Intracranial Germinoma in Two Caucasian American Siblings With Autism Spectrum Disorder.

Intracranial germ cell tumors (IGCTs) comprise 3% to 5% of all pediatric brain tumors in the West, with a significantly higher prevalence in Asia. Although these tumors are histologically diverse, repeated somatic variants have been demonstrated. Chromosomal aneuploidies, such as Klinefelter and Down syndromes, are associated with IGCTs, but no familial germline tumor syndromes are currently known. Here, we report the novel case of 2 American siblings with underlying autism spectrum disorder who developed intracranial germinoma within months of each other, in the absence of external risk factors. Extensive genetic testing was performed, including karyotyping, chromosomal microarray, and whole exome and whole genome sequencing, and did not identify any variants accounting for the phenotypes. Despite the absence of overlapping variants, a recent retrospective review demonstrated a threefold greater prevalence of autism spectrum disorder in patients with intracranial germinoma compared with national prevalence. This report highlights the complexity of tumor development, as well as the need for further research regarding IGCTs in a neurodivergent population.

Central Nervous System Tumor With BCL6 Corepressor Internal Tandem Duplication: Treatment Course of a Long-term Survivor.

Central nervous system (CNS) tumor with BCL6 corepressor (BCOR) internal tandem duplication (ITD) is a newly described CNS tumor, characterized by in-frame ITDs of the BCOR gene. There is no standard practice regarding the management of this tumor. We report the clinical course of a 6-year-old boy who presented to the hospital with worsening headaches. Computed tomography scan showed a large right-sided parietal supratentorial mass and brain magnetic resonance imaging confirmed a 6×8×6.7 cm lobulated, solid but heterogeneous mass in the right parieto-occipital region. While initial pathology suggested a WHO grade 3 anaplastic meningioma, additional investigation with molecular analysis confirmed the diagnosis of high-grade neuroepithelial tumor with BCOR exon 15 ITD. This diagnosis was renamed CNS tumor with BCOR ITD in the 2021 WHO CNS tumor classification. The patient received 54 Gy of focal radiation and has no evidence of disease recurrence after 48 months from the end of treatment. As this is a newly discovered entity with only a few previous reports in the scientific literature, this report presents a unique treatment for this CNS tumor compared with those previously described.

Endophthalmitis as the initial manifestation of invasive fusariosis in an allogeneic stem cell transplant patient: A case report.

Fusarium species manifests as an opportunistic infection with intrinsic resistance to most antifungals. We present a case of a 63-year-old male with myelodysplasia who received allogeneic stem cell transplantation and presented with endophthalmitis as the initial manifestation of invasive fusariosis that progressed to a fatal outcome despite combined intravitreal and systemic antifungal therapies. We urge clinicians to consider this complication of fusarium infection especially with the widespread use of antifungal prophylaxis that may incur selection of more resistant, invasive fungal species.

Pineal Parenchymal Tumor of Intermediate Differentiation and DICER1 Syndrome: A Case Report.

DICER1 syndrome is a rare inherited tumor predisposition syndrome associated with an increased risk for several malignant and benign tumors. We present a patient with pineal parenchymal tumor of intermediate differentiation who was found to have a germline pathogenic variant in DICER1 gene. Pineoblastoma is a known DICER1-related tumor; however, the association between pineal parenchymal tumor of intermediate differentiation and DICER1 mutation is rare with only 1 recent large molecular study that has reported this association. This report adds to the evolving tumor spectrum of DICER1 and highlights the importance of molecular evaluation of pediatric brain tumors, for both therapeutic decisions and long-term surveillance.

Histopathology of new-onset refractory status epilepticus (NORSE) in adults.

