Oren N. Gottfried

Molecular, genetic, and cellular pathogenesis of neurofibromas and surgical implications.

Neurofibromatosis 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors. Significant advances have been made in the research of the cellular, genetic, and molecular biology of NF1. The NF1 gene was identified by positional cloning. The functions of its protein product, neurofibromin, in RAS signaling and in other signal transduction pathways are being elucidated, and the important roles of loss of heterozygosity and haploinsufficiency in tumorigenesis are better understood. The Schwann cell was discovered to be the cell of origin for neurofibromas, but understanding of a more complicated interplay of multiple cell types in tumorigenesis, specifically recruited heterogenous cell types such as mast cells and fibroblasts, has important implications for surgical therapy of these tumors. This review summarizes the most recent NF1 and neurofibroma literature describing the pathogenesis and treatment of nerve sheath tumors. Understanding the biological underpinnings of tumorigenesis in NF1 has implications for future surgical and medical management of neurofibromas.

Central neurocytoma: a review

Central neurocytomas are rare intraventricular neoplasms of the central nervous system, compromising 0.25–0.5% of brain tumors. The diagnosis and management of these tumors remains controversial since most clinical series are small. Typically, patients with central neurocytomas have a favorable prognosis, but in some cases the clinical course is more aggressive. Although histological features of anaplasia do not predict biologic behavior, proliferation markers including MIB-1 might be more useful in predicting relapse. The most important therapeutic modality is surgery, and a safe maximal resection confers the best long-term outcome. In cases of a subtotal resection, standard external beam radiation can be added or radiation can be delayed until tumor progression occurs. Smaller residual tumor volumes or recurrences can be treated with more conformal radiation or focused radiosurgery. Re-operation for recurrence should be considered if the procedure can be safely performed. Chemotherapy may be useful for recurrent central neurocytomas that cannot be resected and have been radiated, although long-term responses have not been reported for chemotherapy. Overall, this paper reviews the findings of the larger studies and highlights some of the important case reports that contribute to the current management of central neurocytomas.

N-myc Can Substitute for Insulin-Like Growth Factor Signaling in a Mouse Model of Sonic Hedgehog–Induced Medulloblastoma

Medulloblastoma is a malignant brain tumor that arises in the cerebellum in children, presumably from granule neuron precursors (GNP). Advances in patient treatment have been hindered by a paucity of animal models that accurately reflect the molecular pathogenesis of human tumors. Aberrant activation of the Sonic hedgehog (Shh) and insulin-like growth factor (IGF) pathways is associated with human medulloblastomas. Both pathways are essential regulators of GNP proliferation during cerebellar development. In cultured GNPs, IGF signaling stabilizes the oncogenic transcription factor N-myc by inhibiting glycogen synthase kinase 3beta-dependent phosphorylation and consequent degradation of N-myc. However, determinants of Shh and IGF tumorigenicity in vivo remain unknown. Here we report a high frequency of medulloblastoma formation in mice following postnatal overexpression of Shh in cooperation with N-myc. Overexpression of N-myc, alone or in combination with IGF signaling mediators or with the Shh target Gli1, did not cause tumors. Thus, Shh has transforming functions in addition to induction of N-myc and Gli1. This tumor model will be useful for testing novel medulloblastoma therapies and providing insight into mechanisms of hedgehog-mediated transformation.

Ruptured intracranial dermoid cysts: clinical, radiographic, and surgical features.

OBJECTIVE Intracranial dermoid cysts are pathologically characterized by a thick, stratified squamous epithelium cyst wall containing dermal elements. Rupture into the subarachnoid spaces and ventricles is extremely rare. We review the clinical, radiographic, and surgical features of eight ruptured dermoid cysts. METHODS We retrospectively evaluated five surgically treated patients with pathologically proven ruptured dermoid cysts. Clinic notes, operative reports, and neuroimaging, including initial computed tomographic and magnetic resonance imaging scans, were reviewed. Imaging was also available on three outside patients reviewed by members of our radiology department. RESULTS The most common presentations were headaches (57%) and seizures (42%), followed by hydrocephalus (29%) from intraventricular rupture. These lesions were consistently hypodense on computed tomographic scans and hyperintense on T1-weighted images with minimal to no enhancement after gadolinium administration. Disseminated fat droplets were present in the subarachnoid space in both cerebral hemispheres in all patients, and five patients had intraventricular rupture with fat-fluid levels in the ventricles. Gross to near-total resection of the primary lesion was achieved in all five surgically treated patients treated at our institution. Four patients had remnant tumor capsules adherent to neurovascular structures that were unresectable. Repeat resection was performed for one recurrence; there were no further recurrences during a follow-up period of 2 to 134 months (mean, 65.6 mo). Two patients with preoperative hydrocephalus eventually required ventriculoperitoneal shunting. CONCLUSION Ruptured intracranial dermoid cysts represent 0.18% of all central nervous system tumors surgically treated in our institution during a 12-year period. The presence of disseminated fat droplets in the subarachnoid space or ventricles on neuroimaging is diagnostic for a ruptured dermoid cyst. Gross total removal is achievable; however, residual tumor capsules adherent to neurovascular structures should be left behind to minimize complications.

