Timothy Ryken - Academia.edu (original) (raw)
Papers by Timothy Ryken
American Journal of Neuroradiology, Apr 1, 2005
The association of high-grade oligodendrogliomas with tumor contrast material enhancement on MR i... more The association of high-grade oligodendrogliomas with tumor contrast material enhancement on MR images has been reported. Some authors have even used contrast enhancement as a criterion for their oligodendroglioma grading system. The purpose of our study was to evaluate if tumor contrast enhancement is a specific finding for anaplastic oligodendroglioma. METHODS: Pretreatment MR images of 24 oligodendrogliomas were reviewed retrospectively, and findings were compared with the histologic grade. The presence or absence and the pattern of tumor contrast enhancement were evaluated qualitatively. A contrast enhancement ratio (CER), a quantitative criterion, was calculated to assess the difference in degree of enhancement between the low-grade and anaplastic tumors. Tumor grade was diagnosed at pathologic examination according to the World Health Organization classification system. RESULTS: Contrast enhancement was noted in nine (56%) of 16 low-grade tumors and in five (62%) of eight anaplastic tumors. A characteristic enhancement pattern, nodular-like enhancement, was found in eight tumors. The CERs were 2.12-40.88 (mean, 20.08) in low-grade tumors and were 3.20-62.52 (mean, 28.73) in anaplastic tumors (P > .05). CONCLUSION: Tumor contrast enhancement was not statistically significantly different between the tumor groups. We believe that the presence or absence of tumor contrast enhancement is not a specific finding for simply discriminating low-grade from anaplastic oligodendrogliomas. Histologic confirmation is necessary even in tumors without contrast enhancement.
• Implantation of biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemo... more • Implantation of biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemotherapeutic modalities to have been evaluated in Phase III trials for treatment of newly diagnosed high-grade glioma and recurrent glioblastoma. • The prospective Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) will evaluate BCNU wafers for treatment of CNS malignancies in contemporary practice. • The VIGILANT registry will critically examine which patients might most benefit from the implantation of BCNU wafers in this new era of molecular tumor analysis. • Enrolling 500 patients at over 30 sites, the VIGILANT registry will be one of the largest prospective observational studies ever conducted to track outcomes and practice patterns for treatment of CNS malignancies. • Subgroup analyses will include tumor type, molecular marker status, and treatment combinations. Implantationof biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemotherapeutic modalities that have been evaluated in Phase III trials and approved by the US FDA for treatment of newly diagnosed high-grade glioma and recurrent glioblastoma. Enrolling up to 500 patients for 3-year follow-up at over 30 sites, the prospective Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) will evaluate BCNU wafers for treatment of CNS malignancies in contemporary practice and in the new era of molecular tumor analysis. Subgroup analyses will include tumor type, molecular marker status, and treatment combinations. Interim analyses from the VIGILANT registry will be reported until complete results are available in 2024.
Neuro-Oncology
INTRODUCTION The Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) ... more INTRODUCTION The Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) was initiated to evaluate the use of BCNU wafers for treatment of CNS malignancies in contemporary practice and in the new era of molecular analysis. METHODS The VIGILANT registry is an observational study. Each patient receives usual care from treating physicians in routine quarterly visits, with no registry-specific visits required. The VIGILANT registry will enroll up to 500 patients at 35 US sites. Patients must be ≥18 years of age with no medical conditions increasing risk through participation. Patient follow-up will last 3 years. RESULTS The interim analysis is ongoing, with the following preliminary data. Of the 143 patients enrolled to date (mean age 59.8 ± 13.41 years, 60.1% male, 82.5% white), BCNU wafers have been implanted for newly diagnosed glioblastoma (GBM) in 49 (34.3%); for recurrent GBM in 48 (33.6%); for brain metastases in 28 (19.6%); for anaplastic oligodendrogliom...
Cureus
Given the rapidly evolving pace of research and technology in the neurosurgical field, it is crit... more Given the rapidly evolving pace of research and technology in the neurosurgical field, it is critical to consider the parameters of valid, practical, and meaningful study outcome measures. Here we review fundamental aspects of selecting outcome measures in the context of neurosurgical research. Exemplifying work in meningiomas and high-grade gliomas, we delineate a proposed framework for identifying an appropriate outcome measure. Four fundamental components of an outcome measure are defined and characterized: understanding characteristics of a good outcome measure; developing a research question to address an outcome measure; defining the outcome measure, and considering limitations of an outcome measure. This four-part framework enhances and promotes the methodology for determining if an outcome measure is valid, practical, and ultimately meaningful.
