Publications by authors named "Kevin Judy"

47 Publications

Phase Ib Clinical Trial of IGV-001 for Patients with Newly Diagnosed Glioblastoma.

Clin Cancer Res 2021 Jan 26. Epub 2021 Jan 26.

Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.

Purpose: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma.

Patients And Methods: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4-6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies.

Results: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; = 0.0003). In IGV-001-treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall ( = 22; = 0.001) and 17.1 months at the highest exposure ( = 10; = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; = 0.044). Stupp-eligible patients with methylated O-methylguanine-DNA methyltransferase promoter ( = 10) demonstrated median PFS of 38.4 months ( = 0.0008). Evidence of immune activation was noted.

Conclusions: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3805DOI Listing
January 2021

Resected WHO grade I meningioma and predictors of local control.

J Neurooncol 2021 Mar 9;152(1):145-151. Epub 2021 Jan 9.

Department of Radiation Oncology, Sidney Kimmel Medical College, Philadelphia, PA, USA.

Introduction: Despite optimal surgical resection, meningiomas may recur, with increasing grade and the degree of resection being predictive of risk. We hypothesize that an increasing Ki67 correlates with a higher risk of recurrence of resected WHO grade I meningiomas.

Methods: The study population consisted of patients with resected WHO grade 1 meningiomas in locations outside of the base of skull. Digitally scanned slides stained for Ki67 were analyzed using automatic image analysis software in a standardized fashion.

Results: Recurrence was observed in 53 (17.7%) of cases with a median follow up time of 25.8 months. Ki67 ranged from 0 to 30%. Median Ki67 was 5.1% for patients with recurrence and 3.5% for patients without recurrence. In unadjusted analyses, high Ki-67 (≥ 5 vs. < 5) vs. ≥ 5) was associated with over a twofold increased risk of recurrence (13.1% vs. 27% respectively; HR 2.1731; 95% CI [1.2534, 3.764]; p = 0.006). After Adjusting for patient or tumor characteristics, elevated Ki-67 remained significantly correlated with recurrence. Grade 4 Simpson resection was noted in 71 (23.7%) of patients and it was associated with a significantly increased risk of recurrence (HR 2.56; 95% CI [1.41, 4.6364]; p = 0.002).

Conclusions: WHO grade 1 meningiomas exhibit a significant rate of recurrence following resection. While Ki-67 is not part of the WHO grading criteria of meningiomas, a value greater than 5% is an independent predictor for increased risk of local recurrence following surgical resection.
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http://dx.doi.org/10.1007/s11060-020-03688-1DOI Listing
March 2021

Feasibility of removable balloon implant for simultaneous magnetic nanoparticle heating and HDR brachytherapy of brain tumor resection cavities.

Int J Hyperthermia 2020 ;37(1):1189-1201

Radiation Oncology Department, Thomas Jefferson University, Philadelphia, PA, USA.

Aim: Hyperthermia (HT) has been shown to improve clinical response to radiation therapy (RT) for cancer. Synergism is dramatically enhanced if HT and RT are combined simultaneously, but appropriate technology to apply treatments together does not exist. This study investigates the feasibility of delivering HT with RT to a 5-10mm annular rim of at-risk tissue around a tumor resection cavity using a temporary thermobrachytherapy (TBT) balloon implant.

Methods: A balloon catheter was designed to deliver radiation from High Dose Rate (HDR) brachytherapy concurrent with HT delivered by filling the balloon with magnetic nanoparticles (MNP) and immersing it in a radiofrequency magnetic field. Temperature distributions in brain around the TBT balloon were simulated with temperature dependent brain blood perfusion using numerical modeling. A magnetic induction system was constructed and used to produce rapid heating (>0.2°C/s) of MNP-filled balloons in brain tissue-equivalent phantoms by absorbing 0.5 W/ml from a 5.7 kA/m field at 133 kHz.

Results: Simulated treatment plans demonstrate the ability to heat at-risk tissue around a brain tumor resection cavity between 40-48°C for 2-5cm diameter balloons. Experimental thermal dosimetry verifies the expected rapid and spherically symmetric heating of brain phantom around the MNP-filled balloon at a magnetic field strength that has proven safe in previous clinical studies.

Conclusions: These preclinical results demonstrate the feasibility of using a TBT balloon to deliver heat simultaneously with HDR brachytherapy to tumor bed around a brain tumor resection cavity, with significantly improved uniformity of heating over previous multi-catheter interstitial approaches. Considered along with results of previous clinical thermobrachytherapy trials, this new capability is expected to improve both survival and quality of life in patients with glioblastoma multiforme.
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http://dx.doi.org/10.1080/02656736.2020.1829103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864554PMC
January 2020

Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System (LAANTERN): 12-Month Outcomes and Quality of Life After Brain Tumor Ablation.

Neurosurgery 2020 09;87(3):E338-E346

Department of Neurosurgery, Washington University, St. Louis, Missouri.

Background: Laser Ablation of Abnormal Neurological Tissue using Robotic NeuroBlate System (LAANTERN) is an ongoing multicenter prospective NeuroBlate (Monteris Medical) LITT (laser interstitial thermal therapy) registry collecting real-world outcomes and quality-of-life (QoL) data.

Objective: To compare 12-mo outcomes from all subjects undergoing LITT for intracranial tumors/neoplasms.

Methods: Demographics, intraprocedural data, adverse events, QoL, hospitalizations, health economics, and survival data are collected; standard data management and monitoring occur.

