Impact of Covid-19 pandemic on neuro-oncology multidisciplinary tumor board in the pre-vaccine era: the Normandy experience.

INTRODUCTION: The COVID19 pandemic had a strong impact on the healthcare system, particularly in oncology. Brain tumor are usually revealed by acute and life threatening symptoms. We wanted to evaluate the possible consequences of the COVID19 pandemic in 2020 on the activity of neuro-oncology multidisciplinary tumor board in a Normandy region (France). METHODS: A descriptive, retrospective, multicenter study was conducted in the four referent centers (two universitary hospitals and two cancer centers). The main objective was to compare the average number of neuro-oncology patients presented per multidisciplinary tumor board per week between a pre-COVID19 reference period (period 1 from December 2018 to December 2019) and the pre-vaccination period (period 2 from December 2019 to November 2020). RESULTS: Across Normandy, 1540 cases were presented in neuro-oncology multidisciplinary tumor board in 2019 and 2020. No difference was observed between period 1 and 2: respectively 9.8 per week versus 10.7, P=0.36. The number of cases per week also did not significantly differ during the lockdown periods: 9.1/week versus 10.4 during the non-lockdown periods, P=0.26. The only difference observed was a higher proportion of tumor resection during the lockdown periods: 81.4% (n=79/174) versus 64.5% (n=408/1366), P=0.001. CONCLUSION: The pre-vaccination era of the COVID19 pandemic did not impact the activity of neuro-oncology multidisciplinary tumor board in the Normandy region. The possible consequences in terms of public health (excess mortality) due to this tumor location should now be investigated.

Impact of EGFRA289T/V mutation on relapse pattern in glioblastoma.

BACKGROUND: Molecular factors influence relapse patterns in glioblastoma. The hotspot mutation located at position 289 of the extracellular domain of the epidermal growth factor receptor (EGFRA289mut) is associated with a more infiltrative phenotype. The primary objective of this study was to explore the impact of the EGFRA289 mutation on the pattern of relapse after chemoradiotherapy-based treatment of patients suffering from newly diagnosed glioblastoma. PATIENTS AND METHODS: An ancillary study from a prospective cohort of patients suffering from glioblastoma was conducted. All patients received radiotherapy and concomitant temozolomide. The population was divided into two groups according to EGFRA289 status (mutated versus wild-type). The primary endpoint was the overlap score (varying from 0 to 1) between the initial irradiated tumor volume (Vinit) and the relapse volume (Vr). Secondary endpoints explored the impact of EGFRA289mut on survival. RESULTS: One hundred twenty-eight patients were included and analyzed: 11% had EGFRA289mut glioblastoma (n = 14/128). EGFRA289mut glioblastomas had a relapse pattern that was more marginal than EGFRA289wt glioblastomas: a median overlap score Vinit/Vr of 0.96 was observed in the EGFRA289mut group versus 1 in the EGFRA289wt group (P = 0.05). Half of the population with EGFRA289mut tumor (n = 7/14) had a marginal relapse (i.e. overlap scoreVr/Vinit ≤ 0.95) compared to 23.7% (n = 27/114) in the EGFRA289wt group, P = 0.035. EGFRA289mut did not influence survival. CONCLUSION: We highlighted a link between the EGFRA289 mutation and the relapse pattern in glioblastoma. The independent role of EGFRA289mut and its clinical implication should now be explored in further studies.

Usefulness of circulating tumor DNA from cerebrospinal fluid in recurrent high-grade glioma.

Molecular documentation at relapse of high-grade glioma is an urgent need for patient care. A prospective pilot study was conducted to assess the rate of mutation detection using targeted deep sequencing on circulating tumor DNA from cerebrospinal fluid (CSF) after chemo-radiotherapy based treatment. Fifteen patients were included: 13 patients with glioblastoma, 1 patient with gliosarcoma and 1 patient with anaplastic astrocytoma. At progression, 10/15 patients (67%) had detectable mutations in the CSF. Among them, 5/10 patients harbored at least one common mutation between initial tumor and ctDNA. CSF protein level and cfDNA concentration were higher, although not significant, in the ctDNA positive group versus ctDNA negative group (1.17g/L vs. 0.79g/L). Molecular documentation obtained from ctDNA in CSF at the time of relapse is informative in around two-thirds of the patients.

In utero alcohol exposure impairs vessel-associated positioning and differentiation of oligodendrocytes in the developing neocortex.

