Recurrent glioblastoma: From molecular landscape to new treatment perspectives

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients

Mononeuritis multiplex following immune checkpoint inhibitors in malignant pleural mesothelioma

IntroductionMononeuritis multiplex is frequently related to vasculitic neuropathy and has been reported only sporadically as an adverse event of immune checkpoint inhibitors.MethodsCase series of three patients with mononeuritis multiplex—all with mesothelioma—identified in the databases of two French clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; OncoNeuroTox, Paris; January 2015–October 2022) set up to collect and investigate n-irAEs on a nationwide level.ResultsThree patients (male; median age 86 years; range 72–88 years) had pleural mesothelioma and received 10, 4, and 6 cycles, respectively, of first-line nivolumab plus ipilimumab combined therapy. In patient 1, the neurological symptoms involved the median nerves, and in the other two patients, there was a more diffuse distribution; the symptoms were severe (common terminology criteria for adverse events, CTCAE grade 3) in all patients. Nerve conduction studies indicated mononeuritis multiplex in all patients. Peripheral nerve biopsy demonstrated necrotizing vasculitis in patients 1 and 3 and marked IgA deposition without inflammatory lesions in patient 2. Immune checkpoint inhibitors were permanently withdrawn, and corticosteroids were administered to all patients, leading to complete symptom regression (CTCAE grade 0, patient 2) or partial improvement (CTCAE grade 2, patients 1 and 3). During steroid tapering, patient 1 experienced symptom recurrence and spreading to other nerve territories (CTCAE grade 3); he improved 3 months after rituximab and cyclophosphamide administration.DiscussionWe report the occurrence of mononeuritis multiplex, a very rare adverse event of immune checkpoint inhibitors, in the three patients with mesothelioma. Clinicians must be aware of this severe, yet treatable adverse event

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients

Dramatic response of STRN-NTRK -fused malignant glioneuronal tumor to larotrectinib in adult

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Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

International audienceGlioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients

Immune checkpoint inhibitors-induced neuromuscular toxicity: from pathogenesis to treatment

Immune checkpoint inhibitors (ICIs) are increasingly used and are becoming the standard of care in the treatment of various tumour types. Despite the favourable results in terms of oncological outcomes, these treatments have been associated with a variety of immune-related adverse events (irAEs). Neurological irAEs are rare but potentially severe. Neuromuscular disorders represent the most common neurological irAEs following anti-PD-1, anti-PDL-1 and anti-CTLA-4 treatment, and include myositis, myasthenia gravis and demyelinating polyradiculoneuropathy. Instrumental findings may differ from typical neuromuscular disorders occurring outside ICIs treatment. Despite initial severity, neurological irAEs often respond to immune-modulating therapies. Prompt irAEs diagnosis, ICIs discontinuation, and early treatment with corticosteroids, together with patient education and a multidisciplinary approach, are important for optimizing clinical outcomes. Intravenous immunoglobulin, plasma exchange and other immune-modulating treatments should be considered in more severe cases. Consideration of rechallenging with the same immunotherapy drug may be given in some cases, based on clinical picture and initial severity of irAEs. This article is protected by copyright. All rights reserved

Anti–Interleukin-6 and Janus Kinase Inhibitors for Severe Neurologic Toxicity of Checkpoint Inhibitors

International audienceBackground and Objectives : To describe the marked clinical and biological responses of a targeted treatment with anti–interleukin-6 (IL-6)–receptor antibody and Janus kinase (JAK) inhibitors in a patient with a severe, corticoresistant CNS toxicity of immune-checkpoint inhibitor (ICI) therapy.Methods: A 58-year-old man was admitted for subacute paraparesis, urinary retention, and ascending paresthesia. He was under treatment with ipilimumab and nivolumab for metastatic melanoma. Spine MRI disclosed multiple T2-hyperintense, contrast-enhancing longitudinally extensive lesions. A diagnosis of ICI-related acute transverse myelitis was made.Results: ICIs were immediately discontinued, and the patient received high-dose glucocorticoids plus 1 session of plasma exchange, but he did not improve. Based on the marked elevation of CSF IL-6 (505 pg/mL), a second-line targeted therapy with anti-IL-6-receptor tocilizumab (8 mg/kg/mo for 3 infusions) plus JAK inhibitor ruxolitinib (50 mg/d) was administered. Patient neurologic status started to improve shortly after, with corresponding radiologic resolution. At 9 months, the patient was able to walk independently, presenting only slight residual disability while remaining in oncologic partial response.Discussion: Our case suggests that some patients with severe, corticoresistant CNS immune-related toxicities of ICIs may benefit from cytokine blockade. Cytokine measurement in serum and CSF might help in selecting patients for personalized treatment strategies

Cytokine dynamics and targeted immunotherapies in autoimmune encephalitis.