Results: A total of 14 centers enrolled 223 subjects; the median follow-up was 223 d. There were 119 (53.4%) females and 104 (46.6%) males. The median age was 54.3 yr (range 3-86) and 72.6% had at least 1 baseline comorbidity. The median baseline Karnofsky Performance Score (KPS) was 90. Of the ablated tumors, 131 were primary and 92 were metastatic. Most patients with primary tumors had high-grade gliomas (80.9%). Patients with metastatic cancer had recurrence (50.6%) or radiation necrosis (40%). The median postprocedure hospital stay was 33.4 h (12.7-733.4). The 1-yr estimated survival rate was 73%, and this was not impacted by disease etiology. Patient-reported QoL as assessed by the Functional Assessment of Cancer Therapy-Brain was stabilized postprocedure. KPS declined by an average of 5.7 to 10.5 points postprocedure; however, 50.5% had stabilized/improved KPS at 6 mo. There were no significant differences in KPS or QoL between patients with metastatic vs primary tumors.

Conclusion: Results from the ongoing LAANTERN registry demonstrate that LITT stabilizes and improves QoL from baseline levels in a malignant brain tumor patient population with high rates of comorbidities. Overall survival was better than anticipated for a real-world registry and comparative to published literature.
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http://dx.doi.org/10.1093/neuros/nyaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534487PMC
September 2020

Initial experience with scalp sparing radiation with concurrent temozolomide and tumor treatment fields (SPARE) for patients with newly diagnosed glioblastoma.

J Neurooncol 2020 May 23;147(3):653-661. Epub 2020 Mar 23.

Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.

Introduction: Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide with tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our initial experience evaluating toxicity and tolerability of scalp-sparing radiation with concurrent TTFields.

Methods: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed glioblastoma were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent temozolomide (75 mg/m daily), and TTFields. Maintenance therapy included standard temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity for concurrent TTFields with chemoradiation in newly diagnosed glioblastoma.

Results: We report the first ten patients on the trial. Eight were male, and two were female, with median age 61 years (range 49 to 73 years). Median KPS was 90 (range 70-90). Median follow-up was 7.9 months (2.8 to 17.9 months). Nine (90%) patients with unmethylated MGMT promotor, and one with methylated. Median time from surgery to radiation was 33 days (28 to 49 days). All patients completed concurrent chemoradiation plus TTFields without radiation or TTFields treatment interruption or discontinuation. Scalp dose constraints were achieved for all patients, with mean dose having a median value of 7.7 Gy (range 4.9 to 13.2 Gy), D20cc median 22.6 Gy (17.7 to 36.8 Gy), and D30cc median 19.8 Gy (14.8 to 33.4 Gy). Average daily use during concurrent phase had median value of 83.5% and 77% for maintenance. There was no related ≥ Grade 3 toxicity. Skin toxicity (erythema, dermatitis, pruritus) was noted in 80% of patients, however, these were limited to Grade 1 or 2 events which resolved spontaneously or responded to topical medications. Eight patients (80%) had progression, with median PFS of 6.9 months (range 2.8 to 9.6 months).

Conclusions: Concurrent TTFields with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trial is warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.

Trial Registration: Clinicaltrials.gov Identifier NCT03477110.
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http://dx.doi.org/10.1007/s11060-020-03466-zDOI Listing
May 2020

Laser Ablation of Abnormal Neurological Tissue Using Robotic Neuroblate System (LAANTERN): Procedural Safety and Hospitalization.

Neurosurgery 2020 04;86(4):538-547

Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota.

Background: Stereotactic laser ablation (SLA) has demonstrated potential utility for a spectrum of difficult to treat neurosurgical pathologies in multiple small and/or retrospective single-institutional series. Here, we present the safety profile of SLA of intracranial lesions from the Laser Ablation of Abnormal Neurological Tissue using Robotic NeuroBlate System (LAANTERN; Monteris Medical) multi-institutional, international prospective observational registry.

Objective: To determine the procedural safety of SLA for intracranial lesions.

Methods: Prospective procedural safety and hospitalization data from the first 100 treated LAANTERN patients was collected and analyzed.

Results: Mean age and baseline Karnofsky Performance Status (KPS) were 51(± 17) yr and 83(± 15), respectively. In total, 81.2% of patients had undergone prior surgical or radiation treatment. Most patients had a single lesion (79%) ablated through 1 burr hole (1.2 ± 0.7 per patient), immediately following a lesion biopsy. In total, >90% of the lesion was ablated in 72% of treated lesions. Average total procedural time was 188.2 ± 69.6 min, and average blood loss was 17.7 ± 55.6 ccs. The average length of intensive care unit (ICU) and hospital stays before discharge were 38.1 ± 62.7 h and 61.1 ± 87.2 h, respectively. There were 5 adverse events (AEs) attributable to SLA (5/100; 5%). After the procedure, 84.8% of patients were discharged home. There was 1 mortality within 30 d of the procedure (1/100; 1%), which was not attributable to SLA.

Conclusion: SLA is a safe, minimally invasive procedure with favorable postprocedural ICU and hospital utilization profiles.
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http://dx.doi.org/10.1093/neuros/nyz141DOI Listing
April 2020

Rapid Early Tumor Progression is Prognostic in Glioblastoma Patients.

Am J Clin Oncol 2019 05;42(5):481-486

Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA.

Objectives: Determine the prognostic significance of rapid early tumor progression before radiation and chemotherapy for glioblastoma patients.

Methods: A retrospective review of glioblastoma patients was performed. Rapid early progression (REP) was defined as new enhancing tumor or >25% increase in enhancement before radiotherapy. The pre/postoperative magnetic resonance imaging was compared with the preradiation magnetic resonance imaging to determine REP. A blinded review of imaging was performed. Kaplan-Meier curves were generated to compare progression-free and overall survival (OS). Univariate analysis was performed using the log-rank test for categorical variables and Cox proportional hazards for continuous variables. Multivariable logistic regression was performed to assess factors related to early progression and Cox proportional hazards model was used for multivariate analysis of OS.

Results: Eighty-seven patients met entry criteria. A total of 52% of patients developed REP. The OS in the REP group was 11.5 months (95% confidence interval [CI]: 7.4-17.6) and 20.1 months (95% CI: 17.8-26.1) without REP (P=0.013). On multivariate analysis including significant prognostic factors, presence of REP was found to increase the risk of death (hazard ratio: 2.104, 95% CI: 1.235-3.583, P=0.006). A total of 74% of patients recurred in the site of REP.

