A Neuroenteric Cyst of the Cavernous Sinus: A Case Report.

Background Neuroenteric cysts (NECs) are benign lesions mostly found as intradural extramedullary lesions in the cervicothoracic spinal cord. NECs in the cavernous sinus are very rare. To the best of our knowledge, this is only the second reported case and the first in an adult. Presentation We present a left cavernous sinus NEC in a 75-year-old female with gradually worsening headache and facial pain unresponsive to medical treatment. Imaging revealed a cystic mass lesion in the left cavernous sinus encasing the distal petrosal and cavernous segment of the internal carotid artery. Initial differential diagnoses included more common pathologies located near the cavernous sinus, including cystic schwannoma, craniopharyngioma, and dermoid and epidermoid tumors. The patient underwent a left pterional craniotomy with an extradural transcavernous approach for surgical exploration and possible resection of this mass lesion. Histopathology revealed an NEC lined with benign respiratory-type epithelium. Postoperative imaging revealed gross total tumor resection. The patient remained neurologically intact with complete resolution of facial pain. Conclusion We present a rare pathology that can easily be misinterpreted as other types of lesions. NECs should be kept in mind for differential diagnosis of cavernous sinus cystic lesions. The surgical aim should be maximal safe excision.

Intramedullary disseminated sporotrichosis in an immunocompetent patient: case report and review of the literature.

BACKGROUND: Disseminated sporotrichosis is a severe opportunistic infection that often affects immunocompromised patients after a cutaneous inoculation. Here we present a rare case of disseminated sporotrichosis discovered as a solitary intramedullary thoracic spinal cord lesion in an immunocompetent patient. CASE DESCRIPTION: A 37-year-old man presented with progressive lower limb weakness and sensory changes over 1 week. A spinal magnetic resonance imaging (MRI) revealed a contrast-enhancing intramedullary lesion centered at T10. The patient was afebrile and reported no history of trauma or cutaneous lesions. The lesion was unresponsive to a trial of corticosteroids. A thoracic laminectomy was performed and a biopsy obtained. A cutaneous lesion on the arm was concurrently discovered, which was also biopsied. Both the skin and spinal cord biopsies showed Sporothrix schenckii by macroscopic and microscopic morphology which were later confirmed by MALDI-TOF mass spectrometry. CONCLUSION: This is a rare case of intramedullary disseminated sporotrichosis affecting the central nervous system of an immunocompetent patient. This unusual presentation should be taken into consideration when such intramedullary lesions are encountered.

TFG regulates secretory and endosomal sorting pathways in neurons to promote their activity and maintenance.

Molecular pathways that intrinsically regulate neuronal maintenance are poorly understood, but rare pathogenic mutations that underlie neurodegenerative disease can offer important insights into the mechanisms that facilitate lifelong neuronal function. Here, we leverage a rat model to demonstrate directly that the TFG p.R106C variant implicated previously in complicated forms of hereditary spastic paraplegia (HSP) underlies progressive spastic paraparesis with accompanying ventriculomegaly and thinning of the corpus callosum, consistent with disease phenotypes identified in adolescent patients. Analyses of primary cortical neurons obtained from CRISPR-Cas9-edited animals reveal a kinetic delay in biosynthetic secretory protein transport from the endoplasmic reticulum (ER), in agreement with prior induced pluripotent stem cell-based studies. Moreover, we identify an unexpected role for TFG in the trafficking of Rab4A-positive recycling endosomes specifically within axons and dendrites. Impaired TFG function compromises the transport of at least a subset of endosomal cargoes, which we show results in down-regulated inhibitory receptor signaling that may contribute to excitation-inhibition imbalances. In contrast, the morphology and trafficking of other organelles, including mitochondria and lysosomes, are unaffected by the TFG p.R106C mutation. Our findings demonstrate a multifaceted role for TFG in secretory and endosomal protein sorting that is unique to cells of the central nervous system and highlight the importance of these pathways to maintenance of corticospinal tract motor neurons.

Cystic Trophoblastic Tumor in a Primary Central Nervous System Post-Chemotherapy Germ Cell Tumor: The First Case Report.

