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Biomedical subjects

Timothy C Ryken

Publications and source records attributed to Timothy C Ryken.

At least 19 recordsLinked to original sources
PubMed2006

Cis-parinaric acid effects, cytotoxicity, c-Jun N-terminal protein kinase, forkhead transcription factor and Mn-SOD differentially in malignant and normal astrocytes.

Cis-parinaric acid (c-PNA), a natural four conjugated polyunsaturated fatty acid, increases free radical production and it is preferentially cytotoxic to malignant glial cells compared to normal astrocytes in-vitro. In order to explain the increased cytotoxicity of c-PNA in malignant glial cells, we compared the effects of c-PNA on the oxidative stress-dependent signal transducing events in 36B10 cells, a malignant rat astrocytoma cell line, and in fetal rat astrocytes. Our results show that c-PNA treatment in 36B10 cells caused a persistent activation of c-Jun N-terminal protein kinase (JNK) at RNA and protein levels. Specific inhibitors of the kinase significantly reversed the cytotoxicity of c-PNA. Additionally, c-PNA caused the phosphorylated inactivation of forkhead transcription factor-3a (FKHR-L1, FOXO3a) and drastically decreased the activity of mitochondrial superoxide dismutase (Mn-SOD) that protects cells from oxidative stress. On the other hand, identical c-PNA treatments in normal astrocytes increased the dephosphorylated activation of FKHR-L1, maintained activity of Mn-SOD and failed to phosphorylate JNK. Taken together, the results imply that a selective activation of JNK and the opposite regulation of FKHR-L1 and Mn-SOD contribute to the differential cytotoxicity of c-PNA in malignant and normal glial cells.

Animals↗
PubMed2006

Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma.

Promoter hypermethylation and histone deacetylation are common epigenetic mechanisms implicated in the transcriptional silencing of tumor suppressor genes in human cancer. We treated two immortalized glioma cell lines, T98 and U87, and 10 patient-derived primary glioma cell lines with trichostatin A (TSA), a histone deacetylase inhibitor, or 5-aza-2'-deoxycytidine (5-AzaC), a DNA methyltransferase inhibitor, to comprehensively identify the cohort of genes reactivated through the pharmacologic reversal of these distinct but related epigenetic processes. Whole-genome microarray analysis identified genes induced by TSA (653) or 5-AzaC treatment (170). We selected a subset of reactivated genes that were markedly induced (greater than two-fold) after treatment with either TSA or 5-AzaC in a majority of glioma cell lines but not in cultured normal astrocytes. We then characterized the degree of promoter methylation and transcriptional silencing of selected genes in histologically confirmed human tumor and nontumor brain specimens. We identified two novel brain expressed genes, BEX1 and BEX2, which were silenced in all tumor specimens and exhibited extensive promoter hypermethylation. Viral-mediated reexpression of either BEX1 or BEX2 led to increased sensitivity to chemotherapy-induced apoptosis and potent tumor suppressor effects in vitro and in a xenograft mouse model. Using an integrated approach, we have established a novel platform for the genome-wide screening of epigenetically silenced genes in malignant glioma. This experimental paradigm provides a powerful new method for the identification of epigenetically silenced genes with potential function as tumor suppressors, biomarkers for disease diagnosis and detection, and therapeutically reversible modulators of critical regulatory pathways important in glioma pathogenesis.

Azacitidine↗
PubMed2006

Radiation induced adult medulloblastoma: a case report.

Adult medulloblastoma is a rare intracranial tumor. Our patient is a 61 year old woman treated with cranial irradiation 15 years previously for a low grade astrocytoma in the left posterior temporal lobe that was recently diagnosed with medulloblastoma in the right cerebellum. This is the first reported case of radiation induced adult medulloblastoma.

Astrocytoma↗
PubMed2006

Trends in brain cancer incidence and survival in the United States: Surveillance, Epidemiology, and End Results Program, 1973 to 2001.

