GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.

Paraneoplastic AQP4-IgG-Seropositive Neuromyelitis Optica Spectrum Disorder Associated With Teratoma: A Case Report and Literature Review.

OBJECTIVES: To assess a case of paraneoplastic aquaporin-4 (AQP4)-immunoglobulin G (IgG)-seropositive neuromyelitis optica spectrum disorder (NMOSD) associated with teratoma and determine whether it is a paraneoplastic neurologic disorder. METHODS: A single case study and literature review of 5 cases. RESULTS: A 27-year-old woman presented with diplopia, facial nerve palsy, paraplegia, sensory dysfunction of lower limbs, dysuria, nausea, and vomiting. Spinal cord MRI detected an extensive longitudinal lesion in the spinal cord, and brain MRI detected abnormal lesions in the right cerebral peduncle and tegmentum of the pons. CSF analysis revealed positive oligoclonal IgG bands (OCBs). The patient tested positive for AQP4-IgG, confirming a diagnosis of NMOSD. An abdominal CT scan detected an ovarian tumor. After steroid therapy and tumor removal, the patient progressively improved, with only mild sensory dysfunction. Histopathologic analysis of the tumor revealed a teratoma and the presence of glial fibrillary acidic protein (GFAP)+ neural tissue with AQP4 immunoreactivity, accompanied by lymphocyte infiltration. Including the present case, there have been 6 reported cases of AQP4-IgG-seropositive NMOSD associated with ovarian teratoma (mean onset age, 32.7 years). Of these patients, 5 (83%) presented with nausea and/or vomiting, positive OCB, and dorsal brainstem involvement. Pathologic analyses of the teratoma were available in 5 cases, including the present case, revealing neural tissue with AQP4 immunoreactivity and lymphocyte infiltration in all cases. CONCLUSIONS: This study suggests that ovarian teratoma may trigger the development of AQP4-IgG-seropositive NMOSD. Further studies are needed to elucidate the pathogenesis of teratoma-associated NMOSD.

Immunotherapy: A Potential Approach for High-Grade Spinal Cord Astrocytomas.

Spinal cord astrocytomas (SCAs) account for 6-8% of all primary spinal cord tumors. For high-grade SCAs, the prognosis is often poor with conventional therapy, thus the urgent need for novel treatments to improve patient survival. Immunotherapy is a promising therapeutic strategy and has been used to treat cancer in recent years. Several clinical trials have evaluated immunotherapy for intracranial gliomas, providing evidence for immunotherapy-mediated ability to inhibit tumor growth. Given the unique microenvironment and molecular biology of the spinal cord, this review will offer new perspectives on moving toward the application of successful immunotherapy for SCAs based on the latest studies and literature. Furthermore, we will discuss the challenges associated with immunotherapy in SCAs, propose prospects for future research, and provide a periodic summary of the current state of immunotherapy for SCAs immunotherapy.

Analysis of PD-L1 expression and T cell infiltration in different molecular subgroups of diffuse midline gliomas.

Diffuse midline gliomas (DMGs) are rare and devastating tumors with limited therapeutic options. Programmed death-ligand 1 (PD-L1) expression represents a potential predictive biomarker for immunotherapy. One hundred and twenty-six DMGs (89 adult and 37 pediatric) were assessed for immune profile (PD-L1, cluster of differentiation (CD3, CD8) and genetic markers (mutation in 27th amino acid of histone H3 (H3K27M), alpha thalassemia/mental retardation syndrome X-linked (ATRX), isocitrate dehydrogenase 1 (IDH1), p53) by immunohistochemistry. Sanger sequencing was done for IDH1 and H3K27M. The thalamus was the commonest site. Four molecular subgroups of DMGs were identified. H3K27M mutation was more frequent in children (P = 0.0001). The difference in median overall survival (OS) was not significant in any of the four molecular subgroups (P > 0.05). PD-L1 expression was significantly higher in H3K27M/IDH1 double-negative adult glioblastomas (GBMs) (P = 0.002). Strong PD-L1 expression was more frequent in grade IV tumors and thalamic location, although the difference was not significant (P = 0.14 and P = 0.19 respectively). Positive PD-L1 expression was significantly associated with high tumor-infiltrating lymphocytes count (P < 0.05). There was no significant difference in median OS in PD-L1-positive versus negative cases among four genetic subgroups (P > 0.05). On univariate analysis, there was no direct correlation of PD-L1 with any genetic alteration, except H3K27M mutation (P = 0.01). CD3 infiltration was similar in both adults and pediatric ages (84.3% and 78.4%, respectively) while CD8 expression was significantly greater in adults compared to children (74.1% vs 37.8%, P = 0.0001). This is the first comprehensive analysis highlighting molecular and immune profiles of DMGs. Despite molecular and clinicopathological diversity, overall survival in DMGs remains dismal. Multicentric studies with larger numbers of cases should be undertaken for stratifying DMGs according to their age, immune and molecular profiles, to develop effective immunotherapies.

A CD99+ primary spinal central PNET in a pregnant patient- therapeutic concerns and issues.

