Publications (23)99.57 Total impact
Article: Gene therapy for high grade gliomas[Show abstract] [Hide abstract] ABSTRACT: High grade gliomas in adults are devastating diseases, with very poor survival despite their lack of distant metastases. Local treatments, such as surgical resection and stereotactic radiosurgery, have been most successful, whereas systemic therapy (for example, chemotherapy and immunotherapy) have been rather disappointing. Several gene therapy systems have been successful in controlling or eradicating these tumours in animal models and are now being tested as a logical addition to current clinical management. This review describes the gene therapy clinical protocols that have been completed or that are ongoing for human gliomas. These include the prodrug activating system, herpes simplex thymidine kinase (HSVtk)/ganciclovir (GCV), utilising either retrovirus vector producer cells or adenovirus vectors; adenovirus mediated p53 gene transfer; adenovirus mediated IFN-beta gene transfer and oncolytic herpes virus and adenovirus vectors. To date, all of the clinical studies have used direct injection of the vector into the glioma. The Phase I clinical studies have demonstrated low to moderate toxicity and variable levels of gene transfer and in some cases anti-tumour effect. Future directions will rely upon improvements in gene delivery as well as gene therapies and combinations of gene therapy with other treatment modalities.
- [Show abstract] [Hide abstract] ABSTRACT: An unusual cause of abdominal soft-tissue masses is accessory splenic tissue. The Tc-99m-sulfur colloid liver-spleen scan is a valuable adjunct in making this diagnosis. This report describes a 47-year-old man who had an abdominal magnetic resonance imaging (MRI) scan as part of a pretransplant evaluation and was found to have multiple soft-tissue masses in the posterior aspect of his abdomen. His history was pertinent for a traumatic rupture of the spleen at the age of 12 years, for which he required a splenectomy. He had no symptoms or physical findings to indicate a lymphoproliferative disorder or other malignant process. His peripheral blood smear was remarkable for the absence of Howell-Jolly bodies. The nuclear scan confirmed the presence of uptake in the soft-tissue masses seen on MRI scan. This finding supports our diagnosis of splenosis in a man with a history of traumatic splenic rupture as a child.
- [Show abstract] [Hide abstract] ABSTRACT: Contralateral cerebellar diaschisis, hypometabolism in the cerebellum contralateral to a cortical lesion, is a well described phenomenon in patients with stroke and brain tumor. However, few reports exist of patients with cerebellar lesions with the finding of contralateral cortical hypometabolism. The authors present a case of a patient with a right cerebellar astrocytoma after surgical resection and radiation therapy in which fluorine-18 fluorodeoxyglucose positron emission tomographic imaging, performed to rule out recurrent tumor, revealed global hypometabolism in the left cerebral cortex. The concept of contralateral cortical diaschisis and possible mechanisms and clinical implications are reviewed.
Article: Gene therapy for malignant gliomas[Show abstract] [Hide abstract] ABSTRACT: Malignant gliomas are attractive targets for gene therapy because of their relatively well-localized distribution. Several new strategies have been devised that target different aspects of glioma biology. Gene transfer can be used to synthesize chemotherapy drugs that block DNA synthesis within these highly mitotic tumors. New genes can be introduced that restore the functions of mutated tumor suppressor genes or block the molecular pathways needed for tumor angiogenesis. Alternatively, the immune response to these tumors can be augmented by the local production of cytokines. Finally, viruses themselves can be used as tumoricidal agents by designing viruses that selectively replicate and destroy tumor cells. The advantages and limitations of these approaches are discussed in the context of their possible application to the treatment of these highly lethal malignancies.
- [Show abstract] [Hide abstract] ABSTRACT: We performed a fluorodeoxyglucose-positron emission tomographic (FDG-PET) study on a patient who had high-grade lymphoma thought to be in complete remission. The patient underwent the PET study before being considered for high-dose consolidation therapy because he was thought to be at high risk for relapse. The whole-body FDG-PET study revealed an unsuspected hypermetabolic mass in the lower spine that was not visualized on computed tomographic (CT) scanning. The other laboratory values were normal, with the exception of mild lactate dehydrogenase elevation. Two weeks later, the patient developed low back pain, and magnetic resonance imaging showed a 2-cm paraspinal mass at the level of L4. Bone-marrow biopsy confirmed recurrent lymphoma. Remission was not achieved after another chemotherapy regimen. Fluorodeoxyglucose-positron emission tomography can be helpful in the restaging of lymphoma patients after induction chemotherapy and may help to detect early recurrence in selected situations.