OBJECT: An increasing incidence of brain cancer has been reported for the last three decades. In this study of brain cancer incidence and patient survival in the US, the authors attempt to update information on trends by examining data provided by the Surveillance, Epidemiology, and End Results (SEER) Program. METHODS: Population-based data from the SEER Program were used to calculate the incidence of and survival rates for people with brain cancer. The approximate Poisson method was used to calculate relative risks for brain cancer and to determine a 95% confidence interval. Annual age-standardized incidence rates were calculated, and time-trend analysis was conducted using joinpoint regression analysis. The relative risks of brain cancer were 1.48 for men compared with women, 3.18 for elderly persons compared with young adults, 1.86 for Caucasian patients compared with African-American patients, and 1.35 for those in metropolitan counties compared with those in nonmetropolitan counties. The incidence of brain cancer increased until 1987, when the annual percentage of change reversed direction, decreasing from 1.68 to 20.44%. The elderly experienced an increase until 1985, but their rates were stable thereafter. Rising trends were noticed for glioblastoma multiforme (GBM), oligodendroglioma, anaplastic astrocytoma, medulloblastoma, and mixed glioma, and falling trends were observed for astrocytoma not otherwise specified and malignant glioma. The survival rate for patients with GBM has not shown improvement in the last two decades. CONCLUSIONS: Increased risk of brain cancer is associated with being male, Caucasian, elderly, and residing in a metropolitan county. The incidence rate of brain cancer in the US is gradually declining, but the rising trend of GBM combined with its poor survival rate is disconcerting and needs further exploration.

Adult↗
PubMed2006

Management of malignant glioma: steady progress with multimodal approaches.

Despite recent successes in the treatment of cancer with multidisciplinary multimodal treatment approaches, the duration of survival for patients with malignant glioma remains limited. Malignant gliomas represent a class of infiltrative, aggressive neoplasms that are generally resistant to combination therapies. The basic approach to treatment has involved a combination of surgery and radiotherapy. The use of chemotherapy has been met with skepticism because of its limited efficacy and the significant side effects demonstrated in clinical trials. Nevertheless, based on findings in randomized trials of new agents, it has been suggested that further evaluation of the role of chemotherapy is warranted. Temozolomide and Gliadel (carmustine wafers) are generally well tolerated due to their limited systemic toxicity. These agents appear particularly well suited for incorporation into multimodal treatment strategies. Proposed investigations and ongoing clinical trials will be conducted to assess the use of these agents in novel combination therapies. Future treatment strategies may include a wide variety of biological response modifiers, but will need to continue to address local control with surgery, radiation, and adjuvant chemotherapy.

Antineoplastic Agents↗
PubMed2006

Radiotoxicity after conformal radiation therapy for benign intracranial tumors.

Acoustic schwannomas, skull base meningiomas, and pituitary adenomas are benign intracranial tumors frequently managed with radiotherapy. Control rates after treatment for each of these tumors are generally high, and toxicity from treatment is relatively low. Side effect profiles depend on the tumor location, the volume treated, the dose delivered, and the presence of nearby critical structures. In addition, patient-specific factors, such as hypertension and diabetes, may increase a patient's risk for complications. This article reviews radiotoxicity after conformal radiation therapy for acoustic schwannomas, skull base meningiomas, and pituitary adenomas.

Brain Neoplasms↗
PubMed2005

Genetic characterization of commonly used glioma cell lines in the rat animal model system.

OBJECT: Animal models have been used extensively to discern the molecular biology of diseases and to gain insight into treatments. Nevertheless, discrepancies in the effects of treatments and procedures have been encountered during the transition from these animal models to application of the information to clinical trials in humans. To assess the genetic similarities between human gliomas and four cell lines used routinely in animal models, the authors used microarray technology to characterize the similarities and differences in gene expression. METHODS: To define the changes in gene expression, normal rat astrocytes were compared with four rat glioma cell lines (C6, 9L, F98, and RG2). The data were analyzed using two different methods: fold-change analysis and statistical analysis with t statistics. The gene products that were highlighted after intersecting the lists generated by the two methods of analysis were scrutinized against changes in gene expression reported in the literature. Tumorigenesis involves three major steps: the accumulation of genetic alterations, uncontrolled growth, and selected survival of transformed cells. The discussion of the results focuses attention on genes whose primary function is in pathways involved in glioma proliferation, infiltration, and neovascularization. A comparative microarray analysis of differentially expressed genes for four of the commonly used rat tumor cell lines is presented here. CONCLUSIONS: Due to the variances between the cell lines and results from analyses in humans, caution must be observed in interpreting as well as in the translation of information learned from animal models to its application in human trials.

Animals↗
PubMed2005

Initial clinical experience with frameless radiosurgery for patients with intracranial metastases.

