Gene therapy for high grade gliomas.

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.

Multiple intraabdominal soft-tissue masses in a man awaiting liver transplantation: a case study and discussion.

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.

Gene therapy for malignant gliomas.

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.

Detection of unsuspected recurrent lymphoma with fluorodeoxyglucose-positron emission tomographic imaging after induction chemotherapy: a case study.

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.

Treatment of advanced CNS malignancies with the recombinant adenovirus H5.010RSVTK: a phase I trial.

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.

PET versus SPECT in distinguishing radiation necrosis from tumor recurrence in the brain.

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.

Signet-ring cell lymphoma. Report of a case diagnosed by fine needle aspiration cytology.

A case of signet-ring cell lymphoma initially diagnosed by fine needle aspiration (FNA) cytology is described. Immediate evaluation of air-dried smears showed a mixture of large and small lymphoid cells, including some signet-ring forms. Immunocytochemical studies of Cytospin preparations of the remaining aspirate yielded a diagnosis of a large-cell-type B-cell signet-ring lymphoma. Subsequent bone marrow biopsies confirmed the diagnosis of a low-grade lymphoma. The advantages of on-site evaluation in aspiration cytology are discussed.

New grading system of cerebral gliomas using positron emission tomography with F-18 fluorodeoxyglucose.

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 [18]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.

Phase II trial of spirogermanium and vindesine in malignant glioma.

Fifty-four adults with recurrent malignant glioma were treated on an Eastern Cooperative Oncology Group (ECOG) trial. All had previous radiation therapy, and 70% had previous chemotherapy. They were assigned to either vindesine 3 mg/m2 weekly or spirogermanium 80 mg/m2 three times weekly with escalation to 120 mg/m2. The response was 4% to vindesine, and 8% to spirogermanium. The duration of response was 53 days for a patient who had clinical improvement only, but greater than 151 days and greater than 1066 days for two patients who had achieved a greater than 50% reduction in tumor size by computed tomography (CT). The toxicities were hematologic for vindesine and neurologic for spirogermanium. Neither agent seems to have sufficient efficacy to warrant further trials in previously treated glioma patients.

Positron emission tomography in patients with glioma. A predictor of prognosis.

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.

Sequential computerized tomography and positron emission tomography studies in a patient with malignant glioma.

Computerized tomography (CT) and positron emission tomography (PET) using fluorine-18-deoxyglucose were performed in a patient with malignant glioma over a one-year period. Postoperatively and during radiation therapy, there was slight improvement in metabolic activity in the hemisphere ipsilateral to the tumor. After radiation therapy and during chemotherapy, there was a rapid and then gradual decline in whole brain metabolic rate by 39%. This might have been explained by radiation effect on brain. The tumor area was metabolically similar to the adjacent brain until one year after diagnosis, when an area of abnormal increased activity was noted. Even though CT scans showed minimal evidence of tumour growth, a large glioblastoma multiforme was found at autopsy at the site of the increased activity. Radiation leukoencephalopathy was also observed at autopsy. It is concluded that PET studies may offer new information regarding the metabolic effects of anti-tumor therapy, and may demonstrate regrowth of tumor prior to CT.

High-dose oral metoclopramide. An effective antiemetic agent.

Seventy-six patients receiving cisplatin and noncisplatin-containing cancer chemotherapy were treated with an outpatient phase II metoclopramide regimen. The program consisted of an outpatient intravenous loading dose of metoclopramide before chemotherapy, followed by oral metoclopramide at 1, 3, 5, and 8 hours after chemotherapy. Three oral dose levels were evaluated. Treatment with 2 mg/kg/dose or 100 mg/dose resulted in no vomiting in 53% of 65 evaluable patients, and 0-2 episodes of emesis in 74%. Oral doses of 50 mg/dose were less effective, preventing emesis in 18%. This trial demonstrated the antiemetic effectiveness of high-dose oral metoclopramide in a new schedule designed for the outpatient setting. The side effects included restlessness (51% of patients), dystonic reactions (9%), and gastrointestinal complaints (41%).

Labeled cells in the investigation of hematologic disorders.

Radiolabeling techniques for white cells, platelets, and erythrocytes are reviewed. The early studies using diisopropylfluoro-32P contributed to an understanding of the production and circulation of the blood elements, and 51Cr proved useful in localizing sites of cell migration or destruction. 111In-oxine has further improved the understanding of blood cell organ sequestration, and permitted combined kinetic and organ imaging studies. Radionuclide labels have been essential for the elucidation of various hematologic disorders, such as the neutropenias, thrombocytopenias, anemias, and polycythemia. Many new treatments, including monoclonal antibodies, have been evaluated with radionuclides.

Sickle cell anemia. Pathophysiology and treatment.

Current concepts of the pathophysiology of the sickling process are reviewed. New approaches to treatment - including induced hyponatremia, membrane-active antisickling agents, and gene manipulation - are described.

Aplastic anemia associated with intravenous chloramphenicol.

A patient is presented who developed aplastic anemia 3 months after exposure to intravenous chloramphenicol. She died of this disease 4 years later. Other cases of marrow aplasia due to parenteral chloramphenicol are reviewed, in order to emphasize that this complication, although rare, is not restricted to the use of oral chloramphenicol.

Hypertension with renal carcinoma. An effect of arterial embolization.

A patient presented with mediastinal metastases from renal adenocarcinoma. Palliative therapy included Gelfoam and steel coil embolization of the right renal artery. Six weeks later he was found to have developed severe hypertension. Arteriogram revealed collateral vessels which supplied the tumor; the renal vein renin activity was four times higher on the right than on the left. We suspect that infarction of the kidney was not complete because of collateral arterial supply, and renin-dependent hypertension was the result. Thus, it may be hazardous to embolize large hypernephromas without subsequent nephrectomy.

Granulocyte transfusions and outcome of alloimmunized patients with gram-negative sepsis.

The effect of white cell alloimmunization on patient outcome during gram-negative sepsis treated with granulocyte transfusions was studied. Twenty-five episodes of sepsis were observed; 19 were associated with resolution of sepsis and six with continuing sepsis and death. Compatibility testing included the granulocyte indirect immunofluorescence test and the lymphocytotoxicity assay. The number of compatible and incompatible granulocyte transfusions determined by the indirect immunofluorescence test compared with patient outcome was significant (X2 = 44, p less than 0.001). The same comparison with the lymphocytotoxicity assay was not significant (X2 = 3, p greater than 0.05). The duration of the granulocytopenia after the first positive blood culture was 10 days or longer in 13 patients, and 12 of the 13 survived. The duration of the granulocytopenia was less than 10 days in 12 patients, and five of the six deaths occurred in this group. These five patients died without evidence of bone marrow recovery and with persistent gram-negative sepsis. Each had granulocyte-specific antibody of broad specificity and none received five consecutive compatible transfusions.