OBJECTIVE: new-onset refractory status epilepticus (NORSE) is defined as de novo refractory seizures occurring in previously healthy adults, without a clear underlying etiology. Due to refractory seizures and insufficient understanding of pathophysiology, management of these patients remains challenging and often leads to poor clinical outcomes. Various infectious and autoimmune mechanisms have been proposed but have not been validated and a large number of patients are thus labeled 'cryptogenic'. Moreover, histopathological findings have rarely been described in NORSE and are usually autopsy evaluations. In this paper, we describe the clinical correlates and histopathological findings in patients presenting with NORSE. METHODS: A case series of five patients with NORSE who underwent neurosurgical intervention and had histopathological examination during their acute clinical course. RESULTS: In all patients,status epileptics was refractory to treatment with antiseizure drugs (ASDs) and anesthetic agents. Autoimmune work-up revealed elevated titer of anti-GAD antibody in one patient but was unremarkable in others. Empiric use of immunomodulation therapy in three patients did not lead to cessation of status epilepticus (SE). Due to failure of prolonged medical management, three patients underwent palliative surgery for resection of epileptogenic tissue whereas the other two had diagnostic brain biopsy. Histopathology obtained during biopsy revealed evidence of vasculitis in one and necrotizing vasculopathy in another. The patient with anti-GAD antibodies had evidence of lymphocytic infiltration in limbic structures. The remaining two had nonspecific histopathological findings. SIGNIFICANCE: Although our findings are limited by a small number of patients, it adds to the growing premise of NORSE being related to an underlying autoimmune process. Additional studies, especially with histopathological data are needed to better understand this devastating disorder.

Molecular insights into malignant progression of atypical choroid plexus papilloma.

Choroid plexus tumors are rare pediatric neoplasms ranging from low-grade papillomas to overtly malignant carcinomas. They are commonly associated with Li-Fraumeni syndrome and germline TP53 mutations. Choroid plexus carcinomas associated with Li-Fraumeni syndrome are less responsive to chemotherapy, and there is a need to avoid radiation therapy leading to poorer outcomes and survival. Malignant progression from choroid plexus papillomas to carcinomas is exceedingly rare with only a handful of cases reported, and the molecular mechanisms of this progression remain elusive. We report a case of malignant transformation of choroid plexus papilloma to carcinoma in a 7-yr-old male with a germline TP53 mutation in which we present an analysis of molecular changes that might have led to the progression based on the next-generation genetic sequencing of both the original choroid plexus papilloma and the subsequent choroid plexus carcinoma. Chromosomal aneuploidy was significant in both lesions with mostly gains present in the papilloma and additional significant losses in the carcinoma. The chromosomal loss that occurred, in particular loss of Chromosome 13, resulted in the losses of two critical tumor suppressor genes, RB1 and BRCA2, which might play a possible role in the observed malignant transformation.

Rapidly Expanding Pediatric Post Radiation Brainstem Cavernoma Presenting with Singultus.

Here we present a pediatric patient status post resection of a primitive neuroectodermal tumor (PNET) with cranial/spinal radiation and development of a medullary cavernoma seven years after radiation therapy. The patient's cavernoma demonstrated rapid symptomatic growth in six weeks resulting in the presentation of intractable hiccups (singultus). The patient underwent resection of the cavernoma with cessation of the hiccups. We also review the pathology and possible mechanisms of such rapid growth of this post-radiation cavernoma as well as advise surveillance for patients with such lesions, as their course may be different from that of sporadic cavernomas.

Investigation of the aryl hydrocarbon receptor and the intrinsic tumoral component of the kynurenine pathway of tryptophan metabolism in primary brain tumors.

INTRODUCTION: There is mounting evidence supporting the role of tryptophan metabolism via the kynurenine pathway (KP) in the pathogenesis of primary brain tumors. Under normal physiological conditions, the KP is the major catabolic pathway for the essential amino acid tryptophan. However, in cancer cells, the KP becomes dysregulated, depletes local tryptophan, and contributes to an immunosuppressive tumor microenvironment. METHODS: We examined the protein expression levels (in 73 gliomas and 48 meningiomas) of the KP rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), as well as, the aryl hydrocarbon receptor (AhR), a carcinogenic transcription factor activated by KP metabolites. In addition, we utilized commercially available small-molecules to pharmacologically modulate IDO1, IDO2, TDO2, and AhR in patient-derived glioma and meningioma cell lines (n = 9 each). RESULTS: We observed a positive trend between the grade of the tumor and the average immunohistochemical staining score for IDO1, IDO2, and TDO2, with TDO2 displaying the strongest immunostaining. AhR immunostaining was present in all grades of gliomas and meningiomas, with the greatest staining intensity noted in glioblastomas. Immunocytochemical staining showed a positive trend between nuclear localization of AhR and histologic grade in both gliomas and meningiomas, suggesting increased AhR activation with higher tumor grade. Unlike enzyme inhibition, AhR antagonism markedly diminished patient-derived tumor cell viability, regardless of tumor type or grade, following in vitro drug treatments. CONCLUSIONS: Collectively, these results suggest that AhR may offer a novel and robust therapeutic target for a patient population with highly limited treatment options.

