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Anthony O. Asemota and Gary L. Gallia

OBJECTIVE

Frailty, a state of decreased physiological reserve, has been shown to significantly impact outcomes of surgery. The authors sought to examine the impact of frailty on the short-term outcomes of patients undergoing transsphenoidal pituitary surgery.

METHODS

Weighted data from the 2000–2014 National (Nationwide) Inpatient Sample were studied. Patients diagnosed with pituitary tumors or disorders who had undergone transsphenoidal pituitary surgery were identified. Frailty was determined using the Johns Hopkins Adjusted Clinical Groups (ACG) frailty-defining diagnoses indicator. Standard descriptive techniques and matched propensity score analyses were used to explore the odds ratios of postoperative complications, discharge dispositions, and costs.

RESULTS

A total of 115,317 cases were included in the analysis. Frailty was present in 1.48% of cases. The mean age of frail versus non-frail patients was 57.14 ± 16.96 years (mean ± standard deviation) versus 51.91 ± 15.88 years, respectively (p < 0.001). A greater proportion of frail compared to non-frail patients had an age ≥ 65 years (37.08% vs 24.08%, respectively, p < 0.001). Frail patients were more likely to be black or Hispanic (p < 0.001), possess Medicare or Medicaid insurance (p < 0.001), belong to lower-median-income groups (p < 0.001), and have greater comorbidity (p < 0.001). Results of propensity score–matched multivariate analysis revealed that frail patients were more likely to develop fluid and electrolyte disorders (OR 1.61, 95% CI 1.07–2.43, p = 0.02), intracranial vascular complications (OR 2.73, 95% CI 1.01–7.49, p = 0.04), mental status changes (OR 3.60, 95% CI 1.65–7.82, p < 0.001), and medical complications including pulmonary insufficiency (OR 2.01, 95% CI 1.13–4.05, p = 0.02) and acute kidney failure (OR 4.70, 95% CI 1.88–11.74, p = 0.01). The mortality rate was higher among frail patients (1.46% vs 0.37%, p < 0.001). Frail patients also demonstrated a greater likelihood for nonroutine discharges (p < 0.001), higher mean total charges ($109,614.33 [95% CI $92,756.09–$126,472.50] vs $56,370.35 [95% CI $55,595.72–$57,144.98], p < 0.001), and longer hospitalizations (9.27 days [95% CI 7.79–10.75] vs 4.46 days [95% CI 4.39–4.53], p < 0.001).

CONCLUSIONS

Frailty in patients undergoing transsphenoidal pituitary surgery is associated with worse postoperative outcomes and higher costs, indicating that state’s potential role in routine preoperative risk stratification.

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Gary L. Gallia, Anthony O. Asemota, Ari M. Blitz, Andrew P. Lane, Wayne Koch, Douglas D. Reh and Masaru Ishii

OBJECTIVE

Olfactory neuroblastoma (ONB) is a rare malignant neoplasm of the sinonasal cavity. Surgery has been and remains a mainstay of treatment for patients with this tumor. Open craniofacial resections have been the treatment of choice for many decades. More recently, experience has been growing with endoscopic approaches in the management of patients with ONB. The object of this study is to report the authors’ experience over the past 11 years with ONB patients treated with purely endonasal endoscopic techniques.

METHODS

The authors performed a retrospective chart review of 20 consecutive patients with ONB who underwent a completely endonasal endoscopic approach for an oncological tumor resection at their institution between January 2006 and January 2017. Patient demographics, tumor stage, pathological grade, frozen section analysis, permanent margin assessment, perioperative complications, postoperative therapy, length of follow-up, and outcomes at last follow-up were collected and analyzed.

RESULTS

Eighteen patients presented with newly diagnosed disease, with a modified Kadish stage of A in 2 cases, B in 3, C in 11, and D in 2. Two patients presented with recurrent tumors. An average of 25.3 specimens per patient were examined by frozen section analysis. Although analysis of intraoperative frozen section margins was negative in all but 1 case, microscopic foci of tumor were found in 7 cases (35%) on permanent histopathological analysis. Perioperative complications occurred in 7 patients (35%) including 1 patient who developed a cerebrospinal fluid leak; there were no episodes of meningitis. All but 1 patient received postoperative radiotherapy, and 5 patients received postoperative chemotherapy. With a mean follow-up of over 5 years, 19 patients were alive and 1 patient died from an unrelated cause. There were 2 cases of tumor recurrence. The 5-year overall, disease-specific, and recurrence-free survival rates were 92.9%, 100%, and 92.9%, respectively.

CONCLUSIONS

The current results provide additional evidence for the continued use of endoscopic procedures in the management of this malignancy.