Neuro-Oncology Advances
SUMMARY: One hundred and thirty cases of craniotomy for tumor utilizing BCNU implantable chemothe... more SUMMARY: One hundred and thirty cases of craniotomy for tumor utilizing BCNU implantable chemotherapy were performed by the authors between including 23 cases for metastatic intracranial disease. The series included 12 woman and 11 men with an average age of 56.9 years. The diagnoses were as follows: non-small lung carcinoma (13), breast cancer (6), small-cell lung cancer (1), colon cancer (1), unknown primary (2). Patients undergoing resection plus implantable chemotherapy following whole brain radiotherapy (5 patients) or following stereotactic radiosurgery (5 patients) were the most common. Only patient developed possible local recurrence (3%). Complications included two cerebrospinal fluid leaks with associated complications requiring reoperations (11%) both following whole brain radiotherapy and 3 patients (17%) with thromboembolic episodes (3 deep venous thromboses, one with a pulmonary embolus and sudural hematoma). In this challenging population, local implantable chemothera...
Cancer research, Jan 21, 2018
The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscore... more The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH MB using immunohistochemical analysis and transcriptome data across 763 primary tumors. RNA sequencing of CD271+ and CD271- cells revealed molecularly distinct, co-existing cellular subsets both in vitro and in vivo. MAPK/ERK signaling was upregulated in the CD271+ population, and inhibiting this pathway reduced endogenous CD271 levels, stem/progenitor cell proliferation, and cell survival as well as cell migration in vitro. Treatment with the MEK inhibitor selumetinib extended survival and reduced CD271 levels in vivo; whereas, treatment with vismodegib, a well-known smoothened (S...
CNS oncology, 2018
Implantation of biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemoth... more Implantation of biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemotherapeutic modalities that have been evaluated in Phase III trials and approved by the US FDA for treatment of newly diagnosed high-grade glioma and recurrent glioblastoma. Enrolling up to 500 patients for 3-year follow-up at over 30 sites, the prospective Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) will evaluate BCNU wafers for treatment of CNS malignancies in contemporary practice and in the new era of molecular tumor analysis. Subgroup analyses will include tumor type, molecular marker status, and treatment combinations. Interim analyses from the VIGILANT registry will be reported until complete results are available in 2024.
Neuro-Oncology
NEURO-ONCOLOGY • NOVEMBER 2016 prognosis, suggesting that EphA receptor activation may have tumor... more NEURO-ONCOLOGY • NOVEMBER 2016 prognosis, suggesting that EphA receptor activation may have tumor-suppressive functions in this subtype. EphA2 and EphA3 kinase function were intact, showing robust activation following stimulation with ephrin ligand. Furthermore, EphA2 activation led to a significant decrease in medulloblastoma cell migration in-vitro. Either EphA2 or EphA3 shRNA mediated knockdown attenuated medulloblastoma cell growth in-vitro and reduced tumor formation in-vivo. As a therapeutic proof of principle, we tested EphA2 and EphA3 specific monoclonal antibody drug conjugate targeting. Robust cell killing was observed in-vitro, while an EphA3-maytansine conjugate significantly reduced the size of developed orthotopic tumors in-vivo with minimal toxicity.
J Neuro Oncol, 1999
Human astrocytomas frequently co-express Fas (APO-1/CD95) and Fas ligand (FasL), yet do not appea... more Human astrocytomas frequently co-express Fas (APO-1/CD95) and Fas ligand (FasL), yet do not appear to be overly susceptible to suicidal, fratricidal and immune-mediated elimination. This suggests that these gliomas have acquired mechanisms to prevent Fas-mediated apoptosis from occurring. Candidates for such a role include transforming growth factor-β 2 (TGFβ2) and B-cell lymphoma / leukemia-2 (Bcl-2). TGFβ2 effectively functions by hiding tumor cells from the immune system. This may potentially prevent the delivery of FasL from cytolytic T cells to Fas bearing astrocytomas. Bcl-2 works by rendering gliomas resistant to Fas-mediated apoptosis. Using immunohistochemistry, we analyzed seventy-six human astrocytomas (11 World Health Organization (WHO) grade I, 17 grade II, 17 grade III, and 31 grade IV) for the expression of Fas, FasL, TGFβ 2 and Bcl-2 in vivo. Positive immunoreactivity was found to significantly increase with increasing tumor grade for Fas (p < 0.0002), FasL (p < 0.0001), TGFβ2 (p < 0.001) and Bcl-2 (p < 0.01). In addition, Fas / FasL co-expression, a counter-intuitive combination of factors in regards to glioma survival, also increased with WHO grade. Forty-five of 76 (59%) astrocytomas co-expressed Fas and FasL. Of those co-expressing Fas and FasL, 44 of 45 (98%) produced TGFβ2, and 26 of 45 (58%) expressed Bcl-2. We found a significant positive correlation between Fas / FasL co-expression and TGFβ2 (p < 0.002) and Bcl-2 (p < 0.005) production. We conclude that Fas and FasL are frequently co-expressed in human astrocytomas and these tumors are likely to produce other immunosuppressive and antiapoptotic factors such as TGFβ2 and Bcl-2.
