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Borimir J. Darakchiev, Robert E. Albright, John C. Breneman and Ronald E. Warnick

Object

Effective treatment options are limited for patients with recurrent glioblastoma multiforme (GBM), and survival is usually <1 year. Novel treatment approaches are needed. Localized adjunct treatment with carmustine (BCNU) wafers or permanent, low-activity 125I seed implants has been shown to be effective for GBM. This study assessed the efficacy and safety of these therapies in combination following tumor resection.

Methods

Thirty-four patients with recurrent GBM were treated with maximal tumor resection followed by implantation of BCNU wafers and permanent 125I seeds into the tumor cavity. Patients were followed up with clinical evaluations and magnetic resonance imaging studies once every 3 months. Survival and progression-free survival (PFS) were evaluated.

Results

During follow-up, local disease progression was observed in 27 patients, and 23 of them died. The median survival period was 69 weeks, and the median PFS was 47 weeks. The 12-month survival and PFS rates were 66 and 32%, respectively. Baseline factors associated with prolonged survival included Karnofsky Performance Scale score ≥ 70, 125I seed activity ≥ 0.8 mCi/cm3 of tumor cavity, and age < 60 years. Brain necrosis developed in 8 patients (24%) and was successfully treated with surgery or hyperbaric oxygen therapy.

Conclusions

The use of adjunct therapy combining BCNU wafers and permanent 125I seeds resulted in survival that compares favorably with data from similar studies performed in patients with recurrent GBM. The incidence of brain necrosis appeared to be higher than that expected with either treatment alone, although the necrosis was manageable and did not affect survival. This novel approach warrants further investigation in recurrent and newly diagnosed GBM.

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Bledi Brahimaj, Michael Lamba, John C. Breneman and Ronald E. Warnick

This case report documents the migration of 3 iodine-125 (125I) seeds from the tumor resection cavity into brain parenchyma over a 7-year period. A 66-year-old woman had a history of metastatic ovarian carcinoma, nickel allergy, and reaction to a titanium hip implant that required reoperation for hardware removal. In this unique case of parenchymal migration, the seed paths seemed to follow white matter tracts, traveling between 18.5 and 35.5 mm from the initial implant site. The patient's initial neurological decline, which was thought to be related to radiation necrosis, appeared to stabilize with medical therapy. She subsequently developed progressive right hemispheric edema that resulted in neurological deterioration and death. Considering her previous reactions to nickel and titanium, the authors now speculate that her later clinical course reflected an allergic reaction to the titanium casing of the 125I seeds. Containing a trace amount of nickel, 125I seeds can elicit a delayed hypersensitivity reaction in patients with a history of nickel dermatitis. Preoperative patch testing is recommended in these patients, and 125I seed implantation should be avoided in those who test positive.

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Ellen L. Air, James L. Leach, Ronald E. Warnick and Christopher M. McPherson

Object

Frameless stereotactic biopsy has been shown in multiple studies to be a safe and effective tool for the diagnosis of brain lesions. However, no study has directly evaluated its safety in lesions located in eloquent regions in comparison with noneloquent locations. In this study, the authors determine whether an increased risk of neurological decline is associated with biopsy of lesions in eloquent regions of the brain.

Methods

Medical records, including imaging studies, were reviewed for 284 cases in which frameless stereotactic biopsy procedures were performed by 19 neurosurgeons at 7 institutions between January 2000 and December 2006. Lesion location was classified as eloquent or noneloquent in each patient. The incidence of neurological decline was calculated for each group.

Results

During the study period, 160 of the 284 biopsies predominately involved eloquent regions of the brain. In evaluation of the complication rate with respect to biopsy site, neurological decline occurred in 9 (5.6%) of 160 biopsies in eloquent brain areas and 10 (8.1%) of 124 biopsies in noneloquent regions; this difference was not statistically significant (p = 0.416). A higher number of needle passes was associated with the presence of a postoperative hemorrhage at the biopsy site, although not with a change in the result of neurological examination.

Conclusions

Frameless stereotactic biopsy of lesions located in eloquent brain regions is as safe and effective as biopsy of lesions in noneloquent regions. Therefore, with careful planning, frameless stereotactic biopsy remains a valuable and safe tool for diagnosis of brain lesions, independent of lesion location.

