Tubulin mutations in human neurodevelopmental disorders.

Mutations causing dysfunction of tubulins and microtubule-associated proteins, also known as tubulinopathies, are a group of recently described entities that lead to complex brain malformations. Anatomical and functional consequences of the disruption of tubulins include microcephaly, combined with abnormal corticogenesis due to impaired migration or lamination and abnormal growth cone dynamics of projecting and callosal axons. Key imaging features of tubulinopathies are characterized by three major patterns of malformations of cortical development (MCD): lissencephaly, microlissencephaly, and dysgyria. Additional distinctive MRI features include dysmorphism of the basal ganglia, midline commissural structure hypoplasia or agenesis, and cerebellar and brainstem hypoplasia. Tubulinopathies can be diagnosed as early as 21-24 gestational weeks using imaging and neuropathology, with possible extreme microlissencephaly with an extremely thin cortex, lissencephaly with either thick or thin/intermediate cortex, and dysgyria combined with cerebellar hypoplasia, pons hypoplasia and corpus callosum dysgenesis. More than 100 MCD-associated mutations have been reported in TUBA1A, TUBB2B, or TUBB3 genes, whereas fewer than ten are known in other genes such TUBB2A, TUBB or TUBG1. Although these mutations are scattered along the α- and ß-tubulin sequences, recurrent mutations are consistently associated with almost identical cortical dysgenesis. Much of the evidence supports that these mutations alter the dynamic properties and functions of microtubules in several fashions. These include diminishing the abundance of functional tubulin heterodimers, altering GTP binding, altering longitudinal and lateral protofilament interactions, and impairing microtubule interactions with kinesin and/or dynein motors or with MAPs. In this review we discuss the recent advances in our understanding of the effects of mutations of tubulins and microtubule-associated proteins on human brain development and the pathogenesis of malformations of cortical development.

French guidelines on TIPS: Indications and modalities.

Transjugular intrahepatic portosystemic shunt (TIPS) has become essential in the treatment or prevention of portal hypertension-related complications. In the early 1990s, the primary indication was refractory bleeding. It is now proposed for the treatment of ascites for the prevention of bleeding and in patients with vascular diseases of the liver. Thus, there are a growing number of patients being treated with TIPS all over the world. The broadening of indications, the involvement of multiple stakeholders, the need for an accurate selection, the positioning in relation to transplantation and the lack of standardization in pre-therapeutic assessment, in the procedure itself and in the follow-up have led the board of the French Association for the Study of the Liver to establish recommendations.

Imaging features to distinguish posterior fossa ependymoma subgroups.

OBJECTIVES: Posterior fossa ependymoma group A (EPN_PFA) and group B (EPN_PFB) can be distinguished by their DNA methylation and give rise to different prognoses. We compared the MRI characteristics of EPN_PFA and EPN_PFB at presentation. METHODS: Preoperative imaging of 68 patients with posterior fossa ependymoma from two centers was reviewed by three independent readers, blinded for histomolecular grouping. Location, tumor extension, tumor volume, hydrocephalus, calcifications, tissue component, enhancement or diffusion signal, and histopathological data (cellular density, calcifications, necrosis, mitoses, vascularization, and microvascular proliferation) were compared between the groups. Categorical data were compared between groups using Fisher's exact tests, and quantitative data using Mann-Whitney tests. We performed a Benjamini-Hochberg correction of the p values to account for multiple tests. RESULTS: Fifty-six patients were categorized as EPN_PFA and 12 as EPN_PFB, with median ages of 2 and 20 years, respectively (p = 0.0008). The median EPN_PFA tumoral volume was larger (57 vs 29 cm3, p = 0.003), with more pronounced hydrocephalus (p = 0.002). EPN_PFA showed an exclusive central position within the 4th ventricle in 61% of patients vs 92% for EPN_PFB (p = 0.01). Intratumor calcifications were found in 93% of EPN_PFA vs 40% of EPN_PFB (p = 0.001). Invasion of the posterior fossa foramina was mostly found for EPN_PFA, particularly the foramina of Luschka (p = 0.0008). EPN_PFA showed whole and homogeneous tumor enhancement in 5% vs 75% of EPN_PFB (p = 0.0008). All mainly cystic tumors were EPN_PFB (p = 0.002). The minimal and maximal relative ADC was slightly lower in EPN_PFA (p = 0.02 and p = 0.01, respectively). CONCLUSION: Morphological characteristics from imaging differ between posterior fossa ependymoma subtypes and may help to distinguish them preoperatively. CLINICAL RELEVANCE STATEMENT: This study provides a tool to differentiate between group A and group B ependymomas, which will ultimately allow the therapeutic strategy to be adapted in the early stages of patient management. KEY POINTS: • Posterior fossa ependymoma subtypes often have different imaging characteristics. • Posterior fossa ependymomas group A are commonly median or lateral tissular calcified masses, with incomplete enhancement, affecting young children and responsible for pronounced hydrocephalus and invasion of the posterior fossa foramina. • Posterior fossa ependymomas group B are commonly median non-calcified masses of adolescents and adults, predominantly cystic, and minimally invasive, with total and homogeneous enhancement.

