Central Nervous System Tumor Classification: An Update on the Integration of Tumor Genetics.

In 2016, the World Health Organization Classification of CNS Tumors introduced molecular abnormalities that refined tumor diagnoses. Around this time, the introduction of large scale genetic mutational analyses quickly advanced our knowledge of recurrent abnormalities in disease. In 2017, the C-IMPACT group was established to render expert consensus opinions regarding the application of molecular findings into central nervous system tumor diagnoses. C-IMPACT have presented their recommendations in 7 peer-reviewed publications; this article details those recommendations that are expected to be incorporated into the upcoming fifth edition of the World Health Organization classification.

Inflammatory myofibroblastic tumor masquerading as an anterior choroidal artery fusiform aneurysm.

BACKGROUND: Inflammatory myofibroblastic tumor is a rare, poorly understood tumor that has been found to occur in almost every organ tissue. Its location within the central nervous system is uncommon, and patients tend to present with nonspecific symptoms. CASE DESCRIPTION: A female in her eighth decade presented to neurosurgery clinic with complaints of headache and dizziness. Initial imaging was consistent with a low-grade, benign brain lesion in the region of the left choroidal fissure. She was recommended for observation but returned 1 month later with progressive symptoms and doubling of the lesion size. She underwent surgical resection and was found to have an IMT arising from the wall of the left anterior choroidal artery. CONCLUSION: Intracranial IMT remains a rare and poorly understood entity. The present case demonstrates a novel presentation of IMT in an adult patient and exemplifies the heterogeneity of the disease presentation.

Orbital metastasis of squamous cell cervical cancer: A case report and review of literature.

Common sites of metastatic disease seen in cervical cancer most often include the lungs and liver. Orbital metastasis secondary to cervical carcinoma is a rare form of metastatic disease. We report a 73-year-old woman who presented with ocular symptoms found to be secondary to orbital metastasis of cervical cancer. She underwent palliative radiation to the orbit and pelvis followed by systemic chemotherapy with carboplatin, paclitaxel, and bevacizumab. Prompt intervention was able to salvage her vision and improve her quality of life significantly. We identified 5 similar reported cases in which orbital metastasis was diagnosed simultaneously at the time of cervical cancer diagnosis. In these five cases, patients were treated with a combination of radiation and chemotherapy. Our case demonstrates an unusual presentation of isolated orbital metastatic disease secondary to squamous cell carcinoma of the cervix. Physicians should be aware that cervical cancer may metastasize to the eye leading to vision loss, and prompt intervention may be able to salvage one's vision and improve quality of life.

Pediatric pathology all grown up - An interesting case of adult tethered spinal cord.

BACKGROUND: Cervical myelopathy in an adult is typically the result of degenerative disease or trauma. Dysraphism is rarely the cause. CASE DESCRIPTION: The authors report the case of a 35-year-old male drywall installer who presented with 2 years of progressive left upper extremity weakness, numbness, and hand clumsiness. Only upon detailed questioning did he mention that he had neck surgery just after birth, but he did not know what was done. He then also reported that he routinely shaved a patch of lower back hair, but denied bowel, bladder, or lower extremity dysfunction. Magnetic resonance imaging of the cervical spine demonstrated T2 hyperintensity at C4-C5 with dorsal projection of the neural elements into the subcutaneous tissues concerning for a retethered cervical myelomeningocele. Lumbar imaging revealed a diastematomyelia at L4. He underwent surgical intervention for detethering and repaired of the cervical myelomeningocele. Four months postoperatively, he had almost complete resolution of symptoms, and imaging showed a satisfactory detethering. The diastematomyelia remained asymptomatic and is being observed. CONCLUSION: Tethered cervical cord is a rare cause for myelopathy in the adult patient. In the symptomatic patient, surgical repair with detethering is indicated to prevent disease progression and often results in clinical improvement.

An Unusual Cause of Intracerebral Hemorrhage: Clinical Pearls Regarding Primary Angiitis of the Central Nervous System.

