Neurosurgery Clerkships in United States Medical Schools: A Survey of Doctor of Medicine-Granting and Doctor of Osteopathic Medicine-Granting Schools.

OBJECTIVE: Exposure to neurosurgery is important for knowledge of neurosurgical conditions that physicians may encounter. The current status of neurosurgery nonsubinternship clerkships in the United States is unknown; this study determined the availability and format of non-subinternship neurosurgery clerkships in DO (Doctor of Osteopathic Medicine)-granting and MD (Doctor of Medicine)-granting U.S. medical schools. METHODS: Association of American Medical Colleges and American Association of Colleges of Osteopathic Medicine websites were used to obtain contact information for all U.S. medical schools. Respondents were asked whether their school offered a non-subinternship neurosurgery clerkship, if it was required, clerkship length, and whether the clerkship was embedded in another clerkship. Nonsubinternship clerkships/electives/selectives were defined as an exploratory neurosurgery rotation. For nonresponding schools, data were collected from school websites. RESULTS: Data were obtained for 180/199 U.S. medical schools; 142 (79%) provided neurosurgery non-subinternships, including 125/150 (83.3%) MD-granting and 17/30 (57%) DO-granting schools. Four MD-granting schools (2.8%) required the clerkship; 87/142 (61%) offered a stand-alone clerkship, 34/142 (24%) an embedded clerkship, and 21/142 (15%) offered both. In total, 200 clerkships were offered across 142 schools. Most were either >1-2 weeks or >3-4 weeks (69/200, 35% and 89/200, 45%, respectively). CONCLUSIONS: Most U.S. medical schools provide elective neurosurgery non-subinternships. Fewer, although still a majority, of DO-granting schools offer a neurosurgery non-subinternship compared with MD-granting schools.

Reactivation of Disseminated Histoplasmosis With Central Nervous System Involvement Following a Primary Gastrointestinal Histoplasmosis Infection: A Case Report.

A 78-year-old white male with chronic pancytopenia presented with acute transient aphasia and dysarthria. He had a National Institutes of Health Stroke Scale (NIHSS) of zero. Physical examination revealed slight aphasia with mild dysarthria. Brain magnetic resonance imaging (MRI) revealed nine ring-enhancing lesions in the left precentral gyrus with significant vasogenic edema. Lung computed tomography (CT) showed no evidence of pulmonary nodules. The serology of blood and urine for infectious organisms was negative. Four weeks later, the patient was re-admitted with worsening dysarthria and right upper extremity weakness. Repeat head MRI showed a slight increase in the size of the multiple supratentorial ring-enhancing lesions. The magnetic resonance spectroscopy (MRS) findings of the evaluated lesion suggested a fungal etiology. Empiric amphotericin B treatment was initiated, which mitigated central nervous system (CNS) ring-enhancing lesions and resolved the patient's neurological deficits. Early empiric medical treatment of CNS histoplasmosis should be considered in the setting of multiple CNS ring-enhancing lesions and a positive history of histoplasmosis infection, despite negative serological studies.

Stereotactic Brain Biopsy Hemorrhage Risk Factors and Implications for Postoperative Care at a Single Institution: An Argument For Postoperative Imaging.

OBJECTIVE: To determine preoperative factors contributing to postoperative hemorrhage after stereotactic brain biopsy (STB), clinical implications of postoperative hemorrhage, and the role of postoperative imaging in clinical management. METHODS: Retrospective review of STB (2005-2018) across 2 institutions including patients aged >18 years undergoing first STB. Patients with prior craniotomy, open biopsy, or prior STB were excluded. Preoperative variables included age, sex, neurosurgeon seniority, STB method. Postoperative variables included pathology, postoperative hemorrhage on computed tomography, immediate and 30-day postoperative seizure, infection, postoperative hospital stay duration, and 30-day return to operating room (OR). Analysis used the Fisher exact tests for categorical variables. RESULTS: Overall, 410 patients were included. Average age was 56.5 (±16.5) years; 60% (n = 248) were men. The majority of biopsies were performed by senior neurosurgeons (66%, n = 270); frontal lobe (42%, n = 182) and glioblastoma (45%, n = 186) were the most common location and pathology. Postoperative hemorrhage occurred in 28% (114) of patients with 20% <0.05 cm3 and 8% >0.05 cm3. Postoperative hemorrhage of any size was associated with increased rate of postoperative deficit within both 24 hours and 30 days, postoperative seizure, and length of hospital stay when controlling for pathology. Hemorrhages >0.05 cm3 had a 16% higher rate of return to the OR for evacuation, due to clinical deterioration as opposed to radiographic progression. CONCLUSIONS: Postbiopsy hemorrhage was associated with higher risk of immediate and delayed postoperative deficit and seizure. Postoperative computed tomography should be used to determine whether STB patients can be discharged same day or admitted for observation; clinical evaluation should determine return to OR for evacuation.

