Toward Precision Oncology in Glioblastoma with a Personalized Cancer Genome Reporting Tool and Genetic Changes Identified by Whole Exome Sequencing.

Precision/personalized medicine in oncology has two key pillars: molecular profiling of the tumors and personalized reporting of the results in ways that are clinically contextualized and triangulated. Moreover, neurosurgery as a field stands to benefit from precision/personalized medicine and new tools for reporting of the molecular findings. In this context, glioblastoma (GBM) is a highly aggressive brain tumor with limited treatment options and poor prognosis. Precision/personalized medicine has emerged as a promising approach for personalized therapy in GBM. In this study, we performed whole exome sequencing of tumor tissue samples from six newly diagnosed GBM patients and matched nontumor control samples. We report here the genetic alterations identified in the tumors, including single nucleotide variations, insertions or deletions (indels), and copy number variations, and attendant mutational signatures. Additionally, using a personalized cancer genome-reporting tool, we linked genomic information to potential therapeutic targets and treatment options for each patient. Our findings revealed heterogeneity in genetic alterations and identified targetable pathways, such as the PI3K/AKT/mTOR pathway. This study demonstrates the prospects of precision/personalized medicine in GBM specifically, and neurosurgical oncology more generally, including the potential for genomic profiling coupled with personalized cancer genome reporting. Further research and larger studies are warranted to validate these findings and advance the treatment options and outcomes for patients with GBM.

Low grade oligodendroglioma seeding around the 4th ventricle.

We report a 45 years old female patient with a left temporal grade II oligodendroglioma that recurred on the wall of the fourth ventricle at grade II oligodendroglioma.

Past, Present, and Future of Therapies for Pituitary Neuroendocrine Tumors: Need for Omics and Drug Repositioning Guidance.

Innovation roadmaps are important, because they encourage the actors in an innovation ecosystem to creatively imagine multiple possible science future(s), while anticipating the prospects and challenges on the innovation trajectory. In this overarching context, this expert review highlights the present unmet need for therapeutic innovations for pituitary neuroendocrine tumors (PitNETs), also known as pituitary adenomas. Although there are many drugs used in practice to treat PitNETs, many of these drugs can have negative side effects and show highly variable outcomes in terms of overall recovery. Building innovation roadmaps for PitNETs' treatments can allow incorporation of systems biology approaches to bring about insights at multiple levels of cell biology, from genes to proteins to metabolites. Using the systems biology techniques, it will then be possible to offer potential therapeutic strategies for the convergence of preventive approaches and patient-centered disease treatment. Here, we first provide a comprehensive overview of the molecular subtypes of PitNETs and therapeutics for these tumors from the past to the present. We then discuss examples of clinical trials and drug repositioning studies and how multi-omics studies can help in discovery and rational development of new therapeutics for PitNETs. Finally, this expert review offers new public health and personalized medicine approaches on cases that are refractory to conventional treatment or recur despite currently used surgical and/or drug therapy.

MicroRNA-Mediated Drug Repurposing Unveiled Potential Candidate Drugs for Prolactinoma Treatment.