Conclusions: REP was common and independently predicted for a worse OS. Integrating REP with MGMT promotor methylation improved prognostic assessment. The site of REP was a common site of tumor progression. Our findings are hypothesis generating and may indicate a particular subset of glioblastoma patients who are resistant to current standard of care therapy. Further study to determine other molecular features of this group are underway.
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http://dx.doi.org/10.1097/COC.0000000000000537DOI Listing
May 2019

Phase I trial of alisertib with concurrent fractionated stereotactic re-irradiation for recurrent high grade gliomas.

Radiother Oncol 2019 03 4;132:135-141. Epub 2019 Jan 4.

Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, United States. Electronic address:

Background And Purpose: We conducted a phase I trial of alisertib, an oral aurora kinase inhibitor, with fractionated stereotactic re-irradiation therapy (FSRT) for patients with recurrent high grade glioma (HGG).

Materials And Methods: Adult patients with recurrent HGG were enrolled from Feb 2015 to Feb 2017. Patients were treated with concurrent FSRT and alisertib followed by maintenance alisertib. Concurrent alisertib dose was escalated from 20 mg to 50 mg twice daily (BID).

Results: 17 patients were enrolled. Median follow-up was 11 months. Median FSRT dose was 35 Gy. There were 6, 6, 3, and 2 patients enrolled in 20 mg, 30 mg, 40 mg, and 50 mg cohort, respectively. Only one DLT was observed. One patient in the 20 mg cohort had severe headache (Grade 3) resolved with steroids. There was no non-hematological grade 3 or higher toxicity. There were two Grade 4 late toxicities (one with grade 4 neutropenia and leukopenia, one with pulmonary embolism). One patient developed radiation necrosis (Grade 3). Sixteen patients finished concurrent treatment and received maintenance therapy (median cycles was 3, range 1-9). OS for all cohorts at 6 months was 88.2% with median survival time of 11.1 months. PFS at 6 months was 35.3% with median time to progression of 4.9 months. The trial stopped early due to closure of alisertib program with only 2 of 3 planned patients enrolled in the 50 mg cohort.

Conclusion: Re-irradiation with FSRT combined with alisertib is safe and well tolerated for HGG with doses up to 40 mg BID. Although no DLT observed in the 50 mg cohort, this cohort was not fully enrolled and MTD was not reached. Clinical outcomes appear comparable to historical results. (NCT02186509).
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http://dx.doi.org/10.1016/j.radonc.2018.12.019DOI Listing
March 2019

Cerebral Amyloidoma Resulting from Central Nervous System Lymphoplasmacytic Lymphoma: A Case Report and Literature Review.

Case Rep Pathol 2018 26;2018:5083234. Epub 2018 Jun 26.

Department of Pathology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA.

Cerebral amyloidomas are rare cerebral mass lesions often associated with significant morbidity. Cerebral amyloid accumulation can be the result of a number of disease states and it is crucial for proper patient care to identify the pathogenic process leading to amyloidoma formation. Low grade clonal B-cell processes are one cause of cerebral amyloidomas. We report a case of an 87-year-old woman who presented with a lymphoplasmacytic lymphoma associated cerebral amyloidoma complicated by cerebral hemorrhage, discuss the proper workup of this disease entity, and present a review of the literature on this topic.
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http://dx.doi.org/10.1155/2018/5083234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038588PMC
June 2018

Patterns of Clinical Use of Stereotactic Laser Ablation: Analysis of a Multicenter Prospective Registry.

World Neurosurg 2018 Aug 14;116:e566-e570. Epub 2018 May 14.

Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address:

Background: Stereotactic laser ablation (SLA), also termed laser interstitial thermal therapy, is a minimally invasive procedure that is increasingly used in neurosurgery. We wished to examine how and whether SLA is changing the landscape of treatment options for neurosurgical patients.

Methods: Patients undergoing stereotactic laser ablation were prospectively enrolled in the Laser Ablation of Abnormal Neurological Tissue (LAANTERN) registry. Data from the first 100 enrolled patients are presented here.

Results: Clinical indications for SLA include treatment of primary intracranial tumors (48%; 81% being high-grade gliomas [HGGs]), brain metastases (BMs, 34%), epilepsy (16%), and other (2%). For HGGs, SLA was equally likely used for newly diagnosed (45%) or previously treated/recurrent lesions (55%, P = 0.54). By contrast, SLA was predominantly used as treatment for BMs in which radiation therapy/radiosurgery had failed (91%), with only 9% of SLAs performed as initial treatment for newly diagnosed lesions (P < 0.001). Of all SLAs performed, 45% of the procedures were in lieu of surgical resection, with 43% performed because the lesion was not accessible by conventional neurosurgical techniques.

Conclusion: HGGs and BMs are the leading indications for SLA in the LAANTERN study. For HGGs, SLA is equally used in the presenting or previously treated/recurrent setting. For BMs, SLA is typically used in the recurrent setting. SLAs are equally likely to be performed for difficult-to-access lesions or in lieu of conventional open surgery.
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http://dx.doi.org/10.1016/j.wneu.2018.05.039DOI Listing
August 2018

Laser ablation after stereotactic radiosurgery: a multicenter prospective study in patients with metastatic brain tumors and radiation necrosis.

J Neurosurg 2018 05;130(3):804-811

2Department of Neurosurgery, Yale University, New Haven, Connecticut.

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.
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http://dx.doi.org/10.3171/2017.11.JNS171273DOI Listing
May 2018

Correction to: Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment.

J Neurooncol 2018 Mar;137(1):179

Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, USA.

The fourth author's name was incorrect in the initial online publication. The original article has been corrected.
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http://dx.doi.org/10.1007/s11060-018-2744-5DOI Listing
March 2018

Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment.

J Neurooncol 2018 Mar 12;137(1):171-177. Epub 2017 Dec 12.

Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, USA.

