Clinical, anatomical, and histological features of the rhomboid lip and considerations for surgery using a retrosigmoid approach: a retrospective study.

OBJECTIVE: The rhomboid lip is a neural tissue encountered during cerebellopontine angle surgery, with differing shape and extent among individuals. This study aimed to investigate the variation of rhomboid lips during posterior fossa surgery. METHODS: In this retrospective study, we examined posterior cranial fossa surgeries performed using a retrosigmoid approach. Rhomboid lips were classified according to thickness, extent, and appearance, with some subjected to histological analysis. T2-weighted magnetic resonance imaging (MRI) of rhomboid lips was conducted. RESULTS: Among 304 surgeries, rhomboid lips were observed in 75 patients who underwent schwannoma or meningioma resection, facial spasm-related neurovascular decompression, and other surgeries (37, 2, 32, and 4 patients, respectively). Rhomboid lips were categorized based on apparent thickness: thin membranous type, resembling an arachnoid membrane, and thick parenchymal type. Rhomboid lip extension was classified by position relative to the choroid plexus: non-extension, lateral extension, and jugular foramen (41, 22, and 12 patients, respectively). Veins were observed on the rhomboid lip surface in 37 cases. The rhomboid lip was visible in only one case (parenchymal jugular foramen type) on MRI. Histologically, the rhomboid lip comprised an ependymal cell layer, a glial layer, and connecting tissue. The glial layer thickness determined the rhomboid lip thickness, which was greater in the parenchymal type than in the membrane type. In 42 patients, the rhomboid lip was dissected, with no complications observed. CONCLUSIONS: Morphological classification of the rhomboid lip and understanding of its anatomical details contribute to safe surgical field development for neurosurgeons.

Implications of DNA Methylation Classification in Diagnosing Ependymoma.

BACKGROUND: Ependymoma is a central nervous system (CNS) tumor that arises from the ependymal cells of the brain's ventricles and spinal cord. The histopathology of ependymomas is indistinguishable regardless of the site of origin, and the prognosis varies. Recent studies have revealed that the development site and prognosis reflect the genetic background. In this study, we used genome-wide DNA methylation array analysis to investigate the epigenetic background of ependymomas from different locations treated at our hospital. METHODS: Four cases of posterior fossa ependymomas and 11 cases of spinal ependymomas were analyzed. RESULTS: DNA methylation profiling using the DKFZ methylation classifier showed that the methylation diagnoses of the 2 cases differed from the histopathological diagnoses, and 2 cases could not be classified. Tumor that spread from the brain to the spinal cord was molecularly distinguishable from other primary spinal tumors. CONCLUSIONS: Although adding DNA methylation classification to conventional diagnostic methods may be helpful, the diagnosis in some cases remains undetermined. This may affect decision-making regarding treatment strategies and follow-up. Further investigations are required to improve the diagnostic accuracy of these tumors.

The surgical intervention for pineal region tumors.

Histological and molecular characterization is essential for the diagnosis of pediatric brain tumors. In the pineal region tumors, it is necessary to remove a sufficient tumor volume to make a diagnosis. However, surgery in this region is challenging due to its deep anatomical location and surrounded by critical structures and complex venous system. Knowledge of the anatomy and function of the pineal region and tumor histological types is imperative for the successful management of pineal region tumors. This article describes surgical approaches to pineal tumors, focusing on the occipital transtentorial approach and adding the author's experience to what has been known in the literature. Recent innovations have made this approach more popular and can be applied to occipital fossa lesions.

Utility of real-time polymerase chain reaction for the assessment of CDKN2A homozygous deletion in adult-type IDH-mutant astrocytoma.

The World Health Organization Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5) introduced a newly defined astrocytoma, IDH-mutant grade 4, for adult diffuse glioma classification. One of the diagnostic criteria is the presence of a CDKN2A/B homozygous deletion (HD). Here, we report a robust and cost-effective quantitative polymerase chain reaction (qPCR)-based test for assessing CDKN2A HD. A TaqMan copy number assay was performed using a probe located within CDKN2A. The linear correlation between the Ct values and relative CDKN2A copy number was confirmed using a serial mixture of DNA from normal blood and U87MG cells. The qPCR assay was performed in 109 IDH-mutant astrocytomas, including 14 tumors with CDKN2A HD, verified either by multiplex ligation-dependent probe amplification (MLPA) or CytoScan HD microarray platforms. Receiver operating characteristic curve analysis indicated that a cutoff value of 0.85 yielded optimal sensitivity (100%) and specificity (99.0%) for determining CDKN2A HD. The assay applies to DNA extracted from frozen or formalin-fixed paraffin-embedded tissue samples. Survival was significantly shorter in patients with than in those without CDKN2A HD, assessed by either MLPA/CytoScan or qPCR. Thus, our qPCR method is clinically applicable for astrocytoma grading and prognostication, compatible with the WHO CNS5.

KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway.

Here, we investigated the detailed molecular oncogenic mechanisms of a novel receptor tyrosine kinase (RTK) fusion, KLC1-ROS1, with an adapter molecule, KLC1, and an RTK, ROS1, discovered in pediatric glioma, and we explored a novel therapeutic target for glioma that possesses oncogenic RTK fusion. When wild-type ROS1 and KLC1-ROS1 fusions were stably expressed in the human glioma cell lines A172 and U343MG, immunoblotting revealed that KLC1-ROS1 fusion specifically activated the JAK2-STAT3 pathway, a major RTK downstream signaling pathway, when compared with wild-type ROS1. Immunoprecipitation of the fractionated cell lysates revealed a more abundant association of the KLC1-ROS1 fusion with JAK2 than that observed for wild-type ROS1 in the cytosolic fraction. A mutagenesis study of the KLC1-ROS1 fusion protein demonstrated the fundamental roles of both the KLC1 and ROS1 domains in the constitutive activation of KLC1-ROS1 fusion. Additionally, in vitro assays demonstrated that KLC1-ROS1 fusion upregulated cell proliferation, invasion, and chemoresistance when compared to wild-type ROS1. Combination treatment with the chemotherapeutic agent temozolomide and an inhibitor of ROS1, JAK2, or a downstream target of STAT3, demonstrated antitumor effects against KLC1-ROS1 fusion-expressing glioma cells. Our results demonstrate that KLC1-ROS1 fusion exerts oncogenic activity through serum-independent constitutive activation, resulting in specific activation of the JAK-STAT pathway. Our data suggested that molecules other than RTKs may serve as novel therapeutic targets for RTK fusion in gliomas.

Intravascular large B-cell lymphoma as a recurrence of primary central nervous system lymphoma after chemotherapy: A case report.

We report about a 48-year-old woman diagnosed with primary central nervous system lymphoma (PCNSL). After chemotherapy and autologous stem cell transplantation, she presented with a continuous high-grade fever. Positron emission tomography-computed tomography revealed prominent hepatosplenomegaly and high diffuse uptake of 18F-fluorodeoxyglucose in the liver, spleen, and lungs. Intravascular large B-cell lymphoma (IVLBCL) was diagnosed using random skin biopsy. There were no symptoms of IVLBCL at the time of diagnosis of PCNSL. The histopathological features of PCNSL and IVLBCL were nearly similar. These findings suggest that IVLBCL was the recurrence of PCNSL rather than a separate entity.

Case of penetrating brain injury caused by a ventriculoperitoneal shunting procedure.

Brain injury with ventricle puncture is a well-known complication of ventriculoperitoneal (VP) shunting. However, parenchymal injuries caused by a shunt tunneller are rare. Herein, we present a case of penetrating brain injury caused by a shunt tunneller during VP shunting. An 83-year-old woman with brainstem glioma underwent VP shunting to control hydrocephalus due to tumour growth. She underwent brainstem tumour biopsy with a lateral suboccipital approach. After the shunting, CT showed a linear haematoma in the left occipital lobe far from the site of the ventricular puncture. MRI revealed a small contusion in the left cerebellar hemisphere, disconnection of the left tentorial membrane and linear haematoma on a straight line. These facts suggested that the shunt tunneller had penetrated the skull through the craniotomy of the posterior fossa. This is a rare complication of VP shunting, with limited cases reported in the literature.

Transformation from adenocarcinoma to squamous cell lung carcinoma with MET amplification after lorlatinib resistance: A case report.

To date, several studies have described the mechanism of resistance to first- or second-generation anaplastic lymphoma kinase (ALK) inhibitors. Secondary ALK mutations, ALK gene amplification, and other bypass signal activations (i.e., KRAS mutation, EGFR mutation, amplification of KIT, and increased autophosphorylation of EGFR) are known as resistance mechanisms. However, little has been previously reported on acquired resistance mechanisms to lorlatinib. Here, we report a case of a patient with ALK-positive lung adenocarcinoma that acquired resistance to lorlatinib during treatment for brain metastasis and showed histological transformation to squamous cell carcinoma with MET amplification. We also review the previous literature on the resistance mechanism to ALK inhibitors.

