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Biomedical subjects

Walter A Hall

Publications and source records attributed to Walter A Hall.

At least 37 records · Page 2Linked to original sources
PubMed2004

Linac-based stereotactic radiosurgery for treatment of trigeminal neuralgia.

Trigeminal neuralgia (TN) is a disabling pain condition that has classically been treated using either surgical or medical techniques. Several researchers have shown that stereotactically delivered radiation can be an effective tool in the amelioration of this condition. For these studies, the Gamma Knife was used to deliver the radiation treatment. The target location was designated as the proximal nerve at the root entry zone, and doses greater than 70 Gy to the maximum point in a single fraction were found to be effective in controlling pain in 80% of the patients treated. LINAC-based stereotactic radiosurgery has been notably absent from the treatment of TN, even though it has many similarities to Gamma Knife-based stereotactic radiosurgery. The aim of this paper is to describe our LINAC-based stereotactic technique for treatment of TN. We also compare treatment of TN using our technique to that using the Gamma Knife. We found that a LINAC-based treatment of TN can be accomplished with accuracy comparable to treatments delivered using the Gamma Knife. The dose distributions are essentially equivalent for the two treatment approaches. The LINAC-based system is easy to plan and offers the ability to reduce the involvement of sensitive structures from the treatment fields as well as the Gamma Knife system does. A disadvantage of the LINAC-based system is the time involved for treatment.

Computer Simulation↗
PubMed2004

A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model.

A bispecific immunotoxin (IT) called DTAT13 was synthesized in order to target simultaneously the urokinase-type plasminogen activator receptor (uPAR)-expressing tumor neovasculature and IL-13 receptor expressing glioblastoma cells with the goal of intratumoral administration for brain tumors. The recombinant hybrid was created using the non-internalizing N-terminal fragment (ATF) of uPA and the IL-13 molecule for binding plus the catalytic and translocation portion of diphtheria toxin (DT) for killing. The 71 kDa protein was highly selective for human glioblastoma in vitro showing no loss on binding compared with DTAT and DTIL13 controls. In vivo, DTAT13 caused the regression of small tumors when administered at 10 micro g/day given on a five-dose schedule every other day. DTAT13 was able to target both overexpressed uPAR and the vasculature, as demonstrated by its ability to kill HUVEC cells. Also, mortality studies indicated that DTAT13 was less toxic than DTAT or DTIL13. These findings indicate that bispecific IT may allow treatment of a broader subset of antigenically diverse patients while simultaneously reducing the exposure to toxin required than if two separate agents were employed.

Animals↗
PubMed2004

A new immune-competent animal model of mucosally derived squamous cell carcinoma.

OBJECTIVES: To develop an immune-competent animal model for mucosally derived squamous cell carcinoma (SCCA). STUDY DESIGN: Fifteen Fischer 344 rats were inoculated with 1, 2, 5, 10, or 20 x 10(6) FAT7 cells in their flanks. The animals were observed for tumor growth and metastasis. RESULTS: All animals developed tumors that grew exponentially. Pulmonary metastases developed in all animals and 13% developed lymph node metastases. CONCLUSION: The FAT7 flank tumor in Fischer 344 rats is a new animal model that closely resembles the behavior of human mucosal head and neck cancer. SIGNIFICANCE: The existence of an immune-competent, mucosally derived, and reliable animal model of SCCA that somewhat resembles human head and neck SCCA gives the opportunity to perform immune-modulating experiments on head and neck cancer in these animals. EBM RATING: B-3.

Animals↗
PubMed2004

Identification of HLA a*0201 glioblastoma multiforme cell lines for immunotherapy by PCR-SSP and DNA sequencing.

Most tumor specific antigens characterized to date are restricted by HLA a*0201, which is the major HLA subtype in many ethnic groups. Cancer cells that express tumor antigens in association with the HLA a*0201 subtype have been shown to be responsive to various immunotherapies. We therefore sought to identify glioma cell lines that also express this HLA subtype and determine whether they had the molecular properties needed for tumor-peptide presentation. The HLA a*0201 allele was identified with PCR using sequence-specific primers followed by DNA sequencing. With this method, we screened 15 glioma cell lines to determine if they were of the HLA a*0201 genotype. Glioma cell lines that express the HLA a*0201 subtype were further studied for the expression of MHC class I and beta-2-microglobulin (beta2m) molecules by flow cytometry, and peptide presentation molecules TAP-1, TAP-2, and tapasin by RT-PCR. We identified six out of fifteen cell lines that were of the HLA a*0201 subtype. These cell lines are U87, T98, U373, U138, CRL2365 and UMN-4. All these six cell lines exhibited high levels of MHC class I and beta2m molecules. In addition, these cell lines all expressed molecules required for peptide presentation as shown by the presence of peptide presentation-related molecules TAP-1, TAP-2 and tapasin. The identification of glioma cell lines that express the HLA a*0201 subtype along with the necessary molecules for peptide-presentation will enable their use in developing new immunotherapeutic approaches for treating brain tumors. The method used to identify HLA a*0201 glioma cells is rapid and inexpensive, and suitable for screening tumor cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Effects of combined granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and interleukin-12 based immunotherapy against intracranial glioma in the rat.

