Pain Inventory questionnaire and ankle pain intensity with a visual analogue scale. Pressure pain thresholds with an algometer assessed pain sensitivity. Spearman correlations were used to calculate interrelations between joint structure, function and pain. RESULTS: Twenty-five PwH (83%) reported ≥1 painful joint, with 67% reporting the ankle as most painful joint. MRI-confirmed abnormalities were seen in 76% of talocrural and 55% of subtalar joints. HEAD-US abnormalities were seen in 93% of the ankles. A large variation was seen in pain sensitivity at the ankle. While moderate to high correlations were observed between ankle structure and HJHS, no meaningful correlations were found between MRI-scores and pain intensity or sensitivity. CONCLUSIONS: Structural joint damage is present in many ankles but is not related to pain in PwH. Further studies should consider somatosensory nervous system dysfunction in PwH as contributing factor to painful ankle arthropathy.

Spontaneous coronary artery dissection (SCAD) has been associated with fibromuscular dysplasia (FMD) and other extracoronary arterial abnormalities. However, the prevalence, severity, and clinical relevance of these abnormalities remain unclear. To assess the prevalence and spectrum of FMD and other extracoronary arterial abnormalities in patients with SCAD vs controls. This case series included 173 patients with angiographically confirmed SCAD enrolled between January 1, 2015, and December 31, 2019. Imaging of extracoronary arterial beds was performed by magnetic resonance angiography (MRA). Forty-one healthy individuals were recruited to serve as controls for blinded interpretation of MRA findings. Patients were recruited from the UK national SCAD registry, which enrolls throughout the UK by referral from the primary care physician or patient self-referral through an online portal. Participants attended the national SCAD referral center for assessment and MRA. Both patients with SCAD and healthy controls underwent head-to-pelvis MRA (median time between SCAD event and MRA, 1 [IQR, 1-3] year). The diagnosis of FMD, arterial dissections, and aneurysms was established according to the International FMD Consensus. Arterial tortuosity was assessed both qualitatively (presence or absence of an S curve) and quantitatively (number of curves ≥45%; tortuosity index). Of the 173 patients with SCAD, 167 were women (96.5%); mean (SD) age at diagnosis was 44.5 (7.9) years. The prevalence of FMD was 31.8% (55 patients); 16 patients (29.1% of patients with FMD) had involvement of multiple vascular beds. Thirteen patients (7.5%) had extracoronary aneurysms and 3 patients (1.7%) had dissections. The prevalence and degree of arterial tortuosity were similar in patients and controls. In 43 patients imaged with both computed tomographic angiography and MRA, the identification of clinically significant remote arteriopathies was similar. Over a median 5-year follow-up, there were 2 nonc

Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are mainly described during acute crises, and many reports do not mention them because hypoglycemia and hyperlactatemia are more frequently in the forefront. Herein, the liver manifestations of 18 patients affected with fructose-1,6-bisphosphatase deficiency are described and the corresponding literature is reviewed. Interestingly, all 18 patients had liver abnormalities either during follow-up (hepatomegaly [n = 8/18], elevation of transaminases [n = 6/15], bright liver [n = 7/11]) or during acute crises (hepatomegaly [n = 10/17], elevation of transaminases [n = 13/16], acute liver failure [n = 6/14], bright liver [n = 4/14]). Initial reports described cases of liver steatosis, when liver biopsy was necessary to confirm the diagnosis by an enzymatic study. There is no clear pathophysiological basis for this fatty liver disease but we postulate that endoplasmic reticulum stress and de novo lipogenesis activation could be key factors, as observed in FBP1 knockout mice. Liver steatosis may expose patients to severe long-term liver complications. As hypoglycemia becomes less frequent with age, most adult patients are no longer monitored by hepatologist. Signs of fructose-1,6-bisphosphatase deficiency may be subtle and can be missed in childhood. We suggest that fructose-1,6-bisphosphatase deficiency should be considered as an etiology of hepatic steatosis, and a liver monitoring protocol should be set up for these patients, during lifelong follow-up.

INTRODUCTION: Recurrent bleeding in severe haemophilia B causes painful hemarthroses and reduces capacity for physical activity. Recombinant factor IX Fc fusion protein (rFIXFc) prophylaxis results in low annualised bleeding rates, with the potential to improve patients' health-related quality of life (HRQoL). AIM: To present a post hoc analysis of data from B-LONG describing change over time in patient-reported outcomes associated with pain and physical activity. METHODS: Patients (≥12 years) who received weekly dose-adjusted or interval-adjusted rFIXFc prophylaxis and completed the Haemophilia-Specific QoL questionnaire for adolescents (Haemo-QoL) or adults (Haem-A-QoL) at baseline (BL) and end of study (EoS). Individual level changes in items of the 'Physical Health' and 'Sports and Leisure' domains, categorised as 'never/rarely/seldom' or 'sometimes/often/all the time', were analysed using McNemar's test to compare distribution of responses at EoS versus BL. RESULTS: At EoS versus BL, a significantly greater proportion of patients did not experience painful swellings (64% vs. 44%; P = .004), painful joints (44% vs. 28%; P = .003) or pain when moving (54% vs. 41%; P = .026). Additionally, at EoS versus BL, patients were less likely to avoid participating in sports like football (30% vs. 8%; P = .002), avoid sports due to their haemophilia (47% vs. 27%; P = .007), or experience difficulty walking as far as they wanted (63% vs. 43%; P = .001). The proportion of patients who played sports as much as the general population was numerically increased (52% vs. 37%; P = .033) at EoS versus BL. CONCLUSION: Results of the analysis suggest that over time, rFIXFc prophylaxis is associated with significant improvements in pain and physical functioning. This contributes to previous evidence of overall HRQoL improvements in patients with haemophilia B treated with rFIXFc.