Yearbook of Neurology and Neurosurgery, 2006
Journal of Neurosurgery: Spine, 2009
Object The objective of this systematic review was to use evidence-based medicine to identify the... more Object The objective of this systematic review was to use evidence-based medicine to identify the best methodology for diagnosis and treatment of anterior pseudarthrosis. Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to pseudarthrosis and cervical spine surgery. s were reviewed, after which studies meeting inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I–III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results Evaluation for pseudarthrosis is warranted, as there may be an association...
Journal of Neurosurgery: Spine, 2009
Object The objective of this systematic review was to use evidence-based medicine to examine the ... more Object The objective of this systematic review was to use evidence-based medicine to examine the efficacy of cervical laminectomy and fusion for the treatment of cervical spondylotic myelopathy (CSM). Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to cervical laminectomy, fusion, and CSM. s were reviewed, after which studies that met the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Class I–III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations which contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer-review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results Cervical laminectomy with fusion (arthrodesis...
Journal of Neurosurgery: Spine, 2009
Object The objective of this systematic review was to use evidence-based medicine to examine the ... more Object The objective of this systematic review was to use evidence-based medicine to examine the efficacy of anterior cervical surgery for the treatment of cervical spondylotic myelopathy (CSM). Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to anterior cervical surgery and CSM. s were reviewed, and studies meeting inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I–III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results Mild CSM (modified Japanese Orthopaedic Association [mJOA] scale s...
… of Neurosurgery: Spine, 2009
Object The objective of this systematic review was to use evidence-based medicine to examine the ... more Object The objective of this systematic review was to use evidence-based medicine to examine the diagnostic and therapeutic utility of intraoperative electrophysiological (EP) monitoring in the surgical treatment of cervical degenerative disease. Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to cervical spine surgery and EP monitoring. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I–III). The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results The reliance on changes in EP monitoring as an indication to alter a surgical plan or administer steroids has not been observed to reduce the incidence of neurological injury during routine surgery for cervical spondylotic myelopathy or cervical radiculopathy (Class III). However, there is an absence of study data examining the benefit of altering a surgical plan due to EP changes. Conclusions Although the use of EP monitoring may serve as a sensitive means to diagnose potential neurological injury during anterior spinal surgery for cervical spondylotic myelopathy, the practitioner must understand that intraoperative EP worsening is not specific—it may not represent clinical worsening and its recognition does not necessarily prevent neurological injury, nor does it result in improved outcome (Class II). Intraoperative improvement in EP parameters/indices does not appear to forecast outcome with reliability (conflicting Class I data).
Oncogene, 2007
Protein kinase CK2 is an ubiquitous and constitutively active kinase, which phosphorylates many c... more Protein kinase CK2 is an ubiquitous and constitutively active kinase, which phosphorylates many cellular proteins and is implicated in the regulation of cell survival, proliferation and transformation. We investigated its possible involvement in the multidrug ...