- [Show abstract] [Hide abstract] ABSTRACT: Primary CNS malignancies are responsible for approximately 12,000 deaths annually in the United States. There has been little change in the outcome for adults with malignant brain tumors over the past few decades, despite improvements in surgical techniques and advances in radiation therapy. These tumors are uniformly fatal one to two years after diagnosis. The morbidity and mortality of this disease arise from the effects of a locally invasive, non-metastasizing lesion. The patients may suffer from seizures, paralysis, incoordination, aphasia, confusion, memory loss, sensory deficits or visual loss, depending on the regions of the brain affected. In addition, they usually require large doses of corticosteroids early and late in their illness, and may experience disabling side effects of this treatment, such as edema, proximal myopathy, diabetes, fungal infections or deep vein thrombosis. Few patients in the older age group are able to work after the diagnosis. Most of the patients are incapable of self-care for several months before death. The localized transfer of new genes into cancer cells potentially permits the expression of proteins with specific biologic functions that may provide a means to alter the biology of tumor growth through a variety of mechanisms including increasing tumor immunogenicity, inducing the local expression of toxic agents, and sensitization of tumors to chemotherapeutic agents. Gene therapy with the transfer of the drug susceptibility gene Herpes virus thymidine kinase (HSV-TK) has shown promise in a number of animal models, including CNS tumors. This study will evaluate the use of adenovirus-mediated transfer of the HSV-TK gene into primary human brain tumors followed by systemic treatment with ganciclovir. The goals of this phase I study are to evaluate the overall safety and efficacy of this treatment and to gain insight into the parameters that may limit the general applicability of this approach. In this phase I study, patients with recurrent gliomas will receive stereotactic-guided injections of the virus into the brain tumor, followed by intravenous ganciclovir for 14 days. Patients eligible to undergo a palliative debulking procedure will receive the same treatment followed by resection on day 7. At the time of resection a second dose of virus will be administered intra-operatively into the residual, unresectable portion of the tumor, and intravenous ganciclovir will be continued for additional 14 days. Tissue removed at the time of resection will be analyzed for evidence of adenovirus infection, thymidine kinase expression and signs of inflammation. The size and metabolic activity of all tumors will be followed by volumetric MRI scans and Position Emission Tomography Scans, respectively. Patients will be enrolled in groups of three, with each group receiving successively larger doses of adenovirus. This study will quantify the toxicity of this therapy, and provide evidence as to the duration of transgene expression and virus induced inflammation.
- [Show abstract] [Hide abstract] ABSTRACT: Two cases of postsurgical brain tumor evaluation in which MRI was inconclusive are discussed. Functional imaging techniques, such as FDG-PET and 201TI SPECT, were used in both cases for distinguishing radiation necrosis from tumor recurrence. These methods proved to be complimentary. For Patient 1, FDG-PET showed more limitations compared to 201TI SPECT. FDG-PET results on the other hand, were consistent with the final diagnosis and the SPECT image was false positive for tumor recurrence in Patient 2.
- [Show abstract] [Hide abstract] ABSTRACT: CT and MRI scans are quite sensitive in detecting brain tumors. However, with both imaging techniques limitations have been reported in distinguishing tumor recurrence from radiation necrosis. Metabolic imaging methods such as PET-FDG and SPECT T1-201 have been utilized for differentiating radiation necrosis from tumor recurrence. However, no study was to compare PET-FDG and SPECT T1-201 in primary brain tumors.
- [Show abstract] [Hide abstract] ABSTRACT: Conventional radiologic and nuclear medicine techniques have been shown to have a limited role in the staging and monitoring of disease activity in patients with lung cancer. Both qualitative and semi-quantitative position emission tomography (PET) using the F-18 FDG technique have been applied to determine the clinical utility of whole body PET-FDG imaging in lung cancer. Nineteen whole body FDG PET scans were performed in 18 patients; 17 with lung cancer (15 non-small cell and 2 small cell) and 1 with squamous cell carcinoma of the trachea.
- [Show abstract] [Hide abstract] ABSTRACT: Although radiotherapy (XRT) is a necessary course of treatment to prolong life expectancy in patients with many types of brain neoplasms, it has damaging effects that are little understood. We used a comprehensive neuropsychological battery to evaluate five patients with low-grade brain tumors prior to XRT and then at 3-month intervals up to 9 months postcompletion of XRT. We matched patients by age and education with six normal control subjects to assess baseline impairment. In intrasubject comparisons, we examined change over time postcompletion of XRT. In spite of varying locations of tumors, all patients showed deterioration in long-term memory at a mean of 1.5 months postcompletion of XRT. Patients also consistently demonstrated a rebound effect between means of 4.7 and 7.6 months post-XRT. We found no changes over time in working memory, attention, visuospatial processes, or on any other neuropsychological test with the exception of information-processing speed, which quickened over time. Functional measures of fatigue and mood did not correlate significantly with the long-term memory scores. Long-term memory appears sensitive to the proposed white matter changes thought to be the mechanism for the early-delayed effects of XRT. Our findings suggest a neurobehavioral model for studying the effects of XRT on brain functioning.