Cytokines play a major role in the regulation of the immune system. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be useful for immunotherapy against glioma because it can stimulate dendritic cells to present tumor antigen. Interleukin-2 (IL-2) is involved in T-cell expansion, and interleukin-12 (IL-12) drives the T-helper cell type I response. Previous studies have shown that each of these cytokines alone can induce the regression of tumor cells. In the present study we postulated that peripheral infusion of GM-CSF along with either IL-2 or IL-12 and irradiated tumor cells can lead to increased survival from 9L brain tumors. 9L gliosarcoma cells (10(6)) were implanted in the brains of syngeneic Fischer 344 rats. Osmotic minipumps were utilized for subcutaneous, continuous delivery of GM-CSF, either alone or with IL-2 or IL-12. Irradiated 9L cells were injected subcutaneously at various time points during treatment. Delayed-type hypersensitivity (DTH) and immunohistological analysis were used to further characterize the anti-tumor response. Treatment with GM-CSF and irradiated tumor cells led to an increase in survival rate in rats with intracranial 9L tumors when compared to untreated animals. The addition of IL-2 or IL-12 to the GM-CSF/tumor cell therapy further increased the survival rate up to 90%. The anti-tumor response was associated with vigorous DTH against 9L cells and increased infiltration of CD4+ and CD8+ lymphocytes into the tumor. These results suggest that the combined infusion of GM-CSF and other cytokines may be effective adjuvants in treating brain tumors.

Animals↗
PubMed2004

Stereotactic radiosurgery versus fractionated stereotactic radiotherapy boost for patients with glioblastoma multiforme.

The aim of this study is to evaluate the efficacy of stereotactic radiotherapy boost (SRB) in patients with glioblastoma multiforme (GBM) by comparing two different regimens, single dose or fractionated treatment. Between December 1994 and January 2000, 24 patients with GBM were treated with SRB in conjunction with external beam radiotherapy (EBRT). Fourteen patients (58%) were treated with stereotactic radiosurgery (SRS) and 10 patients (42%) with fractionated stereotactic radiotherapy (FSRT). Median interval between EBRT and SRS or FSRT was 1.4 months (range -0.4-3.9 months). Actuarial survival rates of the entire 24 patients at one and two years following SRB were 63% and 34% respectively, with median survival time of 16 months. Variables predicting survival were age, extent of surgery, re-operation and the RTOG (Radiation Therapy Oncology Group) classes based on recursive partitioning analysis (RPA). In comparison to historical controls, improved survival benefit after SRB was observed. The median survival times for the RTOG classes 4, 5, and 6 were 28.3, 10.3, and 6.0 months following EBRT+SRB, respectively. Expected values for these classes after EBRT are 11.1, 8.9, and 4.6 months, respectively. This improvement in survival was seen predominantly for the RTOG class 4. There was no difference in survival between SRS and FSRT treated groups. Late complications developed in 4 patients in the SRS group and 1 patients in the FSRT group. Our retrospective data suggest that SRB in conjunction with EBRT may improve survival in patients with GBM with median survival time of 16 months, when compared to historical controls of the RTOG data following EBRT. The addition of SRB appeared to improve the median survival most demonstrably in RTOG RPA class 4 patients. SRS and FSRT are equally effective with similar median survival, but potentially less late complications associated with FSRT. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.

Adolescent↗
PubMed2003

Radiation dose response for supratentorial low-grade glioma--institutional experience and literature review.