T he National Neurosurgery Quality and Outcomes Database (N 2 QOD) is a prospective clinical regi... more T he National Neurosurgery Quality and Outcomes Database (N 2 QOD) is a prospective clinical registry designed to address the need for high-quality outcome data related to care of patients with neurosur-gical disorders. This project description is intended to outline the evolution of the registry and, more broadly, the evolution of practice science methodologies over the past several years. It also attempts to describe the role of this clinical registry in the context of a rapidly changing health care landscape, which is increasingly mandating that clinicians participate in the routine collection, analysis, and application of clinical data related to the safety, quality, and value of care. Health Care Reform and the Emerging Requirement for Quality Data Over the past several decades, the biomedical community has successfully used scientific methodologies to
American Journal of Clinical Oncology, 2003
From 1970 to 1997, 63 patients with medulloblastoma were treated with craniospinal irradiation fo... more From 1970 to 1997, 63 patients with medulloblastoma were treated with craniospinal irradiation followed by a posterior fossa boost. There were 38 males and 25 females with a median age of 9 years (range, 8 months to 53 years). Stage was T1-T3a in 50 (79%) and M0 in 38 patients (60%) according to the Chang staging system. Gross total resection of the primary tumor was achieved in 33 (52%) and median posterior fossa dose was 54 Gy, with 55 (87%) receiving &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 Gy. Median radiotherapy treatment duration was 49 days (range, 30-104 days) with 35 patients (56%) completing radiotherapy in &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 days. The most common reasons for a protracted radiotherapy treatment duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 days were hematologic toxicity (46%) and use of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1.6 Gy fraction size per day (29%). Chemotherapy was used in 22 (35%). Median follow-up time was 10.8 years (range, 2-28.5 years). The 5- and 10-year freedom from progression rates were 58% +/- 13% and 50% +/- 13%, respectively, whereas the 5- and 10-year posterior fossa control rates were 61% +/- 12% and 54% +/- 13%, respectively. On multivariate analysis, age &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =3 years, M0 status, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 Gy PFB dose, radiotherapy treatment duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 days, and use of chemotherapy correlated with better freedom from progression and posterior fossa control rates. The 5- and 10-year freedom from progression rates were 67% +/- 15% and 64% +/- 16%, respectively, for patients with radiotherapy treatment duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 days and were 42% +/- 20% and 29% +/- 18%, respectively, for duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 days ( p= 0.0026, log-rank test). The 5- and 10-year posterior fossa control rates were 70% +/- 15% and 70% +/- 15%, respectively, for radiotherapy treatment duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 days and 46% +/- 20% and 33% +/- 19%, respectively, for duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 days ( p= 0.0037, log-rank test). In addition to age &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =3 years, M0 stage, use of adjuvant chemotherapy, and posterior fossa dose &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 Gy, our findings also reveal that radiotherapy treatment duration…
American Journal of Neuroradiology, Apr 1, 2005
The association of high-grade oligodendrogliomas with tumor contrast material enhancement on MR i... more The association of high-grade oligodendrogliomas with tumor contrast material enhancement on MR images has been reported. Some authors have even used contrast enhancement as a criterion for their oligodendroglioma grading system. The purpose of our study was to evaluate if tumor contrast enhancement is a specific finding for anaplastic oligodendroglioma. METHODS: Pretreatment MR images of 24 oligodendrogliomas were reviewed retrospectively, and findings were compared with the histologic grade. The presence or absence and the pattern of tumor contrast enhancement were evaluated qualitatively. A contrast enhancement ratio (CER), a quantitative criterion, was calculated to assess the difference in degree of enhancement between the low-grade and anaplastic tumors. Tumor grade was diagnosed at pathologic examination according to the World Health Organization classification system. RESULTS: Contrast enhancement was noted in nine (56%) of 16 low-grade tumors and in five (62%) of eight anaplastic tumors. A characteristic enhancement pattern, nodular-like enhancement, was found in eight tumors. The CERs were 2.12-40.88 (mean, 20.08) in low-grade tumors and were 3.20-62.52 (mean, 28.73) in anaplastic tumors (P > .05). CONCLUSION: Tumor contrast enhancement was not statistically significantly different between the tumor groups. We believe that the presence or absence of tumor contrast enhancement is not a specific finding for simply discriminating low-grade from anaplastic oligodendrogliomas. Histologic confirmation is necessary even in tumors without contrast enhancement.