Bevacizumab failure is a major clinical problem in the management of high grade gliomas (HGG), with a median overall survival (OS) of < 4 months. This study evaluated the feasibility and efficacy of fractionated stereotactic re-irradiation (FSRT) for patients progressed after Bevacizumab treatment. Retrospective review was conducted of 36 patients treated with FSRT after progression on bevacizumab. FSRT was most commonly delivered in 3.5 Gy fractions to a total dose of 35 Gy. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were utilized as study endpoints. Univariate and multivariate analysis was performed. The median time from initial bevacizumab treatment to FSRT was 8.5 months. The median plan target volume for FSRT was 27.5 cc. The median OS from FSRT was 4.8 months. FSRT treatment was well tolerated with no grade 3 or higher toxicity. Favorable outcomes were observed in patients with recurrent HGG who received salvage FSRT after bevacizumab failure. The treatment was well tolerated. Prospective study is warranted to further evaluate the efficacy of salvage FSRT for selected patients with recurrent HGG amenable to FSRT, who had failed bevacizumab treatment.
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http://dx.doi.org/10.1007/s11060-017-2709-0DOI Listing
March 2018

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases.

Int J Radiat Oncol Biol Phys 2017 09 26;99(1):22-30. Epub 2017 May 26.

Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University and Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania. Electronic address:

Purpose: We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma.

Methods And Materials: Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507.

Results: The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively.

Conclusions: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.
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http://dx.doi.org/10.1016/j.ijrobp.2017.05.028DOI Listing
September 2017

Fractionated Stereotactic Radiotherapy for Facial Nerve Schwannomas.

J Neurol Surg B Skull Base 2016 Feb 14;77(1):75-80. Epub 2015 Sep 14.

Department of Neurological Surgery, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, United States.

Purpose Data on the clinical course of irradiated facial nerve schwannomas (FNS) are lacking. We evaluated fractionated stereotactic radiotherapy (FSRT) for FNS. Methods Eight consecutive patients with FNS treated at our institution between 1998 and 2011 were included. Patients were treated with FSRT to a median dose of 50.4 Gy (range: 46.8-54 Gy) in 1.8 or 2.0 Gy fractions. We report the radiographic response, symptom control, and toxicity associated with FSRT for FNS. Results The median follow-up time was 43 months (range: 10-75 months). All patients presented with symptoms including pain, tinnitus, facial asymmetry, diplopia, and hearing loss. The median tumor volume was 1.57 cc. On the most recent follow-up imaging, five patients were noted to have stable tumor size; three patients had a net reduction in tumor volume. Additionally, six patients had improvement in clinical symptoms, one patient had stable clinical findings, and one patient had worsened House-Brackmann grade due to cystic degeneration. Conclusion FSRT treatment of FNS results in excellent control of growth and symptoms with a small rate of radiation toxicity. Given the importance of maintaining facial nerve function, FSRT could be considered as a primary management modality for enlarging or symptomatic FNS.
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http://dx.doi.org/10.1055/s-0035-1564056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777614PMC
February 2016

Phase I trial of panobinostat and fractionated stereotactic re-irradiation therapy for recurrent high grade gliomas.

J Neurooncol 2016 May 29;127(3):535-9. Epub 2016 Jan 29.

Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, 111 South 11th Street, Philadelphia, PA, 19107, USA.

Panobinostat is an oral HDAC inhibitor with radiosensitizing activity. We investigated the safety, tolerability and preliminary efficacy of panobinostat combined with fractionated stereotactic re-irradiation therapy (FSRT) for recurrent high grade gliomas. Patients with recurrent high grade gliomas were enrolled in a 3 + 3 dose escalation study to determine dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, tolerability, and preliminary efficacy. FSRT was prescribed to 30-35 Gy delivered in 10 fractions. Panobinostat was administrated concurrently with radiotherapy. Of 12 evaluable patients, 8 had recurrent GBM, and 4 had recurrent anaplastic astrocytoma. There were three grade 3 or higher toxicities in each the 10 and 30 mg cohorts. In the 30 mg cohort, there was one DLT; grade 4 neutropenia. One patient developed late grade 3 radionecrosis. The median follow up was 18.8 months. The PFS6 was 67, 33, and 83 % for 10, 20, and 30 mg cohorts, respectively. The median OS was 7.8, 6.1 and 16.1 months for the 10, 20 and 30 mg cohorts, respectively. Panobinostat administrated with FSRT is well tolerated at 30 mg. A phase II trial is warranted to assess the efficacy of panobinostat plus FSRT for recurrent glioma.
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http://dx.doi.org/10.1007/s11060-016-2059-3DOI Listing
May 2016

Tumor volume threshold for achieving improved conformity in VMAT and Gamma Knife stereotactic radiosurgery for vestibular schwannoma.

Radiother Oncol 2015 May 18;115(2):229-34. Epub 2015 May 18.

Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, United States. Electronic address:

Background And Purpose: Recent advances in multileaf collimator field shaping technology and inverse planning software have resulted in highly conformal LINAC based stereotactic radiosurgery (SRS) plans with minimal dose to critical structures. This modeling study compares Gamma Knife (GK) and LINAC SRS for vestibular schwannoma (VS).

Materials And Methods: 76 treatment plans from nineteen patients with VS were planned using GK forward planning and volumetric arc therapy (VMAT) inverse planning software. VMAT plans were generated with 1 coplanar, 3 and 5 non-coplanar arcs. Dose to normal structures and beam-on time (dose rate 600MU/min) were compared using Kruskal-Wallis and Dunn's post hoc test.

Results: Median tumor volume was 1.2cm(3) (range 0.1-4.8cm(3)). A peripheral tumor dose of 12Gy was prescribed. Tumor coverage was >99.8%. VMAT plans had lower target D2% and mean dose, as well as decreased beam-on time, compared to GK plans (p<0.0001). Paddick conformity index in VMAT 5 arc plans was superior to that of GK plans for targets >0.5cm(3) (p=0.002). Similar dose to cochlea, normal brain tissue and brainstem was observed.