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Ronald E. Warnick, Jack Raisanen, Theodore Kaczmar Jr., Richard L. Davis and Michael D. Prados

✓ A rare case of intradural chordoma is described. The literature contains seven examples of intradural extraosseous chordoma, all reported in a ventral location. This is the first reported case of a primary intradural chordoma distant from the clivus and involving both the supra- and infratentorial compartments.

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Teresa Meier, J. Michael Hazenfield, Saulius Girnius, Matthew Hagen, Ronald E. Warnick and Jordan Kharofa

A 54-year-old female presented with multiple episodes of emesis, intractable headaches, worsening balance, and slowly progressive right facial weakness. Imaging demonstrated a 3-cm mass in the left internal capsule and corona radiata region with associated edema, mass effect, and midline shift concerning for high-grade glioma, lymphoma, or brain metastasis. Stereotactic biopsy of the mass was consistent with amyloid deposition. Systemic workup for amyloidosis was negative, and the mass was thought to represent a focal tumor-like deposit of amyloid, also referred to as “amyloidoma.” In the absence of systemic disease, therapy, which can include surgery or radiotherapy, can be directed at the local process. The location of the patient's lesion was not amenable to resection; therefore, she was treated with fractionated radiotherapy of 30.6 Gy at 1.8 Gy per fraction. Serial brain MRI demonstrated stability 18 months out from therapy. To the authors' knowledge, this is the first documented case of focal fractionated radiotherapy for CNS amyloidoma. The authors concluded that radiotherapy can prevent further progression of amyloidomas in anatomical locations that prohibit resection.

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Philip V. Theodosopoulos, Andrew J. Ringer, Christopher M. McPherson, Ronald E. Warnick, Charles Kuntz IV, Mario Zuccarello and John M. Tew Jr.

Object

Health care reform debate includes discussions regarding outcomes of surgical interventions. Yet quality of medical care, when judged as a health outcome, is difficult to define because of impediments affecting accuracy in data collection, analysis, and reporting. In this prospective study, the authors report the outcomes for neurosurgical treatment based on point-of-care interactions recorded in the electronic medical record (EMR).

Methods

The authors' neurosurgery practice collected outcome data for 19 physicians and ancillary personnel using the EMR. Data were analyzed for 5361 consecutive surgical cases, either elective or emergency procedures, performed during 2009 at multiple hospitals, offices, and an ambulatory spine surgery center. Main outcomes included complications, length of stay (LOS), and discharge disposition for all patients and for certain frequently performed procedures. Physicians, nurses, and other medical staff used validated scales to record the hospital LOS, complications, disposition at discharge, and return to work.

Results

Of the 5361 surgical procedures performed, two-thirds were spinal procedures and one-third were cranial procedures. Organization-wide compliance with reporting rates of major complications improved throughout the year, from 80.7% in the first quarter to 90.3% in the fourth quarter. Auditing showed that rates of unreported complications decreased from 11% in the first quarter to 4% in the fourth quarter. Complication data were available for 4593 procedures (85.7%); of these, no complications were reported in 4367 (95.1%). Discharge dispositions reported were home in 86.2%, rehabilitation center in 8.9%, and nursing home in 2.5%. Major complications included culture-proven infection in 0.61%, CSF leak in 0.89%, reoperation within the same hospitalization in 0.38%, and new neurological deficits in 0.77%. For the commonly performed procedures, the median hospital LOS was 3 days for craniotomy for aneurysm or intraaxial tumor and less than 1 day for angiogram, anterior cervical discectomy with fusion, or lumbar discectomy.

Conclusions

With prospectively collected outcome data for more than 5000 surgeries, the authors achieved their primary end point of institution-wide compliance and data accuracy. Components of this process included staged implementation with physician pilot studies and oversight, nurse participation, point-of-service data capture, EMR form modification, data auditing, and confidential surgeon reports.