Case of Esophageal Perforation and Repair with a Supraclavicular Artery Island Fascial Flap 15 Years After Anterior Spine Surgery.

BACKGROUND: Esophageal perforation represents a rare but potentially life-threatening complication of an anterior cervical diskectomy and fusion (ACDF). Delayed presentations of esophageal perforation more than 10 years following surgery are exceedingly rare and difficult to diagnose. Here, we discuss the case of an 80-year-old man who presented to the emergency department with progressive dysphagia 15 years after his ACDF. CASE DESCRIPTION: While prior outpatient workup was suggestive of a diverticulum, there was no evidence of esophageal perforation. Progressive symptoms and repeat imaging on admission were suggestive of retropharyngeal phlegmon. Operative esophagoscopy revealed that the spinal hardware had eroded through the posterior wall of the esophagus, creating a traction diverticulum. The hardware was removed, and the esophageal perforation was closed primarily and buttressed with vascularized tissue from a supraclavicular artery island fascial flap. CONCLUSIONS: This case emphasizes the importance of considering an esophageal perforation in patients who present with dysphagia at any interval following an ACDF, even in the extremely delayed setting. Furthermore, this is the first report, to the best of our knowledge, using a supraclavicular artery island fascial flap to reconstruct an esophageal perforation following an ACDF, and we introduce a novel strategy for managing these complicated injuries.

Pediatric functional hemispherectomy: operative techniques and complication avoidance.

Functional hemispherectomy/hemispherotomy is a disconnection procedure for severe medically refractory epilepsy where the seizure foci diffusely localize to one hemisphere. It is an improvement on anatomical hemispherectomy and was first performed by Rasmussen in 1974. Less invasive surgical approaches and refinements have been made to improve seizure freedom and minimize surgical morbidity and complications. Key anatomical structures that are disconnected include the 1) internal capsule and corona radiata, 2) mesial temporal structures, 3) insula, 4) corpus callosum, 5) parietooccipital connection, and 6) frontobasal connection. A stepwise approach is indicated to ensure adequate disconnection and prevent seizure persistence or recurrence. In young pediatric patients, careful patient selection and modern surgical techniques have resulted in > 80% seizure freedom and very good functional outcome. In this report, the authors summarize the history of hemispherectomy and its development and present a graphical guide for this anatomically challenging procedure. The use of the osteoplastic flap to improve outcome and the management of hydrocephalus are discussed.

Synchronous identification of a dysembryoplastic neuroepithelial tumor (DNET) and an oligodendroglioma in a patient: A case report.

Synchronous gliomas of different histopathology are quite rare in non-syndromic, non-irradiated patients. Although "mixed" gliomas are not infrequent, and malignant gliomas often contain areas of disparate differentiation (e.g., glioblastoma with ependymal differentiation), it is unusual to find gliomas of different lineage presenting concurrently. We present a case of synchronous gliomas, one dysembryoplastic neuroepithelial tumor (DNET) and the other oligodendroglioma.

EGFR806-CAR T cells selectively target a tumor-restricted EGFR epitope in glioblastoma.