Conclusion: VMAT should be considered as a safe, alternative modality to GK for VS SRS treatment, especially for tumors larger than 0.5cm(3).
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http://dx.doi.org/10.1016/j.radonc.2015.03.031DOI Listing
May 2015

BCNU wafer placement with temozolomide (TMZ) in the immediate postoperative period after tumor resection followed by radiation therapy with TMZ in patients with newly diagnosed high grade glioma: final results of a prospective, multi-institutional, phase II trial.

J Neurooncol 2015 Jun 7;123(2):259-66. Epub 2015 May 7.

Southeast Radiation Oncology Group, Department of Radiation Oncology, Levine Cancer Institute at Carolinas Medical Center, 1021 Morehead Medical Drive, Charlotte, NC, 28204, USA,

Temozolomide (TMZ) and BCNU have demonstrated anti-glioma synergism in preclinical models. We report final data from a prospective, multi-institutional study of BCNU wafers and early TMZ followed by radiation therapy with TMZ in patients with newly diagnosed malignant glioma. 65 patients were consented in 4 institutions, and 46 patients (43 GBM, 3 AA) were eligible for analysis. After resection and BCNU wafer placement, TMZ began on day four postoperatively. Radiation and TMZ (RT/TMZ) were then administered, followed by monthly TMZ at 200 mg/m2 for the first 26 patients, which was reduced to 150 mg/m2 for the remaining 20 patients. Non-hematologic toxicities were minimal. Nine of 27 patients (33 %) who received 200 mg/m2 TMZ, but only 1 of 20 (5 %) who received 150 mg/m2, experienced grade 3/4 thrombocytopenia. Median progression free survival (PFS) and overall survival (OS) period was 8.5 and 18 months, respectively. The 1-year OS rate was 76 %, which is a significant improvement compared with the historical control 1-year OS rate of 59 % (p = 0.023). However, there was no difference in 1-year OS compared with standard RT/TMZ (p = 0.12) or BCNU wafer followed by RT/TMZ (p = 0.87) in post hoc analyses. Early post-operative TMZ can be safely administered with BCNU wafers following resection of malignant glioma at the 150 mg/m2 dose level. Although there was an OS benefit compared to historical control, there was no indication of benefit for BCNU wafers and early TMZ in addition to standard RT/TMZ or early TMZ in addition to regimens of BCNU wafers followed by RT/TMZ.
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http://dx.doi.org/10.1007/s11060-015-1793-2DOI Listing
June 2015

Cryptococcal ventriculoperitoneal shunt infection.

J Clin Neurosci 2014 Nov 12;21(11):2020-1. Epub 2014 Sep 12.

Department of Neurosurgery, Thomas Jefferson University and Jefferson Hospital for Neuroscience, Philadelphia, PA, USA; Thomas Jefferson University, Sidney Kimmel Medical College, 909 Walnut Street, Philadelphia, PA 19107, USA. Electronic address:

The standard treatment of hydrocephalus is placement of a ventriculoperitoneal (VP) shunt. While infection is a common complication, rarely are fungal organisms implicated. Cryptococcus neoformans has been reported in only nine cases of shunt infection to our knowledge. The timing from shunt placement to symptom onset varies widely from 10 days to 15 months. We present a patient who developed a cryptococcal infection of his VP shunt more than two decades following shunt placement.
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http://dx.doi.org/10.1016/j.jocn.2014.08.001DOI Listing
November 2014

Vorinostat as a radiosensitizer for brain metastasis: a phase I clinical trial.

J Neurooncol 2014 Jun 13;118(2):313-319. Epub 2014 Apr 13.

Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

Perform a phase I study to evaluate the safety, and tolerability of vorinostat, an HDAC inhibitor, when combined with whole brain radiation treatment (WBRT) in patients with brain metastasis. A multi-institutional phase I clinical trial enrolled patients with a histological diagnosis of malignancy and radiographic evidence of brain metastasis. WBRT was 37.5 Gy in 2.5 Gy fractions delivered over 3 weeks. Vorinostat was administrated by mouth, once daily, Monday through Friday, concurrently with radiation treatment. The vorinostat dose was escalated from 200 to 400 mg daily using a 3+3 trial design. Seventeen patients were enrolled, 4 patients were excluded from the analysis due to either incorrect radiation dose (n = 1), or early treatment termination due to disease progression (n = 3). There were no treatment related grade 3 or higher toxicities in the 200 and 300 mg dose levels. In the 400 mg cohort there was a grade 3 pulmonary embolus and one death within 30 days of treatment. Both events were most likely related to disease progression rather than treatment; nonetheless, we conservatively classified the death as a dose limiting toxicity. We found Vorinostat administered with concurrent WBRT to be well tolerated to a dose of 300 mg once daily. This is the recommended dose for phase II study.
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http://dx.doi.org/10.1007/s11060-014-1433-2DOI Listing
June 2014

Clinically silent somatotroph adenomas are common.

Eur J Endocrinol 2011 Jul 14;165(1):39-44. Epub 2011 Apr 14.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, 3400 Civic Center Boulevard, 12-135 Translational Research Center, Philadelphia, Pennsylvania 19104, USA.

Objective: Somatotroph adenomas are typically recognized when they secrete GH excessively and cause acromegaly. Both 'silent' somatotroph adenomas (immunohistochemical evidence of GH excess without biochemical or clinical evidence) and 'clinically silent' somatotroph adenomas (immunohistochemical and biochemical evidence but no clinical evidence) have occasionally been reported. The relative frequency of each presentation is unknown. The goal of this study was, therefore, to determine the frequency of clinically silent somatotroph adenomas, a group that is potentially recognizable in vivo.

Design: We retrospectively identified 100 consecutive patients who had surgically excised and histologically confirmed pituitary adenomas.