Cystic trophoblastic tumor (CTT) is an uncommon trophoblastic proliferation of germ cell tumor origin, mostly reported in post-chemotherapy metastases of testicular germ cell tumors and rarely primary untreated testicular tumors. To date, we are not aware of occurrence in a non-testicular tumor. A 12-year-old boy presented with limb swelling, increased appetite, weight gain, and precocious puberty. Evaluation revealed right frontal lobe mass and elevated α-fetoprotein and ß-human chorionic gonadotrophin. After response to neoadjuvant chemotherapy, the tumor was resected. Microscopically, the resection contained predominantly smooth muscle tissue with scattered small foci of glandular teratoma and CTT. Immunohistochemistry (SALL4, glypican 3) revealed no residual yolk sac tumor. Fluorescence in situ hybridization revealed gain of chromosome 12p. The patient has been disease-free for 13 years. This report expands the spectrum of primary central nervous system germ cell tumors with the occurrence of CTT in this site.

Association of Neighborhood-Level Disadvantage With Alzheimer Disease Neuropathology.

Importance: Social determinants of health, such as income, education, housing quality, and employment, are associated with disparities in Alzheimer disease and health generally, yet these determinants are rarely incorporated within neuropathology research. Objective: To establish the feasibility of linking neuropathology data to social determinants of health exposures using neighborhood disadvantage metrics (the validated Area Deprivation Index) and to evaluate the association between neighborhood disadvantage and Alzheimer disease-related neuropathology. Design, Setting, and Participants: This cross-sectional study consisted of decedents with a known home address who donated their brains to 1 of 2 Alzheimer disease research center brain banks in California and Wisconsin between January 1, 1990, and December 31, 2016. Neither site had preexisting social metrics available for their decedents. Neuropathologic features were obtained from each site for data collected using the standardized Neuropathology Data Set form and from autopsy reports. Data were analyzed from June 7 to October 10, 2019. Exposures: Geocoded decedent addresses linked to neighborhood disadvantage as measured by the Area Deprivation Index calculated for the year of death. Main Outcomes and Measures: Presence of Alzheimer disease neuropathology. The association between neighborhood disadvantage and Alzheimer disease neuropathology was evaluated via logistic regression, adjusting for age, sex, and year of death. Results: The sample consisted of 447 decedents (249 men [56%]; mean [SD] age, 80.3 [9.5] years; median year of death, 2011) spanning 24 years of donation. Fewer decedents (n = 24 [5.4%]) originated from the top 20% most disadvantaged neighborhood contexts. Increasing neighborhood disadvantage was associated with an 8.1% increase in the odds of Alzheimer disease neuropathology for every decile change on the Area Deprivation Index (adjusted odds ratio, 1.08; 95% CI, 1.07-1.09). As such, living in the most disadvantaged neighborhood decile was associated with a 2.18 increased odds of Alzheimer disease neuropathology (adjusted odds ratio, 2.18; 95% CI, 1.99-2.39). Conclusions and Relevance: The findings of this cross-sectional study suggest that social determinants of health data can be linked to preexisting autopsy samples as a means to study sociobiological mechanisms involved in neuropathology. This novel technique has the potential to be applied to any brain bank within the United States. To our knowledge, this is the first time Alzheimer disease neuropathology has been associated with neighborhood disadvantage.

Expression of Insulinoma-Associated Protein 1 (INSM1) and Orthopedia Homeobox (OTP) in Tumors with Neuroendocrine Differentiation at Rare Sites.

Insulinoma-associated protein 1 (INSM1) and orthopedia homeobox (OTP) are transcription factors that play a critical role in neuroendocrine (NE) and neuroepithelial cell development. INSM1 has been identified in multiple tumors of NE or neuroepithelial origin, whereas OTP expression has been mainly studied in NE tumors of pulmonary origin. Expression of OTP appears to correlate with poorer prognosis in pulmonary carcinoids; however, its expression patterns in other NE/neuroepithelial tumors need further investigation. Here, we assessed the diagnostic utility of INSM1 and OTP in tumors with NE differentiation at relatively uncommon sites including prostate, breast, and tumors of gynecologic origin. Thirty-two formalin-fixed, paraffin-embedded cases were used to construct a tissue microarray. Immunohistochemistry for INSM1 and OTP was performed and scored semi-quantitatively. INSM1 was diffusely expressed in 60% of gynecologic tumors, 71.4% of mammary carcinoma, and 25% of prostate adenocarcinoma with NE differentiation. Diffuse expression of OTP was detected in 50% of prostate adenocarcinoma with NE differentiation and 100% neuroendocrine carcinoma of the ovary. Immunostain for achaete-scute homolog 1, chromogranin, synaptophysin, and CD56 supported the NE and/or neuroepithelial differentiation of the tumors. In summary, INSM1 is expressed in most of the tumors with NE and neuroepithelial differentiation in this study, confirming the diagnostic utility of INSM1 as a novel and sensitive marker of NE/neuroepithelial differentiation. The expression of OTP in some NE tumors outside of lung expands the spectrum of tumors that may express this biomarker and should be considered when working up a NE tumor of unknown primary site.