Juvenile Xanthogranuloma of the Head and Neck: Imaging Findings in 11 Cases.

BACKGROUND: Juvenile Xanthogranuloma (JXG) is a non-Langerhans cell histiocytosis, occurring mainly in infancy. With an extracutaneous lesion, its diagnosis is difficult, because of a wide clinical spectrum. Here we demonstrate and characterize imaging features of 11 patients with JXG of the head and neck in various locations. MATERIAL AND METHODS: We recorded clinical data and reviewed all imaging studies of 11 patients with JXG of the head and neck. Ultrasonography (US) alone was performed in 1 patient; MRI alone in 6 patients; US and MRI in 1 patient; and US, CT, and MRI in 3 patients. We evaluated the following characteristics in all studies: location and number of lesions, echogenicity and vascularization on US, density on CT, signal intensity on T1- and T2-weighted images, ADC and enhancement on MRI, and tumor boundaries and bone involvement. RESULTS: Lesions were well-defined in 9 cases, and bone erosion was present in 2. On US, lesions were hypoechoic or hyperechoic and with or without vascularization. On CT, lesions were hyper-dense, with no calcification. On MRI, lesions were mildly hyper-intense or iso-intense on T1-weighted images in 8 of 9 patients, hypo-intense on T2-weighted images in 7 of 10, low ADC in 7 of 9, and enhancement in 7 of 7. CONCLUSIONS: The diagnosis of extra cutaneous JXG may be proposed, with the following suggestive criteria: age < 1 year, well-defined lesion, mild hyper-intensity on T1-weighted images, hypo-intensity on T2-weighted images, low ADC, enhancement, and possible adjacent bone involvement.

Association between acute complications in PMM2-CDG patients and haemostasis anomalies: Data from a multicentric study and suggestions for acute management.

OBJECTIVES: Patients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors (antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines. METHODS: In this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or "stroke mimic" (SM: normal brain imaging or evoking a migraine). RESULTS: Thirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found. DISCUSSION: Acute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy. CONCLUSION: Acute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.

Spectrum of neuroradiological manifestations in primary hemophagocytic lymphohistiocytosis: a comparative study of EBV-induced versus non-EBV-induced forms in 75 genetically confirmed pediatric cases.

