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  • Author or Editor: Susan C. Pannullo x
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George K. Lewis Jr., Zachary R. Schulz, Susan C. Pannullo, Teresa L. Southard and William L. Olbricht

Object

In convection-enhanced delivery (CED), drugs are infused locally into tissue through a cannula inserted into the brain parenchyma to enhance drug penetration over diffusion strategies. The purpose of this study was to demonstrate the feasibility of ultrasound-assisted CED (UCED) in the rodent brain in vivo using a novel, low-profile transducer cannula assembly (TCA) and portable, pocket-sized ultrasound system.

Methods

Forty Sprague-Dawley rats (350–450 g) were divided into 2 equal groups (Groups 1 and 2). Each group was divided again into 4 subgroups (n = 5 in each). The caudate of each rodent brain was infused with 0.25 wt% Evans blue dye (EBD) in phosphate-buffered saline at 2 different infusion rates of 0.25 μl/minute (Group 1), and 0.5 μl/minute (Group 2). The infusion rates were increased slowly over 10 minutes from 0.05 to 0.25 μl/minute (Group 1) and from 0.1 to 0.5 μl/minute (Group 2). The final flow rate was maintained for 20 minutes. Rodents in the 4 control subgroups were infused using the TCA without ultrasound and without and with microbubbles added to the infusate (CED and CED + MB, respectively). Rodents in the 4 UCED subgroups were infused without and with microbubbles added to the infusate (UCED and UCED + MB) using the TCA with continuous-wave 1.34-MHz low-intensity ultrasound at a total acoustic power of 0.11 ± 0.005 W and peak spatial intensity at the cannula tip of 49.7 mW/cm2. An additional 4 Sprague-Dawley rats (350–450 g) received UCED at 4 different and higher ultrasound intensities at the cannula tip ranging from 62.0 to 155.0 mW/cm2 for 30 minutes. The 3D infusion distribution was reconstructed using MATLAB analysis. Tissue damage and morphological changes to the brain were assessed using H & E.

Results

The application of ultrasound during infusion (UCED and UCED + MB) improved the volumetric distribution of EBD in the brain by a factor of 2.24 to 3.25 when there were no microbubbles in the infusate and by a factor of 1.16 to 1.70 when microbubbles were added to the infusate (p < 0.001). On gross and histological examination, no damage to the brain tissue was found for any acoustic exposure applied to the brain.

Conclusions

The TCA and ultrasound device show promise to improve the distribution of infused compounds during CED. The results suggest further studies are required to optimize infusion and acoustic parameters for small compounds and for larger molecular weight compounds that are representative of promising antitumor agents. In addition, safe levels of ultrasound exposure in chronic experiments must be determined for practical clinical evaluation of UCED. Extension of these experiments to larger animal models is warranted to demonstrate efficacy of this technique.

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Nitin Agarwal, Michael D. White, Susan C. Pannullo and Lola B. Chambless

OBJECTIVE

Resident attrition creates a profound burden on trainees and residency programs. This study aims to analyze trends in resident attrition in neurological surgery.

METHODS

This study followed a cohort of 1275 residents who started neurosurgical residency from 2005 to 2010. Data obtained from the American Association of Neurological Surgeons (AANS) included residents who matched in neurosurgery during this time. Residents who did not finish their residency training at the program in which they started were placed into the attrition group. Residents in the attrition group were characterized by one of five outcomes: transferred neurosurgery programs; transferred to a different specialty; left clinical medicine; deceased; or unknown. A thorough internet search was conducted for residents who did not complete their training at their first neurosurgical program. Variables leading to attrition were also analyzed, including age, sex, presence of advanced degree (Ph.D.), postgraduate year (PGY), and geographical region of program.

RESULTS

Residents starting neurosurgical residency from 2005 to 2010 had an overall attrition rate of 10.98%. There was no statistically significant difference in attrition rates among the years (p = 0.337). The outcomes for residents in the attrition group were found to be as follows: 33.61% transferred neurosurgical programs, 56.30% transferred to a different medical specialty, 8.40% left clinical medicine, and 1.68% were deceased. It was observed that women had a higher attrition rate (18.50%) than men (10.35%). Most attrition (65.07%) occurred during PGY 1 or 2. The attrition group was also observed to be significantly older at the beginning of residency training, with a mean of 31.69 years of age compared to 29.31 in the nonattrition group (p < 0.001). No significant difference was observed in the attrition rates for residents with a Ph.D. (9.86%) compared to those without a Ph.D. (p = 0.472).

CONCLUSIONS

A majority of residents in the attrition group pursued training in different medical specialties, most commonly neurology, radiology, and anesthesiology. Factors associated with an increased rate of attrition were older age at the beginning of residency, female sex, and junior resident (PGY-1 to PGY-2). Resident attrition remains a significant problem within neurosurgical training, and future studies should focus on targeted interventions to identify individuals at risk to help them succeed in their medical careers.

