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OBJECTIVE A large proportion of healthcare expense is operating room (OR) costs. As a means of cost mitigation, several institutions have implemented surgeon education programs to bring awareness about supply costs. This study evaluates the impact of a surgical cost feedback system (surgical receipt) on the supply costs of endoscopic skull base surgery (ESBS) procedures. METHODS The supply costs of each ESBS surgical case were prospectively collected and analyzed before and after the implementation of a nonincentivized, automated, and itemized weekly surgical receipt system between January 2017 and December 2019. Supply cost data collected 15 months prior to intervention were compared with cost data 21 months after implementation of the surgical receipt system. Demographics, surgical details, and OR time were collected retrospectively. RESULTS Of 105 ESBS procedures analyzed, 36 preceded and 69 followed implementation of cost feedback. There were no significant differences in patient age (p = 0.064), sex (p = 0.489), surgical indication (p = 0.389), or OR anesthesia time (p = 0.51) for patients treated before and after implementation. The mean surgical supply cost decreased from $3824.41 to $3010.35 (p = 0.002) after implementation of receipt feedback. Usage of dural sealants (p = 0.043), microfibrillar collagen hemostat (p = 0.007), and oxidized regenerated cellulose hemostat (p < 0.0001) and reconstructive technique (p = 0.031) significantly affected cost. Mediation analysis confirmed that the overall cost reduction was predominantly driven by reduced use of dural sealant; this cost saving exceeded the incremental cost of greater use of packing materials such as microfibrillar collagen hemostat. CONCLUSIONS Education of surgeons regarding surgical supply costs by a surgical receipt feedback system can reduce the supply cost per case of ESBS operations.

The purpose of this report is to chronicle a 2-decade period of educational innovation and improvement, as well as governance reform, across the specialty of neurological surgery. Neurological surgery educational and professional governance systems have evolved substantially over the past 2 decades with the goal of improving training outcomes, patient safety, and the quality of US neurosurgical care. Innovations during this period have included the following: creating a consensus national curriculum; standardizing the length and structure of neurosurgical training; introducing educational outcomes milestones and required case minimums; establishing national skills, safety, and professionalism courses; systematically accrediting subspecialty fellowships; expanding professional development for educators; promoting training in research; and coordinating policy and strategy through the cooperation of national stakeholder organizations. A series of education summits held between 2007 and 2009 restructured some aspects of neurosurgical residency training. Since 2010, ongoing meetings of the One Neurosurgery Summit have provided strategic coordination for specialty definition, neurosurgical education, public policy, and governance. The Summit now includes leadership representatives from the Society of Neurological Surgeons, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, the American Board of Neurological Surgery, the Review Committee for Neurological Surgery of the Accreditation Council for Graduate Medical Education, the American Academy of Neurological Surgery, and the AANS/CNS Joint Washington Committee. Together, these organizations have increased the effectiveness and efficiency of the specialty of neurosurgery in advancing educational best practices, aligning policymaking, and coordinating strategic planning in order to meet the highest standards of professionalism and promote public health.

High-resolution genome-wide mapping of exact boundaries of chromosomal alterations should facilitate the localization and identification of genes involved in gliomagenesis and may characterize genetic subgroups of glial brain tumors. We have done such mapping using cDNA microarray-based comparative genomic hybridization technology to profile copy number alterations across 42,000 mapped human cDNA clones, in a series of 54 gliomas of varying histogenesis and tumor grade. This gene-by-gene approach permitted the precise sizing of critical amplicons and deletions and the detection of multiple new genetic aberrations. It has also revealed recurrent patterns of occurrence of distinct chromosomal aberrations as well as their interrelationships and showed that gliomas can be clustered into distinct genetic subgroups. A subset of detected alterations was shown predominantly associated with either astrocytic or oligodendrocytic tumor phenotype. Finally, five novel minimally deleted regions were identified in a subset of tumors, containing putative candidate tumor suppressor genes (TOPORS, FANCG, RAD51, TP53BP1, and BIK) that could have a role in gliomagenesis.

