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Arbaz A. Momin, Pranay Soni, Jianning Shao, Amy S. Nowacki, John H. Suh, Erin S. Murphy, Samuel T. Chao, Lilyana Angelov, Alireza M. Mohammadi, Gene H. Barnett, Pablo F. Recinos, and Varun R. Kshettry

OBJECTIVE

After gross-total resection (GTR) of a newly diagnosed WHO grade II meningioma, the decision to treat with radiation upfront or at initial recurrence remains controversial. A comparison of progression-free survival (PFS) between observation and adjuvant radiation fails to account for the potential success of salvage radiation, and a direct comparison of PFS between adjuvant and salvage radiation is hampered by strong selection bias against salvage radiation cohorts in which only more aggressive, recurrent tumors are included. To account for the limitations of traditional PFS measures, the authors evaluated radiation failure-free survival (RFFS) between two treatment strategies after GTR: adjuvant radiation versus observation with salvage radiation, if necessary.

METHODS

The authors performed a retrospective review of patients who underwent GTR of newly diagnosed WHO grade II meningiomas at their institution between 1996 and 2019. They assessed traditional PFS in patients who underwent adjuvant radiation, postoperative observation, and salvage radiation. For RFFS, treatment failure was defined as time from initial surgery to failure of first radiation. To assess the association between treatment strategy and RFFS while accounting for potential confounders, a multivariable Cox regression analysis adjusted for the propensity score (PS) and inverse probability of treatment weighted (IPTW) Cox regression analysis were performed.

RESULTS

A total of 160 patients underwent GTR and were included in this study. Of the 121 patients who underwent observation, 32 (26.4%) developed recurrence and required salvage radiation. PFS at 3, 5, and 10 years after observation was 75.1%, 65.6%, and 45.5%, respectively. PFS at 3 and 5 years after salvage radiation was 81.7% and 61.3%, respectively. Of 160 patients, 39 received adjuvant radiation, and 3- and 5-year PFS/RFFS rates were 86.1% and 59.2%, respectively. In patients who underwent observation with salvage radiation, if necessary, the 3-, 5-, and 10-year RFFS rates were 97.7%, 90.3%, and 87.9%, respectively. Both PS and IPTW Cox regression models demonstrated that patients who underwent observation with salvage radiation treatment, if necessary, had significantly longer RFFS (PS model: hazard ratio [HR] 0.21, p < 0.01; IPTW model: HR 0.21, p < 0.01).

CONCLUSIONS

In this retrospective, nonrandomized study, adjuvant radiation after GTR of a WHO II meningioma did not add significant benefit over a strategy of observation and salvage radiation at initial recurrence, if necessary, but results must be considered in the context of the limitations of the study design.

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Rebecca M. Burke, Ching-Jen Chen, Dale Ding, Thomas J. Buell, Jennifer D. Sokolowski, Cheng-Chia Lee, Hideyuki Kano, Kathryn N. Kearns, Shih-Wei Tzeng, Huai-che Yang, Paul P. Huang, Douglas Kondziolka, Natasha Ironside, David Mathieu, Christian Iorio-Morin, Inga S. Grills, Caleb Feliciano, Gene H. Barnett, Robert M. Starke, L. Dade Lunsford, and Jason P. Sheehan

OBJECTIVE

Stereotactic radiosurgery (SRS) is a treatment option for pediatric brain arteriovenous malformations (AVMs), and early obliteration could encourage SRS utilization for a subset of particularly radiosensitive lesions. The objective of this study was to determine predictors of early obliteration after SRS for pediatric AVMs.

METHODS

The authors performed a retrospective review of the International Radiosurgery Research Foundation AVM database. Obliterated pediatric AVMs were sorted into early (obliteration ≤ 24 months after SRS) and late (obliteration > 24 months after SRS) responders. Predictors of early obliteration were identified, and the outcomes of each group were compared.

RESULTS

The overall study cohort was composed of 345 pediatric patients with obliterated AVMs. The early and late obliteration cohorts were made up of 95 (28%) and 250 (72%) patients, respectively. Independent predictors of early obliteration were female sex, a single SRS treatment, a higher margin dose, a higher isodose line, a deep AVM location, and a smaller AVM volume. The crude rate of post-SRS hemorrhage was 50% lower in the early (3.2%) than in the late (6.4%) obliteration cohorts, but this difference was not statistically significant (p = 0.248). The other outcomes of the early versus late obliteration cohorts were similar, with respect to symptomatic radiation-induced changes (RICs), cyst formation, and tumor formation.