INTRODUCTION: Prolactinomas, also called lactotroph adenomas, are the most encountered type of hormone-secreting pituitary neuroendocrine tumors in the clinic. The preferred first-line therapy is a medical treatment with dopamine agonists (DAs), mainly cabergoline, to reduce serum prolactin levels, tumor volume, and mass effect. However, in some cases, patients have displayed DA resistance with aggressive tumor behavior or are faced with recurrence after drug withdrawal. Also, currently used therapeutics have notorious side effects and impair the life quality of the patients. METHODS: Since the amalgamation of clinical and laboratory data besides tumor histopathogenesis and transcriptional regulatory features of the tumor emerges to exhibit essential roles in the behavior and progression of prolactinomas; in this work, we integrated mRNA- and microRNA (miRNA)-level transcriptome data that exploit disease-specific signatures in addition to biological and pharmacological data to elucidate a rational prioritization of pathways and drugs in prolactinoma. RESULTS: We identified 8 drug candidates through drug repurposing based on mRNA-miRNA-level data integration and evaluated their potential through in vitro assays in the MMQ cell line. Seven repurposed drugs including 5-fluorocytosine, nortriptyline, neratinib, puromycin, taxifolin, vorinostat, and zileuton were proposed as potential drug candidates for the treatment of prolactinoma. We further hypothesized possible mechanisms of drug action on MMQ cell viability through analyzing the PI3K/Akt signaling pathway and cell cycle arrest via flow cytometry and Western blotting. DISCUSSION: We presented the transcriptomic landscape of prolactinoma through miRNA and mRNA-level data integration and proposed repurposed drug candidates based on this integration. We validated our findings through testing cell viability, cell cycle phases, and PI3K/Akt protein expressions. Effects of the drugs on cell cycle phases and inhibition of the PI3K/Akt pathway by all drugs gave us promising output for further studies using these drugs in the treatment of prolactinoma. This is the first study that reports miRNA-mediated repurposed drugs for prolactinoma treatment via in vitro experiments.

Analyses of Copy Number Variations in Myxopapillary Ependymomas of Cauda Equina.

AIM: To identify the copy number variations that are specific to myxopapillary ependymomas (MPEs) of the cauda equina. MATERIAL AND METHODS: The patient cohort included five patients who underwent resection of histologically confirmed MPEs. Tumor samples collected during surgery and stored in liquid nitrogen as well as corresponding blood samples collected were analyzed. Genomic DNA from the venous blood and tumor samples was obtained using standard techniques and hybridized to a Cytoscan 750K Array in accordance with the manufacturer’s introductions. RESULTS: As a novel finding, amplification on chromosome 14q32.33 was detected in all tumor and blood samples, except one tumor sample. All tumor tissues also showed amplification on chromosomes 5, 7, 9, and 16. CONCLUSION: Although further studies with larger cohorts are required to identify genes involved in MPE tumorigenesis and to validate our results, these findings provide a basis for advanced molecular biological and genetic studies of MPEs.

Hereditary spastic paraplegia with recessive trait caused by mutation in KLC4 gene.

We report an association between a new causative gene and spastic paraplegia, which is a genetically heterogeneous disorder. Clinical phenotyping of one consanguineous family followed by combined homozygosity mapping and whole-exome sequencing analysis. Three patients from the same family shared common features of progressive complicated spastic paraplegia. They shared a single homozygous stretch area on chromosome 6. Whole-exome sequencing revealed a homozygous mutation (c.853_871del19) in the gene coding the kinesin light chain 4 protein (KLC4). Meanwhile, the unaffected parents and two siblings were heterozygous and one sibling was homozygous wild type. The 19 bp deletion in exon 6 generates a stop codon and thus a truncated messenger RNA and protein. The association of a KLC4 mutation with spastic paraplegia identifies a new locus for the disease.

Deep brain stimulation as treatment for dystonic storm in pantothenate kinase-associated neurodegeneration syndrome: case report of a patient with homozygous C.628 2 T > G mutation of the PANK2 gene.

Pantothenate kinase-associated neurodegeneration (PKAN) syndrome is an autosomal-recessive neurodegenerative disease that causes progressive generalized dystonia. Currently, the disorder remains pharmacologically intractable. Herein we report the first case in which deep brain stimulation helped to relieve dystonic storm in a patient with PKAN syndrome who had homozygous c.628 2 T > G mutation of the PANK2 gene. A 10-year-old boy with PKAN disease presented with dystonic storm and was admitted to the emergency department. Examination revealed generalized dystonia and impaired breathing due to involvement of the respiratory muscles. The patient underwent surgery for bilateral globus pallidus internus deep brain stimulation. The patient showed marked response to treatment.

Neural tube defect family with recessive trait linked to chromosome 9q21.12-21.31.