Targeting solid tumor antigens with chimeric antigen receptor (CAR) T cell therapy requires tumor specificity and tolerance toward variability in antigen expression levels. Given the relative paucity of unique cell surface proteins on tumor cells for CAR targeting, we have focused on identifying tumor-specific epitopes that arise as a consequence of target protein posttranslational modification. We designed a CAR using a mAb806-based binder, which recognizes tumor-specific untethered EGFR. The mAb806 epitope is also exposed in the EGFRvIII variant transcript. By varying spacer domain elements of the CAR, we structurally tuned the CAR to recognize low densities of EGFR representative of non-gene amplified expression levels in solid tumors. The appropriately tuned short-spacer 2nd generation EGFR806-CAR T cells showed efficient in vitro cytokine secretion and glioma cell lysis, which was competitively blocked by a short peptide encompassing the mAb806 binding site. Unlike the nonselective Erbitux-based CAR, EGFR806-CAR T cells did not target primary human fetal brain astrocytes expressing wild-type EGFR, but showed a similar level of activity compared to Erbitux-CAR when the tumor-specific EGFRvIII transcript variant was overexpressed in astrocytes. EGFR806-CAR T cells successfully treated orthotopic U87 glioma implants in NSG mice, with 50% of animals surviving to 90 days. With additional IL-2 support, all tumors were eradicate without recurrence after 90 days. In a novel human induced pluripotent stem cell (iPSC)-derived teratoma xenograft model, EGFR806-CAR T cells infiltrated but were not activated in EGFR+ epidermal cell nests as assessed by Granzyme B expression. These results indicate that EGFR806-CAR T cells effectively and selectively target EGFR-expressing tumor cells.

Giant Pediatric Rhabdoid Meningioma Associated with a Germline BAP1 Pathogenic Variation: A Rare Clinical Case.

BACKGROUND: Rhabdoid meningiomas are rare World Health Organization grade 3 tumors that tend to follow an aggressive course, with an increased likelihood for local recurrence, remote metastasis, and cerebrospinal fluid dissemination. Genetic testing has found certain genes associated with reduced time to tumor recurrence. BAP1 (BRCA1-associated protein 1) is a tumor suppressor gene that is associated with multiple tumors, including rhabdoid meningiomas. CASE DESCRIPTION: We present a case of a pediatric patient who presented with a rhabdoid meningioma occurring in the right tentorium and invading multiple venous structures, including the right jugular vein. The patient underwent 5 separate operations for management of this tumor. The first surgery was an intracranial tumor debulking with reconstruction of venous structures. Postoperatively, the patient was unable to have the ventricular catheter removed and underwent placement of a ventriculoperitoneal shunt. Significant recurrence of the intracranial portion of tumor was found during preoperative imaging for her second stage procedure. She underwent a second craniotomy for resection of the tumor. Her postoperative magnetic resonance imaging showed significant residual tumor and the patient therefore underwent a third craniotomy for total tumor resection, which involved reconstruction of the superior sagittal sinus. She did well after this surgery, with no new neurologic deficits. Her final operation involved resection of the residual tumor in the neck and chest by both otolaryngology and cardiothoracic surgery. This surgery involved opening the jugular vein and resecting residual tumor from the intima. Pathologic results from all surgeries were consistent with rhabdoid meningioma; however, the tissue from the biopsy and first craniotomy lacked the high-grade features that were found on subsequent resections. Genetic analysis found loss of both BAP1 tumor suppressor genes. Peripheral blood testing showed that this patient was a germline carrier of a pathogenic BAP1 variant. DISCUSSION: Pediatric rhabdoid meningiomas represent a rare disease and are found on recurrent tumors in conjunction with lower-grade meningioma disease. Our patient presented with what was initially believed to be a low-grade meningioma with rhabdoid features, which then transformed into a World Health Organization grade III rhabdoid meningioma on recurrence. This tumor was discovered to have a biallelic loss of BAP-1 mutation and the patient was found to have a germline mutation in 1 of her BAP-1 alleles. Germline mutations in BAP-1 are associated with a cancer syndrome that involves uveal and cutaneous melanoma, malignant mesothelioma, atypical Spitz tumors, and clear-cell renal cell carcinoma. Patients with this mutation are encouraged to undergo annual eye examinations starting at the age of 11 years. The BAP-1 tumor predisposition syndrome is most commonly an inherited mutation associated with incomplete penetrance and variation with nonoverlapping tumor types. CONCLUSIONS: Rhabdoid meningiomas are unlikely to be found in children and have a high rate of local recurrence. Gross total resection has to be balanced with risk of postoperative deficit. Genetic testing of this rare entity should be performed to identify any hereditary germline mutations.

The first report of human primary thoracic spine mast cell sarcoma: a case report.