Prenatal alcohol exposure (PAE) is a major cause of nongenetic mental retardation and can lead to fetal alcohol syndrome (FAS), the most severe manifestation of fetal alcohol spectrum disorder (FASD). FASD infants present behavioral disabilities resulting from neurodevelopmental defects. Both grey and white matter lesions have been characterized and are associated with apoptotic death and/or ectopic migration profiles. In the last decade, it was shown that PAE impairs brain angiogenesis, and the radial organization of cortical microvessels is lost. Concurrently, several studies have reported that tangential migration of oligodendrocyte precursors (OPCs) originating from ganglionic eminences is vascular associated. Because numerous migrating oligodendrocytes enter the developing neocortex, the present study aimed to determine whether migrating OPCs interacted with radial cortical microvessels and whether alcohol-induced vascular impairments were associated with altered positioning and differentiation of cortical oligodendrocytes. Using a 3D morphometric analysis, the results revealed that in both human and mouse cortices, 15 to 40% of Olig2-positive cells were in close association with radial cortical microvessels, respectively. Despite perinatal vascular disorganization, PAE did not modify the vessel association of Olig2-positive cells but impaired their positioning between deep and superficial cortical layers. At the molecular level, PAE markedly but transiently reduced the expression of CNPase and MBP, two differentiation markers of immature and mature oligodendrocytes. In particular, PAE inverted their distribution profiles in cortical layers V and VI and reduced the thickness of the myelin sheath of efferent axons. These perinatal oligo-vascular defects were associated with motor disabilities that persisted in adults. Altogether, the present study provides the first evidence that Olig2-positive cells entering the neocortex are associated with radial microvessels. PAE disorganized the cortical microvasculature and delayed the positioning and differentiation of oligodendrocytes. Although most of these oligovascular defects occurred in perinatal life, the offspring developed long-term motor troubles. Altogether, these data suggest that alcohol-induced oligo-vascular impairments contribute to the neurodevelopmental issues described in FASD.

Tumor-to-tumor metastases: Latent renal cell carcinoma discovered after elective surgical resection of a convexity meningioma.

BACKGROUND: Tumor-to-tumor metastases are extremely rarely reported lesions, which usually involve an indolent lesion hosting a more aggressive neoplasm. We present an unusual initial manifestation of a previously unknown clear cell renal cell carcinoma as a tumor-to-tumor metastasis in a typical meningothelial meningioma. CASE REPORT: A 73-year old patient with transient left slight monoparesis was addressed to our Neurosurgical Department after being evaluated by his general practitioner and passing a cerebral MRI which revealed a right frontotemporal mass attached to the meninge. At presentation, no deficits were identified; therefore an elective surgery was proposed. Histological analysis revealed a typical meningothelial meningioma containing a metastatic clear cell renal cell carcinoma. Additional thoraco-abdominal computer tomography identified a 6cm diameter lesion within the right kidney with radiological features highly suggestive of a primary clear cell renal cell carcinoma. CONCLUSION: Our case highlights the need for a specialized neuropathological approach to clinical and imagistic indolent meningiomas, as they may require important differential diagnosis that can highly impact the treatment and follow-up of brain tumor patients.

[Primary central nervous system lymphoma following immunotherapy for metastatic melanoma]. / Lymphome cérébral primitif après immunothérapie d'un mélanome métastatique.

BACKGROUND: Anti-PD-1 and anti-CTLA-4 monoclonal antibodies are used in melanoma, while anti-PD-1 are also used in Hodgkin's lymphoma. Primary central nervous system lymphoma is a rare form of non-Hodgkin's lymphoma with few effective treatments. However, several recent studies have reported multiple cases of non-Hodgkin's lymphoma and primary central nervous system lymphoma treated by anti-PD-1 antibodies with favourable responses. PATIENTS AND METHODS: This study focuses on the case of a 59-year-old man with metastatic melanoma treated by immunotherapy (anti-CTLA-4 followed by anti-PD-1). He underwent 28 courses of therapy with pembrolizumab. Treatment was stopped after clinical and radiological remission. The patient presented left hemiparesis and a primary central nervous system lymphoma was diagnosed two months after discontinuation of immunotherapy. He started urgent high-dose methotrexate chemotherapy but without significant results. Despite second-line chemotherapy with R-ICE (rituximab-ifosfamide, carboplatin and etoposide), the patient died. DISCUSSION: Several hypotheses may be advanced regarding a possible relationship between immunotherapy and the occurrence of this primary central nervous system lymphoma. The lymphoma may have been pre-existing and controlled by immunotherapy, but progressing rapidly after treatment, or it may have been induced by the immunotherapy. However, immunotherapy may have played no role; the relationship between melanoma and lymphoma is well known. CONCLUSION: While immunotherapy cannot be unequivocally incriminated in primary central nervous system lymphoma, this case raises many questions about the imputability of immunotherapy in the occurrence of secondary cancers, including lymphomas.