• Implantation of biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemo... more • Implantation of biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemotherapeutic modalities to have been evaluated in Phase III trials for treatment of newly diagnosed high-grade glioma and recurrent glioblastoma. • The prospective Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) will evaluate BCNU wafers for treatment of CNS malignancies in contemporary practice. • The VIGILANT registry will critically examine which patients might most benefit from the implantation of BCNU wafers in this new era of molecular tumor analysis. • Enrolling 500 patients at over 30 sites, the VIGILANT registry will be one of the largest prospective observational studies ever conducted to track outcomes and practice patterns for treatment of CNS malignancies. • Subgroup analyses will include tumor type, molecular marker status, and treatment combinations. Implantationof biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemotherapeutic modalities that have been evaluated in Phase III trials and approved by the US FDA for treatment of newly diagnosed high-grade glioma and recurrent glioblastoma. Enrolling up to 500 patients for 3-year follow-up at over 30 sites, the prospective Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) will evaluate BCNU wafers for treatment of CNS malignancies in contemporary practice and in the new era of molecular tumor analysis. Subgroup analyses will include tumor type, molecular marker status, and treatment combinations. Interim analyses from the VIGILANT registry will be reported until complete results are available in 2024.
Neuro-Oncology
INTRODUCTION The Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) ... more INTRODUCTION The Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) was initiated to evaluate the use of BCNU wafers for treatment of CNS malignancies in contemporary practice and in the new era of molecular analysis. METHODS The VIGILANT registry is an observational study. Each patient receives usual care from treating physicians in routine quarterly visits, with no registry-specific visits required. The VIGILANT registry will enroll up to 500 patients at 35 US sites. Patients must be ≥18 years of age with no medical conditions increasing risk through participation. Patient follow-up will last 3 years. RESULTS The interim analysis is ongoing, with the following preliminary data. Of the 143 patients enrolled to date (mean age 59.8 ± 13.41 years, 60.1% male, 82.5% white), BCNU wafers have been implanted for newly diagnosed glioblastoma (GBM) in 49 (34.3%); for recurrent GBM in 48 (33.6%); for brain metastases in 28 (19.6%); for anaplastic oligodendrogliom...
Cureus
Given the rapidly evolving pace of research and technology in the neurosurgical field, it is crit... more Given the rapidly evolving pace of research and technology in the neurosurgical field, it is critical to consider the parameters of valid, practical, and meaningful study outcome measures. Here we review fundamental aspects of selecting outcome measures in the context of neurosurgical research. Exemplifying work in meningiomas and high-grade gliomas, we delineate a proposed framework for identifying an appropriate outcome measure. Four fundamental components of an outcome measure are defined and characterized: understanding characteristics of a good outcome measure; developing a research question to address an outcome measure; defining the outcome measure, and considering limitations of an outcome measure. This four-part framework enhances and promotes the methodology for determining if an outcome measure is valid, practical, and ultimately meaningful.
Neuro-Oncology Advances
SUMMARY: One hundred and thirty cases of craniotomy for tumor utilizing BCNU implantable chemothe... more SUMMARY: One hundred and thirty cases of craniotomy for tumor utilizing BCNU implantable chemotherapy were performed by the authors between including 23 cases for metastatic intracranial disease. The series included 12 woman and 11 men with an average age of 56.9 years. The diagnoses were as follows: non-small lung carcinoma (13), breast cancer (6), small-cell lung cancer (1), colon cancer (1), unknown primary (2). Patients undergoing resection plus implantable chemotherapy following whole brain radiotherapy (5 patients) or following stereotactic radiosurgery (5 patients) were the most common. Only patient developed possible local recurrence (3%). Complications included two cerebrospinal fluid leaks with associated complications requiring reoperations (11%) both following whole brain radiotherapy and 3 patients (17%) with thromboembolic episodes (3 deep venous thromboses, one with a pulmonary embolus and sudural hematoma). In this challenging population, local implantable chemothera...
Cancer research, Jan 21, 2018
The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscore... more The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH MB using immunohistochemical analysis and transcriptome data across 763 primary tumors. RNA sequencing of CD271+ and CD271- cells revealed molecularly distinct, co-existing cellular subsets both in vitro and in vivo. MAPK/ERK signaling was upregulated in the CD271+ population, and inhibiting this pathway reduced endogenous CD271 levels, stem/progenitor cell proliferation, and cell survival as well as cell migration in vitro. Treatment with the MEK inhibitor selumetinib extended survival and reduced CD271 levels in vivo; whereas, treatment with vismodegib, a well-known smoothened (S...
CNS oncology, 2018
Implantation of biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemoth... more Implantation of biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemotherapeutic modalities that have been evaluated in Phase III trials and approved by the US FDA for treatment of newly diagnosed high-grade glioma and recurrent glioblastoma. Enrolling up to 500 patients for 3-year follow-up at over 30 sites, the prospective Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) will evaluate BCNU wafers for treatment of CNS malignancies in contemporary practice and in the new era of molecular tumor analysis. Subgroup analyses will include tumor type, molecular marker status, and treatment combinations. Interim analyses from the VIGILANT registry will be reported until complete results are available in 2024.