A case of solitary subependymal giant cell astrocytoma with histopathological anaplasia and TSC2 gene alteration.

We report a case of subependymal giant cell astrocytoma (SEGA) with anaplastic histological features in a 3-year-old girl. She had no clinical manifestations of tuberous sclerosis complex (TSC) and no relevant family history. A few cases have been reported in which patients with SEGA had no other clinical manifestations of TSC (solitary SEGA). Genetic analysis using a blood sample from the patient showed no germline alterations in TSC1 or TSC2 genes, while the tumor tissue exhibited loss of heterozygosity (LOH) in TSC2. SEGAs are benign, slowly growing tumors that rarely have significant mitotic activity. However, histopathological examination in the present case revealed high mitotic activity and necrosis besides the typical large plump cells arranged in sheets. This may be the first genetically proven case of a solitary SEGA with histopathological anaplastic features. In this report, we reviewed solitary SEGAs and histopathological malignancy in SEGA.

Fibulin-7 is overexpressed in glioblastomas and modulates glioblastoma neovascularization through interaction with angiopoietin-1.

Glioblastoma (GBM) is pathologically characterized by highly malignant neoplastic cells, focal necrosis and aberrant blood vessels composed of disorganized endothelial cells and pericytes. The recent cancer microarray database revealed upregulation of fibulin-7 (Fbln7), a member of the fibulin family, but provided no information on the tissue localization or biological function. In the present study, we demonstrated that Fbln7 is markedly overexpressed by the GBM tissue among astrocytic tumors, and immunolocalized mainly to endothelial cells and pericytes of the glomeruloid and hypertrophied microvessels. The production of Fbln7 by endothelial cells and pericytes was confirmed in cultured human umbilical vein endothelial cells (HUVEC) and human brain vascular pericytes (HBVP) and vascular endothelial growth factor (VEGF) stimulated the Fbln7 expression in HUVEC. Fbln7 bound to angiopoietin-1, but not angiopoietin-2 or Tie2 receptor, through interaction between the N-terminal portions of Fbln7 and angiopoietin-1, and it blocked phosphorylation of Tie2 receptor in HUVEC. In a coculture assay using HUVEC and HBVP, multilayered and irregular-shaped tube-like structures of HUVEC were induced by treatment with a high concentration of VEGF. This was accompanied by Fbln7 overproduction by HUVEC and angiopoietin-1 expression by HBVP. The production of aberrant VEGF-induced tube-like structures was attenuated by treatment with antibody or synthetic peptides specific to the Fbln7 N-terminal domain or knockdown of Fbln7. These data demonstrate that Fbln7 is overexpressed by endothelial cells and pericytes of the abnormal microvessels in GBM, and suggest that Fbln7 may contribute to the aberrant vessel formation by modulation of the angiopoietin-1/angiopoietin-2-Tie2 axis.

A rare presentation of a pediatric neurenteric cyst as an intra-axial pontine lesion: A case report with a 5-year follow-up.

BACKGROUND: Intracranial neurenteric cysts are rare, benign, and slow-growing tumors. However, we encountered a pediatric case that the cyst expansion occurred in a short period of time resulting in rapid deterioration of the patient's symptoms. CASE DESCRIPTION: A previously healthy 7-year-old girl had a week history of dysarthric speech and diplopia along with headaches. Her magnetic resonance images (MRI) showed an abnormal cystic mass in her brainstem. Her symptoms were deteriorated for 1 month and her second MRI revealed an enlargement of the cystic lesion. The tumor biopsy and cyst drainage were carried out and histopathological examination of the cyst wall showed columnar epithelium containing ciliated cells. The final diagnosis of her tumor was neurenteric cyst. CONCLUSION: We report a pediatric case of a neurenteric cyst in the brainstem, which expanded in a short period, and review this rare entity.

A novel surgical approach for intraorbital optic nerve tumors.

Although orbital tumors involving the optic nerve are rare, it is well-known that they are very likely to cause serious visual impairment in a patient. Unfortunately, at present, there are no effective interventions that can reliably preserve visual function while controlling tumor growth into intracranial spaces. To ensure visual function of the non-affected side, transection of the optic nerve together with the tumors involved is necessary in some cases. For this procedure large craniotomy and orbital unroofing are commonly utilized. As an alternative, we propose a novel surgical intervention for transection of the optic nerve having optic nerve tumors, which utilizes a lateral orbitotomy approach. To evaluate the invasiveness of different surgical approaches, we compared the days of hospitalization after surgery across patients who underwent the transcranial, lateral, and anterior approaches, respectively. We successfully removed 2 optic nerve tumors using the lateral approach, which required significantly shorter hospitalization than the transcranial approach. The transection of the optic nerve together with tumor removal by the lateral approach may be one of the novel surgical interventions for optic nerve tumors as this method is considerably less invasive than the transcranial removal method.