Sudden paraplegia due to spontaneous bleeding in a thoracic epidural angiolipoma and literature review.

BACKGROUND: Spinal angiolipomas are rare epidural tumours that are usually revealed by chronic symptoms of medullar irritation. We report a case of acute paraplegia caused by spontaneous bleeding revealing a thoracic angiolipoma. CASE DESCRIPTION: A 17-year-old male patient with no previous medical history was admitted for acute onset of paraplegia with bladder retention and loss of sensation in the lower limbs, preceded by dorsal pain during the three previous days. MRI showed an enhanced T1-weighted image of a T7-T12 epidural lesion. The T1-weighted isosignal and the T2-weighted hyposignal suggested haemorrhagic complications. Due to a mass effect on the spinal cord, an emergency laminectomy was performed. Histopathological examination of the lesion revealed an angiolipoma with spontaneous bleeding. Clinical outcome was favourable after two months. CONCLUSION: This case is one of the first to be reported, although the clinical presentation is similar to that of other rare reported cases of paraplegia due to spinal compression by tumoural bleeding.

[Small fiber neuropathy]. / La neuropathie des petites fibres.

Small fiber neuropathy (SFN) is still unknown. Characterised by neuropathic pain, it typically begins by burning feet, but could take many other expression. SFN affects the thinly myelinated Aδ and unmyelinated C-fibers, by an inherited or acquired mechanism, which could lead to paresthesia, thermoalgic disorder or autonomic dysfunction. Recent studies suggest the preponderant role of ion channels such as Nav1.7. Furthermore, erythromelalgia or burning mouth syndrome are now recognized as real SFN. Various aetiologies of SFN are described. It could be isolated or associated with diabetes, impaired glucose metabolism, vitamin deficiency, alcohol, auto-immune disease, sarcoidosis etc. Several mutations have recently been identified, like Nav1.7 channel leading to channelopathies. Diagnostic management is based primarily on clinical examination and demonstration of small fiber dysfunction. Laser evoked potentials, Sudoscan®, cutaneous biopsy are the main test, but had a difficult access. Treatment is based on multidisciplinary management, combining symptomatic treatment, psychological management and treatment of an associated etiology.

Impact of discrepancies between the Abbott realtime and cobas TaqMan assays for quantification of human immunodeficiency virus type 1 group M non-B subtypes.

Viral loads in 249 clinical samples from individual patients infected with human immunodeficiency virus type 1 non-B subtypes were determined with both the Abbott RealTime and Cobas TaqMan assays. The differences exceeded 0.5 log for about 20% of samples and 1 log for 3%, with higher values always from the Abbott assay in the latter cases.

Viral efficacy maintained and safety parameters improved with a reduced dose of stavudine: a pilot study.

OBJECTIVES: Stavudine (d4T) is a potent but potentially toxic nucleoside reverse transcriptase inhibitor that is still widely used in developing countries. This study's aim was to determine the efficacy and safety profile of lower-dose d4T. METHODS: Multi-centre, open-label, single-arm, pilot, 48-week study in French patients weighing >60 kg with viral load <400 HIV-1 RNA copies/mL who were receiving d4T 40 mg twice daily and then switched to 30 mg twice daily. The primary endpoint was the proportion with plasma viral load <400 copies/mL at week 24. Secondary endpoints included the proportion with <50 copies/mL at weeks 24 and 48, changes in mitochondrial DNA, CD4 cell count and pharmacokinetics, and clinical and laboratory safety. RESULTS: Fifty-seven patients enrolled. Baseline CD4 count was 584 cells/microL; viral loads were <400 copies/mL and <50 copies/mL in 100% and 89%, respectively. Prior antiretroviral drug exposure was 6.9 years, d4T exposure was 6.3 years. Fifty-six out of 57 (98%) patients had viral load <400 copies/mL and 51 (89%) had viral load <50 copies/mL at week 24. Median CD4 count increased by 63 cells/microL at week 48 (P=0.006). At 48 weeks, total cholesterol decreased by 0.24 mmol (P=0.02), high-density lipoprotein cholesterol by 0.15 mmol (P=0.0001) and alanine aminotransferase by 5.74 mg/dL (P=0.01). Paired baseline DNA and week 24 RNA mutations were unchanged. Mitochondrial DNA (copies/cell) content increased from 672+/-254 to 682+/-269. d4T area under the plasma concentration time curve (AUC) decreased by 31% (P=0.003) and C(max) by 44% (P=0.004). Clinical and laboratory parameters improved or were unchanged. CONCLUSIONS: Reduced-dose d4T is effective with improved safety parameters.