PURPOSE: To examine radiation dose response for low-grade glioma (LGG) based on our institutional experience and to review the literature on this topic. METHODS AND MATERIALS: Sixty-seven patients with supratentorial low-grade nonpilocytic astrocytomas (n=36) or oligodendrogliomas (n=31) were treated with postoperative radiation therapy (RT). Twenty-seven patients (group A) received 5520 cGy; 24 patients (group B) received 5940 cGy; and 16 patients (group C) received 6375 cGy. The corresponding median follow-up was 60, 35 and 91 months, respectively. RESULTS: The disease-specific survival (DSS) at 5 and 10 years were 90.2% and 56.2%, 67.6% and 47.3%, and 62.5% and 50% for groups A, B and C, respectively (P=0.40). Only a greater extent of surgical resection and absence of contrast enhancement predicted DSS on multivariate analyses. Patients receiving higher doses of RT had higher complication rates. CONCLUSION: Our data confirmed the lack of radiation dose response for supratentorial LGG as demonstrated in the previous randomized trials. The radiation dose should not exceed 5520 cGy because dose escalation did not result in an improvement of DSS and it also increased the complication rates. Future research should focus on the eradication of radioresistant clones either by the improvement of surgical resection or the use of cytotoxic agents that can target on the radioresistant tumor cells.

Antineoplastic Agents↗
PubMed2003

Convection-enhanced delivery in clinical trials.

The poor prognosis associated with the current management of malignant gliomas has led investigators to develop alternative treatments such as targeted toxin therapy. The optimal method for administering these agents is under development but appears to be convection-enhanced delivery (CED). The direct intratumoral infusion of targeted toxins was first performed in nude mouse flank tumor models of human malignant glioma. After the demonstration of in vivo efficacy, these potent cytotoxic compounds were tested in Phase I and Phase II clinical trials. Using a high-flow microinfusion technique, volumes of up to 180 ml were infused by CED through catheters placed directly into brain tumors. Minor systemic toxicity was seen in the form of hepatic enzyme elevation. Neural toxicity manifested as seizure activity and hemiparesis resulted from peritumoral edema that followed the completion of the infusion. Peritumoral toxicity was believed to be more related to the concentration of the infused immunotoxin than to the infusion volume. In approximately half of patients treated with CED a stable disease course, a partial response, or a complete response was demonstrated in some clinical trials. Targeted toxin therapy has clinical efficacy in patients with malignant gliomas. Convection-enhanced delivery appears to represent an effective method for administering these agents in patients with malignant brain tumors.

Adolescent↗
PubMed2003

Targeting the over-expressed urokinase-type plasminogen activator receptor on glioblastoma multiforme.

A recombinant fusion protein targeting the urokinase-type plasminogen activator receptor (uPAR) and delivering a potent catalytic toxin has the advantage of simultaneously targeting both over-expressed uPAR on glioblastoma cells and on the tumor neovasculature. Such a hybrid protein was synthesized consisting of the noninternalizing amino-terminal fragment (ATF) of urokinase-type plasminogen activator (uPA) for binding, and the catalytic portion of diphtheria toxin (DT) for killing, and the translocation enhancing region (TER) of DT for internalization. The protein was highly selective for human glioblastoma in vitro and in vivo. In vivo, this DT/ATF hybrid called DTAT caused the regression of small subcutaneous uPAR-expressing tumors with minimal toxicity to critical organs. In vitro, DTAT killed only uPAR-positive glioblastoma cell lines and human endothelial cells in the form of the HUVEC cell line. Killing was selective and blockable with specific antibody. DTAT was highly effective against tumor cells cultured from glioblastoma multiforme patients and in vitro mixing experiments combining DTAT with DTIL13 another highly effective anti-glioblastoma agent showed that the mixture was as toxic as the most potent immunotoxin. In this article, we review our progress to date with DTAT.

Animals↗
PubMed2003

Application of diffusion tensor imaging to magnetic-resonance-guided brain tumor resection.

Interventional magnetic resonance imaging (MRI) continues to make a profound impact on the practice of neurosurgery. We describe a new MRI modality, diffusion tensor imaging (DTI), which uses the diffusion energy of water to map white matter fibers. DTI has been established in other disorders such as metabolic, demyelinating and ischemic diseases. We describe the use of DTI in identifying white matter tracts such as optic radiations and avoiding them intraoperatively in 2 children with low-grade glial tumors.

Adolescent↗
PubMed2003

Intraoperative MR-guided instillation of phosphorus-32 for cystic craniopharyngiomas: case report.

Intraoperative magnetic resonance imaging has been applied to a number of neurosurgical disease processes since the late 1990's. The ability to visualize the operative site in near-real time has added a significant degree of safety to the treatment of lesions such as a cystic craniopharyngioma which can be located in regions of the brain where an untoward consequence can result in significant neurological morbidity. Previous surgical techniques, although often successful, did not allow the neurosurgeon to directly visualize whether the goals of surgery had been met or whether there was an inadvertent complication associated with the surgical approach until after the event had occurred. The safe and accurate instillation of radioactive phosphorus into this cystic tumor resulted in clinical improvement and the maintenance of normal pituitary function for this patient. The extreme accuracy and safety of this surgical technique is demonstrated by the imaging examples provided.

