Somatic variants in diverse genes leads to a spectrum of focal cortical malformations.

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.

Impacts of genotypic variants on survival following reoperation for recurrent glioblastoma.

INTRODUCTION: Recurrent glioblastoma (rGBM) prognosis is dismal. In the absence of effective adjuvant treatments for rGBM, re-resections remain prominent in our arsenal. This study evaluates the impact of reoperation on post-progression survival (PPS) considering rGBM genetic makeup. METHODS: To assess the genetic heterogeneity and treatment-related changes (TRC) roles in re-operated or medically managed rGBMs, we compiled demographic, clinical, histopathological, and next-generation genetic sequencing (NGS) characteristics of these tumors from 01/2005 to 10/2019. Survival data and reoperation were analyzed using conventional and random survival forest analysis (RSF). RESULTS: Patients harboring CDKN2A/B loss (p = 0.017) and KDR mutations (p = 0.031) had notably shorter survival. Reoperation or bevacizumab were associated with longer PPS (11.2 vs. 7.4-months, p = 0.006; 13.1 vs 6.2, p < 0.001). Reoperated patients were younger, had better performance status and greater initial resection. In 136/273 (49%) rGBMs undergoing re-operation, CDKN2A/B loss (p = 0.03) and KDR mutations (p = 0.02) were associated with shorter survival. In IDH-WT rGBMs with NGS data (n = 166), reoperation resulted in 7.0-month longer survival (p = 0.004) than those managed medically. This reoperation benefit was independently identified by RSF analysis. Stratification analysis revealed that EGFR-mutant, CDKN2A/B-mutant, NF1-WT, and TP53-WT rGBM IDH-WT subgroups benefit most from reoperation (p = 0.03). Lastly, whether or not TRC was prominent at re-operation does not have any significant impact on PPS (10.5 vs. 11.5-months, p = 0.77). CONCLUSIONS: Maximal safe re-resection significantly lengthens PPS regardless of genetic makeup, but reoperations are especially beneficial for IDH-WT rGBMs with EGFR and CDKN2A/B mutations with TP53-WT, and NF1-WT. Histopathology at recurrence may be an imperfect gauge of disease severity at progression and the imaging progression may be more reflective of the prognosis.

Postmortem study of organ-specific toxicity in glioblastoma patients treated with a combination of temozolomide, irinotecan and bevacizumab.

PURPOSE: Systemic chemotherapy including monotherapy with temozolomide (TMZ) or bevacizumab (BEV); two-drug combinations, such as irinotecan (IRI) and BEV, TMZ and BEV and a three-drug combination with TMZ, IRI and BEV (TIB) have been used in treating patients with progressive high-grade gliomas including glioblastoma (GBM). Most patients tolerated these regimens well with known side effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ- or system- specific toxicities from chemotherapy agents have never been examined by postmortem study. This is the largest cohort used to address this issue in glioma patients. METHODS: Postmortem tissues (from all major systems and organs) were prospectively collected and examined by standard institution autopsy and neuropathological procedures from 76 subjects, including gliomas (N = 68, 44/M, and 24/F) and brain metastases (N = 8, 5/M, and 3/F) between 2009 and 2019. Standard hematoxylin and eosin (H&E) were performed on all major organs including brain specimens. Electronic microscopic (EM) study was carried out on 14 selected subject's kidney samples per standard EM protocol. Medical records were reviewed with adverse events (AEs) analyzed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. A swimmer plot was utilized to visualize the timelines of patient history by treatment group. The binary logistic regression models were performed to explore any associations between treatment strategies and incident myelosuppression. RESULTS: Twenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1-25) cycles] at tumor recurrence. Exposure to IRI significantly increased the frequency of CM (p = 0.05). No unexpected adverse events clinically, or permanent end-organ damage during postmortem examination was identified in glioma subjects who had received standard or prolonged duration of BEV, TMZ or TIB regimen-based chemotherapies except rare events of bone marrow suppression. The most common causes of death (COD) were tumor progression (63.2%, N = 43) followed by aspiration pneumonia (48.5%, N = 33) in glioma subjects. No COD was attributed to acute toxicity from TIB. The study also demonstrated that postmortem kidney specimen is unsuitable for studying renal ultrastructural pathological changes due to autolysis. CONCLUSION: There is no organ or system toxicity by postmortem examinations among glioma subjects who received BEV, TMZ or TIB regimen-based chemotherapies regardless of durations except for occasional bone marrow suppression and reversible myelosuppression clinically. IRI, but not the extended use of TMZ, significantly increased CM in recurrent glioma patients. COD most commonly resulted from glioma tumor progression with infiltration to brain stem and aspiration pneumonia.