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Alexander M. Stessin, Allie Schwartz, Grigorij Judanin, Susan C. Pannullo, John A. Boockvar, Theodore H. Schwartz, Philip E. Stieg and A. Gabriella Wernicke

Object

The aim of this study was to examine the effect of postoperative external-beam radiation therapy (EBRT) on disease-specific survival in patients with nonbenign meningiomas.

Methods

The Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2007 was queried for cases of resected Grades II (atypical) and III (malignant) meningioma. Disease-specific survival outcomes were determined using Kaplan-Meier survival analysis and Cox proportional hazards models. Logistic regression analysis was used to determine the likelihood of receiving EBRT for Grade II versus Grade III. Because atypical and malignant meningiomas underwent WHO reclassification in 2000, the authors carried out an additional analysis of outcomes of these tumors from 2000 to 2008.

Results

There were 657 patients included in the analysis; of these, 244 received adjuvant radiation. Compared with patients with Grade II meningioma, patients with Grade III disease were 41.9% more likely to receive EBRT after gross-total resection and 36.7% more likely to receive it after subtotal resection (95% CI 0.58–3.26). Controlling for grade, extent of resection, size and anatomical location of the tumor, year of diagnosis, race, age, and sex, adjuvant EBRT did not impart a survival benefit (HR 1.492; 95% CI 0.827–2.692). There was also no survival advantage to EBRT in an analysis of cases diagnosed after the WHO 2000 reclassification of meningiomas (HR 0.828; 95% CI 0.350–1.961).

Conclusions

The results of this population-based retrospective analysis demonstrate that the role of radiation remains unclear. They underscore the need for randomized prospective clinical trials to assess the usefulness of adjuvant EBRT in Grades II and III meningioma so as to define more precisely the subset of patients who may benefit from the addition of adjuvant radiation.

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Sandeep Mittal, Neil V. Klinger, Sharon K. Michelhaugh, Geoffrey R. Barger, Susan C. Pannullo and Csaba Juhász

OBJECTIVE

Treatment for glioblastoma (GBM) remains largely unsuccessful, even with aggressive combined treatment via surgery, radiotherapy, and chemotherapy. Tumor treating fields (TTFs) are low-intensity, intermediate-frequency, alternating electric fields that have antiproliferative properties in vitro and in vivo. The authors provide an up-to-date review of the mechanism of action as well as preclinical and clinical data on TTFs.

METHODS

A systematic review of the literature was performed using the terms “tumor treating fields,” “alternating electric fields,” “glioblastoma,” “Optune,” “NovoTTF-100A,” and “Novocure.”

RESULTS

Preclinical and clinical data have demonstrated the potential efficacy of TTFs for treatment of GBM, leading to several pilot studies, clinical trials, and, in 2011, FDA approval for its use as salvage therapy for recurrent GBM and, in 2015, approval for newly diagnosed GBM.

CONCLUSIONS

Current evidence supports the use of TTFs as an efficacious, antimitotic treatment with minimal toxicity in patients with newly diagnosed and recurrent GBM. Additional studies are needed to further optimize patient selection, determine cost-effectiveness, and assess the full impact on quality of life.

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Gabrielle Lynch, Karina Nieto, Saumya Puthenveettil, Marleen Reyes, Michael Jureller, Jason H. Huang, M. Sean Grady, Odette A. Harris, Aruna Ganju, Isabelle M. Germano, Julie G. Pilitsis, Susan C. Pannullo, Deborah L. Benzil, Aviva Abosch, Sarah J. Fouke and Uzma Samadani

OBJECT

The objective of this study is to determine neurosurgery residency attrition rates by sex of matched applicant and by type and rank of medical school attended.

METHODS

The study follows a cohort of 1361 individuals who matched into a neurosurgery residency program through the SF Match Fellowship and Residency Matching Service from 1990 to 1999. The main outcome measure was achievement of board certification as documented in the American Board of Neurological Surgery Directory of Diplomats. A secondary outcome measure was documentation of practicing medicine as verified by the American Medical Association DoctorFinder and National Provider Identifier websites. Overall, 10.7% (n = 146) of these individuals were women. Twenty percent (n = 266) graduated from a top 10 medical school (24% of women [35/146] and 19% of men [232/1215], p = 0.19). Forty-five percent (n = 618) were graduates of a public medical school, 50% (n = 680) of a private medical school, and 5% (n = 63) of an international medical school. At the end of the study, 0.2% of subjects (n = 3) were deceased and 0.3% (n = 4) were lost to follow-up.