Prosthetic material degeneration over time as a possible factor in delayed recurrence of hemifacial spasm after successful microvascular decompression.

BACKGROUND: The effectiveness of microvascular decompression in treating hemifacial spasm is widely accepted. However, some experience recurrence of hemifacial spasm after successful decompression surgery. Especially, delayed recurrence more than 5 years after surgery is rare and the cause of this phenomenon is unknown. CASE DESCRIPTION: A female underwent microvascular decompression to treat her hemifacial spasm 6 years ago. Six years later, her hemifacial spasm recurred and she underwent a second surgery. The second surgery revealed that the sponge had become fragile, losing the ability to absorb the impact of pulsatile compression of the offending artery on the root exit zone of her facial nerve. CONCLUSION: We report a case in which degeneration of material, a sponge (polyurethane), used in decompression surgery caused delayed recurrence of hemifacial spasm. The selection of appropriate prosthetic materials is essential in such functional surgeries.

A Comprehensive Method for Detecting Fusion Genes in Paediatric Brain Tumours.

BACKGROUND: Fusion genes driving tumourigenesis have drawn the attention of researchers and oncologists. Despite the importance of such molecular alterations, there are no comprehensive reproducible methods for detecting fusion genes. MATERIALS AND METHODS: Nineteen paediatric brain tumours of five types, namely pilocytic astrocytoma, oligodendroglioma, anaplastic astrocytoma, glioblastoma and, ganglioglioma, were examined to detect fusion genes using a pyrosequencing-based method following RNA isolation, cDNA synthesis and real-time polymerase chain reaction. RESULTS: Our method successfully detected KIAA1549-v-raf murine sarcoma viral oncogene homolog B1 (BRAF) fusion in 14 out of 19 patients suffering from five types of paediatric brain tumours providing information on fusion breakpoints within 2 h. CONCLUSION: A comprehensive method for detecting fusion genes in paediatric brain tumours was evaluated. This method identified KIAA1549-BRAF fusion variants quickly. Our results may help researchers interested in the role of fusion genes in tumourigenesis.

A functional screening of the kinome identifies the Polo-like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain.

PURPOSE: Malignant rhabdoid tumors (MRTs) are deadly embryonal tumors of the infancy. With poor survival and modest response to available therapies, more effective and less toxic treatments are needed. We hypothesized that a systematic screening of the kinome will reveal kinases that drive rhabdoid tumors and can be targeted by specific inhibitors. METHODS: We individually mutated 160 kinases in a well-characterized rhabdoid tumor cell line (MON) using lentiviral clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). The kinase that most significantly impaired cell growth was further validated. Its expression was evaluated by microarray gene expression (GE) within 111 pediatric tumors, and functional assays were performed. A small molecule inhibitor was tested in multiple rhabdoid tumor cell lines and its toxicity evaluated in zebrafish larvae. RESULTS: The Polo-like kinase 4 (PLK4) was identified as the kinase that resulted in higher impairment of cell proliferation when mutated by CRISPR/Cas9. PLK4 CRISPR-mutated rhabdoid cells demonstrated significant decrease in proliferation, viability, and survival. GE showed upregulation of PLK4 in rhabdoid tumors and other embryonal tumors of the brain. The PLK4 inhibitor CFI-400945 showed cytotoxic effects on rhabdoid tumor cell lines while sparing non-neoplastic human fibroblasts and developing zebrafish larvae. CONCLUSIONS: Our findings indicate that rhabdoid tumor cell proliferation is highly dependent on PLK4 and suggest that targeting PLK4 with small-molecule inhibitors may hold a novel strategy for the treatment of MRT and possibly other embryonal tumors of the brain. This is the first time that PLK4 has been described as a potential target for both brain and pediatric tumors.

Overexpression of TEAD4 in atypical teratoid/rhabdoid tumor: New insight to the pathophysiology of an aggressive brain tumor.