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Rachel Sarabia-Estrada, Alejandro Ruiz-Valls, Sagar R. Shah, A. Karim Ahmed, Alvaro A. Ordonez, Fausto J. Rodriguez, Hugo Guerrero-Cazares, Ismael Jimenez-Estrada, Esteban Velarde, Betty Tyler, Yuxin Li, Neil A. Phillips, C. Rory Goodwin, Rory J. Petteys, Sanjay K. Jain, Gary L. Gallia, Ziya L. Gokaslan, Alfredo Quinones-Hinojosa and Daniel M. Sciubba

OBJECTIVE

Chordoma is a slow-growing, locally aggressive cancer that is minimally responsive to conventional chemotherapy and radiotherapy and has high local recurrence rates after resection. Currently, there are no rodent models of spinal chordoma. In the present study, the authors sought to develop and characterize an orthotopic model of human chordoma in an immunocompromised rat.

METHODS

Thirty-four immunocompromised rats were randomly allocated to 4 study groups; 22 of the 34 rats were engrafted in the lumbar spine with human chordoma. The groups were as follows: UCH1 tumor–engrafted (n = 11), JHC7 tumor–engrafted (n = 11), sham surgery (n = 6), and intact control (n = 6) rats. Neurological impairment of rats due to tumor growth was evaluated using open field and locomotion gait analysis; pain response was evaluated using mechanical or thermal paw stimulation. Cone beam CT (CBCT), MRI, and nanoScan PET/CT were performed to evaluate bony changes due to tumor growth. On Day 550, rats were killed and spines were processed for H & E–based histological examination and immunohistochemistry for brachyury, S100β, and cytokeratin.

RESULTS

The spine tumors displayed typical chordoma morphology, that is, physaliferous cells filled with vacuolated cytoplasm of mucoid matrix. Brachyury immunoreactivity was confirmed by immunostaining, in which samples from tumor-engrafted rats showed a strong nuclear signal. Sclerotic lesions in the vertebral body of rats in the UCH1 and JHC7 groups were observed on CBCT. Tumor growth was confirmed using contrast-enhanced MRI. In UCH1 rats, large tumors were observed growing from the vertebral body. JHC7 chordoma–engrafted rats showed smaller tumors confined to the bone periphery compared with UCH1 chordoma–engrafted rats. Locomotion analysis showed a disruption in the normal gait pattern, with an increase in the step length and duration of the gait in tumor-engrafted rats. The distance traveled and the speed of rats in the open field test was significantly reduced in the UCH1 and JHC7 tumor–engrafted rats compared with controls. Nociceptive response to a mechanical stimulus showed a significant (p < 0.001) increase in the paw withdrawal threshold (mechanical hypalgesia). In contrast, the paw withdrawal response to a thermal stimulus decreased significantly (p < 0.05) in tumor-engrafted rats.

CONCLUSIONS

The authors developed an orthotopic human chordoma model in rats. Rats were followed for 550 days using imaging techniques, including MRI, CBCT, and nanoScan PET/CT, to evaluate lesion progression and bony integrity. Nociceptive evaluations and locomotion analysis were performed during follow-up. This model reproduces cardinal signs, such as locomotor and sensory deficits, similar to those observed clinically in human patients. To the authors’ knowledge, this is the first spine rodent model of human chordoma. Its use and further study will be essential for pathophysiology research and the development of new therapeutic strategies.

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Kaisorn L. Chaichana, Patricia Zadnik, Jon D. Weingart, Alessandro Olivi, Gary L. Gallia, Jaishri Blakeley, Michael Lim, Henry Brem and Alfredo Quiñones-Hinojosa

Object

Glioblastoma is the most common and aggressive type of primary brain tumor in adults. These tumors recur regardless of intervention. This propensity to recur despite aggressive therapies has made many perceive that repeated resections have little utility. The goal of this study was to evaluate if patients who underwent repeat resections experienced improved survival as compared with patients with fewer numbers of resections, and whether the number of resections was an independent predictor of prolonged survival.

Methods

The records of adult patients who underwent surgery for an intracranial primary glioblastoma at an academic tertiary-care institution between 1997 and 2007 were retrospectively reviewed. Multivariate proportionalhazards regression analysis was used to identify an association between glioblastoma resection number and survival after controlling for factors known to be associated with survival, such as age, functional status, periventricular location, extent of resection, and adjuvant therapy. Survival as a function of time was plotted using the Kaplan-Meier method, and survival rates were compared using log-rank analysis.

