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Abstract Repurposing anticancer drugs to vascular malformations has significantly improved patient outcomes. Complex Lymphatic Anomalies (CLA) are part of the spectrum of lymphatic malformations (LMs) that share similar oncogenic mutations to cancer. We report the case of a young patient with highly symptomatic CLA who was initially treated with sirolimus, due to the frequent involvement of the PI3K-AKT-mTOR pathway in CLA pathogenesis. Despite an initial reduction in symptoms, sirolimus progressively lost its effectiveness. After an unsuccessful attempt with trametinib alone, sirolimus was added to trametinib and resulted in a significant, rapid and sustained improvement in symptoms. This suggests that, contrary to current dogmas, combination therapy using sub-therapeutic doses targeting both the PI3K and RAS pathways retains efficacy without generating the toxicity known for combination therapies, and is beneficial in the management of CLAs and potentially other vascular anomalies.

Abstract Background Deoxyguanosine kinase deficiency is mainly manifested by hepatic and neurological damage, hence it belongs to the hepatocerebral form of mitochondrial deoxyribonucleic acid depletion syndrome. The association between deoxyguanosine kinase deficiency and recurrent spontaneous pneumothorax has not currently been reported. Case presentation A 12-year-old Russian boy with deoxyguanosine kinase deficiency, a recipient of a liver transplant with amyotrophy secondary to his mitochondriopathy, presented with recurrent spontaneous bilateral pneumothorax refractory to drainage and surgery. Conclusion To our knowledge, this is the first documented case of deoxyguanosine kinase deficiency associated with recurrent spontaneous pneumothorax, which could be considered a late complication of deoxyguanosine kinase deficiency. At this point, this is only an association and further studies and research need to be performed to help confirm the pathogenesis of this association.

BACKGROUND Slow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODS The Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTS Thirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3–4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSION Sirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATION ClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDING The Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant “ReVAMP” (LFCR grant 21CVD03), the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.

Pleistocene braided-river deposits commonly represent long periods of non-deposition or erosion that are interrupted by rapid and short aggradation phases. When dating these sedimentary sequences with in situ-produced cosmic radionuclides (CRNs), simple concentration depth profiling approaches often fall short, as they assume that the alluvial sedimentary sequence has been deposited with a constant and rapid aggradation rate and been exposed to cosmic radiations afterwards. Numerical modelling of the evolution of CRNs in alluvial sequences permits one to account for aggradation, non-deposition and erosion phases and can simulate which scenarios of aggradation and preservation most likely represent the river dynamics. In this study, such a model was developed and applied to a Middle Pleistocene gravel sheet (Zutendaal gravels) exposed in NE Belgium. The model parameters were optimised to the observed 10Be and 26Al concentrations of 17 sediment samples taken over a depth interval of 7 m that constitutes the top of a gravel sheet up to 20 m thick. In the studied sedimentary sequence, (at least) three individual aggradation phases that were interrupted by non-deposition or erosion can be distinguished, each interruption lasting ∼ 40 kyr. The age for the onset of aggradation of the upper 7 m of the gravel sheet was further constrained to 654-62+218 ka. This age, within error limits, does not invalidate previous correlations of the gravel sheet with the Cromerian Glacial B and Marine Isotope Stage (MIS) 16. The deposition of the entire gravel sheet likely represents more than one climatic cycle and demonstrates the importance of accounting for the depositional modes of braided rivers when applying in situ cosmogenic radionuclide techniques.