Supplementary Figures 1-6, Tables 1-2 from High-Resolution Genome-Wide Mapping of Genetic Alterations in Human Glial Brain Tumors

Supplementary Figure 2 from Functional Network Analysis Reveals Extended Gliomagenesis Pathway Maps and Three Novel MYC-Interacting Genes in Human Gliomas

Background Radiation therapy for intracranial lesions is constrained by dose to neurologic organs at risk. Case Description We report 2 cases, a newly diagnosed chondrosarcoma and a previously irradiated meningioma, with tumors that abutted the optic chiasm following subtotal resection. Definitive radiotherapy would have required either undercoverage of the tumor or treatment of the chiasm with doses posing an unacceptable risk of blindness. Therefore, the patients underwent open surgery with placement of an abdominal fat autograft to provide space between the tumor and the optic structures at risk. Patients received definitive fractionated stereotactic radiotherapy. For each patient, we retrospectively compared the treated plan (with fat autograft) to a second plan generated using the pre-autograft imaging, maintaining similar tumor coverage. For the chondrosarcoma, the fat autograft reduced the optic chiasm maximum dose by 21% (70.4 Gy to 55.3 Gy). For the reirradiated peri-optic meningioma, the optic chiasm maximum dose was reduced by 10% (50.8 Gy to 45.9 Gy), the left optic nerve by 17% (48.9 Gy to 40.4 Gy), and the right optic nerve by 30% (32.3 Gy to 22.6 Gy). Conclusions We demonstrate the utility of abdominal fat autograft placement to maximize coverage of tumor while minimizing dose to intracranial organs at risk.

For intracranial meningiomas that metastasize extracranially, an oligometastatic state exists that is intermediate between incurable, widely metastatic disease and non-metastatic curable disease. Similar to oligometastatic cancer, aggressive local treatment of meningioma oligometastases is warranted, as it may be curable. We present a patient with multiply recurrent intracranial meningiomas over 19 years, with a transformation from grade I to grade II histology, with oligometastatic disease to the C5 vertebral body. Three years following definitive spinal stereotactic radiosurgery, she remains without evidence of other metastatic diseases. Our case highlights the oncologic concept that metastatic meningioma need not be widely disseminated and provides the clinical rationale for aggressive local treatment of an oligometastatic meningioma.

Background We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma (GBM). Methods We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3 + 3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events grades 3–5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis. Results From 2010 to 2015, thirty patients were enrolled. The median age was 66 years (range, 51–86 y). The median target volume was 60 cm3 (range, 14.7–137.3 cm3). DLT occurred in 2 patients: one for posttreatment cerebral edema and progressive disease at 3 weeks (grade 4, dose 40 Gy); another patient died 1.5 weeks following SRS from postoperative complications (grade 5, dose 40 Gy). Late grades 1–2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2–12.6 mo). No grades 3–5 ARE occurred. With a median follow-up of 13.8 months (range 1.7–64.4 mo), the median survival times were: progression-free survival, 8.2 months (95% CI: 4.6–10.5); overall survival, 14.8 months (95% CI: 10.9–19.9); O6-methylguanine-DNA methyltransferase hypermethylated, 19.9 months (95% CI: 10.5–33.5) versus 11.3 months (95% CI: 8.9–17.6) for no/unknown hypermethylation (P = 0.03), and 27.2 months (95% CI: 11.2–48.3) if late ARE occurred versus 11.7 months (95% CI: 8.9–17.6) for no ARE (P = 0.08). Conclusions The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grades 1–2 and did not statistically impact survival.

Background To better understand upper airway tissue regeneration, the exposed cartilage and bone at donor sites of tissue flaps may serve as in vivo "Petri dishes" for active wound healing. The pedicled nasoseptal flap (NSF) for skull-base reconstruction creates an exposed donor site within the nasal airway. The objective of this study is to evaluate whether grafting the donor site with a sinonasal repair cover graft is effective in promoting wound healing. Methods In this multicenter, prospective trial, subjects were randomized to intervention (graft) or control (no graft) intraoperatively after NSF elevation. Individuals were evaluated at 2, 6, and 12 weeks postintervention with endoscopic recordings. Videos were graded (Likert scale) by 3 otolaryngologists blinded to intervention on remucosalization, crusting, and edema. Scores were analyzed for interrater reliability and cohorts compared. Biopsy and immunohistochemistry at the leading edge of wound healing was performed in select cases. Results Twenty-one patients were randomized to intervention and 26 to control. Subjects receiving the graft had significantly greater overall remucosalization (p = 0.01) than controls over 12 weeks. Although crusting was less in the small intestine submucosa (SIS) group, this was not statistically significant (p = 0.08). There was no overall effect on nasal edema (p = 0.2). Immunohistochemistry demonstrated abundant upper airway basal cell progenitors in 2 intervention samples, suggesting that covering grafts may facilitate tissue proliferation via progenitor cell expansion. Conclusion This prospective, randomized, controlled trial indicates that a porcine SIS graft placed on exposed cartilage and bone within the upper airway confers improved remucosalization compared to current practice standards.