Vision loss in glioblastoma: Disease mimicking presumed therapeutic toxicity.

Glioblastoma is the most common and lethal form of primary brain cancer. In the recurrent setting, bevacizumab is a common choice for salvage therapy. Loss of vision in patients initially treated with radiation at the time of diagnosis and later treated with bevacizumab at time of recurrence has been reported, and presumed to be a treatment-related optic neuropathy. Strikingly, only 1 case report described a postmortem biopsy to rule out tumor involvement of the optic tracts. We report the first case of recurrent glioblastoma infiltrating the prechiasmatic and chiasmatic optic nerve, which at the time of vision loss was presumed to be secondary to bevacizumab. It is noteworthy that the MRI findings in the previously reported bevacizumab/radiation-induced optic neuropathy cases (without pathology follow-up) are comparable to our patient.

Frontal lobe intracerebral schwannoma mimicking metastatic lesion in a patient with papillary thyroid carcinoma.

Intracerebral schwannomas are quite rare. Due to their rarity and lack of pathognomonic imaging features, intracerebral schwannoma may be overlooked in the initial differential diagnosis of an intra-axial mass with heterogeneous ring enhancement, such as a high-grade glioma, metastasis or lymphoma. Here, we present a 21-year-old woman with prior diagnosis of papillary thyroid carcinoma and recent history of seizures who had a heterogeneously ring-enhancing left frontal lobe mass. Our presumptive diagnosis was a metastatic tumor since she had a history of thyroid cancer. Because of uncertainty in preoperative differential diagnosis, the decision was made to proceed with excisional biopsy of the tumor via craniotomy. She underwent uneventful gross total resection of the tumor that histopathology revealed as an intracerebral schwannoma.

Overdrainage-related ependymal bands: a postulated cause of proximal shunt obstruction.

OBJECTIVEVentricular shunts have an unacceptably high failure rate, which approaches 50% of patients at 2 years. Most shunt failures are related to ventricular catheter obstruction. The literature suggests that obstructions are caused by in-growth of choroid plexus and/or reactive cellular aggregation. The authors report endoscopic evidence of overdrainage-related ventricular tissue protrusions ("ependymal bands") that cause partial or complete obstruction of the ventricular catheter.METHODSA retrospective review was completed on patients undergoing shunt revision surgery between 2008 and 2015, identifying all cases in which the senior author reported endoscopic evidence of ependymal tissue in-growth into ventricular catheters. Detailed clinical, radiological, and surgical findings are described.RESULTSFifty patients underwent 83 endoscopic shunt revision procedures that revealed in-growth of ventricular wall tissue into the catheter tip orifices (ependymal bands), producing partial, complete, or intermittent shunt obstructions. Endoscopic ventricular explorations revealed ependymal bands at various stages of development, which appear to form secondarily to siphoning. Ependymal bands are associated with small ventricles when the shunt is functional, but may dilate at the time of obstruction.CONCLUSIONSVentricular wall protrusions are a significant cause of proximal shunt obstruction, and they appear to be caused by siphoning of surrounding tissue into the ventricular catheter orifices.

Ocular and uteroplacental pathology in a macaque pregnancy with congenital Zika virus infection.