In this report, we present a 53-year-old woman with primary mast cell sarcoma of the thoracic spine vertebrae. Mast cell sarcoma is an aggressive and rare cancer. To date, no cases of primary mast cell sarcoma have been reported in the spinal vertebrae. The patient initially presented with a 1-month history of pelvic and abdominal pain. Inconclusive gynecological evaluation resulted in a CT of the abdomen and pelvis, demonstrating a destructive lesion centered at the 11th thoracic vertebral body. The patient underwent a two-stage spine operation for T11 corpectomy and T7-L3 posterior spinal fusion. Histopathological, immunohistochemical, and flow cytometry studies of the resection specimens showed the tumor to be mostly composed of CD117-positive and mast cell tryptase-positive cells with features consistent with mast cell sarcoma. This is the first reported case of primary vertebral mast cell sarcoma, which may mimic other destructive lesions of the spine including osteomyelitis, vertebral tuberculosis, or plasmacytoma.
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Cerebral Blood Flow Changes in Glioblastoma Patients Undergoing Bevacizumab Treatment Are Seen in Both Tumor and Normal Brain.

UNLABELLED: Bevacizumab (BEV) is increasingly used to treat recurrent glioblastoma (GBM) with some reported improvement in neurocognitive function despite potential neurotoxicities. We examined the effects of BEV on cerebral blood flow (CBF) within recurrent GBM tumor and in the contralateral middle cerebral artery (MCA) territory.Post-chemoradiation patients with histologically confirmed GBM were treated with BEV and underwent routine, serial tumor imaging with additional pseudocontinuous arterial spin labeling (pcASL) following informed consent. Circular regions-of-interest were placed on pcASL images directly over the recurrent tumor and in the contralateral MCA territory. CBF changes before and during BEV treatment were evaluated in tumor and normal tissue. Linear mixed models were used to assess statistical significance.Fifty-three pcASL studies in 18 patients were acquired. Evaluation yielded lower mean tumoral CBF during BEV treatment compared with pre-treatment (45 ± 27 vs. 65 ± 27 ml/100 g/min, p = 0.002), and in the contralateral MCA territory during, compared with pre-BEV treatment (35 ± 8.4 vs. 41 ± 8.4 ml/100 g/min, p = 0.03). The decrease in mean CBF tended to be greater in the tumoral region than in the contralateral MCA, though the difference did not reach statistical significance (31% vs. 13%; p = 0.082). CONCLUSIONS: BEV administration results in statistically significant global CBF decrease with a potentially preferential decrease in tumor perfusion compared with normal brain tissue.

Transcriptional inhibition of REST by NeuroD2 during neuronal differentiation.

For a progenitor cell to become a neuron, three activities must occur: neuronal differentiation program must be activated, elements repressing neuronal differentiation must be deactivated and competing differentiation programs must be silenced. It is known that NeuroD2 and related bHLH transcription factors induce neuronal differentiation, REST represses neuronal differentiation, and Zfhx1a prevents myogenic gene expression. We demonstrate that NeuroD2 suppresses REST during differentiation in culture. In the hippocampus of NeuroD2 knockout mice, higher level of REST is detected. Functional significance of NeuroD2-REST interplay is uncovered by showing that forced expression of REST interferes with neuronal differentiation in culture. NeuroD2 inhibits REST indirectly by involving the inhibitor of myogenic genes, Zfhx1a, which binds response elements in REST 5'-UTR. Our study supports a model wherein NeuroD2 induces transcription of neuronal genes and Zfhx1a, which in turn de-represses neuronal differentiation by down-regulating REST, and suppresses competing myogenic fate.

E protein dosage influences brain development more than family member identity.

Loss-of-function studies have revealed the role of many basic helix-loop-helix (bHLH) transcription factors at specific points during development; however, the role of E proteins in the development of the nervous system has not been experimentally addressed. E proteins have been speculated to interact selectively with class II bHLH factors to form different neurogenic complexes. In this study, using coimmunoprecipitation in a culture model of neurogenesis (P19 cells), we show that E proteins E12, HEB, and E2-2 interact with neuroD2. Using electrophoretic mobility shift assay and P19 cell culture, we show that these heterodimers bind a neuroD2 preferred E box and induce neurogenesis equally well. We examine the mRNA levels of the three E proteins at 10 time points during brain development and show that E protein gene expression is regulated such that at certain times during development selective interaction between neuroD2 and a single E protein (HEB) is a possibility. This led us to study the brains of HEB and E2A knockout mice, which manifest no gross neuroanatomical, cellular, or behavioral deficits. These findings, together with homology in the primary peptide sequence of E proteins, suggest functional compensation among E proteins during development of the nervous system.

Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci.

Toward the goal of developing an optical imaging contrast agent that will enable surgeons to intraoperatively distinguish cancer foci from adjacent normal tissue, we developed a chlorotoxin:Cy5.5 (CTX:Cy5.5) bioconjugate that emits near-IR fluorescent signal. The probe delineates malignant glioma, medulloblastoma, prostate cancer, intestinal cancer, and sarcoma from adjacent non-neoplastic tissue in mouse models. Metastatic cancer foci as small as a few hundred cells were detected in lymph channels. Specific binding to cancer cells is facilitated by matrix metalloproteinase-2 (MMP-2) as evidenced by reduction of CTX:Cy5.5 binding in vitro and in vivo by a pharmacologic blocker of MMP-2 and induction of CTX:Cy5.5 binding in MCF-7 cells following transfection with a plasmid encoding MMP-2. Mouse studies revealed that CTX:Cy5.5 has favorable biodistribution and toxicity profiles. These studies show that CTX:Cy5.5 has the potential to fundamentally improve intraoperative detection and resection of malignancies.

Suberoylanilide hydroxamic acid is effective in preclinical studies of medulloblastoma.

PURPOSE: Suberoylanilide hydroxamic acid (SAHA) has been studied in adult solid and hematologic malignancies. However, little information has been reported on the effects of SAHA on central nervous system (CNS) tumors including medulloblastoma, the most common malignant brain tumor in children. We investigated SAHA in preclinical medulloblastoma models to determine its anti-cancer efficacy as well as its ability to affect intracranial lesions when administered systemically. EXPERIMENTAL DESIGN AND RESULTS: Tissue culture studies were performed treating primary human fibroblasts, established medulloblastoma cell lines, and primary human medulloblastoma tumors with SAHA. At 10 microM concentration, SAHA had little effect on normal fibroblasts but caused >90% apoptosis in cultured medulloblastoma cells. Primary medulloblastomas from patients were sensitive to SAHA compared to vehicle alone in ex vivo studies. In athymic mice with medulloblastoma xenograft tumors, oral SAHA resulted in apoptosis of tumor tissue and significantly slowed tumor growth. In the ND2:Smo transgenic mouse medulloblastoma model, SAHA treatment caused significant apoptosis in these cerebellar tumors. CONCLUSIONS: SAHA effectively induces cell death in established medulloblastoma cell lines, human patient primary tumor cultures, medulloblastoma xenografts and intracranial spontaneous medulloblastomas. Fibroblasts in culture and mice treated with SAHA did not reveal prohibitive toxicity profiles. These findings support the advancement of SAHA to pediatric clinical trials.

Regulation of neuroD2 expression in mouse brain.

The basic helix-loop-helix (bHLH) transcription factor, neuroD2, induces neuronal differentiation and promotes neuronal survival. Reduced levels of neuroD2 were previously shown to cause motor deficits, ataxia, and seizure propensity. Because neuroD2 levels may be critical for brain function, we studied the regulation of neuroD2 gene in cell culture and transgenic mouse models. In transgenic mice, a 10-kb fragment of the neuroD2 promoter fully recapitulated the endogenous neuroD2 staining pattern. A 1-kb fragment of the neuroD2 promoter drove reporter gene expression in most, but not all neuroD2-positive neuronal populations. Mutation of two critical E-boxes, E4 and E5 (E4 and E5 situated 149 and 305 bp upstream of the transcriptional start site) eliminated gene expression. NeuroD2 expression was diminished in mice lacking neurogenin1 demonstrating that neurogenin1 regulates neuroD2 during murine brain development. These studies demonstrate that neuroD2 expression is highly dependent on bHLH-responsive E-boxes in the proximal promoter region, that additional distal regulatory elements are important for neuroD2 expression in a subset of cortical neurons, and that neurogenin1 regulates neuroD2 expression during mouse brain development.