Methods: Each pituitary adenoma was classified immunohistochemically by pituitary cell type. Somatotroph adenomas were further classified as 'classic' (obvious clinical features of acromegaly and elevated serum IGF1), 'subtle' (subtle clinical features of acromegaly and elevated IGF1), 'clinically silent' (no clinical features of acromegaly but elevated IGF1), and 'silent' (no clinical features of acromegaly and normal IGF1).

Results: Of the 100 consecutive pituitary adenomas, 29% were gonadotroph/glycoprotein, 24% somatotroph, 18% null cell, 15% corticotroph, 6% lactotroph, 2% thyrotroph, and 6% not classifiable. Of the 24 patients with somatotroph adenomas, classic accounted for 45.8%, subtle 16.7%, clinically silent 33.3%, and silent 4.2%.

Conclusions: Clinically silent somatotroph adenomas are more common than previously appreciated, representing one-third of all somatotroph adenomas. IGF1 should be measured in all patients with a sellar mass, because identification of a mass as a somatotroph adenoma expands the therapeutic options and provides a tumor marker to monitor treatment.
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http://dx.doi.org/10.1530/EJE-11-0216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118490PMC
July 2011

Predictors of hearing loss after gamma knife radiosurgery for vestibular schwannomas: age, cochlear dose, and tumor coverage.

Neurosurgery 2011 Sep;69(3):605-13; discussion 613-4

Department of Neurological Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Deterioration in hearing after Gamma Knife radiosurgery of vestibular schwannomas is a well-documented risk. Recent studies suggest a correlation between cochlear radiation dose and hearing preservation.

Objective: This study identifies additional variables that predict hearing loss after radiosurgery.

Methods: Retrospective analysis of 53 patients with audiogram follow-up. Median marginal tumor dose was 12.5 Gy. Mean tumor volume was 1.11 cm. Statistical analysis included multivariate stepwise backward linear regression and multivariate logistic regression. Variables included age, prescription dose, tumor volume, intracanalicular length, and maximum and mean cochlear dose. Dose volume histograms were generated. The percentage of the cochlear volume that received 3.6 Gy or greater, 4.7 Gy or greater, and 5.3 Gy or greater was calculated. Plan conformality indicators were calculated.

Results: Forty-two patients had a less than 20-dB change in their pure tone average, with a hearing preservation rate of 79%. Two statistically significant predictors of hearing loss were identified using multivariate analysis: tumor coverage (odds ratio: 1.38 × 10) and age (odds ratio: 1.1 per year). Multivariate linear regression was used to predict change in pure tone average. Age and percentage of the cochlear volume receiving 5.3 Gy or greater were found to be statistically significant predictor variables.

Conclusion: Older patients are more vulnerable to detrimental effects of Gamma Knife radiosurgery on hearing. We propose that cochlear dose volume histograms be created and used to reduce the percentage of the cochlear volume exposed to radiation doses greater than 5.3 Gy. This is the first report to suggest that the conformity index tumor coverage may be an important predictor of hearing outcomes.
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http://dx.doi.org/10.1227/NEU.0b013e31821a42f3DOI Listing
September 2011

Concurrent Cochlear Implantation with Resection of Skull Base Hemangiopericytoma following Sudden Deafness in an Only Hearing Ear.

Skull Base 2010 Jul;20(4):279-84

Department of Otorhinolaryngology, Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.

A 72-year-old man with a known left acoustic neuroma, left-sided deafness, and a recently diagnosed right infratemporal fossa (ITF) hemangiopericytoma, presented with sudden deafness in his right ear. Imaging revealed right-sided skull base extension and a large intracranial tumor component. The patient underwent a frontotemporal crainiotomy with concomitant ITF approach. Complete tumor resection was possible, though invasion of the otic capsule was present. Immediately postresection, a cochlear implant (CI) was performed via a transmastoid approach. Full electrode insertion was achieved and confirmed by visualization through the dehiscent middle fossa floor. Mastoid obliteration was then performed with a free fat graft. Postoperative imaging confirmed complete tumor resection (Simpson grade I) and adequate CI placement. Follow-up magnetic resonance imaging was performed at 6 and 12 months, and no tumor recurrence was seen. Prior to CI activation, the patient was completely deaf bilaterally. At 18-month follow-up, however, excellent hearing was achieved with the right CI (16 of 22 electrodes active), and the patient is now conversational with no obvious deficit. His cognitive function is excellent, corresponding to preoperative status, and he is independent in his activities of daily living. Following adjuvant radiation, our patient remains disease free at 18 months.
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http://dx.doi.org/10.1055/s-0030-1247633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023313PMC
July 2010

Biodistribution and dosimetry of (18)F-EF5 in cancer patients with preliminary comparison of (18)F-EF5 uptake versus EF5 binding in human glioblastoma.

Eur J Nucl Med Mol Imaging 2010 Nov 29;37(11):2048-59. Epub 2010 Jun 29.

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Purpose: The primary purpose of this study was to assess the biodistribution and radiation dose resulting from administration of (18)F-EF5, a lipophilic 2-nitroimidazole hypoxia marker in ten cancer patients. For three of these patients (with glioblastoma) unlabeled EF5 was additionally administered to allow the comparative assessment of (18)F-EF5 tumor uptake with EF5 binding, the latter measured in tumor biopsies by fluorescent anti-EF5 monoclonal antibodies.

Methods: (18)F-EF5 was synthesized by electrophilic addition of (18)F(2) gas, made by deuteron bombardment of a neon/fluorine mixture in a high-pressure gas target, to an allyl precursor in trifluoroacetic acid at 0° then purified and administered by intravenous bolus. Three whole-body images were collected for each of ten patients using an Allegro (Philips) scanner. Gamma counts were determined in blood, drawn during each image, and urine, pooled as a single sample. PET images were analyzed to determine radiotracer uptake in several tissues and the resulting radiation dose calculated using OLINDA software and standard phantom. For three patients, 21 mg/kg unlabeled EF5 was administered after the PET scans, and tissue samples obtained the next day at surgery to determine EF5 binding using immunohistochemistry techniques (IHC).