Results

Five hundred seventy-eight patients with primary glioblastoma met the inclusion/exclusion criteria. At last follow-up, 354, 168, 41, and 15 patients underwent 1, 2, 3, or 4 resections, respectively. The median survival for patients who underwent 1, 2, 3, and 4 resections was 6.8, 15.5, 22.4, and 26.6 months (p < 0.05), respectively. In multivariate analysis, patients who underwent only 1 resection experienced shortened survival (relative risk [RR] 3.400, 95% CI 2.423–4.774; p < 0.0001) as compared with patients who underwent 2 (RR 0.688, 95% CI 0.525–0.898; p = 0.0006), 3 (RR 0.614, 95% CI 0.388–0.929; p = 0.02), or 4 (RR 0.600, 95% CI 0.238–0.853; p = 0.01) resections. These results were verified in a case-control evaluation, controlling for age, neurological function, periventricular tumor location, extent of resection, and adjuvant therapy. Patients who underwent 1, 2, or 3 resections had a median survival of 4.5, 16.2, and 24.4 months, respectively (p < 0.05). Additionally, the risk of infections or iatrogenic deficits did not increase with repeated resections in this patient population (p > 0.05).

Conclusions

Patients with glioblastoma will inevitably experience tumor recurrence. The present study shows that patients with recurrent glioblastoma can have improved survival with repeated resections. The findings of this study, however, may be limited by an intrinsic bias associated with patient selection. The authors attempted to minimize these biases by using strict inclusion criteria, multivariate analyses, and case-control evaluation.

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Deric M. Park

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I-Mei Siu, Vafi Salmasi, Brent A. Orr, Qi Zhao, Zev A. Binder, Christine Tran, Masaru Ishii, Gregory J. Riggins, Christine L. Hann and Gary L. Gallia

Object

Chordomas are rare tumors arising from remnants of the notochord. Because of the challenges in achieving a complete resection, the radioresistant nature of these tumors, and the lack of effective chemotherapeutics, the median survival for patients with chordomas is approximately 6 years. Reproducible preclinical model systems that closely mimic the original patient's tumor are essential for the development and evaluation of effective therapeutics. Currently, there are only a few established chordoma cell lines and no primary xenograft model. In this study, the authors aimed to develop a primary chordoma xenograft model.

Methods

The authors implanted independent tumor samples from 2 patients into athymic nude mice. The resulting xenograft line was characterized by histopathological analysis and immunohistochemical staining. The patient's tumor and serial passages of the xenograft were genomically analyzed using a 660,000 single-nucleotide polymorphism array.

Results

A serially transplantable xenograft was established from one of the 2 patient samples. Histopathological analysis and immunohistochemical staining for S100 protein, epithelial membrane antigen, and cytokeratin AE1/AE3 of the primary patient sample and the xenografts confirmed that the xenografts were identical to the original chordoma obtained from the patient. Immunohistochemical staining and western blot analysis confirmed the presence of brachyury, a recently described marker of chordomas, in the tumor from the patient and each of the xenografts. Genome-wide variation was assessed between the patient's tumor and the xenografts and was found to be more than 99.9% concordant.

Conclusions

To the best of their knowledge, the authors have established the first primary chordoma xenograft that will provide a useful preclinical model for this disease and a platform for therapeutic development.

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Wesley Hsu, I-Mei Siu, Gustavo Pradilla, Ziya L. Gokaslan, George I. Jallo and Gary L. Gallia

Object

Advances in the diagnosis and management of patients with spinal cord tumors have been limited because of the rarity of the disease and the limitations of current animal models for spinal cord glioma. The ideal spinal cord tumor model would possess a number of characteristics, including the use of human glioma cells that capture the growth pattern and local invasive nature of their human counterpart. In this study, the authors' goal was to develop a novel spinal cord tumor model using a human neurosphere cell line.

Methods

Eighteen female athymic rats were randomized into 3 experimental groups. Animals in the first group (6 rats) received a 3-ml intramedullary injection containing DMEM and were used as controls. Animals in the second group (6 rats) received a 3-ml intramedullary injection containing 100,000 glioblastoma multiforme (GBM) neurosphere cells in 3 ml DMEM. Animals in the third group (6 rats) received a 3-ml intramedullary injection containing 9L gliosarcoma cells in 3 ml DMEM. Functional testing of hindlimb strength was assessed using the Basso-Beattie-Bresnahan (BBB) scale. Once the functional BBB score of an animal was less than or equal to 5 (slight movement of 2 joints and extensive movement of the third), euthanasia was performed.

Results

Animals in the GBM neurosphere group had a mean survival of 33.3 ± 2.0 days, which was approximately twice as long as animals in the 9L gliosarcoma group (16.3 ± 2.3 days). There was a significant difference between survival of the GBM neurosphere and 9L gliosarcoma groups (p < 0.001). None of the control animals died (p < 0.001 for GBM neurosphere group vs controls and 9L vs controls). Histopathological examination of the rats injected with 9L gliosarcoma revealed that all animals developed highly cellular, well-circumscribed lesions causing compression of the surrounding tissue, with minimal invasion of the surrounding gray and white matter. Histopathological examination of animals injected with GBM neurospheres revealed that all animals developed infiltrative lesions with a high degree of white and gray matter invasion along with areas of necrosis.

