Recurrent atypical teratoid/rhabdoid tumors (AT/RT) reveal discrete features of progression on histology, epigenetics, copy number profiling, and transcriptomics.

Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy. They split into four molecular types. The major three (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC) all carry mutations in SMARCB1, the fourth quantitatively smaller type is characterized by SMARCA4 mutations (AT/RT-SMARCA4). Molecular characteristics of disease recurrence or metastatic spread, which go along with a particularly dismal outcome, are currently unclear. Here, we investigated tumor tissue from 26 patients affected by AT/RT to identify signatures of recurrences in comparison with matched primary tumor samples. Microscopically, AT/RT recurrences demonstrated a loss of architecture and significantly enhanced mitotic activity as compared to their related primary tumors. Based on DNA methylation profiling, primary tumor and related recurrence were grossly similar, but three out of 26 tumors belonged to a different molecular type or subtype after second surgery compared to related primary lesions. Copy number variations (CNVs) differed in six cases, showing novel gains on chromosome 1q or losses of chromosome 10 in recurrences as the most frequent alterations. To consolidate these observations, our cohort was combined with a data set of unmatched primary and recurrent AT/RT, which demonstrated chromosome 1q gain and 10 loss in 18% (n = 7) and 11% (n = 4) of the recurrences (n = 38) as compared to 7% (n = 3) and 0% (n = 0) in the primary tumors (n = 44), respectively. Similar to the observations made by DNA methylation profiling, RNA sequencing of our cohort revealed AT/RT primary tumors and matched recurrences clustering closely together. However, a number of genes showed significantly altered expression in AT/RT-SHH recurrences. Many of them are known tumor driving growth factors, involved in embryonal development and tumorigenesis, or are cell-cycle-associated. Overall, our work identifies subtle molecular changes that occur in the course of the disease and that may help define novel therapeutic targets for AT/RT recurrences.

Limbic encephalitis in a child with ovarian teratoma and influenza B. Case report and critical review of the history of autoimmune anti-N-methyl-d-aspartate receptor encephalitis.

We report the appearance of clinical symptoms and signs of N-methyl-d-Aspartate (NMDA) receptor encephalitis in a patient presenting just days after contraction of influenza B. The offending mature ovarian teratoma was identified and removed on the 10th day after the appearance of symptoms, with subsequent nearly complete resolution of symptoms over the subsequent 6 months. We provide a focused literature review of the clinical and pathophysiologic literature of anti-NMDA receptor encephalitis pertaining to influenza B virus and the pediatric population. Taken together, this study contributes to the pathophysiological understanding of anti-NMDA receptor encephalitis and aids clinicians in its early recognition and management.

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.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis Associated with Ovarian Teratoma in South China-Clinical Features, Treatment, Immunopathology, and Surgical Outcomes of 21 Cases.

OBJECTIVE: To study the clinical characteristics and surgical outcomes of anti-NMDAR encephalitis and the immunopathology of associated teratomas. METHODS: Twenty-one patients were enrolled in this retrospective study, who were diagnosed with anti-NMDAR encephalitis with ovarian teratoma and admitted to two tertiary hospitals in South China from July 2014 to December 2019. The clinical data of patients were reviewed. Comparisons were made between the patients with different outcomes after surgery. Immunohistochemical analyses of associated ovarian teratomas were performed. RESULTS: The mean age of the patients was 24.33 ± 5.12 years. The peak seasons of disease onset were autumn and winter (30.61% and 32.65%). The symptoms could be divided into 8 categories, including psychiatric abnormalities, seizures, movement dysfunction, consciousness disorders, autonomic dysregulation, speech disturbance, central hypoventilation, and memory deficits. All patients developed four or more categories of symptoms within the first four weeks. Twelve patients (57.1%) had a maximum mRS of 5, and 11 patients (52.4%) were admitted to ICU. Twenty patients received surgery, and only 3 patients were diagnosed pathologically with immature ovarian teratomas, while the other 17 patients had mature ovarian teratomas. After surgery, 17 patients (85.0%) got clinical improvement. The central hypoventilation symptom and mature ovarian teratomas were associated with surgical outcome. Immunohistochemical analysis revealed that there were NMDAR-positive neural tissues in all 8 teratomas and in which 3 cases also contained large numbers of NMDAR-positive sebaceous glands and squamous epithelial tissues. CONCLUSION: The disease is of high prevalence in autumn and winter. The central hypoventilation symptom and mature ovarian teratomas were associated with surgical outcome. NMDAR-positive neural tissue is not the only etiological factor of encephalitis. We speculate that encephalitis development in some patients may result from NMDAR expression in sebaceous glands and squamous epithelial tissues.