Results: EF5 distributes evenly throughout soft tissue within minutes of injection. Its concentration in blood over the typical time frame of the study (∼3.5 h) was nearly constant, consistent with a previously determined EF5 plasma half-life of ∼13 h. Elimination was primarily via urine and bile. Radiation exposure from labeled EF5 is similar to other (18)F-labeled imaging agents (e.g., FDG and FMISO). In a de novo glioblastoma multiforme patient, focal uptake of (18)F-EF5 was confirmed by IHC.

Conclusion: These results confirm predictions of biodistribution and safety based on EF5's characteristics (high biological stability, high lipophilicity). EF5 is a novel hypoxia marker with unique pharmacological characteristics allowing both noninvasive and invasive measurements.
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http://dx.doi.org/10.1007/s00259-010-1517-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948639PMC
November 2010

The Relationship among Hypoxia, Proliferation, and Outcome in Patients with De Novo Glioblastoma: A Pilot Study.

Transl Oncol 2010 Jun 1;3(3):160-9. Epub 2010 Jun 1.

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

The hypoxia and proliferation index increase with grade in human glial tumors, but there is no agreement whether either has prognostic importance in glioblastomas. We evaluated these end points individually and together in 16 de novo human glioblastomas using antibodies against the 2-nitroimidazole hypoxia detection agent EF5 and the proliferation detection agent Ki-67. Frozen tumor tissue sections were fluorescence-stained for nuclei (Hoechst 33342), hypoxia (anti-EF5 antibodies), and proliferation (anti-Ki-67 antibodies). EF5 binding adjacent to Ki-67+ cells, overall EF5 binding, the ratio of these values, and the proliferation index were evaluated. Patients were classified using recursive partitioning analysis and followed up until recurrence and/or death. Recursive partitioning analysis was statistically significant for survival (P = .0026). Overall EF5 binding, EF5 binding near Ki-67+ cells, and proliferation index did not predict recurrence. Two additional survival analyses based on ratios of the overall EF5 binding to EF5 binding near Ki-67+ cells were performed. High and low ratio values were determined by two cutoff points: (a) the 50% value for the ratio [EF5/Ki-67(Binding)]/[Tumor(binding)] = Ratio(EF5 50%) and (b) the median EF5 value (75.6%) of the ratio [EF5/Ki-67(Binding)]/[Tumor(binding)] = Ratio(patients median). On the basis of the Ratio(EF5 50%), recurrence (P = .0074) and survival (P = .0196) could be predicted. Using the Ratio(patients median), only survival could be predicted (P = .0291). In summary, patients had a worse prognosis if the [EF5/Ki-67(Binding)]/[Tumor(binding)] ratio was high. A hypothesis for the mechanisms and translational significance of these findings is discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887645PMC
http://dx.doi.org/10.1593/tlo.09265DOI Listing
June 2010

Magnetic resonance perfusion-weighted imaging defines angiogenic subtypes of oligodendroglioma according to 1p19q and EGFR status.

J Neurooncol 2009 May 9;92(3):373-86. Epub 2009 Apr 9.

Department of Neurosurgery, University of Pennsylvania, 3 Silverstein 3400 Spruce Street, Philadelphia, PA 19104, USA.

1p19q LOH has been shown to predict radio- and chemosensitivity and prolonged survival in oligodendrogliomas (OLs). We have recently shown that magnetic resonance perfusion-weighted imaging (MR-PWI) may be useful in predicting the histopathological grade or cytogenetic type of oligodendroglial neoplasms. MR-PWI allows noninvasive determination of relative tumor blood volume (rTBV), which may reflect the degree of neoplastic angiogenesis and metabolism. The present study was aimed to correlate rTBV to the angiogenic markers and EGFR expression in oligodendroglial tumors with 1p/19q LOH or 1p LOH (Group 1) and 1p19q intact alleles or 19q LOH (Group 2), respectively. In WHO grade II neoplasms, Group 1 showed significantly greater rTBV than Group 2 (P = 0.013). However, the differences between Group 1 and Group 2 were not significant in grade III tumors. Probe-based real-time RT-PCR analyses showed that 12% of Group 2 high-grade tumors with intact 1p19q exhibited dramatic EGFR overexpression (designated EGFR-high). Grade III neoplasms showed a significantly higher rTBV than grade II neoplasms. Group 1 tumors showed significantly higher rTBV than Group 2 tumors, independent of the EGFR-high subtype. Real-time RT-PCR analyses showed increased expression of VEGF, CD31 and CD105 in Group 1 tumors as compared to Group 2 tumors, excluding the EGFR-high subtype. Multivariable linear regression analysis showed a significant association of rTBV with 1p19q LOH, and expression of EGFR and VEGF. Therefore, the combined use of extensive molecular profiling and advanced MR imaging modalities may improve the accuracy of tumor grading, provide prognostic information, and has the potential to influence treatment decisions.
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http://dx.doi.org/10.1007/s11060-009-9880-xDOI Listing
May 2009

Imaging and analytical methods as applied to the evaluation of vasculature and hypoxia in human brain tumors.

Radiat Res 2008 Dec;170(6):677-90

Department of Radiation Oncology, University of Pennsylvania, Philadephia, PA, USA.