- [Show abstract] [Hide abstract] ABSTRACT: The nutritional implications of learned food aversions were evaluated in patients with newly diagnosed cancer receiving either chemotherapy (n = 53) or radiation therapy (n = 49). Aversion incidence was determined by questionnaires and a food challenge. Measures of dietary and nutritional status included ratings of appetite and chemosensory function; reported shifts of food selection and measured body weight; lymphocyte count; hematocrit; and plasma albumin, transferrin, and hemoglobin levels. Quality of life was assessed by self-ratings of mood and well-being. Subsequent to the initiation of treatments, aversions formed in 56% and 62% of patients receiving chemotherapy and radiation therapy, respectively. The aversions were specific (two to four items per afflicted patient) and transient (mean duration, 0.25-2 months). All types of foods and beverages were targeted. No significant association was observed between food aversion incidence and any measure of dietary complications, nutritional status, or quality of life. Although food aversions are a common sequela of chemotherapy and radiation therapy, they generally have limited clinical significance.
- [Show abstract] [Hide abstract] ABSTRACT: Positron emission tomography (PET) studies (38 scans) were performed using 18F-fluorodeoxyglucose (FDG) in 37 patients with diagnosed cerebral tumors. Suppression of FDG utilization in cerebral cortex was identified in 32 scans (84%). Whereas this suppression involved only a small region of the cerebral cortex immediately adjacent to the tumor on 8 scans, extensive areas of diminished FDG uptake were seen on the remaining 24. A complex relationship between the presence of edema, glucose metabolism of the primary lesion, histological grade of malignancy, and presence or absence of cortical suppression occurred. The strongest correlation was observed between the presence of edema determined by computed tomography andjor magnetic resonance imaging and the degree of cortical suppression of glucose metabolism. Cerebral edema was present in 21 (88%) of 24 patients with extensive cortical suppression but none of the 6 without cortical suppression.
- [Show abstract] [Hide abstract] ABSTRACT: Positron emission tomography (PET) using fluorine-18 (18F)-fluorodeoxyglucose (FDG) has been reported to be a powerful diagnostic and prognostic tool in patients with primary brain tumors. This study was undertaken to compare the prognostic value of: (1) visual grading of FDG uptake in the tumor, (2) the absolute glucose metabolic rate of the tumor (TMRglc), (3) the ratio of glucose metabolism between the tumor and whole brain (T/WB) and (4) between the tumor and contralateral cerebellum (T/CBL). Each of these four parameters was correlated with the survival time in 20 patients with malignant cerebral gliomas. Excellent correlation was obtained with visual grading and reasonably good correlation was obtained with T/WB or T/CBL, but TMRglc alone was only a fair prognostic indicator. Thus, visual grading provides a qualitative analysis and T/WB provides a semi-quantitative analysis neither of which requires arterial blood sampling for quantification of absolute metabolic rates for glucose.
- [Show abstract] [Hide abstract] ABSTRACT: Positron emission tomography (PET) studies have been performed using 18-F-fluorodeoxyglucose in 29 adult subjects with primary brain tumors. Seventy-two percent of the patients were treated previously. The glucose metabolic state in the lesions was increased in 16 patients, and was normal or decreased in 13 patients. The hypermetabolic tumors tended to behave in a more malignant fashion. Patients with hypermetabolic tumors had a median survival of 7 months after PET scan, compared to 33 months for those with hypometabolic lesions. Among the high-grade glioma patients, the PET results separated them into a good prognosis group (hypometabolic, with 78% 1-year survival) and a poor prognosis group (hypermetabolic, with a 29% 1-year survival after PET). These results suggest that glucose metabolic studies may provide an independent measure of the aggressiveness of a brain tumor, and may supplement pathologic grading.
- [Show abstract] [Hide abstract] ABSTRACT: We studied cerebellar metabolism in 118 subjects including young and elderly controls and patients suffering from stroke, supratentorial brain tumor and Alzheimer's disease using fluorine-18 fluorodeoxyglucose ([18F]FDG) and position emission tomography (PET). Alzheimer's disease and normal aging did not alter mean cerebellar metabolism. In stroke and tumor mean cerebellar metabolism was lower in the hemisphere contralateral to the supratentorial lesion. In tumor bilaterally significant reductions in absolute cerebellar metabolism also were noted, unlike stroke. Primary sensory stimulation did not alter absolute or relative cerebellar metabolism. These results show that absolute and relative values for cerebellar metabolism vary depending on the process under study. Thus analysis schemes employing normalization of regional metabolic data to cerebellar values may be subject to error.
University of PennsylvaniaPhiladelphia, Pennsylvania, United States