RESULTS

The total residency completion rate was 86.0% (n = 1171) overall, with 76.0% (n = 111/146) of women and 87.2% (n = 1059/1215) of men completing residency. Board certification was obtained by 79.4% (n = 1081) of all individuals matching into residency between 1990 and 1999. Overall, 63.0% (92/146) of women and 81.3% (989/1215) of men were board certified. Women were found to be significantly more at risk (p < 0.005) of not completing residency or becoming board certified than men. Public medical school alumni had significantly higher board certification rates than private and international alumni (82.2% for public [508/618]; 77.1% for private [524/680]; 77.8% for international [49/63]; p < 0.05). There was no significant difference in attrition for graduates of top 10–ranked institutions versus other institutions. There was no difference in number of years to achieve neurosurgical board certification for men versus women.

CONCLUSIONS

Overall, neurosurgery training attrition rates are low. Women have had greater attrition than men during and after neurosurgery residency training. International and private medical school alumni had higher attrition than public medical school alumni.

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A. Gabriella Wernicke, Andrew W. Smith, Shoshana Taube, Menachem Z. Yondorf, Bhupesh Parashar, Samuel Trichter, Lucy Nedialkova, Albert Sabbas, Paul Christos, Rohan Ramakrishna, Susan C. Pannullo, Philip E. Stieg and Theodore H. Schwartz

OBJECTIVE

Managing patients whose intraparenchymal brain metastases recur after radiotherapy remains a challenge. Intraoperative cesium-131 (Cs-131) brachytherapy performed at the time of neurosurgical resection may represent an excellent salvage treatment option. The authors evaluated the outcomes of this novel treatment with permanent intraoperative Cs-131 brachytherapy.

METHODS

Thirteen patients with 15 metastases to the brain that recurred after stereotactic radiosurgery and/or whole brain radiotherapy were treated between 2010 and 2015. Stranded Cs-131 seeds were placed as a permanent volume implant. Prescription dose was 80 Gy at 5-mm depth from the resection cavity surface. The primary end point was resection cavity freedom from progression (FFP). Resection cavity freedom from progression (FFP), regional FFP, distant FFP, median survival, overall survival (OS), and toxicity were assessed.

RESULTS

The median duration of follow-up after salvage treatment was 5 months (range 0.5–18 months). The patients' median age was 64 years (range 51–74 years). The median resected tumor diameter was 2.9 cm (range 1.0–5.6 cm). The median number of seeds implanted was 19 (range 10–40), with a median activity per seed of 2.25 U (range 1.98–3.01 U) and median total activity of 39.6 U (range 20.0–95.2 U). The 1-year actuarial local FFP was 83.3%. The median OS was 7 months, and 1-year OS was 24.7%. Complications included infection (3), pseudomeningocele (1), seizure (1), and asymptomatic radionecrosis (RN) (1).

CONCLUSIONS

After failure of prior irradiation of brain metastases, re-irradiation with intraoperative Cs-131 brachytherapy implants provides durable local control and limits the risk of RN. The authors' initial experience demonstrates that this treatment approach is well tolerated and safe for patients with previously irradiated tumors after failure of more than 1 radiotherapy regimen and that it results in excellent response rates and minimal toxicity.

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Asif Raza Shafiq, A. Gabriella Wernicke, Charles Alex Riley, Peter F. Morgenstern, Lucy Nedialkova, Susan C. Pannullo, Bhupesh Parashar, Rajiv Magge and Theodore H. Schwartz

There are few therapeutic options available for the treatment of recurrent meningiomas that have failed treatment with surgery and external-beam radiation therapy (EBRT). As additional EBRT is clinically risky, brachytherapy offers an important alternative for optimizing local control. In skull base meningiomas, the endoscopic endonasal approach (EEA) has demonstrated an excellent extent of resection. However, in the case of recurrent, atypical, or residual meningiomas, the EEA alone may not be adequate to address microscopic, residual, highly proliferative disease. In this situation, local radioactive seed brachytherapy has been shown to improve control, but few reports of this technique exist. A 48-year-old right-handed man presented on multiple occasions with recurrence of an anaplastic skull base meningioma, after multiple prior gross-total resections and multiple rounds of radiotherapy had failed. The authors performed a maximally safe neurosurgical tumor resection via EEA supplemented by the intraoperative implantation of 131Cs low-dose permanent brachytherapy seeds. They describe a technique for permanent implantation of brachytherapy seeds and provide operative video of this technique. The authors submit that utilizing this technique in combination with EEA tumor resection renders a minimally invasive approach to improving local control in a patient with a recurrent anaplastic or atypical meningioma of the skull base.

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John A. Boockvar, Apostolos J. Tsiouris, Christoph P. Hofstetter, Ilhami Kovanlikaya, Sherese Fralin, Kartik Kesavabhotla, Stephen M. Seedial, Susan C. Pannullo, Theodore H. Schwartz, Philip Stieg, Robert D. Zimmerman, Jared Knopman, Ronald J. Scheff, Paul Christos, Shankar Vallabhajosula and Howard A. Riina

Object

The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma.

Methods

A total of 30 patients with recurrent malignant glioma were included in the current study.

Results

The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients.

Conclusions

The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.