Craniopharyngioma↗
PubMed2003

Changes in expression of transferrin, insulin-like growth factor 1, and interleukin 4 receptors after irradiation of cells of primary malignant brain tumor cell lines.

Various immunotoxins have been developed for the treatment of cancer. The toxin is internalized by target cells through cell-surface receptors, and it is essential for these receptors to be expressed for the immunotoxin to have specific anti-tumor activity. Radiation therapy is one of the main treatment modalities for primary malignant brain tumors. The purpose of this study was to determine whether radiation influences the expression of cell-surface receptors. Cells of one human medulloblastoma (Daoy) and two glioblastoma (U373-MG and T98-G) cell lines were tested by exposing the cells to a single dose of 5 Gy gamma rays. Expression of transferrin receptors, type-1 insulin-like growth factor receptors (IGF1R), and interleukin 4 receptors (IL4R) was measured by flow cytometry analysis on unirradiated cells and on cells 3 to 120 h after irradiation. In Daoy cells, the absolute expression index of transferrin receptors increased during the 24 h after irradiation with the greatest change of 26% above control at 9 h. The absolute expression index of IGF1R increased 26.5% above control at 12 h. The absolute expression index of IL4R decreased 9 h after irradiation. In U373-MG cells the absolute expression index of transferrin receptors increased during the 24 h after irradiation, and the greatest increase was 45% above control at 9 h. The absolute expression index of IGF1R increased during the 12 h after irradiation with a maximum increase of 33% above control at 6 h. The absolute expression index of IL4R decreased with time after irradiation. In T98-G cells, the absolute expression index of both transferrin receptors and IL4R decreased after irradiation. The results suggest that the expression of growth factor receptors on brain tumor cells may be influenced by radiation. The effect of ionizing radiation on receptor expression should be considered when administration of targeted toxin is combined with radiation. Similar studies with other growth factor receptors used in targeted toxin therapy are recommended.

Brain Neoplasms↗
PubMed2002

Targeting urokinase-type plasminogen activator receptor on human glioblastoma tumors with diphtheria toxin fusion protein DTAT.

BACKGROUND: The prognosis for patients with brain cancer is poor, and new therapies are urgently needed. Recombinant toxic proteins that specifically target tumor cells appear to be promising. Urokinase-type plasminogen activator (uPA) receptor (uPAR) is expressed on the surface of glioblastoma and some other tumor cells and endothelial cells. We synthesized a recombinant fusion protein, DTAT, which contains the catalytic portion of diphtheria toxin (DT) for cell killing fused to the noninternalizing amino-terminal (AT) fragment of uPA, and investigated its effectiveness in targeting uPAR-positive tumor cells. METHODS: In vitro cytotoxicity of DTAT was measured by cell proliferation assays. For in vivo studies, athymic nude mice (four to five animals/group) bearing uPAR-expressing human glioblastoma (U118MG) cell-induced tumors were injected with DTAT or control protein. Tumor volume was assessed over time, and differences between treatments were analyzed by Student's t test. Effects of DTAT on body organ systems were evaluated in normal, tumor-free C57BL/6 mice histologically and functionally by serum enzyme tests. All statistical tests were two-sided. RESULTS: In vitro, DTAT was highly potent and selective in killing uPAR-expressing glioblastoma cells (U118MG, U373MG, and U87MG) and human umbilical vein endothelial cells. In vivo, compared with mice treated with control proteins, DTAT caused a statistically significant (P =.05) regression of small U118MG cell-induced tumors in all mice. Control fusion proteins that did not react with glioblastoma cells had no effect on tumor growth. DTAT given to tumor-free C57BL/6 mice had little effect on kidney, liver, heart, lung, and spleen histologies. Serum analysis in the same mice showed no elevation in blood urea nitrogen, indicating lack of effect on kidney function but a statistically significant (P =.046), albeit non-life-threatening, elevation in liver alanine aminotransferase levels. CONCLUSION: DTAT may have potential for intracranial glioblastoma therapy because of its ability to target tumor cells and tumor vasculature simultaneously and its apparent lack of systemic effects.

Alanine Transaminase↗
PubMed2002

Remotely-controlled approach for stereotactic neurobiopsy.