A Unique Radiologic Case of Optic Nerve Infarction in a Patient With Mucormycosis.

ABSTRACT: This is a rare presentation of a unilateral optic nerve infarction of the left eye caused by mucormycosis in a 51-year-old man with poorly controlled Type 2 diabetes. Diffusion-weighted MRI of the orbit demonstrated extensive infarction of the left optic nerve with ipsilateral cavernous sinus thrombosis and periorbital adnexal inflammation. Left orbital exenteration and sinus debridement were performed, and mucormycosis involving the optic nerve sheath was confirmed on histopathology.

Additional genetic alterations in BRAF-mutant gliomas correlate with histologic diagnoses.

INTRODUCTION: Recently, the term "Diffuse glioma, BRAF V600E-mutant" has been recommended for IDH-wildtype gliomas with BRAF p.V600E mutation and without CDKN2A/B deletion. However, additional alterations in gliomas that coexist with BRAF-mutations are poorly defined. METHODS: We analyzed next-generation sequencing results in 315 cancer-associated genes for 372 gliomas from our institution (2010 to 2017). In addition, we reviewed IDH-WT gliomas with mutation and copy-number alterations available in cBioPortal, to further characterize BRAF-mutant gliomas. RESULTS: Seventeen (4.6%) showed BRAF mutations. Tumor types included 8 glioblastomas, 2 epithelioid glioblastomas (E-GBM), 2 pleomorphic xanthoastrocytomas (PXA), 1 anaplastic oligodendroglioma, 1 diffuse astrocytoma, and 3 pilocytic astrocytomas. Fifty-three percent (53%) of cases exhibited BRAF-alterations other than p.V600E. The majority of the tumors were localized in the temporal lobe (52.9%). In addition to BRAF mutations, glioblastomas showed concomitant mutations in TP53 (3/8), CDKN2A/B-loss (6/8), TERT-promoter (6/8), and/or PTEN (5/8). Both E-GBMs and PXAs showed CDKN2A/B-loss and BRAF p.V600E with absence of TERTp, TP53, and PTEN mutations. Similar findings were observed in BRAF-mutant infiltrating gliomas from cBioPortal. CONCLUSIONS: Knowledge of additional alterations that co-occur with BRAF-mutations in gliomas may improve diagnosis and help identify patients that could benefit from targeted therapies. Furthermore, we provide examples of two patients whose tumors responded to BRAF pathway inhibitors, arguing in favor of these therapies in patients with BRAF-mutant gliomas.

Posttreatment Maturation of Medulloblastoma into Gangliocytoma: Report of 2 Cases.