CONCLUSIONS

Approximately one-quarter of pediatric AVMs that become obliterated after SRS will achieve this radiological endpoint within 24 months of initial SRS. The authors identified multiple factors associated with early obliteration, which may aid in prognostication and management. The overall risks of delayed hemorrhage, RICs, cyst formation, and tumor formation were not statistically different in patients with early versus late obliteration.

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Elsa V. Arocho-Quinones, Sean M. Lew, Michael H. Handler, Zulma Tovar-Spinoza, Matthew Smyth, Robert Bollo, David Donahue, M. Scott Perry, Michael L. Levy, David Gonda, Francesco T. Mangano, Phillip B. Storm, Angela V. Price, Daniel E. Couture, Chima Oluigbo, Ann-Christine Duhaime, Gene H. Barnett, Carrie R. Muh, Michael D. Sather, Aria Fallah, Anthony C. Wang, Sanjiv Bhatia, Kadam Patel, Sergey Tarima, Sarah Graber, Sean Huckins, Daniel M. Hafez, Kavelin Rumalla, Laurie Bailey, Sabrina Shandley, Ashton Roach, Erin Alexander, Wendy Jenkins, Deki Tsering, George Price, Antonio Meola, Wendi Evanoff, Eric M. Thompson, Nicholas Brandmeir, and the Pediatric Stereotactic Laser Ablation Workgroup

OBJECTIVE

This study aimed to assess the safety and efficacy of MR-guided stereotactic laser ablation (SLA) therapy in the treatment of pediatric brain tumors.

METHODS

Data from 17 North American centers were retrospectively reviewed. Clinical, technical, and radiographic data for pediatric patients treated with SLA for a diagnosis of brain tumor from 2008 to 2016 were collected and analyzed.

RESULTS

A total of 86 patients (mean age 12.2 ± 4.5 years) with 76 low-grade (I or II) and 10 high-grade (III or IV) tumors were included. Tumor location included lobar (38.4%), deep (45.3%), and cerebellar (16.3%) compartments. The mean follow-up time was 24 months (median 18 months, range 3–72 months). At the last follow-up, the volume of SLA-treated tumors had decreased in 80.6% of patients with follow-up data. Patients with high-grade tumors were more likely to have an unchanged or larger tumor size after SLA treatment than those with low-grade tumors (OR 7.49, p = 0.0364). Subsequent surgery and adjuvant treatment were not required after SLA treatment in 90.4% and 86.7% of patients, respectively. Patients with high-grade tumors were more likely to receive subsequent surgery (OR 2.25, p = 0.4957) and adjuvant treatment (OR 3.77, p = 0.1711) after SLA therapy, without reaching significance. A total of 29 acute complications in 23 patients were reported and included malpositioned catheters (n = 3), intracranial hemorrhages (n = 2), transient neurological deficits (n = 11), permanent neurological deficits (n = 5), symptomatic perilesional edema (n = 2), hydrocephalus (n = 4), and death (n = 2). On long-term follow-up, 3 patients were reported to have worsened neuropsychological test results. Pre-SLA tumor volume, tumor location, number of laser trajectories, and number of lesions created did not result in a significantly increased risk of complications; however, the odds of complications increased by 14% (OR 1.14, p = 0.0159) with every 1-cm increase in the volume of the lesion created.

CONCLUSIONS

SLA is an effective, minimally invasive treatment option for pediatric brain tumors, although it is not without risks. Limiting the volume of the generated thermal lesion may help decrease the incidence of complications.