Neuro-Oncology
NEURO-ONCOLOGY • NOVEMBER 2016 prognosis, suggesting that EphA receptor activation may have tumor... more NEURO-ONCOLOGY • NOVEMBER 2016 prognosis, suggesting that EphA receptor activation may have tumor-suppressive functions in this subtype. EphA2 and EphA3 kinase function were intact, showing robust activation following stimulation with ephrin ligand. Furthermore, EphA2 activation led to a significant decrease in medulloblastoma cell migration in-vitro. Either EphA2 or EphA3 shRNA mediated knockdown attenuated medulloblastoma cell growth in-vitro and reduced tumor formation in-vivo. As a therapeutic proof of principle, we tested EphA2 and EphA3 specific monoclonal antibody drug conjugate targeting. Robust cell killing was observed in-vitro, while an EphA3-maytansine conjugate significantly reduced the size of developed orthotopic tumors in-vivo with minimal toxicity.
J Neuro Oncol, 1999
Human astrocytomas frequently co-express Fas (APO-1/CD95) and Fas ligand (FasL), yet do not appea... more Human astrocytomas frequently co-express Fas (APO-1/CD95) and Fas ligand (FasL), yet do not appear to be overly susceptible to suicidal, fratricidal and immune-mediated elimination. This suggests that these gliomas have acquired mechanisms to prevent Fas-mediated apoptosis from occurring. Candidates for such a role include transforming growth factor-β 2 (TGFβ2) and B-cell lymphoma / leukemia-2 (Bcl-2). TGFβ2 effectively functions by hiding tumor cells from the immune system. This may potentially prevent the delivery of FasL from cytolytic T cells to Fas bearing astrocytomas. Bcl-2 works by rendering gliomas resistant to Fas-mediated apoptosis. Using immunohistochemistry, we analyzed seventy-six human astrocytomas (11 World Health Organization (WHO) grade I, 17 grade II, 17 grade III, and 31 grade IV) for the expression of Fas, FasL, TGFβ 2 and Bcl-2 in vivo. Positive immunoreactivity was found to significantly increase with increasing tumor grade for Fas (p < 0.0002), FasL (p < 0.0001), TGFβ2 (p < 0.001) and Bcl-2 (p < 0.01). In addition, Fas / FasL co-expression, a counter-intuitive combination of factors in regards to glioma survival, also increased with WHO grade. Forty-five of 76 (59%) astrocytomas co-expressed Fas and FasL. Of those co-expressing Fas and FasL, 44 of 45 (98%) produced TGFβ2, and 26 of 45 (58%) expressed Bcl-2. We found a significant positive correlation between Fas / FasL co-expression and TGFβ2 (p < 0.002) and Bcl-2 (p < 0.005) production. We conclude that Fas and FasL are frequently co-expressed in human astrocytomas and these tumors are likely to produce other immunosuppressive and antiapoptotic factors such as TGFβ2 and Bcl-2.
Yearbook of Neurology and Neurosurgery, 2006
Journal of Neurosurgery: Spine, 2009
Object The objective of this systematic review was to use evidence-based medicine to identify the... more Object The objective of this systematic review was to use evidence-based medicine to identify the best methodology for diagnosis and treatment of anterior pseudarthrosis. Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to pseudarthrosis and cervical spine surgery. s were reviewed, after which studies meeting inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I–III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results Evaluation for pseudarthrosis is warranted, as there may be an association...
Journal of Neurosurgery: Spine, 2009
Object The objective of this systematic review was to use evidence-based medicine to examine the ... more Object The objective of this systematic review was to use evidence-based medicine to examine the efficacy of cervical laminectomy and fusion for the treatment of cervical spondylotic myelopathy (CSM). Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to cervical laminectomy, fusion, and CSM. s were reviewed, after which studies that met the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Class I–III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations which contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer-review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results Cervical laminectomy with fusion (arthrodesis...
Journal of Neurosurgery: Spine, 2009
Object The objective of this systematic review was to use evidence-based medicine to examine the ... more Object The objective of this systematic review was to use evidence-based medicine to examine the efficacy of anterior cervical surgery for the treatment of cervical spondylotic myelopathy (CSM). Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to anterior cervical surgery and CSM. s were reviewed, and studies meeting inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I–III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results Mild CSM (modified Japanese Orthopaedic Association [mJOA] scale s...