Congenital Zika virus (ZIKV) infection impacts fetal development and pregnancy outcomes. We infected a pregnant rhesus macaque with a Puerto Rican ZIKV isolate in the first trimester. The pregnancy was complicated by preterm premature rupture of membranes (PPROM), intraamniotic bacterial infection and fetal demise 49 days post infection (gestational day 95). Significant pathology at the maternal-fetal interface included acute chorioamnionitis, placental infarcts, and leukocytoclastic vasculitis of the myometrial radial arteries. ZIKV RNA was disseminated throughout fetal tissues and maternal immune system tissues at necropsy, as assessed by quantitative RT-PCR for viral RNA. Replicating ZIKV was identified in fetal tissues, maternal uterus, and maternal spleen by fluorescent in situ hybridization for viral replication intermediates. Fetal ocular pathology included a choroidal coloboma, suspected anterior segment dysgenesis, and a dysplastic retina. This is the first report of ocular pathology and prolonged viral replication in both maternal and fetal tissues following congenital ZIKV infection in a rhesus macaque. PPROM followed by fetal demise and severe pathology of the visual system have not been described in macaque congenital ZIKV infection previously. While this case of ZIKV infection during pregnancy was complicated by bacterial infection with PPROM, the role of ZIKV on this outcome cannot be precisely defined, and further nonhuman primate studies will determine if increased risk for PPROM or other adverse pregnancy outcomes are associated with congenital ZIKV infection.

Transcranial Doppler and Microemboli Detection: Relationships to Symptomatic Status and Histopathology Findings.

The purpose of this study was to determine the relationship between symptomatic status, transcranial Doppler (TCD) microemboli presence and plaque histopathology findings. TCD was performed on 60 patients (37 symptomatic, 23 asymptomatic) before undergoing clinically indicated carotid endarterectomy. The frequency of microemboli signals was not significantly different between symptomatic and asymptomatic subject groups (p = 0.88) and there were no differences observed in the macroscopic or histopathology scoring of these plaques (p-values all > 0.05). The presence of microemboli was associated with an ulceration score (regardless of symptomatic or asymptomatic status, p = 0.034), with a one-level increase in ulceration rating associated with an odds ratio of 5.86 (95% [CI] 1.55, 43.4). These findings suggest that both symptomatic and asymptomatic patients may have plaque with similar features of instability and ability to create emboli. Thus, identifying new ways to measure plaque instability may provide important information for optimizing treatment to prevent future stroke.

Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques.

Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.

Administration of Non-Torsadogenic human Ether-à-go-go-Related Gene Inhibitors Is Associated with Better Survival for High hERG-Expressing Glioblastoma Patients.

PURPOSE: Glioblastoma is the most malignant primary brain tumor, with a median survival of less than 2 years. More effective therapeutic approaches are needed to improve clinical outcomes. EXPERIMENTAL DESIGN: Glioblastoma patient-derived cells (GPDC) were isolated from patient glioblastomas and implanted in mice to form xenografts. IHC was performed for human Ether-à-go-go-Related Gene (hERG) expression and tumor proliferation. Sphere-forming assays with the hERG blocker E-4031 were performed on a high and low hERG-expressing lines. A glioblastoma tissue microarray (TMA; 115 patients) was used to correlate hERG expression with patient survival. Clinical data were analyzed to determine whether patient survival was affected by incidental administration of hERG inhibitory drugs and the correlative effect of patient glioblastoma hERG expression levels. RESULTS: hERG expression was upregulated in glioblastoma xenografts with higher proliferative indices. High hERG-expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared with low hERG-expressing GPDCs. Glioblastoma TMA analysis showed worse survival for glioblastoma patients with high hERG expression versus low expression-43.5 weeks versus 60.9 weeks, respectively (P = 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared with patients who did not (P = 0.0015). Subgroup analysis showed that glioblastoma patients with high hERG expression who received hERG blockers had improved survival (P = 0.0458). There was no difference in survival for low hERG-expressing glioblastoma patients who received hERG blockers (P = 0.4136). CONCLUSIONS: Our findings suggest that hERG is a potential glioblastoma survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be repurposed as adjuvant glioblastoma therapy in high hERG-expressing glioblastoma patients. Clin Cancer Res; 23(1); 73-80. ©2016 AACRSee related commentary by Arcangeli and Becchetti, p. 3.

Association of collagen architecture with glioblastoma patient survival.