Conclusions

The authors have established a novel animal model of spinal cord glioma using neurospheres derived from human GBM. When injected into the spinal cords of athymic nude rats, neurospheres gave rise to infiltrative, actively proliferating tumors that were histologically identical to spinal cord glioma in humans. On the basis of their results, the authors conclude that this is a reproducible animal model of high-grade spinal cord glioma based on a human GBM neurosphere line. This model represents an improvement over other models using nonhuman glioma cell lines. Novel therapeutic strategies can be readily evaluated using this model.

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I-Mei Siu, Betty M. Tyler, James X. Chen, Charles G. Eberhart, Ulrich-Wilhelm Thomale, Alessandro Olivi, George I. Jallo, Gregory J. Riggins and Gary L. Gallia

Object

Diffuse brainstem tumors are the most difficult type of pediatric CNS malignancy to treat. These inoperable lesions are treated with radiation alone or in combination with chemotherapy, and the survival rate is less than 10%. It is therefore essential to develop a reliable animal model to screen new therapeutic agents for the treatment of this type of tumor.

Methods

A multipotent human glioblastoma stemlike neurosphere line, 060919, was established from a surgically resected glioblastoma specimen; when cells were implanted intracranially into athymic nude mice, they formed invasive, vascular tumors that exhibited the features of glioblastoma. Ten female Fischer 344 rats received an injection of 75,000 F98 rat glioma cells and 10 female athymic nude rats received an injection of 75,000 060919 human glioblastoma stemlike cells in the pontine tegmentum of the brainstem. A control group of 5 female Fischer rats received an injection of saline in the same location as the animals in the tumor groups. Kaplan-Meier curves were generated for survival, and brains were processed postmortem for histopathological investigation.

Results

Both F98 cells and 060919 cells grew in 100% of the animals injected. Median survival of animals injected with F98 was 15 days, consistent with the authors' previous reports on the establishment of the brainstem tumor model using the F98 rat glioma line. Median survival of animals injected with 060919 was 31 days. Histopathological analysis of the tumors confirmed the presence of brainstem lesions in animals that received brainstem injections of F98 and in animals that received brainstem injections of 060919. The 060919 brainstem tumors histologically resembled glioblastoma.

Conclusions

Tumor take and median survival were consistent for animals injected in the brainstem with either the established F98 rat glioma cell line or the 060919 human glioblastoma stemlike neurosphere line. Histopathological features of the 060919 brainstem tumors resembled glioblastoma. Establishment of this human glioblastoma stemlike brainstem animal model will improve the evaluation and identification of more efficacious agents for the treatment of high-grade brainstem tumors.

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Gary L. Gallia and Charles Teo

✓Spontaneous ventriculocisternostomy, the spontaneous communication between the ventricular system and the subarachnoid space, is rare. The authors report a case of an infant with obstructive hydrocephalus who developed a spontaneous third ventriculocisternostomy. The infant was initially evaluated for progressive ventriculomegaly and increasing head circumference (HC). During follow-up, the patient's HC began to follow percentile lines and magnetic resonance (MR) imaging demonstrated a reduction of the hydrocephalus. Flow-sensitive phase-contrast cine MR images revealed cerebrospinal fluid (CSF) flow through the floor of the third ventricle between the tuber cinereum and the mammillary bodies connecting the ventricular system with the prepontine cistern. Although rare, clinicians should be cognizant of this phenomenon as it may eliminate the need for CSF diversion.

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Gary L. Gallia, Daniel M. Sciubba, Ali Bydon, Ian Suk, Jean-Paul Wolinsky, Ziya L. Gokaslan and Timothy F. Witham

✓The authors describe a technique for total L-5 spondylectomy and reconstruction of the lumbosacral junction. The technique, which involves separately staged posterior and anterior procedures, is reported in two patients harboring neoplasms that involved the L-5 level. The first stage consisted of a posterior approach with removal of all posterior bone elements of L-5 and radical L4–5 and L5–S1 discectomies. Lumbosacral and lumbopelvic instrumentation included pedicle screws as well as iliac screws or a transiliac rod. The second stage consisted of an anterior approach with mobilization of vascular structures, completion of L4–5 and L5–S1 discectomies, and removal of the L-5 vertebral body. Anterior lumbosacral reconstruction included placement of a distractable cage and tension band between L-4 and S-1. Allograft bone was used for fusion in both stages. No significant complications were encountered. At more than 1 year of follow-up, both patients were independently ambulatory, without evidence of recurrent or metastatic disease, and adequate lumbosacral alignment was maintained. The authors conclude that this technique can be safely performed in appropriately selected patients with neoplasms involving L-5.