Primary angiitis of the central nervous system (PACNS) is a rare form of vasculitis. It is a diagnosis of exclusion and often diagnosed post mortem on pathologic evaluation. Cerebral angiography can be suggestive, but biopsy is required. Symptoms can vary from headache to focal cranial nerve deficits. On the more severe spectrum, patients can present with ischemic and vary rarely hemorrhagic stroke. We present in this case report key clinical pearls regarding suspected diagnosis. Younger patients with cortical hemorrhages may have PACNS instead of the more common cerebral amyloid angiopathy. Early suspicion may aid in initiating effective treatment as we highlight in the discussion.

An Incidental Diffuse Midline Glioma Found at Autopsy.

This case shows an unexpected midline glioma found at autopsy. Two siblings were riding on a single bicycle on the side of a road. The 13-year-old brother was seated and steering the bicycle, while the 14-year-old sister held onto the back. The bicycle veered left into traffic and was struck by a vehicle. The siblings were admitted to the local Level 1 trauma center, but both later succumbed to injuries. Autopsies were performed on the children, including brains for neuropathologic evaluation. The brother was found to have an infiltrating astrocytoma located in the left middle cerebellar peduncle, with extension to the pons and medulla. His hospital course included several imaging studies using CT and MRI modalities. However, this lesion was not identified until the postmortem neuropathologic examination. This rare case shows the continued need for postmortem autopsy and the current limitations of medical imaging.

5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency is a monogenic disorder resulting in emphysema due principally to the unopposed effects of neutrophil elastase. We previously reported achieving plasma wild-type alpha-1 antitrypsin concentrations at 2.5%-3.8% of the purported therapeutic level at 1 year after a single intramuscular administration of recombinant adeno-associated virus serotype 1 alpha-1 antitrypsin vector in alpha-1 antitrypsin deficient patients. We analyzed blood and muscle for alpha-1 antitrypsin expression and immune cell response. We also assayed previously reported markers of neutrophil function known to be altered in alpha-1 antitrypsin deficient patients. Here, we report sustained expression at 2.0%-2.5% of the target level from years 1-5 in these same patients without any additional recombinant adeno-associated virus serotype-1 alpha-1 antitrypsin vector administration. In addition, we observed partial correction of disease-associated neutrophil defects, including neutrophil elastase inhibition, markers of degranulation, and membrane-bound anti-neutrophil antibodies. There was also evidence of an active T regulatory cell response (similar to the 1 year data) and an exhausted cytotoxic T cell response to adeno-associated virus serotype-1 capsid. These findings suggest that muscle-based alpha-1 antitrypsin gene replacement is tolerogenic and that stable levels of M-AAT may exert beneficial neutrophil effects at lower concentrations than previously anticipated.

Functional Subclone Profiling for Prediction of Treatment-Induced Intratumor Population Shifts and Discovery of Rational Drug Combinations in Human Glioblastoma.

PURPOSE: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. EXPERIMENTAL DESIGN: Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. RESULTS: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. CONCLUSIONS: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. Clin Cancer Res; 23(2); 562-74. ©2016 AACR.

Bilateral internal auditory canal gangliogliomas mimicking neurofibromatosis Type II.