PURPOSE: Meningomyelocele is one of the most common and socioeconomically, psychologically, and physically debilitating neurodevelopmental diseases. A few chromosomal locus and genes have been identified as responsible for the disease; however, clear evidence still needs to be produced. This study aimed to show evidence of a strong genetic linkage in a novel chromosomal locus in a family with this neural tube defect. METHODS: We identified a neural tube defect family in eastern Turkey, where two of six offspring had operations due to thoracolumbar meningomyelocele. The parents were of a consanguineous marriage. We collected venous blood from six offspring of the family. Whole genome linkage analysis was performed in all offspring. RESULTS: A theoretical maximum logarithm of an odds score of 3.16 was identified on chromosome 9q21.12-21.31. This result shows a strong genetic linkage to this locus. CONCLUSIONS: Our results identified a novel chromosomal locus related to meningomyelocele and provide a base for further investigations toward the discovery of a new causative gene.

A Family with Mental Retardation, Epilepsy and Cerebellar Hypoplasia Showing Linkage to Chromosome 20p11.21-q11.23.

BACKGROUND: Cerebellar hypoplasia (CH) is a rare malformation caused by various etiologies, usually manifesting clinically as nonprogressive cerebellar ataxia with or without mental retardation. The molecular pathogenesis of the autosomal recessive cerebellar ataxias has a wide range of mechanisms. Differential diagnosis and categorization of the recessive cerebellar ataxias, however, need more specific, biochemical and genetic investigation. METHODS: This study applied whole-genome linkage analysis to study a family with nonprogressive cerebellar ataxia and additional mental retardation, epilepsy, and facial dysmorphic features. Genotyping and linkage analysis was done using the GeneChip Mapping 250K NspI Array (Affymetrix Inc., Santa Clara, Calif., USA) for genome-wide linkage analysis of the genotyping data from the affected children and their parents. RESULTS: Allegro software version 1.2 was used for multipoint linkage analysis. We assumed an autosomal recessive inheritance pattern and assigned a penetrance of 0.999. Single-nucleotide polymorphism allele frequencies were estimated from the Affymetrix data of the Caucasian family studied. Using these parameters, a theoretical maximum logarithm of the odds score of 2.69 was identified at chromosome 20p11.21-q11.23. CONCLUSIONS: This chromosomal locus is unprecedented in autosomal recessive and nonprogressive ataxia disorder. Further investigation might reveal a new causative gene generating the CH phenotype.

Mutation in the HTRA1 gene in a patient with degenerated spine as a component of CARASIL syndrome.

AIM: To show the mutation in HTRA1 gene in a patient suffering from CARASIL syndrome with degenerated spine as a component of the disease. MATERIAL AND METHODS: We identified a family that one of the members had CARASIL syndrome in eastern Turkey and collected venous blood from available persons. The HTRA1 gene sequenced in all family members. RESULTS: C to T transition at position 1108 (c.1108 C > T) in exon 6, causing stop codon formation (R370X) was seen in the HTRA1 gene in a homozygous state in the CARASIL patient whereas it was heterozygous in other healthy family members. CONCLUSION: We demonstrated homozygous c.1108 C > T mutation in the HTRA1 gene causing a very rare syndrome, especially in the non- Japanese population, called CARASIL. Patients with degenerated spine and progressive clinical symptoms must be evaluated or reevaluated for other central nervous system symptoms and signs to rule out other diseases or syndromes.

Management of medically intractable genitofemoral and ilioingunal neuralgia.

AIM: To evaluate the effectiveness of invasive procedures in medically intractable genitofemoral and ilioingunal neuralgia. MATERIAL AND METHODS: This is a prospective study of 20 patients with genitofemoral and ilioinguinal neuralgias who were treated at our medical center between 2007 and 2011. Genitofemoral and ilioinguinal nerve blocks were performed in all cases after medical treatment had failed to alleviate the patients' pain. Neurectomy was performed for the patients whose pain did not improve. Patient histories, physical examinations and visual analogue scale scores before and after treatments were analyzed. RESULTS: Fourteen (70%) of the patients were treated with nerve blocks and six (30%) of the patients whose pain did not improve with nerve block application underwent neurectomy which resulted in pain relief. CONCLUSION: For patients with medically intractable genitofemoral and ilioinguinal neuralgias, nerve blocks and neurectomies can be applied safely for pain control.

Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.

BACKGROUND: Klippel-Feil syndrome (KFS) is characterized by the developmental failure of the cervical spine and has two dominantly inherited subtypes. Affected individuals who are the children of a consanguineous marriage are extremely rare in the medical literature, but the gene responsible for this recessive trait subtype of KFS has recently been reported. RESULTS: We identified a family with the KFS phenotype in which their parents have a consanguineous marriage. Radiological examinations revealed that they carry fusion defects and numerical abnormalities in the cervical spine, scoliosis, malformations of the cranial base, and Sprengel's deformity. We applied whole genome linkage and whole-exome sequencing analysis to identify the chromosomal locus and gene mutated in this family. Whole genome linkage analysis revealed a significant linkage to chromosome 17q12-q33 with a LOD score of 4.2. Exome sequencing identified the G > A p.Q84X mutation in the MEOX1 gene, which is segregated based on pedigree status. Homozygous MEOX1 mutations have reportedly caused a similar phenotype in knockout mice. CONCLUSIONS: Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait. Together with another recently reported study and the knockout mouse model, our results suggest that mutations in MEOX1 cause a recessive KFS phenotype in humans.

A novel locus for restless legs syndrome on chromosome 13q.

BACKGROUND: Restless legs syndrome (RLS) is a sensorimotor disorder in which affected individuals suffer from uncomfortable sensations and an urge to move their lower limbs; it occurs mainly in resting situations during the evening or at night. Multiple chromosomal loci have been mapped for RLS through family-based linkage analysis, and genome-wide association studies but causative mutations have not been identified yet. METHOD: We identified an RLS family from the eastern part of central Turkey which has 10 patients suffering from this syndrome. Whole genome linkage analysis was performed in family members who consented for study (9 affected and 2 unaffected). RESULTS: A theoretical maximum logarithm of the odds score of 3.29 was identified at chromosome 13q32.3-33.2. This result shows strong genetic linkage to this locus. CONCLUSIONS: We demonstrated a genetic linkage at chromosome 13 in a RLS family. Further investigation in this linkage area may reveal a causative gene leading to RLS phenotype and may illuminate the pathogenesis of this disease. This study supports the genetic heterogeneity in the pathogenesis of this syndrome.

Etanercept treatment enhances clinical and neuroelectrophysiological recovery in partial spinal cord injury.

PURPOSE: To investigate the effect of an anti-TNF-α agent (etanercept) on recovery processes in a partial spinal cord injury (SCI) model using clinical and electrophysiological tests. METHODS: Twenty-four New Zealand rabbits were divided into three groups: group 1 [SCI + 2 ml saline intramuscular (i.m.), n = 8], group 2 (SCI + 2.5 mg/kg etanercept, i.m., 2-4 h after SCI, n = 8) and group 3 (SCI + 2.5 mg/kg etanercept, i.m., 12-24 h after SCI, n = 8). Rabbits were evaluated before SCI, immediately after SCI, 1 week after, and 2 weeks after SCI, clinically by Tarlov scale and electrophysiologically by SEP. RESULTS: Tarlov scores of groups 2 and 3 were significantly better than group 1, 2 weeks after SCI. SEP recovery was significantly better in groups 2 and 3 than group 1, 2 weeks after SCI. CONCLUSIONS: These results show that blocking TNF-α mediated inflammation pathway by an anti-TNF-α agent enhances clinical and electrophysiological recovery processes in partial SCI model.

Intracranial arachnoid cyst family with autosomal recessive trait mapped to chromosome 6q22.31-23.2.