The mainstay of hemophilia treatment is to prevent bleeding through regular long-term prophylaxis and to control acute breakthrough bleeds. Various treatment options are currently available for prophylaxis, and treatment decision-making is a challenging and multifaceted process of identifying the most appropriate option for each patient. A multidisciplinary expert panel convened to develop a practical, patient-oriented algorithm to facilitate shared treatment decision-making between clinicians and patients. Key variables were identified, and an algorithm proposed based on five variables: bleeding phenotype, musculoskeletal status, treatment adherence, venous access, and lifestyle. A complementary, patient-focused preference tool was also hypothesized, with the aim of exploring individual patients' priorities, preferences, and goals. It is hoped that the proposed algorithm and the hypothesized patient preference tool will assist in selecting a treatment for each patient that is as efficient as possible in preventing bleeds while also accounting for the patient's expectations and priorities.

Background: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by clinical manifestations involving the brain, eye and skin. SWS is commonly caused by somatic mutations in G protein subunit Alpha Q (GNAQ). Subunit Alpha 11 (GNA11) mutations have been reported in 5 cases. It is not clear if their phenotypic features differ. Methods: Within two European multidisciplinary centers we looked for patients with clinical characteristics of SWS and a GNA11 mutation. Clinical and radiological data was collected retrospectively and prospectively. Results: We identified three patients with SWS associated with a somatic GNA11 mutation. They had disseminated capillary malformation (CM) and hyper- or hypotrophy of an extremity. At birth, the CMs of the face, trunk and limbs were pink and patchy, and slowly darkened with age evolving to purple color. Two of the patients had glaucoma. All had neurological symptoms and moderate brain atrophy at a lower degree of severity than classically associated with SWS. Susceptibility-Weighted Images (SWI) and contrast-enhanced (CE) Fluid Attenuated Inversion Recovery (FLAIR) MR views demonstrated best sensitivity to reveal the pial angiomas. Conclusions: We differentiate two distinct clinical/radiological phenotypes of SWS; GNAQ- and GNA11-SWS. The classical GNAQ-SWS is characterized by a homogeneous dark-red CM commonly associated with underlying soft tissue hypertrophy. The CM in GNA11-SWS is more reticulate and darkens with time; neurological picture is milder. SWI and post contrast FLAIR sequences appear to be necessary to demonstrate the leptomeningeal angiomatosis. Yet, anti-epileptic medication or future targeted therapies may be useful, like in classic SWS.

Vascular Anomalies are a heterogenous group of vascular lesions that can be divided, according to the International Society for the Study of Vascular Anomalies Classification, into two main groups : Vascular Tumors and Vascular Malformations. Vascular Malformations can be further subdivided into slow-flow and fast-flow malformations. This clinical and radiological classification allows for a better understanding of vascular anomalies and aims to offer a more precise final diagnosis. Correct diagnosis is essential to propose the best treatment, which traditionally consists of surgery, embolization or sclerotherapy. Since a few years, medical treatment has become an important part of multidisciplinary treatment. Genetic and molecular knowledge of vascular anomalies are increasing rapidly and opens the door for a molecular classification of vascular anomalies according to the underlying pathways involved. The main pathways seem to be: PI3K/AKT/mTOR (PIKopathies) and RAS/RAF/MEK/ERK (RASopathies). Knowing the underlying molecular cascades allows us to use targeted medical therapies. The first part of this article aims to review the vascular anomalies seen in the head and neck region and their underlying molecular causes and involved pathways. The second part will propose an overview of the available targeted therapies based on the affected molecular cascade. This article summarizes theragnostic treatments available in vascular anomalies.