OBJECTIVES: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening condition affecting young children. It is potentially triggered by Epstein-Barr virus (EBV). This study describes the neuroradiological features observed in 75 children with genetically confirmed primary HLH, comparing EBV-induced with non-EBV-induced HLH forms. METHODS: Brain MRIs between 2007 and 2021 from 75 children with HLH according to the 2004 Histiocyte Society criteria and with a confirmed HLH-related mutation, were retrospectively reviewed by two pediatric neuroradiologists blinded to EBV status and to mutation status. At diagnosis, 17 children with EBV viremia above a threshold of 1000 copies/mL were included in the EBV-induced HLH group. The remaining 58 patients were included in the non-EBV-induced HLH group. RESULTS: Of the 75 children initially included, 21 had abnormal MRI (21/75 (28%); 9/17 in the EBV-induced HLH group and 12/58 in the non-EBV-induced HLH group). All patients with abnormal MRI had neurological symptoms. Abnormal MRIs showed white matter lesions; the posterior fossa was affected in all but one case. There was no significant difference between groups regarding the localization or morphology of white matter lesions. The striatum was more frequently affected in the EBV-induced HLH group (8/9 (89%) versus 1/12 (8%), p = 0.00037). All lesions, whether in the white matter or in the basal ganglia, presented increased ADC values on diffusion weighted imaging (DWI). CONCLUSION: In this study of 75 children with genetically confirmed HLH, only children with neurological signs had abnormal brain MRI. Bilateral striatum involvement suggested an EBV-induced form of HLH. KEY POINTS: • In children with genetically proven HLH, only those with neurological signs did have brain abnormalities at MRI. • All patients with abnormal brain MRI had multiple white matter lesions with increased ADC values, including in the posterior fossa in almost all cases. • Basal ganglia and in particular the striatum were bilaterally and symmetrically affected in almost all EBV-induced HLH patients, in contrast to the non-EBV-induced HLH patients.

Clinical and radiological description of 120 pediatric stroke-like episodes.

BACKGROUND AND PURPOSE: Stroke-like episodes (SLEs) are defined as acute onset of neurological symptoms mimicking a stroke and radiological lesions non-congruent to vascular territory. We aimed to analyze the acute clinical and radiological features of SLEs to determine their pathophysiology. METHODS: We performed a monocenter retrospective analysis of 120 SLEs in 60 children over a 20-year period. Inclusion criteria were compatible clinical symptoms and stroke-like lesions on brain magnetic resonance imaging (MRI; performed for all 120 events) with focal hyperintensity on diffusion-weighted imaging in a non-vascular territory. RESULTS: Three groups were identified: children with mitochondrial diseases (n = 22) involving mitochondrial DNA mutations (55%) or nuclear DNA mutations (45%); those with other metabolic diseases or epilepsy disorders (n = 22); and those in whom no etiology was found despite extensive investigations (n = 16). Age at first SLE was younger in the group with metabolic or epilepsy disorders (18 months vs. 128 months; p < 0.0001) and an infectious trigger was more frequent (69% vs. 20%; p = 0.0001). Seizures occurred in 75% of episodes, revealing 50% episodes of SLEs and mainly leading to status epilepticus (90%). Of the 120 MRI scans confirming the diagnosis, 28 were performed within a short and strict 48-h period and were further analyzed to better understand the underlying mechanisms. The scans showed primary cortical hyperintensity (n = 28/28) with decreased apparent diffusion coefficient in 52% of cases. Systematic hyperperfusion was found on spin labeling sequences when available (n = 18/18). CONCLUSION: Clinical and radiological results support the existence of a vicious circle based on two main mechanisms: energy deficit and neuronal hyperexcitability at the origin of SLE.

Abnormal Spontaneous Blood Oxygenation Level Dependent Fluctuations in Children with Focal Cortical Dysplasias: Initial Findings in Surgically Confirmed Cases.