Introduction Hormonal insufficiency of 1 or more pituitary axes can appear after pituitary surgery. Adrenal axis impairment after surgery can lead to serious consequences if not identified and treated. Objective Assess early and late postoperative adrenal insufficiency (AI) and identify the risk factors predicting their occurrence after endoscopic transsphenoidal resection of pituitary adenomas. Method Retrospective review identified 176 pituitary adenomas resected using an endoscopic transsphenoidal approach. Patients taking steroids preoperatively, Cushing disease patients, and patients with incomplete records were excluded. Sixty-nine patients were excluded according to our exclusion criteria. Results The study group thus included 107 patients (total of 111 operations). The median age was 50 years (range, 18–89 years). The median duration of follow-up was 30 months (range, 6–74 months). Eighty-three patients (74.7%) had macroadenomas, and 89 (59.3%) had nonfunctional adenomas. Of the 111 procedures, 61 patients (55%) had early AI. Of the 61 patients, 48 patients (79%) were not taking steroids in long-term follow-up, and only 13 (21%) required long-term replacement. Sixteen of the patients undergoing 111 procedures (14.4%) had AI on long-term follow-up. Of those 16 patients, 13 were already taking steroids and 3 had new diagnoses of AI. Age, male gender, and cerebrospinal fluid (CSF) leaks were associated with persistent postoperative AI (P = 0.018, P = 0.001, P = 0.007, respectively). Conclusion Hypothalamic pituitary adrenal axis insufficiency is common after endoscopic transsphenoidal surgery. Male gender, age greater than 50 years, visual impairment, and intraoperative CSF leak were correlated with late postoperative AI. More than two thirds of patients in whom early AI developed did not require steroids in the long term.

Surgery is the primary treatment for acromegaly. However, surgery may not be curative of some tumors, particularly invasive macroadenomas. Adjuvant radiation, specifically robotic stereotactic radiosurgery (rSRS), may improve the endocrine outcome. We retrospectively reviewed hormonal and radiological data of 22 acromegalic patients with invasive macroadenomas treated with rSRS at Stanford University Medical Center between 2000 and 2016. Prior to treatment, the tumor's median maximal diameter was 19 mm (2.5-50 mm). Cavernous sinus invasion occurred in 19 patients (86.3%) and compression of the optic chiasm in 2 (9.0%). At last follow up, with an average follow up of 43.2 months, all patients had a reduction in their IGF-1 levels (median IGF-1% upper limit of normal (ULN) baseline: 136% vs last follow up: 97%; p = 0.05); 9 patients (40.9%) were cured, and 4 (18.1%) others demonstrated biochemical control of acromegaly. The median time to cure was 50 months and the mean interval to cure or biochemical control was 30.3 months (± 24 months, range 6-84 months). Hypopituitarism was present in 8 patients (36.3%) and new pituitary deficits occurred in 6 patients with a median latency of 31.6 ± 14.5 months. At final radiologic follow-up, 3 tumors (13.6%) were smaller and 19 were stable in size. The mean biologically effective dose (BED) was higher in subjects cured compared to those with persistent disease, 163 Gy3 (± 47) versus 111 Gy3 (± 43), respectively (p = 0.01). No patient suffered visual deterioration. Robotic SRS is a safe and effective treatment for acromegaly: radiation-induced visual complications and hypopituitarism is rare.

PurposeTo determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates.Materials and methodsIn this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2cm, were enrolled in a phase 1, 3+3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400mg orally once daily for 14days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30days.ResultsFrom 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12months (range, 1-64months), Kaplan-Meier overall survival was 13months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2months after SRS.ConclusionsThe MTD of vorinostat with concurrent SRS was established as 400mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases.

Objectives Pituitary adenoma (PA), among the most commonly encountered sellar pathologies, accounts for 10% of primary intracranial tumors. The reported incidence of postoperative diabetes insipidus (DI) is highly variable. In this study, we report our experience with DI following endoscopic transsphenoidal surgery (TSS) for PAs, elucidating the risk factors of postoperative DI, the likelihood of long-term DI, and the impact of DI on the length of stay (LOS). Methods The study included 178 patients who underwent endoscopic resection of PAs. Early DI was defined as that occurring within the first postoperative week. The mean follow-up was 36 months. Long-term DI was considered as DI apparent in the last follow-up visit. Results Of the 178 patients included in the study, 77% of the tumors were macroadenomas. Forty-seven patients (26%) developed early DI. Long-term DI was observed in 18 (10.1%) of the full cohort. Age younger than 50 years was significantly associated with a higher incidence of long-term DI (p = 0.02). Macroadenoma and gross total resection were significantly associated with higher incidence of early DI (p = 0.05 and p = 0.04, respectively). The mean LOS was 4 days for patients with early postoperative DI and 3 days for those without it. Conclusion The reported incidence of postoperative DI is significantly variable. We identified age younger than 50 years a risk factor for developing long-term postoperative DI. Gross total surgical resection and tumor size (> 1 cm) were associated with development of early DI. Early DI increased the LOS on average by 1 day.