Abstract Background Theragnostic management, treatment according to precise pathological molecular targets, requests to unravel patients’ genotypes. We used targeted next-generation sequencing (NGS) or digital droplet polymerase chain reaction (ddPCR) to screen for somatic PIK3CA mutations on DNA extracted from resected lesional tissue or lymphatic endothelial cells (LECs) isolated from lesions. Our cohort (n = 143) was composed of unrelated patients suffering from a common lymphatic malformation (LM), a combined lymphatic malformation [lymphatico-venous malformation (LVM), capillaro-lymphatic malformation (CLM), capillaro-lymphatico-venous malformation (CLVM)], or a syndrome [CLVM with hypertrophy (Klippel-Trenaunay-Weber syndrome, KTS), congenital lipomatous overgrowth-vascular malformations-epidermal nevi -syndrome (CLOVES), unclassified PIK3CA-related overgrowth syndrome (PROS) or unclassified vascular (lymphatic) anomaly syndrome (UVA)]. Results We identified a somatic PIK3CA mutation in resected lesions of 108 out of 143 patients (75.5%). The frequency of the variant allele ranged from 0.54 to 25.33% in tissues, and up to 47% in isolated endothelial cells. We detected a statistically significant difference in the distribution of mutations between patients with common and combined LM compared to the syndromes, but not with KTS. Moreover, the variant allele frequency was higher in the syndromes. Conclusions Most patients with an common or combined lymphatic malformation with or without overgrowth harbour a somatic PIK3CA mutation. However, in about a quarter of patients, no such mutation was detected, suggesting the existence of (an)other cause(s). We detected a hotspot mutation more frequently in common and combined LMs compared to syndromic cases (CLOVES and PROS). Diagnostic genotyping should thus not be limited to PIK3CA hotspot mutations. Moreover, the higher mutant allele frequency in syndromes suggests a wider distribution in patients’ tissues, facilitating detection. Clinical trials have demonstrated efficacy of Sirolimus and Alpelisib in treating patients with an LM or PROS. Genotyping might lead to an increase in efficacy, as treatments could be more targeted, and responses could vary depending on presence and type of PIK3CA-mutation.

Abstract Involution of a rapidly involuting congenital hemangioma is an unknown cause of neonatal ascites. As involution phase is completed by 14 months after birth, conservative management with diuretics and drainage is possible and may avoid surgical resection.

Images captured by unmanned aerial vehicles (UAVs) and processed by structure-from-motion (SfM) photogrammetry are increasingly used in geomorphology to obtain high-resolution topography data. Conventional georeferencing using ground control points (GCPs) provides reliable positioning, but the geometrical accuracy critically depends on the number and spatial layout of the GCPs. This limits the time and cost effectiveness. Direct georeferencing of the UAV images with differential GNSS, such as PPK (post-processing kinematic), may overcome these limitations by providing accurate and directly georeferenced surveys. To investigate the positional accuracy, repeatability and reproducibility of digital surface models (DSMs) generated by a UAV–PPK–SfM workflow, we carried out multiple flight missions with two different camera–UAV systems: a small-form low-cost micro-UAV equipped with a high field of view (FOV) action camera and a professional UAV equipped with a digital single lens reflex (DSLR) camera. Our analysis showed that the PPK solution provides the same accuracy (MAE: ca. 0.02 m, RMSE: ca. 0.03 m) as the GCP method for both UAV systems. Our study demonstrated that a UAV–PPK–SfM workflow can provide consistent, repeatable 4-D data with an accuracy of a few centimeters. However, a few flights showed vertical bias and this could be corrected using one single GCP. We further evaluated different methods to estimate DSM uncertainty and show that this has a large impact on centimeter-level topographical change detection. The DSM reconstruction and surface change detection based on a DSLR and action camera were reproducible: the main difference lies in the level of detail of the surface representations. The PPK–SfM workflow in the context of 4-D Earth surface monitoring should be considered an efficient tool to monitor geomorphic processes accurately and quickly at a very high spatial and temporal resolution.