BACKGROUND: Focal cortical dysplasias (FCD) are a frequent cause of drug-resistant epilepsy in children but are often undetected on structural magnetic resonance imaging (MRI). We aimed to measure and validate the variation of resting state functional MRI (rs-fMRI) blood oxygenation level dependent (BOLD) metrics in surgically proven FCDs in children, to assess the potential yield for detecting and understanding these lesions. METHODS: We prospectively included pediatric patients with surgically proven FCD with inconclusive structural MRI and healthy controls, who underwent a ten-minute rs-fMRI acquired at 3T. Rs-fMRI data was pre-processed and maps of values of regional homogeneity (ReHo), degree centrality (DC), amplitude of low frequency fluctuations (ALFF) and fractional ALFF (fALFF) were calculated. The variations of BOLD metrics within the to-be-resected areas were analyzed visually, and quantitatively using lateralization indices. BOLD metrics variations were also analyzed in fluorodeoxyglucose-positron emission tomography (FDG-PET) hypometabolic areas. RESULTS: We included 7 patients (range: 3-15 years) and 6 aged-matched controls (range: 6-17 years). ReHo lateralization indices were positive in the to-be-resected areas in 4/7 patients, and in 6/7 patients in the additional PET hypometabolic areas. These indices were significantly higher compared to controls in 3/7 and 4/7 patients, respectively. Visual analysis revealed a good spatial correlation between high ReHo areas and MRI structural abnormalities (when present) or PET hypometabolic areas. No consistent variation was seen using DC, ALFF, or fALFF. CONCLUSION: Resting-state fMRI metrics, noticeably increase in ReHo, may have potential to help detect MRI-negative FCDs in combination with other morphological and functional techniques, used in clinical practice and epilepsy-surgery screening.

Neurological features related to influenza virus in the pediatric population: a 3-year monocentric retrospective study.

Influenza virus is generally characterized by fever, myalgia, and respiratory symptoms. Neurological entities have already been described, such as acute necrotizing encephalitis (ANE). We aimed to highlight the non-exceptional nature and explore the clinical spectrum and evolution of neurological features related to influenza virus in children. This monocentric observational study included patients under 18 years old, positive for influenza virus, between January 2017 and April 2019 in a pediatric university hospital. Patients were classified into two groups: those with or without a previous significant neurological or metabolic disorder. Two hundred eighty-nine children were identified with influenza infection. Thirty seven had a neurological manifestation: 14 patients who had previous significant neurological or metabolic disorder and 23 patients with no medical history. We identified several clinical patterns: 22 patients had seizures, 7 behavior disorders, 5 disturbances of consciousness, and 3 motor deficits. Four were diagnosed with a known influenza-associated neurological syndrome: 1 ANE, 1 cytotoxic lesion of the corpus callosum, 1 hemiconvulsion-hemiplegia-epilepsia syndrome, and 1 recurrent encephalitis in the context of a RANBP2 mutation. The neurological outcome was favorable in most cases. None of the patients with previous significant disorder retained sequalae or had a recurrence. Two patients had a fatal outcome, and both had a predisposing disorder. CONCLUSION: Various neurological manifestations can be associated with influenza virus. Certain entities led to a poor prognosis, but in most cases, symptoms improved within a few days. The severity of the neurological manifestations correlated with previous neurological or metabolic disorders. WHAT IS KNOWN: • Influenza viruses are well known pathogens with a seasonal epidemic evolution, particularly affecting children. These viruses cause acute fever with respiratory symptoms, associated with myalgia and headaches. Neurological presentation in influenza-virus infection is a well-established possibility as influenza virus is considered to be responsible for 27 to 36% of childhood encephalitis. Some specific and severe entity as acute necrotizing encephalitis, cytotoxic lesion of the corpus callosum, or Hemiconvulsion-hemiplegia-epilepsy syndrome are well described. WHAT IS NEW: • In a French monocentric cohort of 37 children with influenza-related neurologic manifestations, the majority of these manifestations, including seizure, drowsiness, motor deficiency, hallucination… are self limiting and do not lead to after-effects. In rare cases (4/37), they may reveal severe encephalitis requiring rapid and appropriate treatment. Otherwise, comparison of a group of 14 children with underlying neurological or metabolic disorder with a group of 23 children free of any significant disorder show that the severity of the neurological manifestations was largely related to previous neurological or metabolic disorders highlighting the importance of vaccination in this population.

Heterogeneity of PNPT1 neuroimaging: mitochondriopathy, interferonopathy or both?