No abstract available

Squamous cell carcinoma of the head and neck (SCCHN) is among the most prevalent cancer types worldwide. Despite multimodal therapeutic approaches that include surgical resection, radiation therapy or concurrent chemoradiation, targeted therapy and immunotherapy, SCCHN is still associated with a poor prognosis for patients with locally advanced or recurrent/metastatic (R/M) diseases. Although next-generation sequencing data from thousands of SCCHN patients have provided a comprehensive landscape of the somatic genomic alterations in this disease, genomic-based precision medicine is not implemented yet in routine clinical use since no satisfactory genetic biomarker has been identified for diagnosis, patient outcome prediction and selection of tailored therapeutic options. The lack of significant improvement in SCCHN patient survival over the last decades stresses the need for reliable predictive biomarkers and new therapeutic strategies for personalized clinical management of SCCHN patients. Targeting the SCCHN-associated microenvironment or the interaction of the latter with cancer cells may represent such paradigm shift in the development of new strategies to treat SCCHN patients, as exemplified by the recent implementation of immune checkpoint inhibitors to improve clinical outcomes by increasing anti-tumor immune responses in SCCHN patients. Several clinical trials are in progress in SCCHN patients to evaluate the activity of monoclonal antibodies and small-molecule inhibitors targeting the tumor microenvironment (TME) at different treatment settings, including combinations with adjuvant surgery, radiation therapy and chemotherapy. This review describes the current knowledge about the influence of the TME on intratumoral heterogeneity and clinical relapse in human SCCHN patients. More precisely, the role of hypoxia as well as the presence of non-cancer cells (e.g. cancer-associated fibroblasts and immune cells) on therapy response of SCCHN cells is highlighted. W

Two decades of basic research and several recent clinical trials have turned the long-awaited hope of gene therapy for haemophilia into a reality. The principle is to endow liver cells with the ability to produce clotting factor VIII (FVIII) or IX (FIX), whose genetically induced defect in synthesis characterises haemophilia A and B respectively. The aim is to induce sufficient endogenous production of these clotting factors in the long term, thereby ensuring that no haemorrhages occur, particularly in the joints. [...]

Venous malformations (VMs) are the most common vascular anomalies and have been associated with somatic variants in TEK. Current treatment of VM joint component might be challenging due to the size or location of some lesions or ineffective with recurrence of malformed veins. Targeted molecular therapies after identification of genetic defects might be an alternative. We report a case with intraarticular bleeding due to VM with a TEK pathogenic somatic variant treated with rapamycin. A 26-year-old female patient was evaluated for right calf pain secondary to venous malformation of the right inferior limb with an intraarticular component in the right knee. Hemarthrosis and degenerative chondropathy of the knee were evidenced at MRA. Molecular diagnosis evidenced a pathogenic somatic TEK variant. Rapamycin was introduced to stop bleeding, with good tolerance and efficacy. The TEK receptor signals through the PI3K/AKT/mTOR pathway and TEK mutations have been linked to AKT activation. As rapamycin acts against angiogenesis and reduces phosphorylated-AKT levels, targeted molecular therapy should be discussed as first-line therapy in patients with proven molecular diagnosis and diffuse VM inaccessible to conventional treatment.

New treatment possibilities and modalities are now available globally for patients with haemophilia requiring surgery or invasive procedures. The first is the appropriate application of low-dose protocols of clotting factor concentrates (CFC) achieving adequate perioperative haemostasis in resources constraint environments. The increasing availability of CFC through humanitarian aid programs allows more invasive surgeries to be performed for which efficacy and safety data should be more widely collected and reported. Second, extended half-life CFC that are increasingly available in many countries represent valuable alternatives to standard half-life products in surgical patients allowing reduced number of infusions and lower consumption, in particular for extended half-life factor IX. Third, in the era of recently introduced nonfactor prophylaxis, some minor surgical procedures can now be performed without additional haemostatic treatment, others with few low-dose administrations of CFC or bypassing agents. Additional factor VIII/IX or recombinant activated factor VII has proven to be safe and effective in association with emicizumab for major surgeries and it was effectively given at low doses in association with fitusiran (including activated prothrombin complex concentrate). No thrombotic complications have been reported in the surgical setting so far. A multidisciplinary team/facility remains crucial to manage major surgery in patients on prophylaxis with these new agents.

INTRODUCTION: In early 2021, the European Collaborative Haemophilia Network (ECHN) conducted a survey to determine whether the paradigms of care across the European region have changed with the introduction of novel therapies for people with hemophilia. METHODS: We conducted a survey in 19 ECHN centers from 17 countries in the European region. The aim was to track recent changes in the hemophilia treatment landscape, determine the impact of these changes on hemophilia treatment centers and comprehensive care centers in the region, and to look into the future of care as applied to people with hemophilia. The survey was structured to include three key areas: demographics and organization; current challenges and opportunities; and future directions. DISCUSSION: Our survey provides a snapshot of the current approach to hemophilia treatment that highlights a move toward preventive, rather than reactive care, but that also raises a number of key concerns related to costs and accessibility (particularly as related to novel therapies), time limitations for clinical research, and ongoing issues regarding human resources (particularly in terms of new doctors entering the field) and availability of laboratory resources as the use of novel therapies (some with unique modes of action and unusual adverse events, some with specialized monitoring requirements) becomes commonplace. CONCLUSION: While our survey suggests that specialized care will continue to play a central role in the management of hemophilia, the standards and protocols, as well as the centers themselves, will have to continue to evolve if they are to continue to provide the highest level of care. To meet this requirement, there is a clear need for engaging, ongoing education programs for healthcare professionals working in the field of hemophilia that can be adjusted to the changing landscape of hemophilia therapy and monitoring.