Acute Resective Surgery for the Treatment of Refractory Status Epilepticus.

BACKGROUND: To identify the role of acute surgical intervention in the treatment of refractory status epilepticus (RSE). METHODS: Retrospective review of consecutive patients who underwent epilepsy surgery from 2006 to 2015 was done to identify cases where acute surgical intervention was employed for the treatment of RSE. In addition, the adult and pediatric RSE literature was reviewed for reports of surgical treatment of RSE. RESULTS: Nine patients, aged 20-68 years, with various etiologies were identified to have undergone acute surgical resection for the treatment of RSE, aided by electrocorticography. Patients required aggressive medical therapy with antiepileptic drugs and intravenous anesthetic drugs for 10-54 days and underwent extensive neurodiagnostic testing prior to resective surgery. Eight out of nine patients survived and five patients were seizure-free at the last follow-up. The literature revealed 13 adult and 48 pediatric cases where adequate historical detail was available for review and comparison. CONCLUSIONS: We present the largest cohort of consecutive adult patients who underwent resective surgery in the setting of RSE. We also reveal that surgery can be efficacious in aborting status and in some can lead to long-term seizure freedom. Acute surgical intervention is a viable option in prolonged RSE and proper evaluation for such intervention should be conducted, although the timing and type of surgical intervention remain poorly defined.

Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma.

Increasing evidence demonstrates the immunosuppressive kynurenine pathway's (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[(11)C]-methyl-l-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 patients with GBM. Mice bearing subcutaneous tumors were imaged with AMT-PET, and tumors were analyzed to detect the KP enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, tryptophan 2,3-dioxygenase, kynureninase, and kynurenine 3-monooxygenase. Overall, PET imaging showed robust tumoral AMT uptake in PDX mice with prolonged tracer accumulation over 60 minutes, consistent with AMT trapping seen in humans. Immunostained tumor tissues demonstrated positive detection of multiple KP enzymes. Furthermore, intracranial implantation of GBM cells was performed with imaging at both 9 and 14 days postimplant, with a marked increase in AMT uptake at 14 days and a corresponding high level of tissue immunostaining for KP enzymes. These results indicate that our PDX mouse models recapitulate human GBM, including aberrant tryptophan metabolism, and offer an in vivo system for development of targeted therapeutics for patients with GBM.

Surgical treatment for refractory epileptic spasms: The Detroit series.

OBJECTIVE: We reviewed our experience of surgery for epileptic spasms (ES) with or without history of infantile spasms. METHODS: Data were reviewed from 65 (33 male) patients with ES who underwent surgery between 1993 and 2014; palliative cases were excluded. RESULTS: Mean age at surgery was 5.1 (range 0.2-19) years, with mean postsurgical follow-up of 45.3 (6-120) months. Mean number of anticonvulsants used preoperatively was 4.2 (2-8), which decreased to 1.2 (0-4) postoperatively (p < 0.0001). Total hemispherectomy was the most commonly performed surgery (n = 20), followed by subtotal hemispherectomy (n = 17), multilobar resection (n = 13), lobectomy (n = 7), tuberectomy (n = 6), and lobectomy + tuberectomy (n = 2), with International League Against Epilepsy (ILAE) class I outcome in 20, 10, 7, 6, 3, and 0 patients, respectively (total 46/65 (71%); 22 off medication). Shorter duration of epilepsy (p = 0.022) and presence of magnetic resonance imaging (MRI) lesion (p = 0.026) were independently associated with class I outcome. Of 34 patients operated <3 years after seizure onset, 30 (88%) achieved class I outcome. Thirty-seven (79%) of 47 patients with lesional MRI had class-I outcome, whereas 9 (50%) of 18 with normal MRI had class I outcome. Positron emission tomography (PET) scan was abnormal in almost all patients [61 (97%) of 63 with lateralizing/localizing findings in 56 (92%) of 61 patients, thus helping in surgical decision making and guiding subdural grid placements, particularly in patients with nonlesional MRI. Fifteen patients had postoperative complications, mostly minor. SIGNIFICANCE: Curative epilepsy surgery in ES patients, with or without history of infantile spasms, is best accomplished at an early age and in those patients with lesional abnormalities on MRI with electroencephalography (EEG) concordance. Good outcomes can be achieved even when there is no MRI lesion but positive PET localization.