Tissue hypoxia results from the interaction of cellular respiration, vascular oxygen carrying capacity, and vessel distribution. We studied the relationship between tumor vasculature and regions of low pO(2) using quantitative analysis of binding of the 2-nitroimidazole EF5 given to patients intravenously (21 mg/kg) approximately 24 h preceding surgery. We describe new computer algorithms for determining EF5 binding as a function of radial distance from individual blood vessels and converting this value to tissue pO(2). Tissues from six human brain tumors were assessed. In a hemangiopericytoma, a WHO Grade 2 and WHO Grade 3 glial brain tumor, all tissue pO(2) values calculated by EF5 binding were >20 mmHg (described as "physiologically oxygenated"). In these three tumors, EF5 binding gradients (measured as a function of distance from each observed vessel) were low, with small positive and negative values averaging close to zero. Much lower tissue oxygen levels were found, including near some vessels, in glioblastomas. Gradients of EF5 binding away from vessels were larger in glioblastomas than in the low-grade tumors, but positive and negative values again averaged to near zero. Based on these preliminary data, we hypothesize a new paradigm for tumor blood flow in human brain tumors whereby in-flowing and out-flowing blood patterns may have contrasting effects on average tissue EF5 (and by inference, oxygen) gradients. Our studies also imply that neither distance to the nearest blood vessel nor distance from each observed blood vessel provide reliable estimates of tissue pO(2).
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http://dx.doi.org/10.1667/RR1207.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629387PMC
December 2008

Role of proton magnetic resonance spectroscopy in differentiating oligodendrogliomas from astrocytomas.

J Neuroimaging 2010 Jan;20(1):3-8

Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Background And Purpose: Preoperative differentiation of astrocytomas from oligodendrogliomas is clinically important, as oligodendrogliomas are more sensitive to chemotherapy. The purpose of this study was to assess the role of proton magnetic resonance spectroscopy in distinguishing astrocytomas from oligodendrogliomas.

Methods: Forty-six patients [astrocytomas (n= 17) and oligodendrogliomas (n= 29)] underwent magnetic resonance imaging and multi voxel proton magnetic resonance spectroscopic imaging before treatment. Peak areas for N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myo-inositol (mI), glutamate/glutamine (Glx), and lipids + lactate (Lip+Lac) were analyzed from voxels that exhibited hyperintensity on fluid-attenuated inversion recovery images and were normalized to Cr from each voxel. The average metabolite/Cr ratios from these voxels were then compared between astrocytomas and oligodendrogliomas. Receiver-operating curve analyses were used as measures of differentiation accuracy of metabolite ratios. A threshold value for a metabolite ratio was estimated by maximizing the sum of sensitivity and specificity.

Results: A significant difference in mI/Cr was observed between astrocytomas and oligodendrogliomas (.50 +/- .18 vs. 0.66 +/- 0.20, P < .05). Using a threshold value of .56 for mI/Cr ratio, it was possible to differentiate oligodendrogliomas from astrocytomas with a sensitivity of 72.4% and specificity of 76.4%.

Conclusion: These results suggest that mI/Cr might aid in distinguishing oligodendrogliomas from astrocytomas.
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http://dx.doi.org/10.1111/j.1552-6569.2008.00307.xDOI Listing
January 2010

Differentiation between glioblastomas and solitary brain metastases using diffusion tensor imaging.

Neuroimage 2009 Feb 7;44(3):653-60. Epub 2008 Oct 7.

Department of Radiology, Division of Neuroradiology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.

The purpose of this study is to determine whether diffusion tensor imaging (DTI) metrics including tensor shape measures such as linear and planar anisotropy coefficients (CL and CP) can help differentiate glioblastomas from solitary brain metastases. Sixty-three patients with histopathologic diagnosis of glioblastomas (22 men, 16 women, mean age 58.4 years) and brain metastases (13 men, 12 women, mean age 56.3 years) were included in this study. Contrast-enhanced T1-weighted, fluid-attenuated inversion recovery (FLAIR) images, fractional anisotropy (FA), apparent diffusion coefficient (ADC), CL and CP maps were co-registered and each lesion was semi-automatically subdivided into four regions: central, enhancing, immediate peritumoral and distant peritumoral. DTI metrics as well as the normalized signal intensity from the contrast-enhanced T1-weighted images were measured from each region. Univariate and multivariate logistic regression analyses were employed to determine the best model for classification. The results demonstrated that FA, CL and CP from glioblastomas were significantly higher than those of brain metastases from all segmented regions (p<0.05), and the differences from the enhancing regions were most significant (p<0.001). FA and CL from the enhancing region had the highest prediction accuracy when used alone with an area under the curve of 0.90. The best logistic regression model included three parameters (ADC, FA and CP) from the enhancing part, resulting in 92% sensitivity, 100% specificity and area under the curve of 0.98. We conclude that DTI metrics, used individually or combined, have a potential as a non-invasive measure to differentiate glioblastomas from metastases.
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http://dx.doi.org/10.1016/j.neuroimage.2008.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2655208PMC
February 2009

A Phase I Trial of Ad.hIFN-β Gene Therapy for Glioma.

Mol Ther 2008 Mar 8;16(3):618-626. Epub 2016 Dec 8.

Jennerex Biotherapeutics, San Francisco, California, USA.

Interferon-β (IFN-β) is a pleiotropic cytokine with antitumoral activity. In an effort to improve the therapeutic index of IFN-β by providing local, sustained delivery of IFN-β to gliomas, the safety and biological activity of a human IFN-β (hIFN-β)-expressing adenovirus vector (Ad.hIFN-β) was evaluated in patients with malignant glioma by stereotactic injection, followed 4-8 days later by surgical removal of tumor with additional injections of Ad.hIFN-β into the tumor bed. Eleven patients received Ad.hIFN-β in cohorts of 2 × 10, 6 × 10, or 2 × 10 vector particles (vp). The most common adverse events were considered by the investigator as being unrelated to treatment. One patient, who was enrolled in the cohort with the highest dose levels, experienced dose-limiting, treatment-related Grade 4 confusion following the post-operative injection. Ad.hIFN-β DNA was detected within the tumor, blood, and nasal swabs in a dose-dependent fashion and hIFN-β protein was detectable within the tumor. At the highest doses tested, a reproducible increase in tumor cell apoptosis in post-treatment versus pre-treatment biopsies with associated tumor necrosis was observed. Direct Ad.hIFN-β injection into the tumor and the surrounding normal brain areas after surgical removal was feasible and associated with apoptosis induction.
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http://dx.doi.org/10.1038/sj.mt.6300396DOI Listing
March 2008