Tectonic and geomorphic processes drive landscape evolution over different spatial and temporal scales. In mountainous environments, river incision sets the pace of landscape evolution, and hillslopes respond to channel incision by, e.g., gully retreat, bank erosion, and landslides. Sediment produced during stochastic landslide events leads to mobilization of soil and regolith on the slopes that can later be transported by gravity and water to the river network during phases of hillslope–channel geomorphic coupling. The mechanisms and scales of sediment connectivity mitigate the propagation of sediment pulses throughout the landscape and eventually drive the contribution of landslides to the overall sediment budget of mountainous catchments. However, to constrain the timing of the sediment cascade, the inherent stochastic nature of sediment and transport through landsliding requires an integrated approach accounting for different space scales and timescales. In this paper, we examine the sediment production on hillslopes and evacuation to the river network of one landslide, i.e. the Schimbrig earthflow, affecting the Entle River catchment located in the foothills of the Central Swiss Alps. We quantified sediment fluxes over annual, decadal, and millennial timescales using respectively unmanned aerial vehicle (UAV)–structure-from-motion (SfM) techniques, classic photogrammetry, and in situ produced cosmogenic radionuclides. At the decadal scale, sediment fluxes quantified for the period 1962–1998 are highly variable and are not directly linked to the intensity of sediment redistribution on the hillslope. At the millennial scale, landslide occurrence perturbs the regional positive linear relationship between sediment fluxes and downstream distance as the landslide-affected Schimbrig catchment is characterized by a decrease in sediment fluxes and a strong variability. Importantly, the average decadal sediment flux of the Schimbrig catchment is 2 orders of magnitude higher than millennial sediment fluxes computed over the same spatial extent. The discrepancy between decadal and millennial sediment fluxes, combined to the highly variable annual sediment evacuation from the hillslopes to the channel network suggest that phases of hillslope–channel geomorphic coupling are short and intermittent. During most of the time, the first-order catchments are transport-limited and sediment dynamics in the headwaters are uncoupled from the fluvial systems. In addition, our unique spatio-temporal database of sediment fluxes highlights the transient character of the intense geomorphic activity of the Schimbrig catchment in a regional context. Its decadal sediment flux is of the same order of magnitude as the background sediment flux going out of the entire Entle River catchment. Over the last 50 years, the Schimbrig catchment, which represents ca. 1 % of the entire study area, provides 65 % of the sediments that the entire Entle catchment will supply over the millennial scale. These results suggest that episodic supply of sediment from landslides during intermittent phases of hillslope–channel geomorphic coupling are averaged out when considering sediment fluxes at longer timescales and larger spatial scales.

Las cadenas montañosas en las regiones tropicales se caracterizan por las altas tasas de erosión debido a los eventos de lluvia intensa, terrenos escarpados y al alto grado de meteorización del material parental. Los deslizamientos son fenómenos recurrentes, y son considerados como los procesos más importantes de erosión en las zonas montañosas y las principales fuentes de sedimentos en el sistema fluvial. Con el objetivo de cuantificar la contribución de sedimentos provenientes de los deslizamientos al sistema fluvial, se realizó un estudio de caso en la Cuenca del Río Pangór, Ecuador. En este estudio, se cuantificó las tasas de erosión a escala de cuenca por medio de información derivada de estaciones de aforo de caudales e inventarios de isótopos cosmogénicos en sedimentos fluviales. Después, se evaluó la fiabilidad y validez de la información obtenida con el objetivo de cuantificar la carga de sedimento transportado por el río en regiones montañosas. Finalmente, se analizó la fracción de la carga total de sedimento proveniente de deslizamientos en las laderas. La cuenca del Río Pangór fue seleccionada por su extensa serie de tiempo de datos hidrometeorológicos (1974-2009). La carga de sedimento en el Río Pangór fue estimada por medio de un análisis de magnitudfrecuencia de la información recolectada en una estación hidrométrica y datos de concentración de sedimentos en suspensión. Los resultados muestran un valor de un orden de magnitud menor que la tasa de erosión calculada en función de los inventarios de isótopos cosmogénicos. Esta diferencia se explica por (i) la dificultad de extrapolar la información sobre la frecuencia temporal de los caudales y la carga de sedimento en regímenes hidrológicos no estacionarios, y (ii) el submuestreo de eventos extremos. Bajo estas condiciones, la cuantificación de las tasas de erosión derivadas de los isótopos cosmogénicos proporcionan una metodología alternativa para la cuantificación de la carga total de sedimentos en el sistema fluvial. Un inventario multitemporal (1963-2010) de deslizamientos fue desarrollado a partir de imágenes de satélite y fotografías aéreas. Mediante trabajo de campo se generó información sobre la geometría de los deslizamientos para la cuantificación de volúmenes de sedimento producido por los deslizamientos. En la cuenca del Río Pangór las altas tasas de erosión producida por los deslizamientos varían entre 1688+901−326 y 630+300−108 t.km2.y-1, valores que son similares a las tasas de erosión derivadas de isotopos cosmogénicos. Los resultados indican que los deslizamientos son las principales fuentes de sedimento en esta cuenca montañosa.