Multi-modal imaging of tumor cellularity and Tryptophan metabolism in human Gliomas.

BACKGROUND: To assess gliomas using image-based estimation of cellularity, we utilized isotropic diffusion spectrum imaging (IDSI) on clinically feasible diffusion tensor imaging (DTI) and compared it with amino acid uptake measured by α[(11)C]methyl-L-tryptophan positron emission tomography (AMT-PET). METHODS: In 10 patients with a newly-diagnosed glioma, metabolically active tumor regions were defined in both FLAIR hyperintense areas and based on increased uptake on AMT-PET. A recently developed independent component analysis with a ball and stick model was extended to perform IDSI in clinical DTI data. In tumor regions, IDSI was used to define tumor cellularity which was compared between low and high grade glioma and correlated with the glioma proliferative index. RESULTS: The IDSI-derived cellularity values were elevated in both FLAIR and AMT-PET-derived regions of high-grade gliomas. ROC curve analysis found that the IDSI-derived cellularity can provide good differentiation of low-grade from high-grade gliomas (accuracy/sensitivity/specificity of 0.80/0.80/0.80). . Both apparent diffusion coefficient (ADC) and IDSI-derived cellularity showed a significant correlation with the glioma proliferative index (based on Ki-67 labeling; R = 0.95, p < 0.001), which was particularly strong when the tumor regions were confined to areas with high tryptophan uptake excluding areas with peritumoral edema. CONCLUSION: IDSI-MRI combined with AMT-PET may provide a multi-modal imaging tool to enhance pretreatment assessment of human gliomas by evaluating tumor cellularity and differentiate low-grade form high-grade gliomas.

Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas.

BACKGROUND: Increased tryptophan metabolism via the kynurenine pathway (KP) is a key mechanism of tumoral immune suppression in gliomas. However, details of tryptophan metabolism in meningiomas have not been elucidated. In this study, we evaluated in vivo tryptophan metabolism in meningiomas and compared it with gliomas using α-[(11)C]-methyl-L-tryptophan (AMT)-PET. We also explored expression patterns of KP enzymes in resected meningiomas. METHODS: Forty-seven patients with MRI-detected meningioma (n = 16) and glioma (n = 31) underwent presurgical AMT-PET scanning. Tumoral AMT uptake and tracer kinetic parameters (including K and k3' evaluating unidirectional uptake and trapping, respectively) were measured, correlated with meningioma grade, and compared between meningiomas and gliomas. Patterns of KP enzyme expression were assessed by immunohistochemistry in all meningiomas. RESULTS: Meningioma grade showed a positive correlation with AMT k3' tumor/cortex ratio (r = 0.75, P = .003), and this PET parameter distinguished grade I from grade II/III meningiomas with 92% accuracy. Kinetic AMT parameters could differentiate meningiomas from both low-grade gliomas (97% accuracy by k3' ratios) and high-grade gliomas (83% accuracy by K ratios). Among 3 initial KP enzymes (indoleamine 2,3-dioxygenase 1/2, and tryptophan 2,3-dioxygenase 2 [TDO2]), TDO2 showed the strongest immunostaining, particularly in grade I meningiomas. TDO2 also showed a strong negative correlation with AMT k3' ratios (P = .001). CONCLUSIONS: PET imaging of tryptophan metabolism can provide quantitative imaging markers for differentiating grade I from grade II/III meningiomas. TDO2 may be an important driver of in vivo tryptophan metabolism in these tumors. These results can have implications for pharmacological targeting of the KP in meningiomas.