PURPOSE: To review the initial clinical experience with frameless stereotactic radiosurgery (SRS) for treating intracranial metastatic disease. METHODS AND MATERIALS: Sixty-four patients received frameless SRS for intracranial metastatic disease. Minimum follow-up was 6 months with none lost to follow-up. Patients had a median of 2 metastases and a maximum of 4. The median number of isocenters was 2 with median arcs of 10 and median dose of 17.5 Gy. Thirteen patients were treated for progressive/recurrent disease after surgical resection or whole brain radiotherapy (WBRT). Fifty-one patients were treated with frameless SRS as an an adjunct to initial treatment. Of the total treated, 17 were treated with SRS alone, 20 were treated with WBRT plus SRS, 16 were treated with surgical resection plus SRS, and the remaining 11 were treated with surgical resection plus WBRT plus SRS. RESULTS: With a median actuarial follow-up period of 8.2 months, ultimate local control was 88%. The median time to progression was 8.1 months. The median overall survival was 8.7 months. Of the 17 patients treated with SRS alone, 86% had ultimate local control with mean overall survival of 7.1 months. Of the 13 patients who received surgical resection plus SRS without WBRT as primary treatment, there was 85% ultimate local control with an overall survival of 10.3 months. Three patients treated with initial surgery alone had recurrence treated with SRS 2-3 months after resection. All these patients obtained local control and median survival was >10 months. Of the 13 patients who received WBRT followed by SRS as boost treatment, 92% had local control and mean overall survival was 7.3 months. Of 7 patients who received SRS after recurrence after WBRT, 100% had local control with median survival of 8.2 months. For 8 patients who received surgery followed by WBRT and SRS, local control was 50%; however, ultimate intracranial control was achieved in 7 of 8 patients with repeat SRS and surgical resection. The overall survival in this group of patients was 14.7 months. No patient had a serious (Grade 3 or higher) complication requiring intervention. CONCLUSIONS: Frameless optically guided radiosurgery is less invasive, can be performed as a standard radiotherapy-based simulation procedure, and maintains submillimetric accuracy. Our initial results with frameless SRS for metastatic disease suggest survival times and local control (88%) eqiuvalent to frame-based methodologies. Practical noninvasive delivery makes treatment and potential retreatment to avoid WBRT more feasible.

Adult↗
PubMed2005

Fluid-attenuated inversion-recovery MR imaging in assessment of intracranial oligodendrogliomas.

This retrospective study consisted of 17 consecutive patients with oligodendrogliomas. We qualitatively and quantitatively assessed the diagnostic value of fluid-attenuated inversion-recovery (FLAIR) images compared with T2-weighted fast spin-echo (FSE) images for evaluating intracranial oligodendrogliomas. Qualitative evaluations of signal intensity, tumor conspicuity, definition of tumor margin, distinction between solid and cystic-like parts within tumor, and calcification were performed. Quantitative criteria comparing FLAIR to T2-weighted FSE images included tumor-to-background contrast and contrast-to-noise ratio (CNR) and tumor-to-cerebrospinal fluid (CSF) contrast and CNR. Our results demonstrate that the FLAIR sequence can replace the T2-weighted FSE sequence for evaluating oligodendrogliomas.

Adolescent↗
PubMed2005

Atypical teratoid/rhabdoid tumor case report: treatment with surgical excision, radiation therapy, and alternative medicines.

Intracranial atypical teratoid/rhabdoid tumors (AT/RT) are rare with a poor prognosis. We report one case of a 7-year old girl living over 17 months after the diagnosis of AT/RT in the left frontal lobe. Treatment was partial surgical resection and post-operative radiation therapy. Radiation therapy resulted in complete response with no evidence of residual or recurrent disease more than 17 months after diagnosis. The patient has been maintained on an extensive regimen of alternative therapies since completion of radiation therapy.

Brain Neoplasms↗
PubMed2005

Can tumor contrast enhancement be used as a criterion for differentiating tumor grades of oligodendrogliomas?

BACKGROUND AND PURPOSE: 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.

Adolescent↗
PubMed2003

Evidence-based review of the surgical management of vertebral column metastatic disease.

OBJECT: Significant controversy exists over the most appropriate treatment for patients with metastatic disease of the vertebral column. Treatment options include surgical intervention, radiotherapy, or a combination of the two; nevertheless, a standard of care that yields the best survival, outcome, and quality of life has not been established. The purpose of this review was to determine the foundation in the literature of views favoring surgical intervention for spinal metastatic disease. METHODS: A search of the English-language literature published between 1964 and 2003 was performed for the subject of spinal metastatic disease. Papers were selected based on the inclusion criteria described, and evidentiary information was compiled and graded using previously described methods. CONCLUSIONS: Although there is insufficient evidence to support a standard for surgical treatment in patients with metastatic spinal disease, the authors present guidelines and recommendations based on the evidence provided by the current literature.

Combined Modality Therapy↗
PubMed2003

Complications of revision spinal surgery.