Delta-24-RGD, an Oncolytic Adenovirus, Increases Survival and Promotes Proinflammatory Immune Landscape Remodeling in Models of AT/RT and CNS-PNET.

PURPOSE: Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells. EXPERIMENTAL DESIGN: Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in vitro in a battery of CNS-PNET and AT/RT cell lines. In vivo, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34+-NSG-SGM3). RESULTS: Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC50 value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. In vivo, a single intratumoral Delta-24-RGD injection (107 or 108 PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD-treated tumors revealed increased CD8+ T-cell infiltration. CONCLUSIONS: Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.

Co-expression of NMDA-receptor subunits NR1, NR2A, and NR2B in dysplastic neurons of teratomas in patients with paraneoplastic NMDA-receptor-encephalitis: a retrospective clinico-pathology study of 159 patients.

OBJECTIVE: To comprehensively describe the pathological features of neurons in patients with ovarian teratomas and paraneoplastic anti-NMDAR encephalitis (anti-NMDARE), emphasizing on NMDA-receptor expression and infiltrating lymphocytes. METHODS: A retrospective study was performed in a large series of 159 patients from the West China Hospital. We retrospectively identified 12 patients with paraneoplastic anti-NMDARE (11 case with ovarian teratomas and 1 case with mixed germ cell tumor), which were compared to 35 patients with teratomas and no encephalitis and to 147 patients with anti-NMDARE and no evidence for tumors. Patient history and outcome were reviewed from the clinical charts and compared between all three groups. Histopathological examination, including double-immunofluorescence of NMDAR subunits and IgG was performed in all teratoma tissues. Magnetic Luminex Assay Human Premixed Multi-Analyte Kit was performed to investigate cytokines profile of CSF. RESULTS: Patients with paraneoplastic anti-NMDARE had a more severe clinical presentation, i.e. they required more mechanical ventilation and intensive care (p < 0.001). Though immunotherapy was initiated earlier in this group, repeated intravenous immunoglobulin administration (IVIG) was more common (p = 0.002) and with higher cerebrospinal fluid (CSF) antibody titres (p = 0.004). Following tumor resection, the outcome did not differ between groups. A peculiar population of floating-frog like dysplastic neurons were observed only in teratomas of patients with paraneoplastic anti-NMDARE, co-expressing NR1, NR2A, NR2B subunits and IgG. Also, CD20 positive B-cells were more common in anti-NMDARE teratomas. In CSF of paraneoplastic anti-NMDARE patients, TNF-α, IL-10 and GM-CSF concentrations were higher than in negative symptom control and VEGF-A and IL-1a were lower than in anti-NMDARE patients (0.25 < p < 0.05). CONCLUSIONS: Patients with teratomas and paraneoplastic anti-NMDARE revealed a cellular population of dysplastic neurons co-expressing NMDAR subunits, which were the potential source of autoantigens triggering anti-NMDARE. Some inflammatory cytokines may be involved in pathogenesis of paraneoplastic anti-NMDARE.

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.

XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary.

Molecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.

Natural Killer Cells Prevent the Formation of Teratomas Derived From Human Induced Pluripotent Stem Cells.

The safe utilization of induced pluripotent stem cell (iPSC) derivatives in clinical use is attributed to the complete elimination of the risk of forming teratomas after transplantation. The extent by which such a risk exists in immune-competent hosts is mostly unknown. Here, using humanized mice reconstituted with fetal hematopoietic stem cells and autologous thymus tissue (bone-liver-thymus humanized mice [Hu-BLT]) or following the adoptive transfer of peripheral blood mononuclear cells(PBMCs) (Hu-AT), we evaluated the capacity of immune cells to prevent or eliminate teratomas derived from human iPSCs (hiPSCs). Our results showed that the injection of hiPSCs failed to form teratomas in Hu-AT mice reconstituted with allogeneic or autologous PBMCs or purified natural killer (NK) cells alone. However, teratomas were observed in Hu-AT mice reconstituted with autologous PBMCs depleted from NK cells. In line with these results, Hu-BLT, which do not have functional NK cells, could not prevent the growth of teratomas. Finally, we found that established teratomas were not targeted by NK cells and instead were efficiently rejected by allogeneic but not autologous T cells in Hu-AT mice. Overall, our findings suggest that autologous hiPSC-derived therapies are unlikely to form teratomas in the presence of NK cells.

Anti-N-methyl-D-aspartate receptor encephalitis induced by bilateral ovarian teratomas with distinct histopathologic types: A case report and brief literature review.