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Ching-Jen Chen, Cheng-Chia Lee, Hideyuki Kano, Kathryn N. Kearns, Dale Ding, Shih-Wei Tzeng, Ahmet Atik, Krishna Joshi, Gene H. Barnett, Paul P. Huang, Douglas Kondziolka, David Mathieu, Christian Iorio-Morin, Inga S. Grills, Thomas J. Quinn, Zaid A. Siddiqui, Kim Marvin, Caleb Feliciano, Andrew Faramand, L. Dade Lunsford, and Jason P. Sheehan

OBJECTIVE

Contrary to the better described obliteration- and hemorrhage-related data after stereotactic radiosurgery (SRS) of brain arteriovenous malformations (AVMs) in pediatric patients, estimates of the rarer complications, including cyst and tumor formation, are limited in the literature. The aim of the present study was to assess the long-term outcomes and risks of SRS for AVMs in pediatric patients (age < 18 years).

METHODS

The authors retrospectively analyzed the International Radiosurgery Research Foundation pediatric AVM database for the years 1987 to 2018. AVM obliteration, post-SRS hemorrhage, cyst formation, and tumor formation were assessed. Cumulative probabilities, adjusted for the competing risk of death, were calculated.

RESULTS

The study cohort comprised 539 pediatric AVM patients (mean follow-up 85.8 months). AVM obliteration was observed in 64.3% of patients, with cumulative probabilities of 63.6% (95% CI 58.8%–68.0%), 77.1% (95% CI 72.1%–81.3%), and 88.1% (95% CI 82.5%–92.0%) over 5, 10, and 15 years, respectively. Post-SRS hemorrhage was observed in 8.4% of patients, with cumulative probabilities of 4.9% (95% CI 3.1%–7.2%), 9.7% (95% CI 6.4%–13.7%), and 14.5% (95% CI 9.5%–20.5%) over 5, 10, and 15 years, respectively. Cyst formation was observed in 2.1% of patients, with cumulative probabilities of 5.5% (95% CI 2.3%–10.7%) and 6.9% (95% CI 3.1%–12.9%) over 10 and 15 years, respectively. Meningiomas were observed in 2 patients (0.4%) at 10 and 12 years after SRS, with a cumulative probability of 3.1% (95% CI 0.6%–9.7%) over 15 years.

CONCLUSIONS

AVM obliteration can be expected after SRS in the majority of the pediatric population, with a relatively low risk of hemorrhage during the latency period. Cyst and benign tumor formation after SRS can be observed in 7% and 3% of patients over 15 years, respectively. Longitudinal surveillance for delayed neoplasia is prudent despite its low incidence.

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Baha’eddin A. Muhsen, Krishna C. Joshi, Bryan S. Lee, Bicky Thapa, Hamid Borghei-Razavi, Xuefei Jia, Gene H. Barnett, Samuel T. Chao, Alireza M. Mohammadi, John H. Suh, Michael A. Vogelbaum, and Lilyana Angelov

OBJECTIVE

Gamma Knife radiosurgery (GKRS) as monotherapy is an option for the treatment of large (≥ 2 cm) posterior fossa brain metastases (LPFMs). However, there is concern regarding possible posttreatment increase in peritumoral edema (PTE) and associated compression of the fourth ventricle. This study evaluated the effects and safety of GKRS on tumor and PTE control in LPFM.

METHODS

The authors performed a single-center retrospective review of 49 patients with 51 LPFMs treated with GKRS. Patients with at least 1 clinical and radiological follow-up visit were included. Tumor, PTE, and fourth ventricle volumetric measurements were used to assess efficacy and safety. Overall survival was a secondary outcome.

RESULTS

Fifty-one lesions in 49 consecutive patients were identified; 57.1% of patients were male. At the time of GKRS, the median age was 61.5 years, and the median Karnofsky Performance Status score was 90. The median number of LPFMs and overall brain metastases were 1 and 2, respectively. The median overall tumor, PTE, and fourth ventricle volumes at diagnosis were 4.96 cm3 (range 1.4–21.1 cm3), 14.98 cm3 (range 0.6–71.8 cm3), and 1.23 cm3 (range 0.3–3.2 cm3), respectively, and the median lesion diameter was 2.6 cm (range 2.0–5.07 cm). The median follow-up time was 7.3 months (range 1.6–57.2 months). At the first follow-up, 2 months posttreatment, the median tumor volume decreased by 58.66% (range −96.95% to +48.69%, p < 0.001), median PTE decreased by 78.10% (range −99.92% to +198.35%, p < 0.001), and the fourth ventricle increased by 24.97% (range −37.96% to +545.6%, p < 0.001). The local control rate at first follow-up was 98.1%. The median OS was 8.36 months. No patient required surgical intervention, external ventricular drainage, or shunting between treatment and first follow-up. However, 1 patient required a ventriculoperitoneal shunt at 23 months from treatment. Posttreatment, 65.30% received our general steroid taper, 6.12% received no steroids, and 28.58% required prolonged steroid treatment.