An estimated 20%25 of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung, breast and colorectal cancers, melanoma or renal cell carcinoma. Brain metastases are thought to occur via seeding of circulating tumour cells into the brain microvasculature; within this unique microenvironment, tumour growth is promoted and the penetration of systemic medical therapies is limited. Development of brain metastases remains a substantial contributor to overall cancer mortality in patients with advanced-stage cancer because prognosis remains poor despite multimodal treatments and advances in systemic therapies, which include a combination of surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Thus, interest abounds in understanding the mechanisms that drive brain metastases so that they can be targeted with preventive therapeutic strategies and in understanding the molecular characteristics of brain metastases relative to the primary tumour so that they can inform targeted therapy selection. Increased molecular understanding of the disease will also drive continued development of novel immunotherapies and targeted therapies that have higher bioavailability beyond the blood-tumour barrier and drive advances in radiotherapies and minimally invasive surgical techniques. As these discoveries and innovations move from the realm of basic science to preclinical and clinical applications, future outcomes for patients with brain metastases are almost certain to improve.

Successful management of malignant pathology of the clivus and extending into the posterior fossa continues to be a formidable challenge to the skull base surgeon. While legends of surgery invented approaches to the skull base, these often came at significant morbidity to the patient and were difficult to inculcate to subsequent generations given the narrow surgical corridors one could use to access these central parts of the skull base. With the advent of extended endonasal skull base surgery and advances in endoscopy, instrumentation, and surgical navigation technologies, transclival skull base surgery for chordoma and chondrosarcoma has gained promising new momentum and evidence for efficacy. In this chapter, we highlight the advantages, disadvantages, anatomy, surgical principles, postoperative considerations, and complications associated with endoscopic transclival approaches to the skull base for resection of chordomas and chondrosarcomas.

Introduction Gangliogliomas rarely occur in the sella or suprasellar region and are almost never seen in the pituitary stalk. Seven cases of gangliogliomas occurring in this region have been reported; only one case involved a tumor within the pituitary stalk. Of the six tumors external to the pituitary stalk, two occurred in the neurohypophysis, one was in the adenohypophysis, the location of one was unspecified, and two extensively invaded the optic chiasm, hypothalamus and brainstem. This is only the second reported case of a pituitary stalk ganglioglioma, and it is unique in its use of an extended endoscopic endonasal approach for biopsy. Case report A 51-year old woman presented with an eleven-month history of polydipsia and polyuria leading to the diagnosis of diabetes insipidus. Magnetic Resonance Imaging of the brain revealed contrast-enhanced thickening and anterior bowing of the hypophyseal stalk. An extended endoscopic endonasal approach permitted midline removal of the tuberculum sella, opening of underlying dura, and exposure of the pituitary stalk. A firm, white, 4 mm diameter mass, integral to the right side of the enlarged pituitary stalk was seen and biopsied. Histopathological analysis was consistent with WHO grade 1 ganglioglioma. The patient tolerated the procedure well and required no endocrinologic treatment other than desmopressin. Conclusion Pituitary stalk gangliogliomas are extremely rare. The diagnosis should be considered in patients with pituitary stalk enlargement. Endoscopic endonasal approach is a safe surgical approach to establish a tissue diagnosis which is essential for pathologic certainty given the wide differential diagnosis of stalk lesions.

Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus.

PURPOSE: To investigate ferumoxytol-enhanced MRI as a noninvasive imaging biomarker of macrophages in adults with high-grade gliomas. MATERIALS AND METHODS: In this prospective study, adults with high-grade gliomas were enrolled between July 2015 and July 2017. Each participant was administered intravenous ferumoxytol (5 mg/kg) and underwent 3.0-T MRI 24 hours later. Two sites in each tumor were selected for intraoperative sampling on the basis of the degree of ferumoxytol-induced signal change. Susceptibility and the relaxation rates R2* (1/T2*) and R2 (1/T2) were obtained by region-of-interest analysis by using the respective postprocessed maps. Each sample was stained with Prussian blue, CD68, CD163, and glial fibrillary acidic protein. Pearson correlation and linear mixed models were performed to assess the relationship between imaging measurements and number of 400× magnification high-power fields with iron-containing macrophages. RESULTS: Ten adults (four male participants [mean age, 65 years ± 9 {standard deviation}; age range, 57–74 years] and six female participants [mean age, 53 years ± 12 years; age range, 32–65 years]; mean age of all participants, 58 years ± 12 [age range, 32–74 years]) with high-grade gliomas were included. Significant positive correlations were found between susceptibility, R2*, and R2’ and the number of high-power fields with CD163-positive (r range, 0.64–0.71; P < .01) and CD68-positive (r range, 0.55–0.57; P value range, .01–.02) iron-containing macrophages. No significant correlation was found between R2 and CD163-positive (r = 0.33; P = .16) and CD68-positive (r = 0.24; P = .32) iron-containing macrophages. Similar significance results were obtained with linear mixed models. At histopathologic analysis, iron particles were found only in macrophages; none was found in glial fibrillary acidic protein–positive tumor cells. CONCLUSION: MRI measurements of susceptibility, R2*, and R2’ (R2* – R2) obtained after ferumoxytol administration correlate with iron-containing macrophage concentration, and this shows their potential as quantitative imaging markers of macrophages in malignant gliomas. © RSNA, 2018 Online supplemental material is available for this article.