Hemophilia B is a bleeding disorder caused by a deficiency of coagulation factor IX (FIX). Treatment with FIX replacement products can increase FIX activity levels to minimize or prevent bleeding events. However, frequent dosing with standard-acting FIX products can create a high treatment burden. Long-acting products have been developed to maintain bleed protection with extended dosing intervals. Recombinant factor IX-albumin fusion protein (rIX-FP) is a long-acting product indicated for the treatment and prophylaxis of bleeding events and perioperative management in adult and pediatric patients. This review outlines data from all previously treated patients in the Prophylaxis and On-Demand Treatment using Longer Half-Life rIX-FP (PROLONG-9FP) clinical trial program and summarizes real-world data evaluating the use of rIX-FP in routine clinical practice. In the PROLONG-9FP program, rIX-FP demonstrated effective hemostasis in all patients at dose regimens of up to 21 days in patients aged ≥ 18 years and up to 14 days in patients aged < 12 years. rIX-FP has a favorable pharmacokinetic profile and an excellent safety and tolerability profile. Extended dosing intervals with rIX-FP led to high levels of adherence and reduced consumption compared with other FIX therapies. Data from real-world practice are encouraging and reflect the results of the clinical trials.

Pyoderma gangrenosum (PG) is one of the neutrophilic dermatosis, a heterogenous group of rare inflammatory diseases affecting the skin. It is often associated with systemic diseases such as inflammatory bowel disease, rheumatoid arthritis or hematological malignancies. Classical PG is characterized by painful ulcers with violaceous, undermined border, often developing at sites of injury because of the typical pathergy phenomenon. Because of its polymorphic presentation, misdiagnosis and delayed diagnosis are common. We present a case of PG occurring after transcutaneous electrical nerve stimulation (TENS) in a young female patient with ulcerative colitis. Although electric current has previously been incriminated as a trigger for PG, to the best of our knowledge this is the first case precipitated by TENS. We report a typical case of PG occurring after an unusual stimulus and highlight the challenges that the diagnosis of this relatively rare pathology poses to the clinician.

Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a "Question Mark Ear" (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations.

Infantiele hemangiomen zijn goedaardige vaattumoren die voorkomen bij 5-10% van de zuigelingen. De diagnose wordt meestal klinisch gesteld. Meestal is geen behandeling vereist. Enkel gecompliceerde infantiele hemangiomen die levensbedreigend zijn of functionele of esthetische restletsels kunnen nalaten, worden behandeld. Sinds meerdere jaren is propranolol per os de eerstelijnstherapie. Dat moet zo snel mogelijk worden toegediend, idealiter tussen de leeftijd van 5 weken en 5 maanden, om de kans op latere restletsels zoveel mogelijk verkleinen.

Haemophilia B is a rare X-linked genetic deficiency of coagulation factor IX (FIX) that, if untreated, can cause recurrent and disabling bleeding, potentially leading to severe arthropathy and/or life-threatening haemorrhage. Recent decades have brought significant improvements in haemophilia B management, including the advent of recombinant FIX and extended half-life FIX. This therapeutic landscape continues to evolve with several non-factor replacement therapies and gene therapies under investigation. Given the rarity of haemophilia B, the evidence base and clinical experience on which to establish clinical guidelines are relatively sparse and are further challenged by features that are distinct from haemophilia A, precluding extrapolation of existing haemophilia A guidelines. Due to the paucity of formal haemophilia B-specific clinical guidance, an international Author Group was convened to develop a clinical practice framework. The group comprised 15 haematology specialists from Europe, Australia, Japan, Latin America and North America, covering adult and paediatric haematology, laboratory medicine and biomedical science. A hybrid approach combining a systematic review of haemophilia B literature with discussion of clinical experience utilized a modified Delphi format to develop a comprehensive set of clinical recommendations. This approach resulted in 29 recommendations for the clinical management of haemophilia B across five topics, including product treatment choice, therapeutic agent laboratory monitoring, pharmacokinetics considerations, inhibitor management and preparing for gene therapy. It is anticipated that this clinical practice framework will complement existing guidelines in the management of people with haemophilia B in routine clinical practice and could be adapted and applied across different regions and countries.

Een patiënte van 46 jaar komt naar de consultatie voor een asymptomatische rozeachtige laesie op de rechterborst. De laesie vergroot traag en is een jaar geleden verschenen.

The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus statements on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-face meetings and in multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with severe and rare IH in a practical manner; we present an algorithmic view of the results of our work.