RATIONALE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder that is most frequently induced by ovarian teratoma in young females. The condition can be controlled and reversed via ovarian tumor resection and immunotherapy. However, anti-NMDAR encephalitis induced by bilateral ovarian teratomas with distinct histopathologic types is rarely reported in the literature. PATIENT CONCERNS: A 23-year-old woman presented with seizures. DIAGNOSES: The diagnosis was anti-NMDAR encephalitis associated with ovarian teratomas based on positive anti-NMDAR antibody tests in both the cerebrospinal fluid and serum, and the detection of bilateral ovarian lesions on pelvic computed tomography. The postoperative histopathologic examination confirmed that the left lesion was an immature teratoma, and the right lesion was a mature teratoma. INTERVENTIONS: We performed surgical resection of the ovarian teratomas and administered immunotherapy for the control of anti-NMDAR encephalitis. Chemotherapy was administered for the immature teratoma. OUTCOMES: The patient recovered without any postoperative complications. She has been confirmed to be in complete clinical remission, and has not had a recurrence during 18 months of follow-up. LESSONS: Anti-NMDAR encephalitis induced by bilateral ovarian teratomas of differing histopathologic types (1 immature and 1 mature) is rare. Early diagnosis and treatment with tumor resection, immunotherapy, and chemotherapy are critical for a good prognosis.

Are We Missing Subtle Forms of Anti-N-Methyl-D-Aspartate Encephalitis With the Current Diagnostic Approach? A Case Report.

Encephalitis related to antibodies against the N-methyl-D-aspartate receptor (NMDAr) is a recently described clinical entity in which IgG autoantibodies against the NR1 subunit of the NMDAr lead to the appearance of complex neuropsychiatric symptoms. As psychiatric symptoms predominate in early stages, anti-NMDAr encephalitis is frequently mistaken as a primary psychiatric disorder which delays treatment and has serious consequences for patients. This report presents the case of a 24-year-old woman with a subacute onset of psychotic and catatonic symptoms in whom current diagnostic criteria for probable anti-NMDAr encephalitis were not fulfilled. On the basis of the red flags that have been proposed to raise suspicion of anti-NMDAr encephalitis, a study of fluorodeoxyglucose positron emission tomography was requested and demonstrated bilateral occipital hypometabolism consistent with clinical suspicion of anti-NMDAr encephalitis. Once the appropriate treatment was established, the patient recovered completely. This case supports the need to maintain clinical suspicion of anti-NMDAr encephalitis, even when conventional diagnostic tests have been normal. Psychiatrists should be familiar with this entity to promote timely diagnosis and prompt treatment.

Using the Inducible Caspase-9 Suicide-Safeguard System with iPSC and Bioluminescent Tracking.

For scientists working within the field of induced pluripotent stem cells (iPSCs), this protocol will provide a thorough walk-through on how to conduct in vitro and in vivo experiments that validate the function of a particular safeguard system technology. In short, we provide instructions on how to generate inducible Caspase-9 (iC9) safeguard system with human iPSCs that act as normal or abnormal models of the cells for therapeutics to be tried after differentiation. These iC9-iPSCs should be modified prior to beginning this protocol by constitutively expressing luciferase, an enzyme capable of generating bioluminescent signals through the oxidation of the substrate luciferin. Monitoring the bioluminescent signal over time provides the information on whether a safeguard system is working or not.

Neurogenic bladder in an adolescent woman with an ovarian tumour: an unusual presentation of anti-NMDA-receptor encephalitis.

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is rarely seen in women with ovarian teratoma. It is characterised by neuropsychiatric symptoms and may also cause autonomic imbalance. We present the case of a 16-year-old nulliparous woman who presented with an acute history of seizures and neurogenic bladder. Antiviral and antiepileptic therapy conferred no therapeutic benefit. A cystic pelvic mass measuring 185×140×92 mm was identified separate from the bladder. Serum titres of NMDA receptor antibodies were significantly elevated. The mass was surgically removed and histology revealed benign ovarian teratoma with NMDA receptors. The patient made a rapid improvement and had full resolution of urinary and neuropsychiatric symptoms within 1 year. This case demonstrates that increased awareness in adolescents is crucial for avoiding symptom dismissal, misdiagnosis and inappropriate treatment of this condition. Surgical removal of the teratoma should be the first line therapy of anti-NMDA-receptor encephalitis as this often leads to symptom resolution soon after.

Teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis: A case report and literature review.