The objective of this study was to develop, demonstrate, and validate a remotely controlled operation scheme coupled with prospective magnetic resonance imaging (MRI)-based stereotaxy for in vivo neurosurgical applications. The novel concept of the prospective guidance scheme is to employ tomographical imaging feedback, such as MRI or CT, to facilitate prospectively the targeting process of a biopsy needle at near-real-time speed (1 image/s). Because the orientation of a biopsy needle pivoted at an entry point on the patient's skull has 2 degrees of freedom, the alignment of its trajectory to a target point can be guided by two-dimensional (2D) images whose plane is placed perpendicular to the desired trajectory. Using near-real-time 2D visual feedback during the adjustment of the alignment guide, the required trajectory alignment can be translated into a simple targeting task on a computer monitor employing a suitable graphic presentation. Also, both adjustments for the alignment and introduction of the biopsy needle were accomplished remotely with image-based feedback. The use of the method in actual MR-guided brain lesion biopsy procedures at 1.5 T showed an improved tissue yield due to the improved targeting accuracy even in the presence of brain shift. Furthermore, the postalignment trajectory can be validated immediately using near-real-time MRI scans in two orthogonal views before needle insertion. Because the final needle position is always visualized and confirmed, the consequent tissue sampling is performed with greater certainty, even in the case of a negative diagnosis. The actual targeting error was 1.53 +/- 0.17 mm from an intended target location, with the maximum distance error of 1.72 mm at a depth of 85 mm. This remotely controlled surgical approach with intraoperative MRI guidance is feasible at 1.5 T, and has allowed neurosurgeons to perform neurobiopsies comfortably and efficiently in a routine clinical MR scanner. This scheme provides a unique alternative stereotactic procedure that can take full advantage of the prospective guidance potential offered by various modern tomographic imaging systems.

Biopsy, Needle↗
PubMed2002

Metastatic head and neck squamous cell carcinoma to the brain.

BACKGROUND: To evaluate the natural history of patients with metastatic squamous cell carcinoma (SCCA) of the head and neck to the brain. METHODS: A retrospective review of patients with brain metastases treated over a 20-year period identified five that had a head and neck SCCA primary. RESULTS: Five cases of patients with SCCA of the head and neck that developed brain metastases are presented in detail. CONCLUSION: In patients with aggressive disease, large infiltrative lesions, and in late survivors with initially advanced disease, metastasis to the brain should be considered. Perineural metastasis appears to be the most common mode of spread of head and neck SCCA to the brain. Pain, paresis, or paresthesias in the distribution of cranial nerves or other neurological symptoms should alert the otolaryngologist to neural or central nervous system involvement in patients with SCCA of the head and neck. Surgery with or without post-operative whole brain radiation therapy is the mainstay of treatment in most patients. Stereotactic radiosurgery may play a major role in treating brain metastases from head and neck primary tumors.

Aged↗
PubMed2002

Single dose versus fractionated stereotactic radiotherapy for meningiomas.

OBJECTIVE: To evaluate the safety and efficacy of stereotactic radiosurgery (SRS) compared to fractionated stereotactic radiation therapy (FSRT) for meningiomas treated over a seven year period. METHODS AND MATERIALS: Of the 53 patients (15 male and 38 female) with 63 meningiomas, 35 were treated with SRS and the 18 patients with tumors adjacent to critical structures or with large tumors were treated with FSRT. The median doses for the SRS and the FSRT groups were 1400 cGy (500-4500 cGy) and 5400 cGy (4000-6000 cGy) respectively. Median target volumes for SRS and FSRT were 6.8 ml and 8.8 ml respectively. The median follow-up for the SRS and FSRT groups were 38 months (4.1-97 months) and 30.5 months (6.0-63 months) respectively. RESULTS: The five-year tumor control probability (TC) for benign versus atypical meningiomas were 92.7% vs. 31% (P = .006). The three-year TC were 92.7% vs. 93.3% for SRS vs. FSRT groups respectively (P = .62). For benign meningiomas, the three-year TC were 92.9% vs. 92.3% for the SRS group (29 patients) vs. FSRT group (14 patients) respectively (P = .77). Two patients in the SRS group and one in the FSRT group developed late complications. CONCLUSION: Preliminary data suggest that SRS is a safe and effective treatment for patients with benign meningiomas. Fractionated stereotactic radiation therapy with conventional fractionation appeared to be an effective and safe treatment alternative for patients not appropriate for SRS. A longer follow-up is required to determine the long-term efficacy and the toxicity of these treatment modalities.

Dose Fractionation, Radiation↗