2012 Young Investigator Award winner: The distribution of body mass as a significant risk factor for lumbar spinal fusion postoperative infections.

Study Design. A retrospective review. Objective. The purpose of this study was to determine the role in body habitus and weight distribution on developing a surgical site infection (SSI). Summary of Background Data. SSI after lumbar spine surgery remains a significant cause of morbidity. The literature demonstrates an increased risk of postoperative infections associated with obesity, diabetes, and multilevel surgeries. Methods. A retrospective review was performed on a consecutive cohort of 298 adult patients who underwent lumbar spine fusion surgeries between 2006 and 2008 at the Duke University Medical Center. Previously identified risk factors (i.e., number of levels, diabetes, body mass index [BMI]) were collected, as well as the horizontal distance from the lamina to the skin surface (measured at L4) and thickness of subcutaneous fat at the surgical site. Results. Among the 298 patients, 24 (8%) had postoperative infections. Of the previously identified risk factors, number of levels (P = 0.0078) was found to be significantly associated with infections, whereas BMI (P = 0.16) and diabetes (P = 0.13) were found not to be statistically significant. Obesity (BMI ≥30) (P = 0.025), skin to lamina distance (P = 0.046), and thickness of the subcutaneous fat (P = 0.035) were found to be significant risk factors for SSI. Conclusion. Our findings suggest that in obese patients, the distribution of body mass is more predictive of SSI than the absolute BMI and deserves attention in preoperative evaluation.

Neurofibromatosis Type 1 and tumorigenesis: Molecular mechanisms and therapeutic implications

Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors, and less frequently by malignant peripheral nerve sheath tumors (MPNSTs) and optic nerve gliomas. Significant advances have been made in elucidating the cellular, genetic, and molecular biology involved in tumor formation in NF1. Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. Multiple key pathways are involved with the development of tumors in NF1, including Ras/mitogen-activated protein kinase (MAPK) and Akt/mammalian target of rapamycin (mTOR). Interestingly, recent studies demonstrate that multiple other developmental syndromes (in addition to NF1) share phenotypic features resulting from germline mutations in genes responsible for components of the Ras/MAPK pathway. In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation. Importantly, a complex series of interactions with these other cell types in neurofibroma tumorigenesis is mediated by abnormal expression of growth factors and their receptors and modification of gene expression, a key example of which is the process of recruitment and involvement of the NF1(+/-) heterozygous mast cell. In general, for malignant transformation to occur, there must be accumulation of additional mutations of multiple genes including INK4A/ARF and P53, with resulting abnormalities of their respective signal cascades. Further, abnormalities of the NF1 gene and molecular cascade described above have been implicated in the tumorigenesis of NF1 and some sporadically occurring gliomas, and thus, these treatment options may have wider applicability. Finally, increased knowledge of molecular and cellular mechanisms involved with NF1 tumorigenesis has led to multiple preclinical and clinical studies of targeted therapy, including the mTOR inhibitor rapamycin, which is demonstrating promising preclinical results for treatment of MPNSTs and gliomas.

Spinopelvic parameters in postfusion flatback deformity patients

BACKGROUND CONTEXT Fixed sagittal imbalance (FSI) may result from loss of adequate lumbar lordosis (LL) after spinal fusion. Pelvic incidence (PI) is a fixed anatomical parameter that determines LL and overall spinal sagittal alignment. PURPOSE We describe the spinopelvic parameters in a series of patients with postfusion FSI. We hypothesize that patients who develop postfusion FSI may have a high PI and are thus more at risk from a loss of adequate LL. STUDY DESIGN Retrospective chart and image review. PATIENT SAMPLE Consecutive patients with degenerative spine disease with clinically significant postoperative FSI after fusion. METHODS/OUTCOME MEASURES: We evaluated 36-in full spine films for PI, LL, pelvic tilt (PT), thoracic kyphosis (TK), and C7 plumb line. RESULTS Fifteen patients with clinically significant FSI were identified: 13 women and 2 men (mean age, 63.3 years). They had undergone a mean of 2.9 prior spine surgeries. The mean PI was elevated at 66.7 degrees (normal 48-55 degrees ), mean PT was elevated at 35.5 degrees (normal 12-18 degrees ), mean LL was reduced at 11.8 degrees (normal 43-61 degrees ), mean TK was reduced at 19.3 degrees (normal 41-48 degrees ), and mean C7 plumb line was elevated at 13.1cm (normal <3cm). CONCLUSIONS In the current series, patients with FSI after spinal fusion had an elevated PI and inadequate LL. They attempted to compensate for FSI with reduced TK and with increased pelvic retroversion (PT). Overall, it is important to identify sagittal spinopelvic parameters and promote sagittal balance when performing lumbar fusions.