RATIONALE: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disease associated with the NMDA receptor and has a good response to treatment. However, only few cases related to teratoma have been reported. Here, we report a case of teratoma-associated anti-NMDAR encephalitis. PATIENT CONCERNS: A 25-year-old woman presenting with fever for 20 days and psychiatric symptoms for 9 days was admitted to the hospital. The patient progressed to a minimally conscious state consistent with encephalitis. DIAGNOSIS: Considering the possibility of autoantibody-mediated encephalitis, laboratory tests were conducted to detect anti-NMDAR antibodies in cerebrospinal fluid and serum. Results confirmed the diagnosis of anti-NMDAR encephalitis. Furthermore, gynecological ultrasound investigation detected teratoma in the left ovary. INTERVENTIONS: After resection of the teratoma with laparoscopic adnexectom, the patient was treatment with immunosuppressive therapy. OUTCOMES: The patient recovered gradually and was discharged 2 months after the operation. LESSONS: Anti-NMDAR encephalitis remains difficult to diagnose because of its vague manifestations, and no clinical practice guidelines for prevention and treatment of the disease have been established yet. The clinical data of a case of teratoma-related anti-NMDAR encephalitis were analyzed, and relevant studies were reviewed.

Ovarian Teratomas in Women With Anti-N-methyl-D-Aspartate Receptor Encephalitis: Topography and Composition of Immune Cell and Neuroglial Populations Is Compatible With an Autoimmune Mechanism of Disease.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune syndrome in young women that is often accompanied by an ovarian teratoma (NMDAR-E teratoma). A prevailing theory implicates that the generation of autoantibodies to NMDAR on neurons in the central nervous system is triggered by neuroglial tissue in the associated teratoma. The histopathology of NMDAR-E teratomas has not been fully elucidated but limited studies have focused on alterations in neuroglial tissues and immune cell populations. We hypothesized that evidence of antibody generation in NMDAR-E teratomas could be detected by colocalized neuroglial tissue and lymphoid aggregates with germinal centers as well as by alterations in the composition and morphology of neuroglial tissues. The study compared 12 NMDAR-E teratomas (11 ovarian, 1 mediastinal) with 61 control teratomas containing neuroglial tissue from women without NMDAR-E. NMDAR-E teratomas were significantly smaller and were composed of a higher percentage of neuroglial tissue than control teratomas. Many NMDAR-E teratomas did not exhibit typical gross pathologic features of a mature cystic teratoma, but were composed of predominately solid tissue (so-called Rokitansky nodule). Colocalized neuroglial tissue and lymphoid aggregates with germinal centers were present in 11/12 NMDAR-E teratomas, predominantly within the Rokitansky nodule, but only in 4/61 control teratomas (P<0.0001). There was a relative paucity of mature neurons in NMDAR-E teratomas as well as a hypercellular astrocyte population, while there were less prominent or no differences in the presence or composition of diffuse inflammatory infiltrates, lymphoid aggregates without germinal centers, ganglion cell clusters or oligodendrocytes between NMDAR-E teratomas and control teratomas. We conclude that the presence of colocalized neuroglial tissue and lymphoid aggregates with germinal centers along with a general paucity of neurons should prompt clinical consideration for NMDAR-E even in asymptomatic women, as the symptoms may occasionally develop after an otherwise incidental oophorectomy. Tissue sampling should be directed to the Rokitansky nodule, when present, to identify neuroglial tissues; complete microscopic examination of the ovarian specimen should be considered if gross pathologic features of teratoma are not present. The significance of the altered neuroglial cell populations and potential relationship to the pathogenesis of NMDAR-E merit further study.

Immunopathological characterization of ovarian teratomas associated with anti-N-methyl-D-aspartate receptor encephalitis.

Encephalitis with anti-NMDAR antibodies (NMDAR-E) is a severe autoimmune neurological disorder, defined by a clinical presentation of encephalitis and the presence of IgG targeting the GluN1 subunit of NMDA receptors in the CSF. An underlying ovarian teratoma is commonly associated with this autoimmune disease suggesting a role of the tumor in immunopathogenesis. In this study, we characterized the salient histopathological features of 27 ovarian teratomas associated with NMDAR-E (3 immature and 24 mature teratomas) and 40 controls without associated encephalitis. All but one NMDAR-E-associated teratomas contained a nervous tissue component, while less than 40% of control teratomas did (p < 0.001). GluN1 expression by teratomatous nervous tissue seemed to be more often glial in NMDAR-E teratomas than in control teratomas (73% vs. 29%, p < 0.05). Strikingly, 3 out of 24 NMDAR-E-associated mature teratomas contained neuroglial tissue exhibiting histopathological features of central nervous system neuroglial tumor, while such glioma-like features are exceptionally described in the literature on ovarian teratomas. Moreover, NMDAR-E associated teratomas differed from sporadic ovarian teratomas by consistent and prominent infiltration of the nervous tissue component by immune cells, comprised of T- and B-cells and mature dendritic cells organized in tertiary lymphoid structures, with IgG and IgA deposits and plasma cells in close contact to the neuroglial tissue.These data demonstrate an association between massive infiltration of NMDAR-E-associated teratomas by immune cells and particular glial features of its neuroglial component, suggesting that this glial tissue might be involved in triggering or sustaining the anti-tumor response associated with the auto-immune neurological disease.