BACKGROUND: Biallelic variants in PNPT1 cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs. OBJECTIVE AND METHODS: To document neuroimaging data in six patients with PNPT1 highlighting novel findings. RESULTS: Two patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection. CONCLUSION: We suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations.

The PEARL Approach for CT-guided Lung Biopsy: Assessment of Complication Rate.

Background Percutaneous CT-guided biopsy of lung nodules is an established method with high diagnostic accuracy but a high rate of pneumothorax and chest tube insertion compared with endobronchial methods. Purpose To investigate the effect of a protocol combining patient positioning biopsy-side down, needle removal during expiration, autologous blood patch sealing, rapid rollover, and pleural patching (PEARL) on complication rate after percutaneous CT-guided lung biopsy, especially chest tube insertion. Materials and Methods In a secondary analysis of both prospectively and retrospectively acquired data from December 2019 to November 2020, consecutive participants underwent biopsy with use of the PEARL protocol (prospective data) and were compared with patients who underwent biopsy at the same tertiary cancer center according to the standard method without any additional techniques (controls, retrospective data). Patient demographics, lesion characteristics, intraprocedural data, complications, and histologic results were recorded and compared. Results One hundred patients in the control group (mean age ± standard deviation, 63 years ± 12; 61 men) and 100 participants in the PEARL group (mean age, 64 years ± 12; 48 men) were evaluated. No differences were found in patient and lesion characteristics. The emphysema rate was 47 of 100 patients (47%) in both groups. The rate of pneumothorax was 37 of 100 patients (37%) in the control group versus 16 of 100 (16%) in the PEARL group (P = .001). Of the pneumothoraxes that occurred, fewer were during the intervention in the PEARL group, with 21 of 37 onsets (57%) in the control group versus three of 16 onsets (19%) in the PEARL group (P < .001). A chest tube was inserted in 13 of 100 patients (13%) in the control group and only in one of 100 (1%) in the PEARL group (P = .002). Histologic findings were diagnostic in 94 of 100 patients (94%) in the control group and 95 of 100 (95%) in the PEARL group (P > .99). Conclusion During CT-guided percutaneous lung biopsy, a protocol of positioning biopsy-side down, needle removal during expiration, autologous blood patch sealing, rapid rollover, and pleural patching, or PEARL, reduced rates of pneumothorax and chest tube insertion. © RSNA, 2021.

Neuroinflammatory Disease following Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children.

OBJECTIVE: To describe neurologic, radiologic and laboratory features in children with central nervous system (CNS) inflammatory disease complicating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. STUDY DESIGN: We focused on CNS inflammatory diseases in children referred from 12 hospitals in the Paris area to Necker-Sick Children Reference Centre. RESULTS: We identified 19 children who had a history of SARS-CoV-2 infection and manifest a variety of CNS inflammatory diseases: encephalopathy, cerebellar ataxia, acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, or optic neuritis. All patients had a history of SARS-CoV-2 exposure, and all tested positive for circulating antibodies against SARS-CoV-2. At the onset of the neurologic disease, SARS-CoV-2 PCR results (nasopharyngeal swabs) were positive in 8 children. Cerebrospinal fluid was abnormal in 58% (11/19) and magnetic resonance imaging was abnormal in 74% (14/19). We identified an autoantibody co-trigger in 4 children (myelin-oligodendrocyte and aquaporin 4 antibodies), representing 21% of the cases. No autoantibody was found in the 6 children whose CNS inflammation was accompanied by a multisystem inflammatory syndrome in children. Overall, 89% of patients (17/19) received anti-inflammatory treatment, primarily high-pulse methylprednisolone. All patients had a complete long-term recovery and, to date, no patient with autoantibodies presented with a relapse. CONCLUSIONS: SARS2-CoV-2 represents a new trigger of postinfectious CNS inflammatory diseases in children.

Systemic inflammatory syndrome in children with FARSA deficiency.