INTRODUCTION: We report 2 cases of medulloblastoma maturing into gangliocytoma after receiving multimodal therapy. Here we present 2 cases of diagnosed medulloblastoma which on re-resection were noted to be gangliocytoma without heterogeneity, which is an extremely rare occurrence. CASE PRESENTATION: The first patient, an 11-year-old boy diagnosed with high-risk (non-WNT, non-SHH) medulloblastoma, was treated with near-total surgical resection followed by craniospinal radiation therapy with weekly vincristine. He then received maintenance chemotherapy with vincristine, cyclophosphamide, and cisplatin. On surveillance MR imaging studies residual tumor in the lateral aspect of the tumor bed was noted to be slowly growing, eliciting gross-total resection of the residual tumor. Histopathology showed benign gangliocytoma without residual medulloblastoma. The second patient, a 3-year-old girl, was diagnosed with medulloblastoma, desmoplastic nodular variant. She was initially treated with gross total resection and chemotherapy with etoposide, carboplatin, and high-dose methotrexate. At 4 months off therapy, she was noted to have local recurrence along the resection cavity. Second-line therapy was started with irinotecan and temozolomide, but MRI assessment during treatment showed further disease progression. She then received craniospinal radiation. Eleven months off therapy, further radiographic progression was noted, and the patient underwent second-look surgery, with pathology showing gangliocytoma and treatment-related gliosis. DISCUSSION/CONCLUSION: The maturation of medulloblastoma into a ganglion cell-rich lesion is very rare, with few well-characterized previous reports. Given the rare nature of this entity, it would be of great value to understand the process of posttreatment maturation and the genetic and treatment factors which contribute to this phenomenon.

A Unique Presentation of Levamisole-Induced Antineutrophil- Cytoplasmic-Antibody-Positive Vasculitis Presenting as Inflammatory Orbitopathy.

A 35-year-old woman with a history of cocaine abuse presented with progressively worsening OS pain. Neuroimaging revealed a 3-cm ill-defined left orbital lesion involving the intraconal and extraconal spaces. The orbital mass was biopsied via an anterior orbitotomy approach. Pathology demonstrated prominent angiocentric granulomatous and lymphoplasmacytic inflammation consistent with vasculitis. Laboratory tests were significant for neutropenia, positive perinuclear antineutrophil cytoplasmic antibodies with high titer, and positive myeloperoxidase antibodies, consistent with levamisole-induced vasculitis. To the authors' knowledge, this is the first reported case of cocaine-levamisole-induced vasculitis presenting as orbitopathy.

Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-ß in Tg2576 Mice.

Amyloid plaques in Alzheimer's disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (Aß) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the Aß burden prior to brain, highlighting gut-brain axis (GBA) interaction in neurodegenerative disorders. We used pre-symptomatic (6-months) and symptomatic (15-months) Tg2576 mouse model of AD compared to their age-matched littermate WT control. We identified that dysfunction of intestinal epithelial barrier (IEB), dysregulation of absorption, and vascular Aß deposition in the IEB occur before cerebral Aß aggregation is detectible. These changes in the GBA were associated with elevated inflammatory plasma cytokines including IL-9, VEGF and IP-10. In association with reduced cerebral myelin tight junction proteins, we identified reduced levels of systemic vitamin B12 and decrease cubilin, an intestinal B12 transporter, after the development of cerebral Aß pathology. Lastly, we report Aß deposition in the intestinal autopsy from AD patients with confirmed cerebral Aß pathology that is not present in intestine from non-AD controls. Our data provide evidence that gut dysfunction occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve the early manipulation of gut physiology and its microbiota.

Activation of extracellular regulated kinase and mechanistic target of rapamycin pathway in focal cortical dysplasia.

Neuropathology of resected brain tissue has revealed an association of focal cortical dysplasia (FCD) with drug-resistant epilepsy (DRE). Recent studies have shown that the mechanistic target of rapamycin (mTOR) pathway is hyperactivated in FCD as evidenced by increased phosphorylation of the ribosomal protein S6 (S6) at serine 240/244 (S(240/244) ), a downstream target of mTOR. Moreover, extracellular regulated kinase (ERK) has been shown to phosphorylate S6 at serine 235/236 (S(235/236) ) and tuberous sclerosis complex 2 (TSC2) at serine 664 (S(664) ) leading to hyperactive mTOR signaling. We evaluated ERK phosphorylation of S6 and TSC2 in two types of FCD (FCD I and FCD II) as a candidate mechanism contributing to mTOR pathway dysregulation. Tissue samples from patients with tuberous sclerosis (TS) served as a positive control. Immunostaining for phospho-S6 (pS6(240/244) and pS6(235/236) ), phospho-ERK (pERK), and phospho-TSC2 (pTSC2) was performed on resected brain tissue with FCD and TS. We found increased pS6(240/244) and pS6(235/236) staining in FCD I, FCD II and TS compared to normal-appearing tissue, while pERK and pTSC2 staining was increased only in FCD IIb and TS tissue. Our results suggest that both the ERK and mTOR pathways are dysregulated in FCD and TS; however, the signaling alterations are different for FCD I as compared to FCD II and TS.