CONCLUSIONS

In this retrospective analysis, patients with LPFMs treated with GKRS had a statistically significant posttreatment reduction in tumor size and PTE and marked opening of the fourth ventricle (all p < 0.001). This study demonstrates that GKRS is well tolerated and can be considered in the management of select cases of LPFMs, especially in patients who are poor surgical candidates.

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Krishna C. Joshi, Alankrita Raghavan, Baha’eddin Muhsen, Jason Hsieh, Hamid Borghei-Razavi, Samuel T. Chao, Gene H. Barnett, John H. Suh, Gennady Neyman, Varun R. Kshettry, Pablo F. Recinos, Alireza M. Mohammadi, and Lilyana Angelov

OBJECTIVE

Gamma Knife radiosurgery (GKRS) has been successfully used for the treatment of intracranial meningiomas given its steep dose gradients and high-dose conformality. However, treatment of skull base meningiomas (SBMs) may pose significant risk to adjacent radiation-sensitive structures such as the cranial nerves. Fractionated GKRS (fGKRS) may decrease this risk, but until recently it has not been practical with traditional pin-based systems. This study reports the authors’ experience in treating SBMs with fGKRS, using a relocatable, noninvasive immobilization system.

METHODS

The authors performed a retrospective review of all patients who underwent fGKRS for SBMs between 2013 and 2018 delivered using the Extend relocatable frame system or the Icon system. Patient demographics, pre- and post-GKRS tumor characteristics, perilesional edema, prior treatment details, and clinical symptoms were evaluated. Volumetric analysis of pre-GKRS, post-GKRS, and subsequent follow-up visits was performed.

RESULTS

Twenty-five patients met inclusion criteria. Nineteen patients were treated with the Icon system, and 6 patients were treated with the Extend system. The mean pre-fGKRS tumor volume was 7.62 cm3 (range 4.57–13.07 cm3). The median margin dose was 25 Gy delivered in 4 (8%) or 5 (92%) fractions. The median follow-up time was 12.4 months (range 4.7–17.4 months). Two patients (9%) experienced new-onset cranial neuropathy at the first follow-up. The mean postoperative tumor volume reduction was 15.9% with 6 patients (27%) experiencing improvement of cranial neuropathy at the first follow-up. Median first follow-up scans were obtained at 3.4 months (range 2.8–4.3 months). Three patients (12%) developed asymptomatic, mild perilesional edema by the first follow-up, which remained stable subsequently.

CONCLUSIONS

fGKRS with relocatable, noninvasive immobilization systems is well tolerated in patients with SBMs and demonstrated satisfactory tumor control as well as limited radiation toxicity. Future prospective studies with long-term follow-up and comparison to single-session GKRS or fractionated stereotactic radiotherapy are necessary to validate these findings and determine the efficacy of this approach in the management of SBMs.

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Diogo Cordeiro, Zhiyuan Xu, Gautam U. Mehta, Dale Ding, Mary Lee Vance, Hideyuki Kano, Nathaniel Sisterson, Huai-che Yang, Douglas Kondziolka, L. Dade Lunsford, David Mathieu, Gene H. Barnett, Veronica Chiang, John Lee, Penny Sneed, Yan-Hua Su, Cheng-chia Lee, Michal Krsek, Roman Liscak, Ahmed M. Nabeel, Amr El-Shehaby, Khaled Abdel Karim, Wael A. Reda, Nuria Martinez-Moreno, Roberto Martinez-Alvarez, Kevin Blas, Inga Grills, Kuei C. Lee, Mikulas Kosak, Christopher P. Cifarelli, Gennadiy A. Katsevman, and Jason P. Sheehan

OBJECTIVE

Recurrent or residual adenomas are frequently treated with Gamma Knife radiosurgery (GKRS). The most common complication after GKRS for pituitary adenomas is hypopituitarism. In the current study, the authors detail the timing and types of hypopituitarism in a multicenter, international cohort of pituitary adenoma patients treated with GKRS.