BACKGROUND: Gangliogliomas are rare low grade, typically well-differentiated, tumors that are composed of mature ganglion cells and neoplastic glial cells. These tumors can appear at virtually any location along the neuroaxis but classically occur in the temporal lobe of young patients. In a small number of cases, gangliogliomas have presented as masses in the brainstem or involving cranial nerves. With the exception of vestibular schwannomas, bilateral tumors in the region of the internal auditory canal (IAC) or cerebellopontine angle (CPA) are exceedingly rare. CASE DESCRIPTION: We report a case of a 58-year-old male who presented with hearing loss, tinnitus, and vertigo. Initial magnetic resonance imaging revealed bilateral nonenhancing IAC/CPA tumors. Based on this finding, a presumptive diagnosis of neurofibromatosis Type II was made, which was initially managed conservatively with close observation. He returned for follow-up with worsening vertigo and tinnitus, thus prompting the decision to proceed with surgical resection of the symptomatic mass. Intriguingly, pathological study demonstrated a WHO Grade I ganglioglioma. DESCRIPTION: We report a case of a 58-year-old male who presented with hearing loss, tinnitus, and vertigo. Initial magnetic resonance imaging revealed bilateral nonenhancing IAC/CPA tumors. Based on this finding, a presumptive diagnosis of neurofibromatosis Type II was made, which was initially managed conservatively with close observation. He returned for follow-up with worsening vertigo and tinnitus, thus prompting the decision to proceed with surgical resection of the symptomatic mass. Intriguingly, pathological study demonstrated a WHO Grade I ganglioglioma. CONCLUSION: This is the first reported case of bilateral IAC/CPA gangliogliomas. When evaluating bilateral IAC/CPA lesions with unusual imaging characteristics, ganglioglioma should be included in the differential diagnosis.

Murine Aß over-production produces diffuse and compact Alzheimer-type amyloid deposits.

INTRODUCTION: Transgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human in sequence or have humanized Aß sequences can produce Alzheimer-type amyloidosis in mice, provided the transgenes also encode mutations linked to familial Alzheimer's Disease (FAD). Although transgenic mice have been produced that overexpress wild-type mouse APP, no mice have been generated that express mouse APP with FAD mutations. Here we describe two different versions of such mice that produce amyloid deposits consisting of entirely of mouse Aß peptides. One line of mice co-expresses mouse APP-Swedish (moAPPswe) with a human presenilin exon-9 deleted variant (PS1dE9) and another line expresses mouse APP-Swedish/Indiana (APPsi) using tetracycline-regulated vectors (tet.moAPPsi). RESULTS: Both lines of mice that produce mouse Aß develop amyloid deposits, with the moAPPswe/PS1dE9 mice developing extracellular compact, cored, neuritic deposits that primarily localize to white matter tracts and meningial layers, whereas the tet.moAPPsi mice developed extracellular diffuse cortical/hippocampal deposits distributed throughout the parenchyma. CONCLUSIONS: These findings demonstrate that murine Aß peptides have the capacity to produce amyloid deposits that are morphologically similar to deposits found in human AD provided the murine APP gene harbors mutations linked to human FAD.

RAN Translation in Huntington Disease.

Huntington disease (HD) is caused by a CAG ⋅ CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other polyglutamine diseases.

Serpin treatment suppresses inflammatory vascular lesions in temporal artery implants (TAI) from patients with giant cell arteritis.

Giant cell arteritis (GCA) and Takayasu's disease are inflammatory vasculitic syndromes (IVS) causing sudden blindness and widespread arterial obstruction and aneurysm formation. Glucocorticoids and aspirin are mainstays of treatment, predominantly targeting T cells. Serp-1, a Myxomavirus-derived serpin, blocks macrophage and T cells in a wide range of animal models. Serp-1 also reduced markers of myocardial injury in a Phase IIa clinical trial for unstable coronary disease. In recent work, we detected improved survival and decreased arterial inflammation in a mouse Herpesvirus model of IVS. Here we examine Serp-1 treatment of human temporal artery (TA) biopsies from patients with suspected TA GCA arteritis after implant (TAI) into the aorta of immunodeficient SCID (severe combined immunodeficiency) mice. TAI positive for arteritis (GCApos) had significantly increased inflammation and plaque when compared to negative TAI (GCAneg). Serp-1 significantly reduced intimal inflammation and CD11b+ cell infiltrates in TAI, with reduced splenocyte Th1, Th17, and Treg. Splenocytes from mice with GCApos grafts had increased gene expression for interleukin-1 beta (IL-1ß), IL-17, and CD25 and decreased Factor II. Serp-1 decreased IL-1ß expression. In conclusion, GCApos TAI xenografts in mice provide a viable disease model and have increased intimal inflammation as expected and Serp-1 significantly reduces vascular inflammatory lesions with reduced IL-1ß.

Optic nerve pilomyxoid astrocytoma in a patient with Noonan syndrome.