Brain metastasis of crystal-deficient, CD68-positive alveolar soft part sarcoma: ultrastructural features and differential diagnosis.

We report a case of alveolar soft part sarcoma (ASPS) presenting as an isolated frontal lobe metastasis. The tumor demonstrated little or no immunoreactivity for a broad panel of antibodies yet strong, diffuse immunoreactivity with CD68. On electron microscopy, the characteristic rectangular to rhomboid crystalline inclusions of ASPS were not present. Electron-dense granules resembling peroxisomes were present, sometimes in association with elongated granular structures having a periodic, lattice-like arrangement. Metastatic ASPS was confirmed by demonstration of an ASPSCR1-TFE3 fusion and imaging studies that excluded metastatic Xp11.2 translocation renal cell carcinoma. The primary site was subsequently identified in the lower extremity.

Ovarian microcystic stromal tumor: report of a new entity with immunohistochemical and ultrastructural studies.

Microcystic stromal tumor is a recently described rare subtype of ovarian tumor for which there has been no previously reported ultrastructural study. We report a case with the characteristic histological and immunohistochemical features and the first ultrastructural study. The immunohistochemical findings of strong and diffuse nuclear staining for beta catenin and P27 are suggestive of dysregulation of more than one genetic pathway. The ultrastructural findings are supportive of the previous postulation of an ovarian stromal origin of the neoplastic cells.

The identification of a Distinct Astrocyte Subtype that Diminishes in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the presence of two hallmark pathologies: the accumulation of Amyloid beta (Aß) and tau proteins in the brain. There is a growing body of evidence suggesting that astrocytes, a type of glial cell in the brain, play crucial roles in clearing Aß and binding to tau proteins. However, due to the heterogeneity of astrocytes, the specific roles of different astrocyte subpopulations in response to Aß and tau remain unclear. To enhance the understanding of astrocyte subpopulations in AD, we investigated astrocyte lineage cells based on single-nuclei transcriptomic data obtained from both human and mouse samples. We characterized the diversity of astrocytes and identified global and subpopulation-specific transcriptomic changes between control and AD samples. Our findings revealed the existence of a specific astrocyte subpopulation marked by low levels of GFAP and the presence of AQP4 and CD63 expression, which showed functional enrichment in Aß clearance and tau protein binding, and diminished in AD. We verified this type of astrocytes in mouse models and in AD patient brain samples. Furthermore, our research also unveiled significant alterations of the ligand-receptor interactions between astrocytes and other cell types. These changes underscore the complex interplay between astrocytes and neighboring cells in the context of AD. Overall, our work gives insights into astrocyte heterogeneity in the context of AD and reveals a distinct astrocyte subpopulation that holds potential for therapeutic interventions in AD. Targeting specific astrocyte subpopulations may offer new avenues for the development of novel treatments for AD.

Fatal Hemophagocytic Lymphohistiocytosis Resulting in the Death of a Previously Healthy 49-Year-Old Man in Ten Days.