… of Neurosurgery: Spine, 2009
Object The objective of this systematic review was to use evidence-based medicine to examine the ... more Object The objective of this systematic review was to use evidence-based medicine to examine the diagnostic and therapeutic utility of intraoperative electrophysiological (EP) monitoring in the surgical treatment of cervical degenerative disease. Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to cervical spine surgery and EP monitoring. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I–III). The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results The reliance on changes in EP monitoring as an indication to alter a surgical plan or administer steroids has not been observed to reduce the incidence of neurological injury during routine surgery for cervical spondylotic myelopathy or cervical radiculopathy (Class III). However, there is an absence of study data examining the benefit of altering a surgical plan due to EP changes. Conclusions Although the use of EP monitoring may serve as a sensitive means to diagnose potential neurological injury during anterior spinal surgery for cervical spondylotic myelopathy, the practitioner must understand that intraoperative EP worsening is not specific—it may not represent clinical worsening and its recognition does not necessarily prevent neurological injury, nor does it result in improved outcome (Class II). Intraoperative improvement in EP parameters/indices does not appear to forecast outcome with reliability (conflicting Class I data).
Oncogene, 2007
Protein kinase CK2 is an ubiquitous and constitutively active kinase, which phosphorylates many c... more Protein kinase CK2 is an ubiquitous and constitutively active kinase, which phosphorylates many cellular proteins and is implicated in the regulation of cell survival, proliferation and transformation. We investigated its possible involvement in the multidrug ...
T he National Neurosurgery Quality and Outcomes Database (N 2 QOD) is a prospective clinical regi... more T he National Neurosurgery Quality and Outcomes Database (N 2 QOD) is a prospective clinical registry designed to address the need for high-quality outcome data related to care of patients with neurosur-gical disorders. This project description is intended to outline the evolution of the registry and, more broadly, the evolution of practice science methodologies over the past several years. It also attempts to describe the role of this clinical registry in the context of a rapidly changing health care landscape, which is increasingly mandating that clinicians participate in the routine collection, analysis, and application of clinical data related to the safety, quality, and value of care. Health Care Reform and the Emerging Requirement for Quality Data Over the past several decades, the biomedical community has successfully used scientific methodologies to
American Journal of Clinical Oncology, 2003
From 1970 to 1997, 63 patients with medulloblastoma were treated with craniospinal irradiation fo... more From 1970 to 1997, 63 patients with medulloblastoma were treated with craniospinal irradiation followed by a posterior fossa boost. There were 38 males and 25 females with a median age of 9 years (range, 8 months to 53 years). Stage was T1-T3a in 50 (79%) and M0 in 38 patients (60%) according to the Chang staging system. Gross total resection of the primary tumor was achieved in 33 (52%) and median posterior fossa dose was 54 Gy, with 55 (87%) receiving &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 Gy. Median radiotherapy treatment duration was 49 days (range, 30-104 days) with 35 patients (56%) completing radiotherapy in &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 days. The most common reasons for a protracted radiotherapy treatment duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 days were hematologic toxicity (46%) and use of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1.6 Gy fraction size per day (29%). Chemotherapy was used in 22 (35%). Median follow-up time was 10.8 years (range, 2-28.5 years). The 5- and 10-year freedom from progression rates were 58% +/- 13% and 50% +/- 13%, respectively, whereas the 5- and 10-year posterior fossa control rates were 61% +/- 12% and 54% +/- 13%, respectively. On multivariate analysis, age &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =3 years, M0 status, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 Gy PFB dose, radiotherapy treatment duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 days, and use of chemotherapy correlated with better freedom from progression and posterior fossa control rates. The 5- and 10-year freedom from progression rates were 67% +/- 15% and 64% +/- 16%, respectively, for patients with radiotherapy treatment duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 days and were 42% +/- 20% and 29% +/- 18%, respectively, for duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 days ( p= 0.0026, log-rank test). The 5- and 10-year posterior fossa control rates were 70% +/- 15% and 70% +/- 15%, respectively, for radiotherapy treatment duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 days and 46% +/- 20% and 33% +/- 19%, respectively, for duration &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 days ( p= 0.0037, log-rank test). In addition to age &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =3 years, M0 stage, use of adjuvant chemotherapy, and posterior fossa dose &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =50 Gy, our findings also reveal that radiotherapy treatment duration…