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Elias Dagnew, Jeffrey Kanski, Michael W. McDermott, Penny K. Sneed, Christopher McPherson, John C. Breneman and Ronald E. Warnick

Object

Whole-brain radiotherapy (WBRT) after resection of a single brain metastasis can cause long-term radiation toxicity. The authors evaluated the efficacy of resection and placement of 125I seeds (without concomitant WBRT) for newly diagnosed single brain metastases.

Methods

In a retrospective review from two institutions (1997–2003), 15 women and 11 men (mean age 55 years) with single brain metastasis underwent gross-total resection and placement of permanent low-activity 125I seeds. Primary systemic cancer sites varied. Patients were monitored clinically and radiographically. With neuroimaging evidence of local recurrence or new distant metastasis, further treatment was administered at the physician's discretion. By the median follow-up evaluation (12 months), the local tumor control rate was 96%. Distant metastases occurred in three patients within 3 months, suggesting synchronous metastasis, and in six patients more than 3 months after treatment, indicating metachronous metastasis. Treatment in these cases included radio-surgery in seven patients, WBRT in two, and resection together with 125I seed placement in one. Two patients who suffered radiation necrosis required operative intervention (lesion diameter > 3 cm, total activity > 40 mCi). All 26 patients who had been treated using resection and placement of 125I seeds had a stable or an improved Karnofsky Performance Scale score. At the last review, nine of 16 living patients showed no evidence of treatment failure. The median actuarial survival rate was 17.8 months (Kaplan–Meier method).

Conclusions

Permanent 125I brachytherapy applied at the initial operation without WBRT provided excellent local tumor control. Local control and patient survival rates were at least as good as those reported for resection combined with WBRT. Although the authors noted a higher incidence of distant metastases compared with that reported in other studies of initial WBRT, these metastases were generally well controlled with a combination of surgery, stereotactic radiosurgery, and, less often, WBRT. Twenty-four patients (92%) never required WBRT, thus avoiding potential long-term radiation-induced neurotoxicity.

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Jason P. Sheehan, Inga Grills, Veronica L. Chiang, Huamei Dong, Arthur Berg, Ronald E. Warnick, Douglas Kondziolka and Brian Kavanagh

OBJECTIVE

Stereotactic radiosurgery (SRS) is increasingly used for the treatment of brain metastasis. To date, most studies have focused on survival, radiological response, or surrogate quality endpoints such as Karnofsky Performance Scale status or neurocognitive indices. The current study prospectively evaluated pre-procedural factors impacting quality of life in brain metastasis patients undergoing SRS.

METHODS

Using a national, cloud-based platform, patients undergoing SRS for brain metastasis were accrued to the registry. Quality of life prior to SRS was assessed using the 5-level EQ-5D (EQ5D-L) validated tool; additionally, patient and treatment attributes were collected. Patient quality of life was assessed as part of routine follow-up after SRS. Factors predicting a difference in the aggregate EQ5D-L score or the subscores were evaluated. Pre-SRS covariates impacting changes in EQ5D-L were statistically evaluated. Statistical analyses were conducted using multivariate linear regression models.

RESULTS

EQ5D-L results were available for 116 patients. EQ5D-L improvement (average of 0.387) was noted in patients treated with earlier SRS (p = 0.000175). Worsening overall EQ5D-L (average of 0.052 per lesion) was associated with an increased number of brain metastases at the time of initial presentation (p = 0.0399). Male sex predicted a risk of worsening (average of 0.347) of the pain and discomfort subscore at last follow-up (p = 0.004205). Baseline subscores of pain/discomfort were not correlated with pain/discomfort subscores at follow-up (p = 0.604), whereas baseline subscores of anxiety/depression were strongly positively correlated with the anxiety/depression follow-up subscores (p = 0.0039).

CONCLUSIONS

After SRS, quality of life was likely to improve in patients treated early with SRS and worsen in those with a greater number of brain metastases. Sex differences appear to exist regarding pain and discomfort worsening after SRS. Those with high levels of anxiety and depression at SRS may benefit from medical treatment as this particular quality of life factor generally remains unchanged after SRS.