Les hémangiomes infantiles sont des tumeurs vasculaires bénignes touchant 5 à 10% des nourrissons. Le diagnostic est le plus souvent clinique. La majorité des HI ne nécessiteront pas de prise en charge thérapeutique. Seuls les hémangiomes infantiles compliqués entraînant un risque vital ou un risque de séquelles fonctionnelles ou esthétiques seront traités. Depuis plusieurs années, le propranolol per os est devenu le traitement de première intention. Ce dernier doit être administré au plus vite, idéalement entre l’âge de 5 semaines et 5 mois de vie, afin de limiter au maximum le risque de séquelles ultérieures.

This review compares the methodology of published clinical studies investigating the extended-half-life (EHL) factor VIII (FVIII) products, rFVIIIFc (efmoroctocog alfa, Elocta®/Eloctate®), BAY 94-9027 (damoctocog alfa pegol, Jivi®), BAX 855 (rurioctocog alfa pegol, Adynovate®) and N8-GP (turoctocog alfa pegol, Esperoct®) including the phase 2/3 studies, A-LONG (NCT01181128), PROTECT VIII (NCT01580293), PROLONG-ATE (NCT01736475) and pathfinder2 (NCT01480180), respectively, and their corresponding pediatric studies and extensions. Study results are interpreted from a treating physician's perspective, translating into evidence-based, real-life use of the different EHL recombinant FVIII products for personalized prophylaxis. The similarities between the studies include methodology, objectives, study design and cohort size. The differences include duration, prophylactic dosing intervals, number of patient arms, use of control group and randomization, and treatment allocation. Comparing these studies broadens physicians' understanding of each treatment's applicability. Further evaluation of study data and future real-world studies should help physicians to confidently individualize and select treatment for each patient.

Lymph node metastasis (LNM) from primary tumors of the central nervous system (CNS) is an infrequent condition, and classically it was thought that CNS tumors could not spread via the lymphatic route. Recent discoveries about this route of dissemination make its knowledge necessary for surgeons and pathologists to avoid delays in diagnosis and unnecessary treatments. The aim of this paper is to review the literature and to discuss the relevant pathogenetic mechanism and the cytologic features along with recommendations for surgical treatment of these cervical LNM. Using PRISMA guidelines, we conducted a systematic review of the literature published from 1944 to 2021, updating the comprehensive review published in 2010 by our group. Our review includes data of 143 articles obtaining 174 patients with LNM from a primary CNS tumor. The mean age of the patients was 31.9 years (range, 0.1-87) and there were 61 females (35.1%) and 103 males (59.2%), and in 10 cases (5.7%) the gender was not specified. The more frequent sites of distant metastasis were bones (23%), lungs (11.5%) and non-cervical lymph nodes (11%). Cervical LNM from CNS tumors is infrequent. Pathologic diagnosis can be obtained by fine-needle aspiration cytology in most cases, giving surgeons the option to plan the appropriate surgical treatment. Given the poor prognosis of these cases, the most conservative possible cervical dissection is usually the treatment of choice.

INTRODUCTION : Medicine is rapidly developing, and publications are produced at an enormous rate making it impossible for a single individual to remain up to date in all areas. As a result, clinical guidelines utilising all the evidence are now available in almost all areas of medicine. The Institute of Medicine defined clinical guidelines as “systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances”. [...]

Une patiente âgée de 46 ans se présente en consultation pour cette lésion rosée asymptomatique du sein droit. La lésion, de croissance lente, est apparue il y a un an.

An 82-year-old man presented with unilateral oedema of the right lower limb overlaid with multiple sporotrichoid distributed panniculitis lesions. These symptoms appeared in a context of immunodepression and were associated with significant weight loss and a deterioration in general condition. The patient's medical history, the histological findings, PCR testing, and bacterial culture led to a diagnosis of cutaneous tuberculosis due to Mycobacterium bovis. This infection occurred as a late complication of intravesical bacillus Calmette-Guérin (BCG) instillations that the patient had received as an adjunctive immunotherapy for bladder cancer. This is an unusual clinical presentation and aetiology of cutaneous tuberculosis. Indeed, the observed sporotrichoid pattern is uncommon for tuberculous mycobacteria. Moreover, the occurrence of tuberculous skin lesions after intravesical BCG instillations is extremely rare, with only a few cases described, and, to the authors' knowledge, none with such a clinical presentation. This case report suggests that a medical history of BCG immunotherapy should always be considered when assessing any infectious-type cutaneous lesions and that skin should be regarded as a possible late localization of infectious complications of this treatment.