OBJECTIVE Rathke's cleft cyst (RCC) is a common sellar lesion which may cause visual impairment, hypopituitarism and headaches from mass effect. The natural history of these lesions is currently unclear. We investigated the natural history of RCCs and compared surgically treated patients with those treated conservatively. METHODS We performed a retrospective cohort study of patients diagnosed with a RCC between 1996 and 2016 at Stanford University and Ospedale Maggiore Policlinico di Milano. RESULTS Patients were divided into 2 cohorts: Group A, 72 subjects who underwent surgical resection of a symptomatic RCC, and Group B, 62 subjects managed conservatively. Compared to Group B, Group A subjects had larger RCCs (79% vs 22% had a largest diameter >10 mm, P

Introduction Maximizing extent of surgical resection with the least morbidity remains critical for survival in glioblastoma patients, and we hypothesize that it can be improved by enhancements in intraoperative tumor detection. In a clinical study, we determined if therapeutic antibodies could be repurposed for intraoperative imaging during resection. Methods Fluorescently labeled cetuximab-IRDye800 was systemically administered to three patients 2 days prior to surgery. Near-infrared fluorescence imaging of tumor and histologically negative peri-tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue. Results The mean TBR was significantly higher in tumor tissue of contrast-enhancing (CE) tumors on preoperative imaging (4.0 ± 0.5) compared to non-CE tumors (1.2 ± 0.3; p = 0.02). The TBR was higher at a 100 mg dose than at 50 mg (4.3 vs. 3.6). The smallest detectable tumor volume in a closed-field setting was 70 mg with 50 mg of dye and 10 mg with 100 mg. On sections of paraffin embedded tissues, fluorescence positively correlated with histological evidence of tumor. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (73.0% for 50 mg dose, 98.2% for 100 mg dose) and specific (66.3% for 50 mg dose, 69.8% for 100 mg dose) for viable tumor tissue in CE tumors while normal peri-tumoral tissue showed minimal fluorescence. Conclusion This first-in-human study demonstrates the feasibility and safety of antibody based imaging for CE glioblastomas.

To better understand upper airway tissue regeneration, the exposed cartilage and bone at donor sites of tissue flaps may serve as in vivo "Petri dishes" for active wound healing. The pedicled nasoseptal flap (NSF) for skull-base reconstruction creates an exposed donor site within the nasal airway. The objective of this study is to evaluate whether grafting the donor site with a sinonasal repair cover graft is effective in promoting wound healing.In this multicenter, prospective trial, subjects were randomized to intervention (graft) or control (no graft) intraoperatively after NSF elevation. Individuals were evaluated at 2, 6, and 12 weeks postintervention with endoscopic recordings. Videos were graded (Likert scale) by 3 otolaryngologists blinded to intervention on remucosalization, crusting, and edema. Scores were analyzed for interrater reliability and cohorts compared. Biopsy and immunohistochemistry at the leading edge of wound healing was performed in select cases.Twenty-one patients were randomized to intervention and 26 to control. Subjects receiving the graft had significantly greater overall remucosalization (p = 0.01) than controls over 12 weeks. Although crusting was less in the small intestine submucosa (SIS) group, this was not statistically significant (p = 0.08). There was no overall effect on nasal edema (p = 0.2). Immunohistochemistry demonstrated abundant upper airway basal cell progenitors in 2 intervention samples, suggesting that covering grafts may facilitate tissue proliferation via progenitor cell expansion.This prospective, randomized, controlled trial indicates that a porcine SIS graft placed on exposed cartilage and bone within the upper airway confers improved remucosalization compared to current practice standards.