NMDA receptor antibody in teratoma-related opsoclonus-myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS) is a brainstem/cerebellar syndrome producing disabling multi-directional saccadic oscillations with oscillopsia, with or without somatic myoclonus and cerebellar ataxia (Wong et al., 2001; Armangué et al., 2016). OMS is presumed to have an autoimmune basis and patients with it are tested for antineuronal antibodies and have imaging to locate any tumors. Here we report a unusual case of a young woman who had NMDAR antibody (NMDAR-ab) positive, teratoma-related, isolated OMS without encephalopathy. Removal of her ovarian teratoma, and immunotherapy with steroids, intravenous immunoglobulin (IVIg), plasma exchange (PLEX), and ultimately with B-cell depletion with rituximab resulted in total recovery after 3 months. Patients with teratoma-related OMS very rarely have NMDAR-ab which suggests that it is not the NMDAR-ab per se that causes the OMS.

PD-1/PD-L1 and immune-related gene expression pattern in pediatric malignant brain tumors: clinical correlation with survival data in Korean population.

BACKGROUND: PD-L1 expression has been evaluated as a predictive biomarker for immunotherapy in numerous tumor types. However, very limited data are available in pediatric brain tumors. The aim of this study was to characterize PD-1 and PD-L1 expressions of four pediatric malignant brain tumors and gene expression profile. METHODS: This study included 89 pediatric patients receiving standard treatment at Seoul National University Children's Hospital and Seoul National University Bundang Hospital between 1990 and 2014: atypical teratoid/rhabdoid tumor (AT/RT) 20; ependymoma (EPN) 20; high grade glioma (HGG) 21; and medulloblastoma (MBL) 28. We performed immunohistochemistry assays for PD-1 and PD-L1. To characterize the gene expression, a custom immune-response focused gene panel was used. RESULTS: PD-1 expression was positive in 7 (35%) AT/RT, 7 (35%) EPN, 4 (19%) HGG, and 3 (11%) MBL patients. PD-L1 expression was positive in 8 (40%) AT/RT, 4 (20%) EPN, and 4 (19%) HGG; negative in all MBL patients. There was no statistically significant difference in the overall survival of PD-L1 positive patients. The gene expression analysis demonstrated differences in two clustering functional categories: cell-cell signaling and antigen presentation pathway. CONCLUSIONS: AT/RT, EPN, and HGG showed a relatively higher expression rate of PD-L1 (19-40%). This suggests these tumor types might be good candidates for PD-1 checkpoint blockade. We determined that gene expression may potentially serve as a molecular tool in predicting which patients will respond to immunotherapy. Further investigation is required to better understand the predictive and prognostic role of PD-L1 in pediatric brain tumors.

Fulminant course in a patient with anti-N-methyl-D-aspartate receptor encephalitis with bilateral ovarian teratomas: A case report and literature review.

RATIONALE: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune disorder that can be controlled and reversed by immunotherapy. The presentation of NMDA receptor encephalitis varies, but NMDA receptor encephalitis is seldom reported in patients with both bilateral teratomas and preexisting brain injury. PATIENT CONCERNS: A 28-year-old female with a history of traumatic intracranial hemorrhage presented acute psychosis, seizure, involuntary movement, and conscious disturbance with a fulminant course. Anti-NMDA receptor antibody was identified in both serum and cerebrospinal fluid, confirming the diagnosis of anti-NMDA receptor encephalitis. Bilateral teratomas were also identified during tumor survey. DIAGNOSES:: anti-N-methyl-D-aspartate receptor encephalitis. INTERVENTIONS: Tumor resection and immunotherapy were performed early during the course. OUTCOMES: The patient responded well to tumor resection and immunotherapy. Compared with other reports in the literature, her symptoms rapidly improved without further relapse. LESSONS: This case report demonstrates that bilateral teratomas may be related to high anybody titers and that the preexisting head injury may be responsible for lowering the threshold of neurological deficits. Early diagnosis and therapy are crucial for a good prognosis in such patients.