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive, life-threatening condition with sudden onset of a systemic inflammatory response syndrome. The triggers can be apparently non-specific, and the clinical presentations can be very deceptive during a rapidly deteriorating clinical course. Herein, we report a case of a 49-year-old White/Caucasian male with no known past medical history who presented with multi-organ failure, including liver, kidney, and bone marrow, along with disseminated intravascular coagulation. He had a high probability of HLH. Unfortunately, he died ten days after the initial presentation. At autopsy, the liver was necrotic and immunostains revealed diffuse positivity for HSV-1 & 2. The bone marrow was markedly hypocellular with phagocytes containing intact and fragmented red blood cells. There was also disseminated fungal infection involving almost all tissues. PCR, done on frozen tissue samples, revealed Aspergillus fumigatus. The rapid and fatal course of this patient illustrates the sometimes-aggressive course of HLH and the importance of autopsy examination in revealing the underlying etiology for this patient's death.

Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy.

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development.

Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.

Diagnosis of giant cell arteritis using clinical, laboratory, and histopathological findings in patients undergoing temporal artery biopsy.

OBJECTIVE: To identify the clinical, laboratory, and histopathological features that may predict the diagnosis of giant cell arteritis (GCA). METHODS: A retrospective chart review was performed on patients who underwent temporal artery biopsy (TAB) between January 1, 2011 and March 31, 2019. Patient demographics, clinical characteristics, laboratory features, histopathological features, and biopsy results were collected. GCA status was determined by a neuro-ophthalmologist (OOA). Stepwise logistic regression analysis was performed to identify features that predict GCA status. RESULTS: Of 101 patients who underwent TAB, 31 (31%) were diagnosed with GCA. Age was found to be statistically significant for the diagnosis of GCA (P = 0.009), with an average age of 74.4 years ( ± 8.1) in those with GCA vs. 68.9 years ( ± 10.0) in those without. The incidence of transient vision loss was higher in GCA than non-GCA patients (P = 0.005). Anterior arteritic ischemic optic neuropathy (n = 3), ophthalmic artery occlusion (n = 2), and posterior ischemic optic neuropathy (n = 1) were seen only in the GCA group. Of the 31 GCA patients, 15 had active GCA (48%), 3 (10%) had healed temporal arteritis (HTA), 8 (26%) had suggested HTA, and 5 (16%) had false negative biopsies. Of the 70 non-GCA patients, 63 (90%) had negative biopsies, 2 (3%) had HTA, and 5 (7%) had suggested HTA. Histopathological analysis revealed that CD68 staining had a sensitivity of 69% and specificity of 86%. Both presence of multinucleated giant cells (MNGC) and transmural inflammation had 100% specificity; however, sensitivity was ≤ 50%. In patients with negative TABs and complete risk factor data available (n = 66), the odds of GCA increased 2.16-fold every 5 years of age, and 1.08-fold every mg/day of oral steroid use. A biopsy result of HTA had an odds ratio of 84.7 and suggested HTA of 49.2 against a negative TAB for diagnosis of GCA. CONCLUSION: Age at time of biopsy, HTA, and suggested HTA are predictive for the diagnosis of GCA. Transient vision loss is more commonly seen in GCA, and anterior arteritic ischemic optic neuropathy, ophthalmic artery occlusion, and posterior ischemic optic neuropathy are important ophthalmic manifestations of GCA. CD68 staining is more sensitive but less specific for diagnosing GCA in comparison to other histopathologic findings such as presence of MNGC and transmural inflammation. Further work is recommended to investigate the importance of the specific histopathologic finding of CD68 staining in the diagnosis of GCA.

Cyclin D1 expression in Rosai-Dorfman disease: a near-constant finding that is not invariably associated with mitogen-activated protein kinase/extracellular signal-regulated kinase pathway activation.