Abdominal coarctations are rare. Surgical treatment is difficult and requires re-interventions to adjust the graft material to patient growth. We report effective treatment by interventional catheterization in an infant with the concern to allow adjustment for growth and prevention of vessel damage. After the diagnosis of abdominal coarctation at 27 weeks of gestation, an infant developed hypertension (170/70 mmHg) at 3 months of age despite medical therapy. Angio CT confirmed a 2 mm diameter, 2.3-cm-long coarctation of the descending aorta. At 4 months, a dilatation was performed using a 3 mm cutting balloon and a 5 mm Opta® balloon, Cordis®. Two noncovered Palmaz® Genesis™ XD PG1910P stents were required to keep the aortic lumen open. At 15 months, an Adventa™ V12 vascular 12 × 61 mm long covered stent was implanted to exclude an aneurysm which developed between the two stents. At 3 and 9.5 years, the stents were further dilated with a high-pressure balloon to reach 11 mm aortic diameter with no residual pressure gradient, and normal blood pressure. The use of cutting balloons and stent implantation is an effective way to relieve severe obstruction in middle aortic syndrome in neonates. The technical issues encountered were the need for a low profile sheath and material to avoid femoral artery damage, and the need to use stents that can be further expanded to adult size.

Ultrasound (US) is widely used in pediatric musculoskeletal pathology at all ages. Although the focus is often on soft tissues, joints and cartilage, the examiner might be confronted with changes in the underlying bone surface that are important to understand and integrate in the diagnosis. This article illustrates the normal US aspects of the cortical bone surface and periosteum, as well as the most common US anomalies seen in infections, trauma and bone tumors in children.

Vascular anomalies are a heterogenous group of vascular lesions that can be divided, according to the International Society for the Study of Vascular Anomalies Classification, into two main groups: vascular tumors and vascular malformations. Vascular malformations can be further subdivided into slow-flow and fast-flow malformations. This clinical and radiological classification allows for a better understanding of vascular anomalies and aims to offer a more precise final diagnosis. Correct diagnosis is essential to propose the best treatment, which traditionally consists of surgery, embolization, or sclerotherapy. Since a few years, medical treatment has become an important part of multidisciplinary treatment. Genetic and molecular knowledge of vascular anomalies are increasing rapidly and opens the door for a molecular classification of vascular anomalies according to the underlying pathways involved. The main pathways seem to be PI3K/AKT/mTOR and RAS/RAF/MEK/ERK. Knowing the underlying molecular cascades allows us to use targeted medical therapies. The first part of this article aims to review the vascular anomalies seen in the head and neck region and their underlying molecular causes and involved pathways. The second part will propose an overview of the available targeted therapies based on the affected molecular cascade. This article summarizes theragnostic treatments available in vascular anomalies.

INTRODUCTION: Despite the fact that joint bleeds (haemarthrosis) frequently occur in people with haemophilia (PwH) with invalidating arthropathies as result, the clinical pain experience has received only limited attention. A sudden increase in pain intensity can be linked to a bleed, but in most cases, no acute bleed is confirmed. Nevertheless, a patient's perception of an acute bleed as cause of the pain might impact the patients' behaviour in response to pain. It is therefore essential to gain more insight into pain coping strategies seen in PwH. AIM: This systematic review aims to identify the range of pain coping behaviour strategies used among PwH and the factors associated with pain coping behaviour. METHODS: This review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines (PRISMA). PubMed and Web of Science were systematically screened for relevant literature using keyword combinations related to adult PwH, pain and pain coping behaviour strategies. Risk of bias was assessed with the modified Newcastle-Ottowa Scale. RESULTS: Eleven full text articles (nine cross-sectional and two comparative studies) consisting of 1832 PwH met the inclusion criteria. Due to the heterogeneity of the study samples, quality of evaluation instruments and varying risk of bias, it was difficult to draw conclusions regarding the used pain coping behaviour strategies and associated factors. CONCLUSION: Literature on pain coping behaviour strategies and associated factors in PwH is still scarce and describes heterogenous results. Validated haemophilia-specific instruments are warranted to inventory pain coping behaviour in a standardized way.

OBJECTIVES: Biological variation (BV) data obtained in a standardized way is valuable to assess the analytical requirements and the utility of a reference interval. Our study aimed to determine the short-term BV of thrombophilia (protein S, protein C, activated protein C resistance (APCR) and factor VIII) and hemophilia (factors VIII, IX and XI) parameters in plasma. Coagulation factors V and XII were also evaluated. Based on the obtained data, we assessed analytical performance specifications for the parameters. Finally, we intended to provide a robust tool for comparison of serial measurements of factors V, VIII, IX and XI. METHODS: A blood draw was performed weekly in 19 apparently healthy Caucasian adults for five weeks at Saint-Luc University Hospital (Brussels, Belgium). Parameters were measured in duplicate. BV components were calculated with a nested analysis of variance after exclusion of outliers. RESULTS: The analytical coefficient of variation (CV) varied from 1.5 to 4.6%, the within-subject CV from 1.6 to 8.9% and the between-subject CV from 3.8 to 24.1%. All parameters showed high individuality. For most parameters, the analytical goal was met with our assays. Reference change values (RCV) of -16.7% to +20.0%, -20.7% to +26.0%, -15.3% to +18.1% and -13.1% to +15.1% were obtained for factors V, VIII, IX and XI respectively. CONCLUSIONS: All studied parameters were highly individualized. The assessment of BV data can guide setting analytical goal specifications. Comparison of serial measurements in the follow-up of patients suffering from hepatic failure or mild hemophilia is facilitated by evaluation of the RCV.