Spinal tumours in pregnancy are rare. Spinal tumours account for only 10-15% of all primary central nervous system (CNS) tumours. Most spinal tumours in pregnant women have been described as meningiomas or vascular tumours. We present the unique case of a pregnant patient presenting with a CD 99+ primary spinal central PNET.

Rosette-Forming Glioneuronal Tumor Originating From the Spinal Cord: Report of 2 Cases and Literature Review.

Rosette-forming glioneuronal tumor (RGNT) is a recently recognized and rarely encountered tumor occurring in the fourth ventricle. RGNT was first described as a new entity for the distinct clinicopathologic features by Komori et.al. in 2002. Histologically, it is composed of 2 distinct features: a glial component, resembling pilocytic astrocytoma, and a neurocytic component forming neurocytic rosettes and/or perivascular rosettes. We report 2 extremely rare cases of RGNT arising from the spinal cord, which were misdiagnosed as ependymoma and astrocytoma preoperatively. Symptoms included dissociated sensory disturbances and episodic pain and fatigue of 2 years' duration in case 1, as well as motor disturbance for 2 months' duration in case 2. Magnetic resonance imaging (MRI) revealed these masses in the thoracolumbar (T7-L1) and cervicothoracic (C3-C7) spinal cord. The solid component appeared hypointense in T1-weighted MRI sequences, hyperintense in the T2-weighted MRI sequences, and heterogeneous in MRI images enhanced with gadolinium contrast medium in both cases. Gross total resection was performed via a median laminectomy. Postoperative pathological examination confirmed the diagnosis of RGNT. In addition, extensive analysis of genetic mutations was performed to explore the relationship with glioma, including telomerase reverse transcriptase promoter, isocitrate dehydrogenase 1/2, BRAF-V600E, and O(6)-methylguanine-DNA methyltransferase promoter. No radiotherapy or chemotherapy were performed in these two cases. As of the latest follow-up, both patients had a good prognosis. Given the widely varying clinical characteristics of, prognosis of, and treatments for spinal tumors, differential diagnosis is of great importance before surgery. Consideration of the tumor location and the patient's age and sex, in combination with the imaging features, may be the best approach to narrowing the differential diagnosis. Surgery is the preferred treatment for RGNT. We do not recommend to implement adjuvant radiotherapy and chemotherapy in these patients except the invasive or recurrent tumors. Further examination and routine follow-up should be recommended to estimate the long-term prognosis.

A rosette-forming glioneuronal tumor of the spinal cord: the first case of a rosette-forming glioneuronal tumor originating from the spinal cord.

Rosette-forming glioneuronal tumors of the fourth ventricle are rare brain tumors, and only 19 such lesions have been previously reported. This report presents the first case of a rosette-forming glioneuronal tumors arising from the spinal cord. A 44-year-old woman presented with a 15-year history of dissociated sensory disturbance of the lower extremities that gradually spread through her upper extremities. She also experienced continuing motor disturbance. Magnetic resonance imaging demonstrated a mass in the cervicothoracic spinal cord that suggested an intramedullary spinal tumor. A total gross resection of the tumor was performed. As is typical of rosette-forming glioneuronal tumors of the fourth ventricle, this spinal cord example manifested neurocytic and astrocytic components. Neurocytic rosettes were detected in the neurocytic component, and the center of rosettes showed positive immunostaining for synaptophysin. The astrocytic component showed characteristic features of a pilocytic astrocytoma, as is often the case in the fourth ventricle examples.

Therapeutic total plasma exchange in a child with neuroblastoma-related anti-Hu syndrome.

A 5-year-old boy underwent total plasma exchange to remove anti-neuronal anti-Hu autoantibodies as a complication of neuroblastoma, leading to autonomic bowel dysfunction. Total plasma exchange (TPE) resulted eventually in a reduction of autoantibody levels, but, more importantly, led to improvement of bowel function. TPE proved to be a safe and effective treatment option in neuroblastoma-related anti-Hu syndrome in a child.

Adult T-cell lymphoma involving the leptomeninges associated with a spinal cord schwannoma.

Adult T-cell lymphoma (ATL-L) developing initially in the meninges is rare. An autopsy case of ATL-L with an acute onset of meningitis and generalized lymphadenopathy in association with a cervical cord schwannoma is reported here. A 78-year-old woman with sensori-motor weakness of both arms over a 1-year period, developed febrile episodes and drowsiness with neck stiffness. Lumbar puncture revealed an increased protein content (161 mg/dL) and increased cell count (463/3) consisting of 99% of lymphocytes which contained atypical lymphocytes with multilobulated nuclei ('flower cells'), which are characteristic of ATL-L. Viral titers were positive only for HTLV-I antibodies (serum X 640: CSF X 16). Biopsy of an enlarged retroperitoneal lymph node revealed malignant lymphoma of the T-cell type. Brain MRI was negative, whereas an intradural extramedullary mass was found at the C4 level. With a diagnosis of ATL-L stage IV, chemotherapy was commenced, which was effective in reducing the generalized lymphadenopathy as well as the cervical mass and restoring the CSF findings to normality. The cervical cord mass was verified to be a solitary schwannoma, and ATL-L involvement was found not only in the leptomeninges, but also within the cervical cord schwannoma.