Chordomas and chondrosarcomas are rare bone cancers that share many clinicoradiological similarities. Nevertheless, they are distinct pathological entities that markedly differ regarding their origin, history, and prognosis. Chordomas represent 3% of primary bone tumors, develop from remnants of the primitive notochord, and may affect the skull base and any part of the spine. Chondrosarcomas represent 7% of primary bone tumors, appear to develop from cartilaginous rests during the process of ossification, and most commonly involve the long bones of the appendicular skeleton, although they may also affect the axial skeleton. Given the importance of distinguishing between these neoplasms for proper management, this chapter will review demographic and clinical data emphasizing their differences.

The surgical treatment of clivus chordomas and chondrosarcomas presents a challenge to neurosurgeons and ENT-surgeons. These tumors are rare and the complex anatomy of the clivus region and their infiltrative behavior make radical resection very difficult. Aggressive surgery with removal of the infiltrated bone is the treatment of choice. Several surgical approaches have been used. Recently, endoscopic approaches are increasingly used. Endoscopy permits a better visualization of the lesion but large dura defects are difficult to close with this technique. There is no postoperative curative therapy. Radiation therapy with proton beam and radiosurgery are indicated in the majority of cases. These tumors are refractory to currently used chemotherapy drugs. Better knowledge of the phenotype and molecular profile of these lesions may in the future help in the development of new target therapies.

Select chordomas and chondrosarcomas have extensions to the posterior cavernous sinus and to the petrous apex. These lesions may be best approached by an anterior transpetrosal approach, either alone or in combination with an anterolateral or a posterolateral technique. The anterior transpetrosal technique may be performed either via an intradural or an extradural technique. These techniques are described in detail for a lateral approach to resect these lesions from the posterior cavernous sinus, the medial cerebellopontine angle, and the petroclival regions.

Chordomas and chondrosarcomas are distinct pathological entities that share many clinical–radiological similarities. Furthermore, a variety of different tumors may also be a part of their differential diagnosis. These include other primary osseous tumors, cartilaginous, soft tissue, and central nervous system neoplasms as well as congenital, nonneoplastic, and metastatic secondary lesions. Proper management of cranial base and spinal tumors depends, among other factors, on accurate diagnosis. A multidisciplinary team of physicians with significant experience with complex skull base and spinal pathologies should, ideally, evaluate these patients so as to decrease the likelihood of diagnostic errors and treatment delays. This chapter discusses the clinical, radiological, and histological characteristics of cranial base and spinal tumors by which they can be distinguished from chordomas and chondrosarcomas.

Surgical resection is considered the mainstay treatment modality of most skull base chordomas and chondrosarcomas. Adequate exposure for maximal safe tumor resection while reducing the risks of complications and properly reconstructing the skull base defect created during the approach are the fundamental principles of skull base surgery. Nevertheless, the choice of surgical approach to these tumors requires a thorough understanding of the anatomy of the central skull base from which they most commonly arise. This chapter will review important considerations in the management of patients harboring skull base chordomas and chondrosarcomas with emphasis on surgical treatment and will include a comprehensive description of open transcranial and endoscopic endonasal approaches, which should ultimately assist the reader in selecting the most appropriate surgical approach and treatment strategy for individual patients.

Chordomas and chondrosarcomas are different histopathological entities with markedly different natural history and clinical outcomes. Sharing a similar clinical and radiological presentation, their definite identification is confirmed only by immunohistological stain (cytokeratin, EMA, and brachyury). One common prognostic feature is the radicality achieved with surgical resection. Due to their large or giant size at presentation or their extension to multiple anatomical compartments, radical resection of these tumors often requires more than one approach or one surgical procedure, and staged surgery becomes necessary. The pursuit of gross total removal improves the disease-free survival in chordoma, knowing that a high-dose radiation therapy will be given in addition, whereas in chondrosarcoma, achieving total removal would eliminate the need for radiation. Multiple and staged surgery requires thorough planning that takes into consideration the recovery time, reconstruction, donor site of autologous tissue, and the potential complications of the approach, particularly of cerebrospinal fluid leak. As a rule, the surgical treatment of chordomas and chondrosarcomas should aim to achieve total and radical removal. This will require mastering and utilizing various skull base approaches and employing all the technical advancements available in our armamentarium and the availability of intraoperative imaging and navigation.

Prolactinomas are the most common form of endocrinologically active pituitary adenoma; they account for ∼ 45% of pituitary adenomas encountered in clinical practice. Giant adenomas are those > 4 cm in diameter. Less than 0.5% of pituitary adenomas encountered in neurosurgical practice are giant prolactinomas. Patients with giant prolactinomas typically present with highly elevated prolactin levels, endocrinologic disturbances, and neurologic symptoms from mass-induced pressure. Described here is an unusual case of a giant prolactinoma presenting with neck pain and structural compromise of the occipital condyles. Transnasal biopsy of the nasopharyngeal portion of the mass obtained tissue consistent with an atypical prolactinoma with p53 reactivity and a high Ki-67 index of 5%. Despite the size and invasiveness of the tumor, the patient had resolution of his clinical symptoms, dramatic reduction of his hyperprolactinemia, and near-complete disappearance of his tumor following medical treatment.