The last few decades have been marked by major advances for people with haemophilia. They concern the understanding of the mechanisms, diagnosis, treatment and care of clotting factor VIII and IX deficiencies and other inherited bleeding disorders. [...]

BACKGROUND: Mild haemophilia (MH) is mainly characterized by haemorrhages secondary to surgery/invasive procedures or trauma. Haemostatic treatment in MH ranges from on demand to short prophylaxis according to the type of bleeding events and the basal clotting factor level. Oral surgery and dental extractions can represent a frequent haemostatic challenge in MH requiring appropriate treatment. However, only few studies on limited numbers of patients are available in the literature regarding the implications of dental management in patients with MH. OBJECTIVES: The purpose of the study was to evaluate the impact of dental care on the burden of haemostatic treatment in patients affected by MH. METHODS: We conducted a retrospective multicentre study evaluating adult patients with MH regularly examined at the Haemophilia Treatment Centres (HTCs) of the Saint-Luc University Hospital, Brussels (Belgium) and of Paolo Giaccone Hospital, Palermo (Italy). The population consisted of 107 male patients with MH, with a mean age of 39 years (range 18-81 years). RESULTS: The majority of patients (86/107, 79%) needed at least one treatment within the study period, and 44% (38/86) of them received haemostatic therapy for dental care. Haemostatic therapy in our study varied from antifibrinolytic therapy alone and perioperative factor replacement to the absence of treatment at all. The great majority of oral interventions (27/42, 64%) were managed with clotting factor concentrate. CONCLUSION: This study demonstrates that dental care currently represents a major reason for haemostatic treatments in patients with MH. Maintaining good oral health appears as a priority to minimize avoidable replacement therapy and optimize resources.

Dear Editor, During phase 3 clinical trials and since its commercialization, emicizumab (Hemlibra), a bispecific monoclonal antibody acting as a substitute for activated coagulation factor VIII (FVIII), has proven effective for bleeding prevention in persons with haemophilia A (PwHA) with and without inhibitors. [...]

Les hémangiomes infantiles (HI) sont des tumeurs vasculaires bénignes touchant 5 à 10% des nourrissons. Le diagnostic est le plus souvent clinique. La majorité des HI ne nécessiteront pas de prise en charge thérapeutique. Seuls les hémangiomes infantiles compliqués entraînant un risque vital ou un risque de séquelles fonctionnelles ou esthétiques seront traités. Depuis plusieurs années, le propranolol per os est devenu le traitement de première intention. Ce dernier doit être administré au plus vite, idéalement entre l’âge de 5 semaines et 5 mois de vie, afin de limiter au maximum le risque de séquelles ultérieures.

Infantiele hemangiomen zijn goedaardige vaattumoren die voorkomen bij 5-10% van de zuigelingen. De diagnose wordt meestal klinisch gesteld. Meestal is geen behandeling vereist. Enkel gecompliceerde infantiele hemangiomen die levensbedreigend zijn of functionele of esthetische restletsels kunnen nalaten, worden behandeld. Sinds meerdere jaren is propranolol per os de eerstelijnstherapie. Dat moet zo snel mogelijk worden toegediend, idealiter tussen de leeftijd van 5 weken en 5 maanden, om de kans op latere restletsels zoveel mogelijk verkleinen.

In de oncologische orthopedie moeten chirurgische ingrepen curatief zijn. ‘En bloc’-resecties van bottumoren zijn vaak lange, ingrijpende en risicovolle interventies. Eén van de risico’s is een recidief van de tumor als de tumor niet volledig verwijderd werd. Dat is een uiterst ernstige complicatie die de overleving van de patiënt in het gedrang kan brengen in het geval van maligne bottumoren. Patiëntspecifieke instrumenten (patient specific instrument, PSI), of op maat gemaakte snijgeleiders zijn tools die ons kunnen helpen om die risico’s op recidieven tot nagenoeg nul te herleiden. De snijgeleiders leiden het zaagblad van de chirurg en garanderen zo dat alle snijvlakken van het bot vrije snijranden hebben. PSI’s worden gemaakt aan de hand van een nauwkeurig plan op basis van de beeldvormingsonderzoeken van de patiënt, waarbij ingenieurs en chirurgen samenwerken. PSI’s verkorten de operatieduur en indirect ook de complicaties die daarmee samenhangen (bloedverlies, risico op infectie, enz.) en het aantal plaatselijke recidieven. PSI’s maken het mogelijk om kleinere resectiemarges te hanteren, waardoor anatomische structuren behouden kunnen worden die anders verloren gaan. Ze kunnen ook gebruikt worden om een allotransplant op maat uit te snijden en verlagen in dat geval het aantal botcomplicaties (pseudoartrose).