Variants in aminoacyl-tRNA synthetases (ARSs) genes are associated to a broad spectrum of human inherited diseases. Patients with defective PheRS, encoded by FARSA and FARSB, display brain abnormalities, interstitial lung disease and facial dysmorphism. We investigated four children from two unrelated consanguineous families carrying two missense homozygous variants in FARSA with significantly reduced PheRS-mediated aminoacylation activity. In addition to the core ARS-phenotype, all patients showed an inflammatory profile associated with autoimmunity and interferon score, a clinical feature not ascribed to PheRS-deficient patients to date. JAK inhibition improved lung disease in one patient. Our findings expand the genetic and clinical spectrum of FARSA-related disease.

Combined local treatments for vertebral metastases with limited epidural extension.

OBJECTIVES: Vertebral metastases with limited epidural extension (VMLEE) are frequently encountered in cancer patients; they can cause severe and debilitating symptoms including pain and neurological impairment and are usually treated by radiotherapy. In this study, we mainly evaluated the safety of combined local treatments (CLT), associating radiofrequency ablation (RFA) with vertebroplasty and radiotherapy (RT) to treat VMLEE. Also, we aimed to evaluate the short-term efficacy of CLT on bone metastases palliation and long-term prevention of skeletal-related events. METHODS: We retrospectively reviewed treatment complications, pain palliation, and skeletal complications after combined local treatments (CLT) for vertebral metastasis with limited epidural extension (VMLEE). RESULTS: Eighteen consecutive patients had CLT for 24 VMLEE, between June 2016 and January 2021. No major post-treatment complication was recorded. Nine patients had pain before the initiation of CLT. One month after CLT, only 3 patients had residual pain with a significant decrease of visual analogue scale (VAS), from 7.3 ± 2.4 to 2 ± 0 (p = .008), as well as the mean morphine milligram equivalent dose from 196.6 ± 135.7 to 38.5 ± 26, p = .008. Mean follow-up was 16.7 ± 11.5 months. Only one vertebra showed an increase of a preexisting vertebral fracture. Nine VMLEE had evidence of residual disease, including 2 which resulted in spinal cord compression (2, 11 months). CONCLUSION: CLT was safe and effective for pain palliation and long-term prevention of skeletal-related events for treatment of patients with VMLEE. The effectiveness of this combined treatment on tumor control and epidural involvement on the long term needs further investigation.

Thermal ablation in the management of oligometastatic colorectal cancer.

PURPOSE: To review available evidence on thermal ablation of oligometastatic colorectal cancer. METHODS: Technical and cancer specific considerations for percutaneous image-guided thermal ablation of oligometastatic colorectal metastases in the liver and lung were reviewed. Ablation outcomes are compared to surgical and radiation therapy literature. RESULTS: The application of thermal ablation varies widely based on tumor burden, technical expertise, and local cancer triage algorithms. Ablation can be performed in combination or in lieu of other cancer treatments. For surgically non-resectable liver metastases, a randomized trial has demonstrated the superiority of thermal ablation combined with chemotherapy compared to systemic chemotherapy alone in term of progression-free survival and overall survival (OS), with 5-, and 8-year OS of 43.1% and 35.9% in the combined arm vs. 30.3% and 8.9% in the chemotherapy alone arm. As ablation techniques and technology improve, the role of percutaneous thermal ablation may expand even into surgically resectable disease. Many of the prognostic factors for better OS after local treatment of lung metastases are the same for surgery and thermal ablation, including size and number of metastases, disease-free interval, complete resection/ablation, negative carcinoembryonic antigen, neoadjuvant chemotherapy, and controlled extra-pulmonary metastases. When matched for these factors, thermal ablation for lung and liver metastases appears to provide equivalent overall survival as surgery, in the range of 50% at 5 years. Thermal ablation has limitations that should be respected to optimize patient outcomes and minimize complications including targets that are well-visualized by image guidance, measure <3cm in diameter, and be located at least 3mm distance from prominent vasculature or major bronchi. CONCLUSIONS: The routine incorporation of image-guided thermal ablation into the therapeutic armamentarium for the treatment of oligometastatic colorectal cancer can provide long survival and even cure.

Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations.

BACKGROUND AND PURPOSE: Mitochondrial aminoacyl-tRNA synthetases-encoded by ARS2 genes-are evolutionarily conserved enzymes that catalyse the attachment of amino acids to their cognate tRNAs, ensuring the accuracy of the mitochondrial translation process. ARS2 gene mutations are associated with a wide range of clinical presentations affecting the CNS. METHODS: Two senior neuroradiologists analysed brain MRI of 25 patients (age range: 3 d-25 yrs.; 11 males; 14 females) with biallelic pathogenic variants of 11 ARS2 genes in a retrospective study conducted between 2002 and 2019. RESULTS: Though several combinations of brain MRI anomalies were highly suggestive of specific aetiologies (DARS2, EARS2, AARS2 and RARS2 mutations), our study detected no MRI pattern common to all patients. Stroke-like lesions were associated with pathogenic SARS2 and FARS2 variants. We also report early onset cerebellar atrophy and calcifications in AARS2 mutations, early white matter involvement in RARS2 mutations, and absent involvement of thalami in EARS2 mutations. Finally, our findings show that normal brain MRI results do not exclude the presence of ARS2 mutations: 5 patients with normal MRI images were carriers of pathogenic IARS2, YARS2, and FARS2 variants. CONCLUSION: Our study extends the spectrum of brain MRI anomalies associated with pathogenic ARS2 variants and suggests ARS2 mutations are largely underdiagnosed.

Biallelic IARS2 mutations presenting as sideroblastic anemia.

Not available.

Risk factors for local tumor progression after RFA of pulmonary metastases: a matched case-control study.

OBJECTIVES: Curative treatment of oligometastatic pulmonary disease aims at eradication of all metastases. Radiofrequency ablation (RFA) has been shown to be an efficient method and the frequency of local tumor progression (LTP) should be minimized. The objective of this study was to determine the morphological and treatment-related risk factors for LTP after RFA of pulmonary metastases. MATERIALS AND METHODS: All patients treated with RFA for pulmonary metastases from 2002 to 2014 were reviewed. All LTPs from 2011 to 2014 were individually matched on the basis of tumor size, number, and histology. In total, 48 LTPs and 112 controls were blindly analyzed for morphological factors including vicinity of bronchus and vessels as well as treatment-related factors such as the size of the ablation zone and ablation margins. RESULTS: In the simple regression analysis, the significant predictive variables were ≤ 5-mm distance to a large bronchus (OR = 4.94; p = 0.0095) or large vessel (OR = 7.09; p < 0.001), minimal ablation margin (≤ 5 mm (OR = 42.67; p < 0.001), and a central-peripheral ablation offset/ablation zone size > 0.36 (OR = 13.83; p = 0.013). In the multiple regression model, only a minimal ablation margin ≤ 5 mm remained a significant risk factor for LTP. CONCLUSION: Only the minimal ablation margin remains significant in the multiple regression analysis; the other factors are presumably surrogates of an insufficient ablation margin. Improvement of lung RFA outcomes can probably be obtained by immediate post RFA evaluation of ablation margins to ensure a minimal ablation margin of at least 5 mm. KEY POINTS: • A distance < 5 mm to a bronchus or vessel of over 3 mm diameter is associated with insufficient ablation margin and thus risk factors for local tumor progression after pulmonary radiofrequency ablation. • A minimal ablation margin of > 5 mm after pulmonary RFA is associated with significantly less local tumor progression and should be looked for at the end of treatment session before needle removal in order to decrease local tumor progression. • Tumor location, pleural contact, occurrence of intra-alveolar hemorrhage, pulmonary atelectasis, and pneumothorax are not associated with an increased risk of local tumor progression.