METHODS

Seventeen institutions pooled clinical data obtained from pituitary adenoma patients who were treated with GKRS from 1988 to 2016. Patients who had undergone prior radiotherapy were excluded. A total of 1023 patients met the study inclusion criteria. The treated lesions included 410 nonfunctioning pituitary adenomas (NFPAs), 262 cases of Cushing’s disease (CD), and 251 cases of acromegaly. The median follow-up was 51 months (range 6–246 months). Statistical analysis was performed using a Cox proportional hazards model to evaluate factors associated with the development of new-onset hypopituitarism.

RESULTS

At last follow-up, 248 patients had developed new pituitary hormone deficiency (86 with NFPA, 66 with CD, and 96 with acromegaly). Among these patients, 150 (60.5%) had single and 98 (39.5%) had multiple hormone deficiencies. New hormonal changes included 82 cortisol (21.6%), 135 thyrotropin (35.6%), 92 gonadotropin (24.3%), 59 growth hormone (15.6%), and 11 vasopressin (2.9%) deficiencies. The actuarial 1-year, 3-year, 5-year, 7-year, and 10-year rates of hypopituitarism were 7.8%, 16.2%, 22.4%, 27.5%, and 31.3%, respectively. The median time to hypopituitarism onset was 39 months.

In univariate analyses, an increased rate of new-onset hypopituitarism was significantly associated with a lower isodose line (p = 0.006, HR = 8.695), whole sellar targeting (p = 0.033, HR = 1.452), and treatment of a functional pituitary adenoma as compared with an NFPA (p = 0.008, HR = 1.510). In multivariate analyses, only a lower isodose line was found to be an independent predictor of new-onset hypopituitarism (p = 0.001, HR = 1.38).

CONCLUSIONS

Hypopituitarism remains the most common unintended effect of GKRS for a pituitary adenoma. Treating the target volume at an isodose line of 50% or greater and avoiding whole-sellar radiosurgery, unless necessary, will likely mitigate the risk of post-GKRS hypopituitarism. Follow-up of these patients is required to detect and treat latent endocrinopathies.

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Mayur Sharma, Jason L. Schroeder, Paul Elson, Antonio Meola, Gene H. Barnett, Michael A. Vogelbaum, John H. Suh, Samuel T. Chao, Alireza M. Mohammadi, Glen H. J. Stevens, Erin S. Murphy, and Lilyana Angelov

OBJECTIVE

Glioblastoma (GBM) is the most malignant form of astrocytoma. The average survival is 6–10 months in patients with recurrent GBM (rGBM). In this study, the authors evaluated the role of stereotactic radiosurgery (SRS) in patients with rGBMs.

METHODS

The authors performed a retrospective review of their brain tumor database (1997–2016). Overall survival (OS) and progression-free survival (PFS) after salvage SRS were the primary endpoints evaluated. Response to SRS was assessed using volumetric MR images.

RESULTS

Fifty-three patients with rGBM underwent salvage SRS targeting 75 lesions. The median tumor diameter and volume were 2.55 cm and 3.80 cm3, respectively. The median prescription dose was 18 Gy (range 12–24 Gy) and the homogeneity index was 1.90 (range 1.11–2.02). The median OS after salvage SRS was estimated to be 11.0 months (95% CI 7.1–12.2) and the median PFS after salvage SRS was 4.4 months (95% CI 3.7–5.0). A Karnofsky Performance Scale score ≥ 80 was independently associated with longer OS, while small tumor volume (< 15 cm3) and less homogeneous treatment plans (homogeneity index > 1.75) were both independently associated with longer OS (p = 0.007 and 0.03) and PFS (p = 0.01 and 0.002, respectively). Based on these factors, 2 prognostic groups were identified for PFS (5.4 vs 3.2 months), while 3 were identified for OS (median OS of 15.2 vs 10.5 vs 5.2 months).

CONCLUSIONS

SRS is associated with longer OS and/or PFS in patients with good performance status, small-volume tumor recurrences, and heterogeneous treatment plans. The authors propose a prognostic model to identify a cohort of rGBM patients who may benefit from SRS.