Abstract Background Extensive and complex vascular malformations often cause chronic pain and severe functional restraint. Conventional treatments, such as surgery and/or sclerotherapy, are rarely curative, underscoring the great need for new therapeutic modalities. Recent preclinical and clinical data demonstrated that sirolimus could offset the progression of vascular malformations and significantly improve quality of life of patients through inhibition of the Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathway. The purpose of this prospective study was to assess the efficacy and safety of this treatment in patients with extensive or complex slow-flow vascular malformations. Methods Sirolimus was administered orally on a continuous dosing schedule with pharmacokinetic-guided target serum concentration level of 10 to 15 ng/ml. Patients were seen every month for the first three months and subsequently every three months. The primary endpoints were safety and efficacy, based on clinical, biological and radiological evaluations, as well as a quality of life questionnaire. Results Nineteen patients, from 3 to 64 years old, with lymphatic (LM), venous (VM) or complex slow-flow malformations, refractory to standard care, were enrolled and received sirolimus continuously. After 12 months of follow-up, 16 patients were available for assessment of efficacy and safety: all had a significant and rapid improvement of their symptoms and quality of life. In two patients, sirolimus treatment permitted sclerotherapy and surgery, initially evaluated unfeasible. Sirolimus was well tolerated, with mucositis as the most common (10% of patients) grade 3 adverse event. Conclusions Sirolimus was efficient in extensive LM, VM and/or complex malformations that were refractory to conventional treatments and was well tolerated.

Accurately assessing geo-hazards and quantifying landslide risks in mountainous environments are gaining importance in the context of the ongoing global warming. For an in-depth understanding of slope failure mechanisms, accurate monitoring of the mass movement topography at high spatial and temporal resolutions remains essential. The choice of the acquisition framework for high-resolution topographic reconstructions will mainly result from the trade-off between the spatial resolution needed and the extent of the study area. Recent advances in the development of unmanned aerial vehicle (UAV)-based image acquisition combined with the structure-from-motion (SfM) algorithm for three-dimensional (3-D) reconstruction make the UAV-SfM framework a competitive alternative to other high-resolution topographic techniques. In this study, we aim at gaining in-depth knowledge of the Schimbrig earthflow located in the foothills of the Central Swiss Alps by monitoring ground surface displacements at very high spatial and temporal resolution using the efficiency of the UAV-SfM framework. We produced distinct topographic datasets for three acquisition dates between 2013 and 2015 in order to conduct a comprehensive 3-D analysis of the landslide. Therefore, we computed (1) the sediment budget of the hillslope, and (2) the horizontal and (3) the three-dimensional surface displacements. The multitemporal UAV-SfM based topographic reconstructions allowed us to quantify rates of sediment redistribution and surface movements. Our data show that the Schimbrig earthflow is very active, with mean annual horizontal displacement ranging between 6 and 9 m. Combination and careful interpretation of high-resolution topographic analyses reveal the internal mechanisms of the earthflow and its complex rotational structure. In addition to variation in horizontal surface movements through time, we interestingly showed that the configuration of nested rotational units changes through time. Although there are major changes in the internal structure of the earthflow in the 2013–2015 period, the sediment budget of the drainage basin is nearly in equilibrium. As a consequence, our data show that the time lag between sediment mobilization by landslides and enhanced sediment fluxes in the river network can be considerable.

Cerebral germinoma is rare. Although the imaging of the germinoma is very evocative, it’s very polymorphic clinical expression is at the origin of misguided diagnosis, as illustrated in our case. We report the case of a 10-year-old girl with diabetes insipidus evolving for 12 months associated with a decrease in visual acuity. Brain MRI (Magnetic Resonance Imaging) revealed a tumor process in the suprasellar region. The stereotaxic biopsy of the tumor confirmed the diagnosis of the hypothalamic germinoma, which allowed the patient to be treated by radiotherapy and chemotherapy. The incidence of cerebral germinoma, its clinical (principally diabetes insipidus) and radiological features as well as therapeutic strategies are discussed hereby.

A 15-year-old female had been followed in our department of pediatric radiology since the age of 11, in order to control a solitary osteochondroma (exostosis) of the right distal femur.