Pit-1 immunostaining is not routinely used in the characterization of pituitary adenomas, and its utility in distinguishing adenomas dedicated towards the lactotroph, somatotroph, and thyrotroph lineage from null cell adenomas warrants further evaluation. Pituitary adenomas that were negative for expression of a basic panel of hormonal markers (ACTH, prolactin, and growth hormone) were further evaluated for TSH, SF-1, and Pit-1 expression using a tissue microarray. Among the 147 identified pituitary adenomas that were negative for ACTH, prolactin, growth hormone, and TSH, expression of SF-1 was present in 68 cases (46%). Of the remaining 72 cases with sufficient tissue for further analysis, four were Pit-1 positive (6% of the adenomas negative for ACTH, prolactin, growth hormone, TSH, and SF-1); the remaining 68 were potentially null cell adenomas. Two of the Pit-1-positive adenomas displayed a paranuclear CAM 5.2 staining pattern suggestive of a sparsely granulated somatotroph adenoma; however, only one case contained fibrous bodies within a majority of the adenoma cells. Our data suggests that Pit-1 can be utilized as a second tier immunostain in cases of clinically non-functioning adenomas that are immunonegative for ACTH, prolactin, growth hormone, TSH, and SF-1 in order to further segregate rare cases of Pit-1-positive adenomas from null cell adenomas. Pit-1 immunostaining can recognize rare cases of sparsely granulated somatotroph adenomas that appear immunonegative for growth hormone, as well as rare cases of other Pit-1-positive adenomas that are negative for Pit-1 lineage hormones. Overall, pituitary adenomas of the Pit-1 lineage that do not produce prolactin, growth hormone, or TSH are rare, with only four cases identified in the current study.

Surgery is the primary treatment for Cushing disease. When surgery is unsuccessful in normalizing hypercortisolism, adjuvant radiation, such as stereotactic radiosurgery, may be useful to improve biochemical control.This retrospective study included a cohort of consecutive patients treated with CyberKnife (CK) radiosurgery for active Cushing disease at Stanford Hospital and Clinics.As first-line treatment, all patients underwent transsphenoidal surgery with histologic demonstration of an adrenocorticotropic hormone-producing pituitary adenoma. CK was performed as adjuvant therapy for persistent or recurrent disease. The median time between surgery and CK was 14 ± 34 months. Before CK, median maximal diameter of tumors was 9 mm (range, 7-32 mm), with cavernous sinus invasion in all patients (100%) and abutment of the optic chiasm in 1 patient (14.2%). With an average follow-up of 55.4 months, normalization of hypercortisolism was achieved in 4 patients (57.1%): 2 patients (28.5%) achieved normalization of the hypothalamic-pituitary-adrenal axis without glucocorticoid replacement, and 2 patients developed hypoadrenalism (28.5%). The median time to biochemical remission was 12.5 months. Hypopituitarism occurred in only 1 patient (14.2%), and no patients had visual complications. Time between surgery and radiotherapy of14 months was associated with a significantly improved biochemical remission rate (P = 0.02).In a cohort of patients with Cushing disease, we demonstrate that CK is an effective treatment with rare complications.

Background Efforts to address resident errors and to enhance patient safety have included systemic reforms, such as the Accreditation Council for Graduate Medical Education's (ACGME's) mandated duty-hour restrictions, and specialty-specific initiatives such as the neurosurgery Milestone Project. However, there is currently little data describing the basis for these errors or outlining trends in neurosurgical resident error. Methods An online questionnaire was distributed to program directors of 108 U.S. neurosurgery residency training programs to assess the frequency, most common forms and causes of resident error, the resulting patient outcomes, and the steps taken by residency programs to address these errors. Results Thirty-one (28.7%) responses were received. Procedural/surgical error was the most commonly observed type of error. Transient injury and no injury to the patient were perceived to be the 2 most frequent outcomes. Inexperience or resident mistake despite adequate training were cited as the most common causes of error. Twenty-three (74.2%) respondents stated that a lower post graduate year level correlated with an increased incidence of errors. There was a trend toward an association between an increased number of residents within a program and the number of errors attributable to a lack of supervision (r = 0.36; P = 0.06). Most (93.5%) program directors do not believe that mandated duty-hour restrictions reduce error frequency. Conclusions Program directors believe that procedural error is the most commonly observed form of error, with post graduate year level believed to be an important predictor of error frequency. The perceived utility of systemic reforms that aim to reduce the incidence of resident error remains unclear.