En orthopédie oncologique, les chirurgies se doivent d’être curatives. Les résections «en bloc» des tumeurs osseuses sont souvent des interventions longues, délabrantes et risquées. L’un des risques est la récidive tumorale si toute la tumeur n’a pas été enlevée. Cette complication est extrêmement grave et met en péril le pronostic vital du patient dans les cas de tumeurs osseuses malignes. Les instruments spécifiques au patient (patient specific instrument, PSI), ou guides de coupe sur mesure, sont des outils qui nous aident à réduire ces risques de récidives tumorales pratiquement à zéro. En guidant la lame de la scie du chirurgien, ces guides de coupe assurent des marges de résections saines sur tous les plans de découpe osseuse. Créés à partir d’une planification minutieuse basée sur les imageries du patient et la collaboration entre des ingénieurs et des chirurgiens, ces PSI réduisent le temps opératoire et indirectement les complications inhérentes à ce phénomène (perte de sang, risque d’infection, etc.) et le taux de récidive locale. Les PSI permettent de planifier des marges de résection plus petites permettant de préserver des structures anatomiques autrefois sacrifiées. Ils peuvent aussi servir à découper une allogreffe de reconstruction sur mesure et diminuent alors les complications osseuses (pseudarthroses).

L’année 2021 nous permet d’éclairer l’impact des techniques mini-invasives en chirurgie d’arthroplastie de hanche, la poursuite des progrès dans l’arthroplastie du genou, la place de stratégies non conventionnelles dans le contrôle des infections d’implants et l’intérêt d’une nouvelle installation pour la réalisation des techniques d’arthroscopie de l’épaule. L’optimisation des techniques chirurgicales en arthroplastie de hanche permet d’identifier les patients pour lesquels un contrôle sanguin postopératoire s’avère nécessaire mais aussi, dès lors d’optimiser les patients avant l’intervention afin de réduire le risque d’anémie postopératoire et la nécessité d’une transfusion. Le bénéfice de l’arthroplastie du genou n’a jusqu’à présent pas égalé celui de la hanche. Néanmoins, le développement des stratégies de resurfaçage respectant l’anatomie individuelle du patient soutenu par la technologie moderne et particulièrement la robotisation et le recours aux implants sur mesures laisse augurer de progrès significatifs. L’infection constitue une complication redoutable de la chirurgie d’arthroplastie. Aux stratégies classiques viennent s’ajouter de nouvelles approches thérapeutiques comme la chirurgie deux temps en un et une meilleure définition de la place de l’antibiothérapie suppressive au long cours. Enfin, Il semble qu’une position optimale pour les patients qui bénéficient d’arthroscopies de l’épaule soit celle en décubitus dorsal, évitant les inconvénients des positions semi-assise et en décubitus latéral, la première étant associée à un risque anesthésique accru et la deuxième à des difficultés chirurgicales en cas de conversion vers une voie ouverte et un risque de lésion du plexus brachial., [2021 innovations in orthopedic surgery and traumatology] The year 2021 enabled us to shed light on the impact of minimally invasive techniques in hip arthroplasty surgery, continued progress in knee arthroplasty, place of unconventional strategies in the control of implant infections, and interest of a new surgical positioning for performing shoulder arthroscopy techniques. The optimization of surgical techniques in hip arthroplasty renders it now possible to identify those patients for whom a postoperative blood control proves necessary but also, therefore, for optimizing the patients before the intervention in order to reduce the risk of postoperative anemia and transfusion requirement. The benefit of knee replacement surgery has so far not matched that of hip replacement. Nevertheless, the development of resurfacing strategies respecting the individual anatomy of the patient, supported by modern technology and particularly robotization and using custom-made implants, augurs well for significant progress. Infection is a serious complication of arthroplasty surgery. To the classic strategies were added new therapeutic approaches, such as two-stage surgery in one stage and a better definition of the place of long-term suppressive antibiotic therapy. Finally, an optimal position for patients benefitting from shoulder arthroscopy is that in the supine position, avoiding the disadvantages of semi-sitting and lateral decubitus positions, with the first associated with increased anesthetic risks and the second with surgical difficulties in the event of conversion to an open approach, with a risk of injury to the brachial plexus.

L’angioedème (AO) qu'il soit lié à la libération d'histamine ou à la présence excessive de bradykinine représente un motif fréquent d’admission en salle d’urgence. Il s’agit aussi d’une affection potentiellement grave voire fatale. Sa prise en charge diagnostique et thérapeutique peut se révéler difficile. Cet article détaille la gestion pratique de l’AO en salle d’urgence, en particulier sa forme bradykinique, ainsi que les modalités et objectifs du bilan allergologique spécialisé fréquemment indiqué. Finalement, cet article accorde une place toute particulière à l’AO héréditaire, une maladie rare justifiant une prise en charge thérapeutique spécialisée et récemment révolutionnée par de nouvelles molécules très prometteuses.