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Manmeet Ahluwalia, Gene H. Barnett, Di Deng, Stephen B. Tatter, Adrian W. Laxton, Alireza M. Mohammadi, Eric Leuthardt, Roukoz Chamoun, Kevin Judy, Anthony Asher, Marco Essig, Jorg Dietrich, and Veronica L. Chiang

OBJECTIVE

Laser Ablation After Stereotactic Radiosurgery (LAASR) is a multicenter prospective study of laser interstitial thermal (LITT) ablation in patients with radiographic progression after stereotactic radiosurgery for brain metastases.

METHODS

Patients with a Karnofsky Performance Scale (KPS) score ≥ 60, an age > 18 years, and surgical eligibility were included in this study. The primary outcome was local progression-free survival (PFS) assessed using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Secondary outcomes were overall survival (OS), procedure safety, neurocognitive function, and quality of life.

RESULTS

Forty-two patients—19 with biopsy-proven radiation necrosis, 20 with recurrent tumor, and 3 with no diagnosis—were enrolled. The median age was 60 years, 64% of the subjects were female, and the median baseline KPS score was 85. Mean lesion volume was 6.4 cm3 (range 0.4–38.6 cm3). There was no significant difference in length of stay between the recurrent tumor and radiation necrosis patients (median 2.3 vs 1.7 days, respectively). Progression-free survival and OS rates were 74% (20/27) and 72%, respectively, at 26 weeks. Thirty percent of subjects were able to stop or reduce steroid usage by 12 weeks after surgery. Median KPS score, quality of life, and neurocognitive results did not change significantly for either group over the duration of survival. Adverse events were also similar for the two groups, with no significant difference in the overall event rate. There was a 12-week PFS and OS advantage for the radiation necrosis patients compared with the recurrent tumor or tumor progression patients.

CONCLUSIONS

In this study, in which enrolled patients had few alternative options for salvage treatment, LITT ablation stabilized the KPS score, preserved quality of life and cognition, had a steroid-sparing effect, and was performed safely in the majority of cases.

Clinical trial registration no.: NCT01651078 (clinicaltrials.gov)

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Michael A. Vogelbaum, Cathy Brewer, Gene H. Barnett, Alireza M. Mohammadi, David M. Peereboom, Manmeet S. Ahluwalia, and Shenqiang Gao

OBJECTIVE

Progress in management of high-grade gliomas (HGGs) has been hampered by poor access of potential therapeutics to the CNS. The Cleveland Multiport Catheter (CMC), which deploys 4 independent delivery microcatheters, was developed to be a reliable, high-volume delivery device for delivery of therapeutic agents to the brain and other solid organs. The authors undertook this first-in-human clinical trial effort to evaluate the delivery characteristics of the CMC in patients with HGGs.

METHODS

A series of pilot studies were launched after approval of a sponsor-investigator IND (investigational new drug) application to evaluate the delivery of topotecan and gadolinium-DTPA (Gd-DTPA) via the CMC in patients with recurrent HGG. The first pilot trial evaluated delivery into enhancing tumor and nonenhancing, tumor-infiltrated brain. Two catheters were placed with the use of a conventional frameless stereotactic technique following a biopsy to confirm tumor recurrence, and drug infusion was performed both intraoperatively and postoperatively for a total of 96 hours with the same rate for all microcatheters. Delivery was assessed by intermittent MRI.

RESULTS

Three patients were enrolled in the first pilot study. MRI demonstrated delivery from all 6 catheters (24 microcatheters). The volume of distribution (Vd) of Gd-DTPA was heavily dependent upon CMC location (enhancing vs nonenhancing) with an approximately 10-fold difference in Vd observed (p = 0.005). There were no hemorrhages related to catheter placement or removal, and all 3 patients completed the protocol-defined treatment.

CONCLUSIONS

The CMC is capable of providing backflow-resistant drug delivery to the brain and brain tumors. The volume of distribution is heavily dependent upon the integrity of the blood-brain barrier. Assessment of delivery is essential for development of loco-regionally applied therapeutics in the CNS.

Clinical trial registration no.: NCT02278510 (clinicaltrials.gov)