Noonan syndrome (NS; MIM 163950) is an autosomal dominant syndrome which is clinically diagnosed by the distinct facial features, short stature, cardiac anomalies and developmental delay. About 50% of cases are associated with gain of function mutations in PTPN11 gene which leads to activation of the RAS/mitogen-activated protein kinase signaling pathway. This is known to have a role in tumorigenesis. Despite this, only limited reports of solid tumors (Fryssira H, Leventopoulos G, Psoni S, et al. Tumor development in three patients with Noonan syndrome. Eur J Pediatr 2008;167:1025-1031; Schuettpelz LG, McDonald S, Whitesell K et al. Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr Blood Cancer 2009;53:1147-1149; Sherman CB, Ali-Nazir A, Gonzales-Gomez I, et al. Primary mixed glioneuronal tumor of the central nervous system in a patient with Noonan syndrome. J Pediatr Hematol Oncol 2009;31:61-64; Sanford RA, Bowman R, Tomita T, et al. A 16 year old male with Noonan's syndrome develops progressive scoliosis and deteriorating gait. Pediatr Neurosurg 1999;30:47-52) and no prior reports of optic gliomas have been described in patients with NS. We present here a patient with NS with a PTPN11 mutation and an optic pathway pilomyxoid astrocytoma.

An independent elderly woman with rapid onset of coma.

A 75-year-old woman was transferred from a local hospital because of rapid progression to coma preceded by lower back pain and recurrent falls. Cerebrospinal fluid analysis at the local hospital revealed increased protein with a slightly elevated white blood cell count. Our imaging studies revealed multiple punctate foci with nodular enhancement in the brain and multifocal cystic lesions on the chest and abdomen. The patient was empirically treated with antibiotics and corticosteroids without improvement. She died 3 days after transfer, and autopsy was performed. The differential diagnosis, pathologic findings, and final diagnosis are discussed.

Hemangioblastoma in the lung: metastatic or primary lesions?

Hemangioblastoma primarily occurs in the CNS, most commonly in the posterior fossa. Extracranial locations are less common, and metastatic tumor involving the lung is exceedingly rare with only three cases previously reported. Two were autopsy studies in patients who died of complications of the CNS hemangioblastomas in 1943 and 1981, and the third was mentioned in a case report addendum providing follow-up information on hepatic hemangioblastoma in 1991. We report a case of a 48-year-old man who presented with multiple lung nodules treated by surgical excision. Pathological study revealed features classic for hemangioblastoma. The patient had a remote history of hemangioblastomas having been excised from the posterior fossa 7 and 20 years previously. This report details a fourth case of metastatic pulmonary hemangioblastoma. It is the first report on surgically resected hemangioblastomas from the lung of a living patient with histological and immunohistochemical characterization.

Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression.

Recombinant adeno-associated virus (rAAV) vectors have shown promise for the treatment of several diseases; however, immune-mediated elimination of transduced cells has been suggested to limit and account for a loss of efficacy. To determine whether rAAV vector expression can persist long term, we administered rAAV vectors expressing normal, M-type α-1 antitrypsin (M-AAT) to AAT-deficient subjects at various doses by multiple i.m. injections. M-specific AAT expression was observed in all subjects in a dose-dependent manner and was sustained for more than 1 year in the absence of immune suppression. Muscle biopsies at 1 year had sustained AAT expression and a reduction of inflammatory cells compared with 3 month biopsies. Deep sequencing of the TCR Vß region from muscle biopsies demonstrated a limited number of T cell clones that emerged at 3 months after vector administration and persisted for 1 year. In situ immunophenotyping revealed a substantial Treg population in muscle biopsy samples containing AAT-expressing myofibers. Approximately 10% of all T cells in muscle were natural Tregs, which were activated in response to AAV capsid. These results suggest that i.m. delivery of rAAV type 1-AAT (rAAV1-AAT) induces a T regulatory response that allows ongoing transgene expression and indicates that immunomodulatory treatments may not be necessary for rAAV-mediated gene therapy.