Description of neurotoxicity in a series of patients treated with CAR T-cell therapy.

Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1-2 severity and 34% had grade 3-4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3-4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.

Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies.

OBJECTIVE: To describe the main syndrome and clinical course in a large cohort of patients with anti-Ri-associated paraneoplastic neurologic syndrome (Ri-PNS). METHODS: Twenty-year retrospective nationwide study and systematic review of the literature. RESULTS: Thirty-six patients with complete clinical information were identified (median age 66 years, range: 47-87 years). In this French cohort, the majority were women (78%). At onset, 4 main patterns were observed: cerebellar syndrome (39%), isolated tremor (24%), oculomotor disturbances (17%), and other symptoms (19%). Course was multistep for 78% of cases. At the time the disease reached the plateau phase (median 12 weeks, range: 1-64 weeks; 28% >3 months), 24 (67%) showed an overt cerebellar syndrome, which was isolated in 3 patients, and was most frequently (21/24 cases) part of a multisystem neurologic disease. Patients manifested a variety of movement disorders, including myoclonus (33%), dystonia (17%), either cervical or oromandibular, and parkinsonism (17%). Most patients had cancer (92%), mainly breast cancer (n = 22). Misdiagnoses concerned 22% of patients (n = 8) and included atypical parkinsonism (n = 2), MS (n = 2), Bickerstaff encephalitis (n = 1), hyperekplexia (n = 1), vestibular neuritis (n = 1), and functional neurologic disorder (n = 1). Survival at 12 months was 73% (95% CI [0.54-0.85]), at 24 months 62% (95% CI [0.41-0.78]), and at 36 months 47% (95% CI [0.25-0.65]). There was no major clinical difference between cases retrieved from the systematic review of the literature (n = 55) and the French cohort. CONCLUSIONS: Ri-PNS is a multisystem neurologic syndrome with prominent cerebellum/brainstem involvement. Opsoclonus-myoclonus is less common than expected, and the disorder can mimic neurodegenerative diseases.

Implication of the product of the bovine herpesvirus type 1 UL25 gene in capsid assembly.

The UL25 ORF of bovine herpesvirus type 1 (BHV-1) was demonstrated recently to represent a gene encoding a 63 kDa viral protein. To investigate the role of this gene in virus replication, a BHV-1 UL25 deletion mutant was constructed. Although the UL25 mutant synthesizes late viral proteins and viral DNA, it fails to produce virus progeny in cells that do not express the UL25 gene, demonstrating that the UL25 protein is essential for the replicative cycle of BHV-1. Moreover, Southern blotting analyses of HindIII-digested DNA from infected non-complementing cells probed with the leftward terminal fragment of the BHV-1 linear genome revealed that the cleavage of the viral DNA produced is not impaired. However, the packaging of this cleaved DNA is compromised severely, since only few full C capsids were observed in infected non-complementing cells by transmission electron microscopy.

Transcriptional and translational expression kinetics of the bovine herpesvirus 1 UL51 homologue gene.

We characterized the expression kinetics of the transcript and protein generated from the bovine herpesvirus 1 (BHV1) homologue of the herpes simplex virus 1 (HSV1) UL51 gene. The BHV1 UL51 ORF, located at positions 7236-->7967 of the viral genome, generated a major 1.05 kb transcript accumulating at very low abundance as soon as 3 h post-infection (p.i.), after which its levels increased to reach a plateau from 6 to 12 h p.i., and then slowly decreased up to 24 h p.i. As determined by S1 nuclease protection assays, UL51 transcription initiated at two distinct sites located at 191 and 196 bases upstream from the initiation codon, corresponding to positions 7045 and 7040 of the viral genome, respectively. Western blotting of BHV1-infected protein cell lysates, using a BHV1-specific antiserum generated against a recombinant protein expressed in Escherichia coli, detected a 28 kDa protein of the expected size (24985 Da) whose expression kinetics followed that of its transcript. As evidenced by in situ immunofluorescence assays, the protein mainly localized to the cytoplasm and the perinuclear region of infected cells. In contrast to HSV1 UL51 which is classified as a gamma2 gene, BHV1 UL51 belongs to viral genes of the gamma1 class as expression of its transcript is partially dependent on viral DNA synthesis.