Measuring HIV-1 RNA and interferon-alpha in the cerebrospinal fluid of AIDS patients: insights into the pathogenesis of AIDS Dementia Complex.

The aim of this work was to study the role of HIV replication and the role of endogenous secretion of interferon-alpha in the pathogenesis of AIDS Dementia Complex (ADC). To accurately establish the diagnosis of ADC, 39 consecutive HIV-positive patients who presented with immune and intellectual deficiency underwent an extensive neurological evaluation. This included magnetic resonance imaging, neuropsychological testing and a lumbar puncture. The levels of HIV-1 RNA were measured in the cerebrospinal fluid (CSF) and blood by HIV Monitor (Roche Diagnostics) and those of interferon-alpha by an in-house biological assay. The diagnosis of ADC was established in 22 cases, which included nine out of the ten patients who had a high CSF viral load (above 4 log HIV-1 RNA copy per ml). Patients receiving highly active antiretroviral therapy had low viral loads in blood and CSF. In all 22 ADC patients, viral load in the CSF correlated with the staging of ADC (r=0.46, P=0.03), the CSF level of interferon-alpha (r=0.42, P=0.05) and with the bicaudate ratio (r=0.43, P=0.06), a measure of cerebral atrophy in the region of the caudate nucleus. No correlation was observed between CSF and plasma HIV-1 RNA. These results show that HIV may play a role in the neurological impairment of ADC patients possibly in part through the deleterious effect of interferon-alpha on the central nervous system and that highly active combination therapy should reduce or prevent these complications.

The 2.46 A resolution structure of the pancreatic lipase-colipase complex inhibited by a C11 alkyl phosphonate.

Pancreatic lipase belongs to the serine esterase family and can therefore be inhibited by classical serine reagents such as diisopropyl fluoride or E600. In an attempt to further characterize the active site and catalytic mechanism, we synthesized a C11 alkyl phosphonate compound. This compound is an effective inhibitor of pancreatic lipase. The crystal structure of the pancreatic lipase-colipase complex inhibited by this compound was determined at a resolution of 2.46 A and refined to a final R-factor of 18.3%. As was observed in the case of the structure of the ternary pancreatic lipase-colipase-phospholipid complex, the binding of the ligand induces rearrangements of two surface loops in comparison with the closed structure of the enzyme (van Tilbeurgh et al., 1993b). The inhibitor, which could be clearly observed in the active site, was covalently bound to the active site serine Ser152. A racemic mixture of the inhibitor was used in the crystallization, and there exists evidence that both enantiomers are bound at the active site. The C11 alkyl chain of the first enantiomer fits into a hydrophobic groove and is though to thus mimic the interaction between the leaving fatty acid of a triglyceride substrate and the protein. The alkyl chain of the second enantiomer also has an elongated conformation and interacts with hydrophobic patches on the surface of the open amphipathic lid. This may indicate the location of a second alkyl chain of a triglyceride substrate. Some of the detergent molecules, needed for the crystallization, were also observed in the crystal. Some of them were located at the entrance of the active site, bound to the hydrophobic part of the lid. On the basis of this crystallographic study, a hypothesis about the binding mode of real substrates and the organization of the active site is proposed.

Digestive lipases: inactivation by phosphonates.

Phosphonates mimicking the transition state which occurs during carboxyester hydrolysis were synthesized and investigated as potential inactivators of human pancreatic (HPL) and gastric (HGL) lipases. Their efficiency as inactivators was studied on the basis of the alkyl chain length, the nature of the leaving group and the influence of the ester substituent. In each case, HGL was found to be more sensitive than HPL towards these phosphonates. The released p-nitrophenol to enzyme ratio indicates that a 1:1 complex was formed. In the absence of substrate, the most powerful inactivator was O-methyl O-(p-nitrophenyl) n-pentylphosphonate (4A), which has a short alkyl chain, a small methoxy substituent and a good leaving group.