Implications of spinopelvic alignment for the spine surgeon.

The relation of the pelvis to the spine has previously been overlooked as a contributor to sagittal balance. However, it is now recognized that spinopelvic alignment is important to maintain an energy-efficient posture in normal and disease states. The pelvis is characterized by an important anatomic landmark, the pelvic incidence (PI). The PI does not change after adolescence, and it directly influences pelvic alignment, including the parameters of pelvic tilt (PT) and sacral slope (SS) (PI = PT 1 SS), overall sagittal spinal balance, and lumbar lordosis. In the setting of an elevated PI, the spineadapts with increased lumbar lordosis. To prevent or limit sagittal imbalance, the spine may also compensate with increased PT or pelvic retroversion to attempt to maintain anupright posture. Abnormal spinopelvic parameters contribute to multiple spinal conditions including isthmic spondylolysis, degenerative spondylolisthesis, deformity, and impact outcome after spinal fusion. Sagittal balance, pelvic incidence, and all spinopelvic parameters are easily and reliably measured on standing, full-spine (lateral) radiographs, and it is essential to accurately assess and measure these sagittal values to understand their potential role in the disease process, and to promote spinopelvic balance at surgery. In this article, we provide a comprehensive review of the literature regarding the implications of abnormal spinopelvic parameters and discuss surgical strategies for correction of sagittal balance. Additionally, the authors rate and critique the quality of the literature cited in a systematic review approach to give the reader an estimate of the veracity of the conclusions reached from these reports.

Biportal thoracoscopic sympathectomy: surgical techniques and clinical results for the treatment of hyperhidrosis.

OBJECTIVE To describe a bilateral thoracoscopic sympathectomy procedure, using a biportal approach, for the treatment of severe hyperhidrosis. METHODS Between May 1996 and September 2000, 103 consecutive patients underwent thoracoscopic sympathectomy procedures to treat bilateral hyperhidrosis (206 procedures). Operative results, complications, and patient satisfaction were determined by reviews of hospital and office charts and by follow-up assessments in the outpatient clinic. Long-term results were determined with clinical examinations, follow-up office visits, and follow-up questionnaires. RESULTS Ninety-three patients presented with primary palmar hyperhidrosis, eight with primary axillary hyperhidrosis, and two with primary craniofacial hyperhidrosis. Rates of complete resolution in the primary area affected were 100% in palmar and craniofacial cases and 75% in axillary cases. The average length of hospitalization was 1.06 days, and 96 patients (93.2%) were discharged on or before the end of the first postoperative day. Of 59 patients (57.3%) who developed compensatory hyperhidrosis, only 11 patients (10.7%) reported that it was bothersome and none considered it disabling. All postoperative complications were transient; five patients experienced unilateral Horner’s syndrome, three patients experienced intercostal neuralgia, and two patients required a chest tube after surgery because of a pneumothorax. CONCLUSION Thoracoscopic sympathectomy using a biportal approach effectively treats hyperhidrosis and is associated with short hospital stays, high patient satisfaction rates, and low rates of compensatory hyperhidrosis or other complications.

Experience with intrawound vancomycin powder for spinal deformity surgery.

Study Design. Retrospective cohort study. Objective. To evaluate the ability of local vancomycin powder to prevent deep wound infection after thoracolumbar and lumbar spinal fusion for open deformity cases. Summary of Background Data. Recent studies report that local delivery of vancomycin powder is associated with a decrease in spinal surgical site infection (SSI). This study compares deformity fusion cases before and after the routine application of spinal vancomycin powder. Methods. Posterior spinal deformity surgical procedures by a single institution were reviewed from January 2011 to April 2013. Routine application of vancomycin powder started in April 2012. Inclusion criteria included adult patients who underwent posterior fusion for deformity pathologies, including spondylolisthesis, kyphosis, sagittal imbalance, and scoliosis. Each cohorts baseline characteristics including infection risk factors, operative data, and rates of wound infection were compared. Associations between infection and vancomycin powder, with and without propensity score adjustment for risk factors were determined using logistic regression. Results. A total of 306 patients were included in the study. All measured baseline and operative variables were statistically similar between untreated (n = 150) and those who received vancomycin powder (n = 156). No significant change in deep wound infection rate was seen between the control (5.3%) and intervention group (5.1%, P = 0.936). Logistic regression with and without propensity score adjusted for risk factors demonstrated that the use of vancomycin powder did not impact the development of SSI (odds ratio [95% confidence interval]: 1.01 [0.36–2.79], P = 0.9910) and (odds ratio [95% confidence interval]: 0.87 [0.31–2.42], P = 0.7876), respectively. Conclusion. The local application of powdered vancomycin was not associated with a significant difference in the rate of deep SSI after spinal deformity surgery, and other treatment modalities are necessary to limit infection for this high-risk group. This study is in contrary to prior studies, which have reported a decrease in SSI with vancomycin powder. Level of Evidence: 2