Spinal oligodendroglioma with diffuse arachnoidal dissemination in a Japanese Black heifer.

A gelatinous focus with cystic spaces, was found in the posterior funiculus of the 2nd to 3rd lumbar levels of the spinal cord of a Japanese Black heifer, 2 years old, with clinical signs of severe dysstasia. Histopathological examination revealed that the spinal lesion consisted of multifocal and diffuse proliferation of round cells with abundant vacuolar cytoplasm and hyperchromatic nuclei. In the lesions there was a number of cystic spaces containing aggregates of small round cells. The neoplastic foci showed a honeycomb structure divided by thin blood vessels, representing typical lesions of oligodendroglioma. Diffuse and multifocal proliferation of these round cells were also recognized in the subarachnoidal space in the sacral spinal cord. Immunohistochemically, the proliferating round cells were negative for glial fibrillary acidic protein. Based on these morphological features, the case was diagnosed as lumbar spinal oligodendroglioma with diffuse arachnoidal dissemination.

Cell kinetic analysis in pediatric brain and spinal tumors: a study of 117 cases with Ki-67 quantitation and flow cytometry.

We present cell kinetic data including Ki-67 quantitation and flow cytometry on 117 pediatric brain/spinal cord tumors and review the literature. Although, in general, these proliferation indices are in agreement with the histologic grade, they are useful in prognostication in some instances when the histological features of malignancy are equivocal. Specific examples in which flow cytometry may prove particularly useful in this context are childhood ependymomas, which do not show frank anaplasia but have cellular foci with focal increase in mitoses, and choroid plexus neoplasms, where elevated S phase fractions have been associated with an adverse outcome. Thus Ki-67 quantitation and flow cytometry not only serve as useful adjuncts to conventional histologic grading but also in specific instances may provide new information on tumor prognosis.

The growth potential of ependymomas with varying grades of malignancy measured by the Ki-67 labelling index and mitotic index.

The prognostic significance of histopathological grade for postoperative outcome is not yet known for ependymomas. Data on proliferation kinetics of these tumors are few. In our study, the growth fraction was immunohistochemically determined by labelling cell nuclei with the monoclonal antibody Ki-67 in 24 tumors of the ependymoma group (2 malignant ependymomas grade III, 11 ependymomas grade II, 8 spinal ependymomas, and 3 subependymomas). The results were compared with the mitotic index in the same tumor areas. Both growth parameters are related to the grade of malignancy. The differences between the results of spinal ependymomas (grade I) and of intracranial tumors (grade II) were statistically significant. Malignant ependymomas had the highest values. Variable growth potentials could be demonstrated in a few tumors. A non-linear relationship between growth fraction and mitotic index was found, indicating a variable generation time in ependymomas (as in astrocytomas). Thus, with rising grade of malignancy the growth fraction increases and the generation time decreases.

Lipocortin-1 immunoreactivity in central and peripheral nervous system glial tumors.

We examined the cellular distribution of lipocortin-1 (L-1), a major physiologic substrate for the epidermal growth factor receptor/kinase, in 122 central nervous system (CNS) and peripheral nervous system (PNS) neoplasms using the peroxidase-antiperoxidase technique with a polyclonal antibody specific for L-1. Extensive L-1 immunoreactivity was demonstrated in many CNS tumors; in 11 of 21 glioblastoma multiformes, in five of 12 anaplastic astrocytomas, and in five of 14 astrocytomas. Significant numbers of immunoreactive ependymocytes or astrocytes were also seen in six of 13 ependymomas. In contrast, no immunostaining was detected in the oligodendrocytes in any of ten oligodendrogliomas. PNS tumors, found in two of five malignant nerve sheath tumors, 13 of 15 schwannomas, 13 of 17 neurofibromas, and 14 of 15 traumatic neuromas, also contained considerable L-1 immunoreactivity in Schwann cells or mast cells. These findings raise the possibility that L-1 may participate in the proliferation or subsequent differentiation of neoplastic astrocytes, ependymocytes, and Schwann cells.

Vascular response in experimental spinal cord gliomas of the rat.

Reported is the immunoreactivity of tumoral and peritumoral vessels of 7 spinal cord gliomas induced in rats by means of ethylnitrosourea. Immunostaining for Factor VIII/RAg has been more strongly pronounced in endothelial cells of newly formed vessels at the tumor periphery, in comparison with tumoral vessels, and this is likely to suggest a differentiation process during extensive neovascularization of the tumor periphery. Endothelial distribution of vimentin in the peripheral vessels is more intensive than within the tumors, suggesting its relation to rapid new blood vessel formation. Immunostaining for GFAP and vimentin overlaps in astrocytes trapped within neoplasms, in astrocytes at the tumor periphery, and in the peritumoral zone.