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Nobusada Shinoura, Lin Chen, Maqsood A. Wani, Young Gyu Kim, Jeffrey J. Larson, Ronald E. Warnick, Matthias Simon, Anil G. Menon, Wan Li Bi and Peter J. Stambrook

✓ The expression of connexin43, the primary gap-junction constituent of glial cells, was evaluated at the messenger RNA and protein levels in different grades of astrocytoma to investigate the relevance of gap junctions in herpes simplex virus—thymidine kinase (HSV-tk)—mediated gene therapy of brain tumors. Transduction of the retroviral-mediated HSV-tk gene into tumor cells with subsequent administration of ganciclovir has recently been used as an experimental therapeutic strategy for treatment of brain tumors. One aspect of this approach is the bystander effect, which augments the efficacy of this therapeutic approach. Glioblastoma cells with minimum levels of connexin43 protein were transfected with a connexin43 complementary DNA. These cells manifested a marked increase in the in vitro bystander effect, supporting the contention that the in vitro bystander effect is a consequence of metabolic cooperation between cells mediated by gap junctions. To assess relative levels of gap-junction protein expression in the relevant tumor type, we examined primary astrocytomas, primary astrocytoma cell cultures, and glioblastoma cell lines. Although most astrocytoma tumor samples expressed connexin43, they differed in the level of expression, with the greatest variation exhibited in high-grade astrocytomas. Primary glioblastoma cell cultures and established glioblastoma cell lines also displayed some variability in connexin43 levels. In aggregate, our results anticipate that glioblastomas will have a varied bystander effect during HSV-tk gene therapy depending on the level of connexin43 expression.

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Jaime Vengoechea, Andrew E. Sloan, Yanwen Chen, Xiaowei Guan, Quinn T. Ostrom, Amber Kerstetter, Devan Capella, Mark L. Cohen, Yingli Wolinsky, Karen Devine, Warren Selman, Gene H. Barnett, Ronald E. Warnick, Christopher McPherson, E. Antonio Chiocca, J. Bradley Elder and Jill S. Barnholtz-Sloan

Object

Although most meningiomas are benign, about 20% are atypical (Grade II or III) and have increased mortality and morbidity. Identifying tumors with greater malignant potential can have significant clinical value. This validated genome-wide methylation study comparing Grade I with Grade II and III meningiomas aims to discover genes that are aberrantly methylated in atypical meningiomas.

Methods

Patients with newly diagnosed meningioma were identified as part of the Ohio Brain Tumor Study. The Infinium HumanMethylation27 BeadChip (Illumina, Inc.) was used to interrogate 27,578 CpG sites in 14,000 genes per sample for a discovery set of 33 samples (3 atypical). To verify the results, the Infinium HumanMethylation450 BeadChip (Illumina, Inc.) was used to interrogate 450,000 cytosines at CpG loci throughout the genome for a verification set containing 7 replicates (3 atypical), as well as 12 independent samples (6 atypical). A nonparametric Wilcoxon exact test was used to test for difference in methylation between benign and atypical meningiomas in both sets. Heat maps were generated for each set. Methylation results were validated for the 2 probes with the largest difference in methylation intensity by performing Western blot analysis on a set of 20 (10 atypical) samples, including 11 replicates.

Results

The discovery array identified 95 probes with differential methylation between benign and atypical meningiomas, creating 2 distinguishable groups corresponding to tumor grade when visually examined on a heat map. The validation array evaluated 87 different probes and showed that 9 probes were differentially methylated. On heat map examination the results of this array also suggested the existence of 2 major groups that corresponded to histological grade. IGF2BP1 and PDCD1, 2 proteins that can increase the malignant potential of tumors, were the 2 probes with the largest difference in intensity, and for both of these the atypical meningiomas had a decreased median production of protein, though this was not statistically significant (p = 0.970 for IGF2BP1 and p = 1 for PDCD1).

Conclusions

A genome-wide methylation analysis of benign and atypical meningiomas identified 9 genes that were reliably differentially methylated, with the strongest difference in IGF2BP1 and PDCD1. The mechanism why increased methylation of these sites is associated with an aggressive phenotype is not evident. Future research may investigate this mechanism, as well as the utility of IGF2BP1 as a marker for pathogenicity in otherwise benign-appearing meningiomas.