OBJECTIVE Glioblastoma (GBM) is the most malignant primary brain tumor. Collagen is present in low amounts in normal brain, but in GBMs, collagen gene expression is reportedly upregulated. However, to the authors' knowledge, direct visualization of collagen architecture has not been reported. The authors sought to perform the first direct visualization of GBM collagen architecture, identify clinically relevant collagen signatures, and link them to differential patient survival. METHODS Second-harmonic generation microscopy was used to detect collagen in a GBM patient tissue microarray. Focal and invasive GBM mouse xenografts were stained with Picrosirius red. Quantitation of collagen fibers was performed using custom software. Multivariate survival analysis was done to determine if collagen is a survival marker for patients. RESULTS In focal xenografts, collagen was observed at tumor brain boundaries. For invasive xenografts, collagen was intercalated with tumor cells. Quantitative analysis showed significant differences in collagen fibers for focal and invasive xenografts. The authors also found that GBM patients with more organized collagen had a longer median survival than those with less organized collagen. CONCLUSIONS Collagen architecture can be directly visualized and is different in focal versus invasive GBMs. The authors also demonstrate that collagen signature is associated with patient survival. These findings suggest that there are collagen differences in focal versus invasive GBMs and that collagen is a survival marker for GBM.

T cell-derived interleukin (IL)-21 promotes brain injury following stroke in mice.

T lymphocytes are key contributors to the acute phase of cerebral ischemia reperfusion injury, but the relevant T cell-derived mediators of tissue injury remain unknown. Using a mouse model of transient focal brain ischemia, we report that IL-21 is highly up-regulated in the injured mouse brain after cerebral ischemia. IL-21-deficient mice have smaller infarcts, improved neurological function, and reduced lymphocyte accumulation in the brain within 24 h of reperfusion. Intracellular cytokine staining and adoptive transfer experiments revealed that brain-infiltrating CD4(+) T cells are the predominant IL-21 source. Mice treated with decoy IL-21 receptor Fc fusion protein are protected from reperfusion injury. In postmortem human brain tissue, IL-21 localized to perivascular CD4(+) T cells in the area surrounding acute stroke lesions, suggesting that IL-21-mediated brain injury may be relevant to human stroke.

Calorie restriction attenuates astrogliosis but not amyloid plaque load in aged rhesus macaques: a preliminary quantitative imaging study.

While moderate calorie restriction (CR) in the absence of malnutrition has been consistently shown to have a systemic, beneficial effect against aging in several animals models, its effect on the brain microstructure in a non-human primate model remains to be studied using post-mortem histopathologic techniques. In the present study, we investigated differences in expression levels of glial fibrillary acid protein (GFAP) and ß-amyloid plaque load in the hippocampus and the adjacent cortical areas of 7 Control (ad libitum)-fed and 6 CR male rhesus macaques using immunostaining methods. CR monkeys expressed significantly lower levels (∼30% on average) of GFAP than Controls in the CA region of the hippocampus and entorhinal cortex, suggesting a protective effect of CR in limiting astrogliosis. These results recapitulate the neuroprotective effects of CR seen in shorter-lived animal models. There was a significant positive association between age and average amyloid plaque pathology in these animals, but there was no significant difference in amyloid plaque distribution between the two groups. Two of the seven Control animals (28.6%) and one of the six CR animal (16.7%) did not express any amyloid plaques, five of seven Controls (71.4%) and four of six CR animals (66.7%) expressed minimal to moderate amyloid pathology, and one of six CR animals (16.7%) expressed severe amyloid pathology. That CR affects levels of GFAP expression but not amyloid plaque load provides some insight into the means by which CR is beneficial at the microstructural level, potentially by offsetting the increased load of oxidatively damaged proteins, in this non-human primate model of aging. The present study is a preliminary post-mortem histological analysis of the effects of CR on brain health, and further studies using molecular and biochemical techniques are warranted to elucidate underlying mechanisms.

Microsurgical anatomy of the dorsal thoracic rootlets and dorsal root entry zones.