Surgical treatment for symptomatic cervical and lumbar spondylosis has become prevalent in recent years. With this increased intervention, increasing numbers of patients experience persistent symptoms and require revision spinal surgery. Although many aspects of the workup and operation are similar for both primary and revision surgery, there are special considerations that must be examined when determining if a patient is a candidate for revision surgery. Preoperative workup should include evaluation for spinal instability. Intraoperatively, scar tissue may complicate the procedure, and care must be taken to avoid incidental durotomy. The prognosis for a revision surgery can be predicted best by the patient's outcome after the primary surgery. As with any surgical procedure, patient selection is imperative for successful outcome.

Antibiotic Prophylaxis↗
PubMed2003

Ultrasound-guided extracranial radiosurgery: technique and application.

PURPOSE: Stereotactic radiosurgery is an effective treatment modality for many intracranial lesions, but target mobility limits its utility for extracranial applications. We have developed a new technique for extracranial radiosurgery based on optically guided three-dimensional ultrasound (3DUS). The 3DUS system provides the ability to image the target volume and critical structures in real time and determine any misregistration of the target volume with the linear accelerator. In this paper, we describe the system and its initial clinical application in the treatment of localized metastatic disease. METHODS AND MATERIALS: The extracranial stereotactic system consists of an ultrasound unit that is optically tracked and registered with the linear accelerator coordinate system. After an initial patient positioning based on computed tomographic (CT) simulation, stereotactic ultrasound images are acquired and correlated with the CT-based treatment plan to determine any soft-tissue shifts between the time of the planning CT and the actual treatment. Optical tracking is used to correct any patient offsets that are revealed by the real-time imaging. RESULTS: Preclinical testing revealed that the ultrasound-based stereotactic navigation system is accurate to within 1.5 mm in comparison with an absolute coordinate phantom. Between March 2001 and March 2002, the system was used to deliver extracranial radiosurgery to 17 metastatic lesions in 16 patients. Treatments were delivered in 1 or 2 fractions, with an average fractional dose of 16 Gy (range 12.5-24 Gy) delivered to the 80% isodose surface. Before each fraction, the target misalignment from isocenter was determined using the 3DUS system and the misalignments averaged over all patients were anteroposterior = 4.8 mm, lateral = 3.6 mm, axial = 2.1 mm, and average total 3D displacement = 7.4 mm (range = 0-21.0 mm). After correcting patient misalignment, each plan was delivered as planned using 6-11 noncoplanar fields. No acute complications were reported. CONCLUSIONS: A system for high-precision radiosurgical treatment of metastatic tumors has been developed, tested, and applied clinically. Optical tracking of the ultrasound probe provides real-time tracking of the patient anatomy and allows computation of the target displacement before treatment delivery. The patient treatments reported here suggest the feasibility and safety of the technique.

Aged↗
PubMed2003

Protracted radiotherapy treatment duration in medulloblastoma.

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 > or =50 Gy. Median radiotherapy treatment duration was 49 days (range, 30-104 days) with 35 patients (56%) completing radiotherapy in <50 days. The most common reasons for a protracted radiotherapy treatment duration > or =50 days were hematologic toxicity (46%) and use of <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 > or =3 years, M0 status, > or =50 Gy PFB dose, radiotherapy treatment duration <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 <50 days and were 42% +/- 20% and 29% +/- 18%, respectively, for duration > 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 <50 days and 46% +/- 20% and 33% +/- 19%, respectively, for duration > or =50 days ( p= 0.0037, log-rank test). In addition to age > or =3 years, M0 stage, use of adjuvant chemotherapy, and posterior fossa dose > or =50 Gy, our findings also reveal that radiotherapy treatment duration <50 days has a favorable prognostic outcome in patients with medulloblastoma.

Adolescent↗
PubMed2002

Guidelines for the use of discography for the diagnosis of painful degenerative lumbar disc disease.

OBJECT: Discography has been used as a diagnostic test in the evaluation of patients with recalcitrant low-back pain. Recently, its usefulness has been questioned because of the occurrence of false-positive results as well as the influence of psychological factors on test results. The purpose of this review is to establish the literature support for and against the use of discography. A search of the English-language literature published between 1966 and 2001 was performed. Papers were selected based on inclusion criteria described in the text, and the quality of information was graded using previously described methods. CONCLUSIONS: The authors propose a set of practice parameters based on the literature. Although the data were not judged adequate for the determination of a treatment standard, parameters for the use of discography are provided at a guideline and option level.

Humans↗