Activating mutations in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway have been shown in nearly half of the cases of Rosai-Dorfman disease (RDD). Cyclin D1, a key cell cycle regulator, constitutes a major downstream target of the MAPK/ERK pathway. In this study, we aim to further understand the pathogenesis of RDD by assessing the lesional histiocytes for cyclin D1, p-ERK, Ki-67, and BCL-2 by immunohistochemistry. We assessed 35 samples of RDD and a control group of histiocyte-rich reactive lesions. Cyclin D1 was expressed in about 90% of cases of RDD. Cyclin D1 was positive in 25-95% (median, 85%) of lesional histiocytes, was moderately/strongly expressed in 97% of cyclin D1-positive cases, and was significantly higher than in control specimens. p-ERK was positive in 16 of 30 (53%) cases of RDD and was negative in all controls. All p-ERK-positive RDD cases had concurrent cyclin D1 expression, whereas more than a third of cyclin D1-positive cases were negative for p-ERK. Ki-67 was low in RDD (median, 3%). BCL-2 was positive in lesional histiocytes in nine of 10 RDD cases assessed. Overall, these findings point to unexpected, potential roles of these molecules in the pathogenesis of RDD. Overexpression of cyclin D1 in the absence of ERK phosphorylation in a subset of RDD cases opens the possibility of oncogenic mechanisms bypassing ERK and supports the notion that cyclin D1 overexpression in RDD is multifactorial. Moreover, the observed lack of correlation between cyclin D1 with Ki-67 proliferative index suggests that prosurvival actions of cyclin D1 are, at least in part, cell cycle independent. Finally, expression of BCL-2 and the low Ki-67 index suggest that RDD might be driven by antiapoptotic rather than proproliferative oncogenic mechanisms.

Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation?

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) cleaves the phosphodiester bond between a covalently stalled topoisomerase I (Topo I) and the 3' end of DNA. Stalling of Topo I at DNA strand breaks is induced by endogenous DNA damage and the Topo I-specific anticancer drug camptothecin (CPT). The H493R mutation of Tdp1 causes the neurodegenerative disorder spinocerebellar ataxia with axonal neuropathy (SCAN1). Contrary to the hypothesis that SCAN1 arises from catalytically inactive Tdp1, Tdp1-/- mice are indistinguishable from wild-type mice, physically, histologically, behaviorally, and electrophysiologically. However, compared to wild-type mice, Tdp1-/- mice are hypersensitive to CPT and bleomycin but not to etoposide. Consistent with earlier in vitro studies, we show that the H493R Tdp1 mutant protein retains residual activity and becomes covalently trapped on the DNA after CPT treatment of SCAN1 cells. This result provides a direct demonstration that Tdp1 repairs Topo I covalent lesions in vivo and suggests that SCAN1 arises from the recessive neomorphic mutation H493R. This is a novel mechanism for disease since neomorphic mutations are generally dominant.

Hemorrhagic Giant Cell Tumor of the Occipital Skull Base: A Case Report and Literature Review.

Giant cell tumor of bone is a benign but locally aggressive osteolytic neoplasm that represents 3% to 5% of all primary bone tumors, primarily found at the epiphyses of long bones. Less than 1% are of calvarial origin. Herein, we report a rare case of a nine-year-old girl with a hemorrhagic giant cell tumor of the left occipital skull base.

Molecular Alterations in Meningioangiomatosis Causing Epilepsy.

Meningioangiomatosis (MA) is a rare process at the intersection of cerebral developmental and neoplastic disorders that often results in epilepsy. We evaluated molecular alterations in MA to characterize its biology and pathogenesis. We searched a comprehensive institutional database for patients with MA treated between 2004 and 2019. Demographic, clinical, surgical, and radiographical data were collected. MA and associated meningioma tissues were evaluated using a next-generation sequencing assay interrogating 1425 cancer-related genes. We studied 5 cases: 3 with MA and 2 with MA associated with a meningioma. Of the MAs associated with a meningioma, 1 had deletions in the NF2 gene in both the MA and the meningioma components, whereas the other had an NF2 deletion in only the MA component. Additional mutations were identified in the MA components, suggesting that MA arises from the meningioma rather than the meningioma resulting from a transformation of the MA. The 3 cases of pure MA showed variants of unknown significance with no alterations in known oncogenic drivers. Our findings provide a starting point to a better understanding of the pathogenesis of this rare lesion. Our study indicates that MA-meningiomas have a neoplastic nature that differs from the hamartomatous/developmental nature of pure MA.