BACKGROUND: For successful DREZ (dorsal root entry zone) surgery, optimal neuroanatomical orientation and precise microsurgical dissection are required. Although cervical, lumbar, and sacral spinal segments have been studied in detail, such information is not available for thoracic segments. The objective of this anatomical study is to comprehensively illustrate the microanatomical features of the thoracic DREZs and their variations. METHODS: Fifteen formalin-fixed adult cadaveric spinal cords from T1 to T12 were used. The dorsal rootlet numbers, distance between the posteromedial and posterolateral sulcus, length of each DREZ, length of each segment, and mean length of the dorsal rootlets were measured under a surgical microscope. RESULTS: The longest DREZs were observed at the T6, T7, and T8 segments with mean values of 15.3 mm, 15.6 mm, and 15.4 mm, respectively. The longest segment was observed at the T10 segment with a mean value of 21.0 mm, and the shortest segment was observed at the T1 segment with a mean value of 13.5 mm. CONCLUSIONS: The highest dorsal rootlet density is at the T1 segment of the spinal cord, can be easily distinguished visually, and may be a useful surgical landmark. The DREZs in T6-7 segments are longest, while these two segments have the least number of rootlets. Because the dorsolateral tract is remarkably narrow and the dorsal horn is exceedingly deep, DREZ surgery at the thoracic level may be difficult and risky for the dorsal column and corticospinal tract. Acquaintance with the microanatomy of the DREZ in the thoracic spinal cord is crucial to DREZ surgery.

Differential expression of 2',3'-cyclic-nucleotide 3'-phosphodiesterase and neural lineage markers correlate with glioblastoma xenograft infiltration and patient survival.

PURPOSE: Glioblastoma multiforme (GBM) is a poorly treated human brain cancer with few established clinically useful molecular prognostic markers. We characterized glioblastoma stem-like cells (GSC) according to developmental neural lineage markers and correlated their expression with patient survival. EXPERIMENTAL DESIGN: Immunoblot array of neural lineage markers classified five independently isolated human GSC lines into three classes exhibiting differential expression of oligodendrocyte progenitor cells (OPC), astrocyte progenitor cells (APC), and neural progenitor cells (NPC) markers. Immunodeficient mice were orthotopically implanted with each cell line to evaluate tumor infiltration and recipient survival. 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNP) antigenic expression was used to evaluate a clinically annotated GBM tissue microarray with 115 specimens. RESULTS: We report that molecular classification of patient-derived GSCs using neural lineage markers show association with differential xenograft invasiveness, and also show significant correlation to survival in both the mouse model and human patients. Orthotopic implantation into immunodeficient mice showed Ki-67 proliferative index independent xenograft infiltration: class I GSCs (OPC and NPC positive) established focal lesions, class II GSCs (NPC positive) formed minimally invasive lesions, and class III GSCs (APC positive) established highly infiltrative lesions. The OPC marker, CNP also exhibited high expression in focal xenografts versus low expression in invasive xenografts. Differential CNP expression correlated with mouse model survival, and CNP immunoassay of a large GBM tissue microarray also showed significant differential patient survival. CONCLUSIONS: GSC classification with developmental neural lineage markers revealed CNP as a novel and potentially useful clinical prognosis marker, and suggests clinical importance for patient-specific GSC analysis.

Significant association of multiple human cytomegalovirus genomic Loci with glioblastoma multiforme samples.

Viruses are appreciated as etiological agents of certain human tumors, but the number of different cancer types induced or exacerbated by viral infections is unknown. Glioblastoma multiforme (GBM)/astrocytoma grade IV is a malignant and lethal brain cancer of unknown origin. Over the past decade, several studies have searched for the presence of a prominent herpesvirus, human cytomegalovirus (HCMV), in GBM samples. While some have detected HCMV DNA, RNA, and proteins in GBM tissues, others have not. Therefore, any purported association of HCMV with GBM remains controversial. In most of the previous studies, only one or a select few viral targets were analyzed. Thus, it remains unclear the extent to which the entire viral genome was present when detected. Here we report the results of a survey of GBM specimens for as many as 20 different regions of the HCMV genome. Our findings indicate that multiple HCMV loci are statistically more likely to be found in GBM samples than in other brain tumors or epileptic brain specimens and that the viral genome was more often detected in frozen samples than in paraffin-embedded archival tissue samples. Finally, our experimental results indicate that cellular genomes substantially outnumber viral genomes in HCMV-positive GBM specimens, likely indicating that only a minority of the cells found in such samples harbor viral DNA. These data argue for the association of HCMV with GBM, defining the virus as oncoaccessory. Furthermore, they imply that, were HCMV to enhance the growth or survival of a tumor (i.e., if it is oncomodulatory), it would likely do so through mechanisms distinct from classic tumor viruses that express transforming viral oncoproteins in the overwhelming majority of tumor cells.