Following stereotactic radiosurgery (SRS) for brain metastases, the median time range to develop adverse radiation effect (ARE) or radiation necrosis is 7-11 months. Similarly, the risk of local tumor recurrence following SRS is 5% after 18 months. With improvements in systemic therapy, patients are living longer and are at risk for both late (defined as 18 months after SRS) tumor recurrence and late ARE, which have not previously been well described. An IRB-approved, retrospective review identified patients treated with SRS who developed new MRI contrast enhancement 18 months following SRS. ARE was defined as stabilization/shrinkage of the lesion over time or pathologic confirmation of necrosis, without tumor. Local failure (LF) was defined as continued enlargement of the lesion over time or pathologic confirmation of tumor. We identified 16 patients, with a median follow-up of 48.2 months and median overall survival of 73.0 months, who had 19 metastases with late imaging changes occurring a median of 32.9 months (range 18.5-63.2 months) after SRS. Following SRS, 12 lesions had late ARE at a median of 33.2 months and 7 lesions had late LF occurring a median of 23.6 months. As patients with cancer live longer and as SRS is increasingly utilized for treatment of brain metastases, the incidence of these previously rare imaging changes is likely to increase. Clinicians should be aware of these late events, with ARE occurring up to 5.3 years and local failure up to 3.8 years following SRS in our cohort.

Background Patient stratification to identify subtypes with different disease manifestations, severity, and expected survival time is a critical task in cancer diagnosis and treatment. While stratification approaches using various biomarkers (including high-throughput gene expression measurements) for patient-to-patient comparisons have been successful in elucidating previously unseen subtypes, there remains an untapped potential of incorporating various genotypic and phenotypic data to discover novel or improved groupings. Methods Here, we present HOCUS, a unified analytical framework for patient stratification that uses a community detection technique to extract subtypes out of sparse patient measurements. HOCUS constructs a patient-to-patient network from similarities in the data and iteratively groups and reconstructs the network into higher order clusters. We investigate the merits of using higher-order correlations to cluster samples of cancer patients in terms of their associations with survival outcomes. Results In an initial test of the method, the approach identifies cancer subtypes in mutation data of glioblastoma, ovarian, breast, prostate, and bladder cancers. In several cases, HOCUS provides an improvement over using the molecular features directly to compare samples. Application of HOCUS to glioblastoma images reveals a size and location classification of tumors that improves over human expert-based stratification. Conclusions Subtypes based on higher order features can reveal comparable or distinct groupings. The distinct solutions can provide biologically- and treatment-relevant solutions that are just as significant as solutions based on the original data. Electronic supplementary material The online version of this article (doi:10.1186/s12920-017-0256-3) contains supplementary material, which is available to authorized users.

Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.

Purpose We report a longitudinal assessment of health-related quality of life (HRQOL) in patients with glioblastoma (GBM) treated on a prospective dose escalation trial of 5-fraction stereotactic radiosurgery (25-40 Gy in 5 fractions) with concurrent and adjuvant temozolomide. Methods HRQOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) general, the EORTC quality of life questionnaire-brain cancer specific module (QLQ-BN20), and the M.D. Anderson Symptom Inventory–Brain Tumor (MDASI-BT). Questionnaires were completed at baseline and at every follow-up visit after completion of radiosurgery. Changes from baseline for 9 predefined HRQOL measures (global quality of life, physical functioning, social functioning, emotional functioning, motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty) were calculated at every time point. Results With a median follow-up time of 10.4 months (range, 0.4-52 months), 139 total HRQOL questionnaires were completed by the 30 patients on trial. Compliance with HRQOL assessment was 76% at 12 months. Communication deficit significantly worsened over time, with a decline of 1.7 points per month ( P =.008). No significant changes over time were detected in the other 8 scales of our primary analysis, including global quality of life. Although 8 patients (27%) experienced adverse radiation effects (ARE) on this dose escalation trial, it was not associated with a statistically significant decline in any of the primary HRQOL scales. Disease progression was associated with communication deficit, with patients experiencing an average worsening of 13.9 points per month after progression compared with 0.7 points per month before progression ( P =.01). Conclusion On this 5-fraction dose escalation protocol for newly diagnosed GBM, overall HRQOL remained stable and appears similar to historical controls of 30 fractions of radiation therapy. Tumor recurrence was associated with worsening communication deficit, and ARE did not correlate with a decline in HRQOL.