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor that occurs mainly in early childhood. Although most of the tumors are characterized by inactivating mutations of the tumor suppressor gene, SMARCB1, the biological basis of its tumorigenesis and aggressiveness is still unknown. PROCEDURE: We performed high-throughput copy number variation analysis of primary cell lines generated from primary and relapsed tumors from one of our patients to identify new genes involved in AT/RT biology. The expression of the identified gene was validated in 29 AT/RT samples by gene expression profiling, quantitative real-time polymerase chain reaction, and immunohistochemistry (IHC). Furthermore, we investigated the function of this gene by mutating it in rhabdoid tumor cells. RESULTS: TEAD4 amplification was detected in the primary cell lines and its overexpression was confirmed at mRNA and protein levels in an independent cohort of AT/RT samples. TEAD4's co-activator, YAP1, and the downstream targets, MYC and CCND1, were also found to be upregulated in AT/RT when compared to medulloblastoma. IHC showed TEAD4 and YAP1 overexpression in all samples. Cell proliferation and migration were significantly reduced in TEAD4-mutated cells. CONCLUSIONS: We report the overexpression of TEAD4 in AT/RT, which is a key component of Hippo pathway. Recent reports revealed that dysregulation of the Hippo pathway is implicated in tumorigenesis and poor prognosis of several human cancers. Our results suggest that TEAD4 plays a role in the pathophysiology of AT/RT, which represents a new insight into the biology of this aggressive tumor.

Loss of expression of the Neural Cell Adhesion Molecule 1 (NCAM1) in atypical teratoid/rhabdoid tumors: a new diagnostic marker?

Background: Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive embryonal tumors of the central nervous system. They are largely characterized by inactivating mutations of the SMARCB1 tumor suppressor gene. AT/RT patients have a very poor prognosis and no standard therapeutic protocol has been defined yet. Recently, multimodal therapy with multiple drug combinations has slightly improved the overall survival, however drug toxicity remains high. In this scenario, a better understanding of the pathophysiology of the disease is needed. Methods: We evaluated the gene expression profile of AT/RT samples to find new genetic factors contributing to the pathophysiology of the disease. We found target genes significantly differentially expressed between AT/RT and medulloblastoma (MB), the most common embryonal brain tumor. The mRNA expression was validated by quantitative real-time PCR and, at the protein level, expression was validated by immunohistochemistry in an independent set of tumors. Results: The Neural cell adhesion molecule 1 (NCAM1) gene was found to be consistently downregulated in AT/RT samples when compared to MB and normal brain tissue. Immunohistochemistry showed that the expression of NCAM1 in AT/RT was significantly lower than that of MB. Conclusion: NCAM1 is an important molecule involved in neuron-to-neuron and neuron-to-muscle adhesion during development. Downregulation of NCAM1 has been implicated in several human cancers suggesting that it might have a tumor repressor role. In this study we found a significantly reduced expression of NCAM1 in AT/RT when compared to MB and we suggest that this feature can be used as a diagnostic marker, along with demonstration of SMARCB1 (INI1) or SMARCA4 (BRG1) inactivation. The roles of NCAM1 in the pathophysiology of AT/RT are still to be determined (AU)

Spontaneous involution of pediatric low-grade gliomas: high expression of cannabinoid receptor 1 (CNR1) at the time of diagnosis may indicate involvement of the endocannabinoid system.

BACKGROUND: Pediatric low-grade gliomas (P-LGG) consist of a mixed group of brain tumors that correspond to the majority of CNS tumors in children. Notably, they may exhibit spontaneous involution after subtotal surgical removal (STR). In this study, we investigated molecular indicators of spontaneous involution in P-LGG. METHODS: We performed an integrated molecular analysis including high throughput gene expression (GE), microRNA (miRNA) expression data of primary, untreated tumors from patients with P-LGG who underwent STR at our institution, with at least 10 years follow-up. RESULTS: We identified a set of protein-coding genes and miRNAs significantly differentially expressed in P-LGG that presented spontaneous involution (involution-I) or without progression (stable-S) after STR alone. The cannabinoid receptor 1 (CNR1 or CB1) gene (FC = 2.374; p value = 0.007) was at the top of the list and predicted to be regulated by hsa-miR-29b-3p (FC = -2.353, p value = 0.0001). CNR1 also showed a trend to be higher expressed in S/I by immunohistochemistry. CONCLUSIONS: The P-LGG, which remained stable or that presented spontaneous involution after STR, showed significantly higher CNR1 expression at the time of diagnosis. We hypothesize that high expression levels of CNR1 provide tumor susceptibility to the antitumor effects of circulating endocannabinoids like anandamide, resulting in tumor involution. This corroborates with reports suggesting that CNR1 agonists and activators of the endocannabinoid system may represent therapeutic opportunities for children with LGG. We also suggest that CNR1 may be a prognostic marker for P-LGG. This is the first time spontaneous involution of P-LGG has been suggested to be induced by endocannabinoids.