Radiogenomics of diffuse intrinsic pontine gliomas (DIPGs): correlation of histological and biological characteristics with multimodal MRI features.

OBJECTIVES: The diffuse intrinsic pontine gliomas (DIPGs) are now defined by the type of histone H3 mutated at lysine 27. We aimed to correlate the multimodal MRI features of DIPGs, H3K27M mutant, with their histological and molecular characteristics. METHODS: Twenty-seven treatment-naïve children with histopathologically confirmed DIPG H3K27M mutant were prospectively included. MRI performed prior to biopsy included multi-b-value diffusion-weighted imaging, ASL, and dynamic susceptibility contrast (DSC) perfusion imaging. The ADC and cerebral blood flow (CBF) and blood volume (CBV) were measured at the biopsy site. We assessed quantitative histological data, including microvascular density, nuclear density, and H3K27M-positive nuclear density. Gene expression profiling was also assessed in the samples. We compared imaging and histopathological data according to histone subgroup. We correlated MRI quantitative data with histological data and gene expression. RESULTS: H3.1K27M mutated tumors showed higher ADC values (median 3151 µm2/s vs 1741 µm2/s, p = 0.003), and lower perfusion values (DSC-rCBF median 0.71 vs 1.43, p = 0.002, and DSC-rCBV median 1.00 vs 1.71, p = 0.02) than H3.3K27M ones. They had similar microvascular and nuclear density, but lower H3K27M-positive nuclear density (p = 0.007). The DSC-rCBV was positively correlated to the H3K27M-positive nuclear density (rho = 0.74, p = 0.02). ADC values were not correlated with nuclear density nor perfusion values with microvascular density. The expression of gated channel activity-related genes tended to be inversely correlated with ADC values and positively correlated with DSC perfusion. CONCLUSIONS: H3.1K27M mutated tumors have higher ADC and lower perfusion values than H3.3K27M ones, without direct correlation with microvascular or nuclear density. This may be due to tissular edema possibly related to gated channel activity-related gene expression. KEY POINTS: • H3.1K27M mutant DIPG had higher apparent diffusion coefficient (p = 0.003), lower α (p = 0.048), and lower relative cerebral blood volume (p = 0.02) than H3.3K27M mutant DIPG at their biopsy sites. • Biopsy samples obtained within the tumor's enhancing portion showed higher microvascular density (p = 0.03) than samples obtained outside the tumor's enhancing portion, but similar H3K27M-positive nuclear density (p = 0.84). • Relative cerebral blood volume measured at the biopsy site was significantly correlated with H3K27M-positive nuclear density (rho = 0.74, p = 0.02).

Cerebral blood flow and acute episodes of Leigh syndrome in neurometabolic disorders.

AIM: To investigate cerebral blood flow (CBF) in acute episodes of Leigh syndrome compared with basal state in patients carrying pathogenic mitochondrial disease gene variants responsible for neurometabolic disorders. METHOD: Arterial spin labelling (ASL) magnetic resonance imaging (MRI) sequences were used to measure CBF in 27 patients with mitochondrial respiratory chain enzyme deficiencies, ascribed to pathogenic variants of reported disease genes who were undergoing either urgent neuroimaging for acute episodes of Leigh syndrome (Group I: 15 MRI, seven females, eight males; mean age 7y; range 7mo-14y) or routine brain MRI (Group II: 15 MRI, eight females, seven males; mean age 5y 2mo; range 2mo-12y). RESULTS: Patients displayed markedly increased CBF in the striatum (2.8-fold greater, p<0.001 [1.05-2.53]) during acute episodes of Leigh syndrome compared to basal conditions. Detection of elevated CBF preceded identification of structural MRI lesions in four out of 15 cases. INTERPRETATION: Our results suggest that increased CBF is an overt hallmark of Leigh syndrome episodes and ASL MRI sequences should facilitate early diagnosis of acute episodes of Leigh syndrome, especially during the first attack in young children, when structural MRI is insufficiently informative.