Autoimmune encephalitides constitute a diverse group of immune-mediated central nervous system disorders mainly characterized by the presence of antibodies targeting neuronal or glial antigens. Despite the notable contribution of antibody discovery to the understanding of their physiopathology, the specific immune cells and inflammatory mediators involved in autoimmune encephalitis are still poorly defined. However, cytokines have recently emerged as crucial signalling molecules in the pathogenesis of autoimmune encephalitis. Cytokines are biologically active, soluble, low-molecular-weight proteins or glycoproteins involved in a wide variety of physiological functions, including central nervous system development and homeostasis, immune surveillance, as well as proliferation and maturation of immune cells. Since unbalanced cytokine expression is considered a hallmark of many autoimmune central nervous system disorders, their identification and quantification has become an essential element in personalized medicine applied to the field of neuroimmunology. Several studies have explored the cytokine profile of autoimmune encephalitis, but their interpretation and comparison is challenging due to their small sample sizes and extremely high heterogeneity, especially regarding the cytokines analysed, type of sample used, and associated neural antibody. Only the cytokine profile of anti-N-methyl-D-aspartate receptor encephalitis has extensively been investigated, with findings suggesting that, although humoral immunity is the main effector, T cells may also be relevant for the development of this disorder. A better understanding of cytokine dynamics governing neuroinflammation might offer the opportunity of developing new therapeutic strategies against specific immune cells, cytokines, antibodies, or intracellular signalling cascades, therefore leading to better outcomes and preventing undesired side effects of the presently used strategies. In this review, we first summarize the current knowledge about the role of cytokines in the pathogenesis of autoimmune encephalitis, combining theoretical analysis with experimental validations, to assess their suitability as clinical biomarkers. Second, we discuss the potential applicability of the novel targeted immunotherapies in autoimmune encephalitis depending on the immunobiology of the associated antibody, their limitations, as well as the main limitations that should be addressed in future studies

Leptomeningeal spread in glioblastoma: diagnostic and therapeutic challenges

International audienceBackgroundGlioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. Leptomeningeal spread (LMS) is a severe complication of GBM, raising diagnostic and therapeutic challenges in clinical routine.MethodsWe performed a review of the literature focused on LMS in GBM. MEDLINE and EMBASE databases were queried from 1989 to 2019 for articles describing diagnosis and therapeutic options in GBM LMS, as well as risk factors and pathogenic mechanisms.ResultsWe retrieved 155 articles, including retrospective series, case reports, and early phase clinical trials, as well as preclinical studies. These articles confirmed that LMS in GBM remains (a) a diagnostic challenge with cytological proof of LMS obtained in only 35% of cases and (b) a therapeutic challenge with a median overall survival below 2 months with best supportive care alone. For patients faced with suggestive clinical symptoms, whole neuroaxis magnetic resonance imaging and cerebrospinal fluid analysis are both recommended. Liquid biopsies are under investigation and may help prompt a reliable diagnosis. Based on the literature, a multimodal and personalized therapeutic approach of LMS, including surgery, radiotherapy, systemic cytotoxic chemotherapy, and intrathecal chemotherapies, may provide benefits to selected patients. Interestingly, molecular targeted therapies appear promising in case of actionable molecular target and should be considered.ConclusionAs the prognosis of glioblastoma is improving over time, LMS becomes a more common complication. Our review highlights the need for translational studies and clinical trials dedicated to this challenging condition in order to improve diagnostic and therapeutic strategies

Brain Metabolic Alterations in Seropositive Autoimmune Encephalitis: An ¹⁸F-FDG PET Study

Introduction: Autoimmune encephalitis (AE) diagnosis and follow-up remain challenging. Brain 18F-fluoro-deoxy-glucose positron emission tomography (FDG PET) has shown promising results in AE. Our aim was to investigate FDG PET alterations in AE, according to antibody subtype. Methods: We retrospectively included patients with available FDG PET and seropositive AE diagnosed in our center between 2015 and 2020. Brain PET Z-score maps (relative to age matched controls) were analyzed, considering metabolic changes significant if |Z-score| ≥ 2. Results: Forty-six patients were included (49.4 yrs [18; 81]): 13 with GAD autoantibodies, 11 with anti-LGI1, 9 with NMDAR, 5 with CASPR2, and 8 with other antibodies. Brain PET was abnormal in 98% of patients versus 53% for MRI. The most frequent abnormalities were medial temporal lobe (MTL) and/or striatum hypermetabolism (52% and 43% respectively), cortical hypometabolism (78%), and cerebellum abnormalities (70%). LGI1 AE tended to have more frequent MTL hypermetabolism. NMDAR AE was prone to widespread cortical hypometabolism. Fewer abnormalities were observed in GAD AE. Striatum hypermetabolism was more frequent in patients treated for less than 1 month (p = 0.014), suggesting a relation to disease activity. Conclusion: FDG PET could serve as an imaging biomarker for early diagnosis and follow-up in AE