BACKGROUND: Arachnoid cysts are congenital fluid-filled compartments within the cerebrospinal fluid cisterns and cerebral fissures. They most commonly occur sporadically, and familial occurrence has rarely been reported. In this study, we showed the first genetic linkage in the literature in a pure intracranial arachnoid cyst family with autosomal recessive trait. METHODS: We identified an intracranial arachnoid cyst family in southern Turkey whose six of seven offspring had intracranial arachnoid cysts in different localizations, and collected venous blood from seven offspring of the family. Whole-genome linkage analysis was performed in all offspring. RESULTS: A theorical maximum logarithm of the odds score of 4.6 was identified at chromosome 6q22.31-23.2. This result shows strong genetic linkage to this locus. CONCLUSIONS: We present the first genetic linkage analysis result in a pure intracranial arachnoid cyst family in literature. Further investigation of this linkage area can reveal a causative gene causing the intracranial arachnoid cyst phenotype and can illuminate the pathogenesis of this disease.

Perineural cyst presenting like cubital tunnel syndrome.

Perineural cysts are believed to be asymptomatic; however, they rarely cause symptoms related to nerve root compression. Cervical symptomatic perineural cysts are in fact exceedingly rare. There are no reported cervical perineural cysts in the literature that present like cubital tunnel syndrome. A patient with motor weakness of the abductor and adductor muscles of the fingers of the left hand and hypoesthesia in the hypothenar region of the left hand presented at our clinic. A neurological examination, and neuroradiological and electrophysiological evaluations supported the finding that the patient's clinical condition was caused by a perineural cyst located around the C8 neural root. The neurological symptoms of the patient markedly improved after medical treatment. We reported the first cervical perineural cyst as presenting like cubital tunnel syndrome patient in the literature. The visualization of perineural cyst may need extra magnetic resonance imaging (MRI) sections in order to view the nerve root through the neural foramen or extraforaminal area. These lesions are benign, and the appropriate treatment is curative.

Variation in the BRCA2 gene in a child with medulloblastoma and a family history of breast cancer.

The fact that BRCA genes operate as tumor suppressors is evident from the genetics of the different human disorders caused by inherited mutations. Germline mutations affecting 1 allele of either BRCA1 or BRCA2 confer susceptibility to different types of cancers such as breast cancer and medulloblastoma. A family with a history of cancer was identified in Eastern Turkey in which one of the family members (a 13-year-old boy) had medulloblastoma. Venous blood was collected from available family members. The BRCA1 and BRCA2 genes were sequenced in the patient with medulloblastoma and the healthy father. An Asn372His homozygous variation was noted in the BRCA2 gene in the patient with medulloblastoma whereas the variation was heterozygous in the healthy father. A biallelic homozygous variation was demonstrated in the BRCA2 gene, which is important in medulloblastoma suppression, and may have caused medulloblastoma formation in the 13-year-old boy. Further investigations in large human populations with medulloblastoma are necessary for further delineation of BRCA gene malfunctions and their relationship to medulloblastoma formation, and to clarify the therapeutic implications of these malfunctions.

Intraventricular hemorrhage as an unusual presenting form of Sneddon syndrome.

BACKGROUND: Intraventricular hemorrhage, which has a poor prognosis, is an extremely rare presenting symptom of central nervous system vasculitis. Sneddon syndrome, which is a systemic vasculitic disease, generally presents with ischemic stroke and livedo reticularis. Intraventricular hemorrhage is extremely rare in Sneddon syndrome and has not been reported as the presenting complaint. METHODS: We report a 37-year-old woman who presented with acute intraventricular hemorrhage, and on further evaluation her condition was diagnosed as Sneddon syndrome. RESULTS: Patient underwent ventriculoperitoneal shunting operation for hydrocephalus and her condition markedly improved 6 months later; she was independent in her activities of daily living. CONCLUSIONS: In this report, we emphasize the importance of multisystemic evaluation of patients, especially those with obscure angiography findings.