Treatment of malignant gliomas in adults with BCNU plus metronidazole

Summary Twenty-six adult patients with astrocytomas were treated with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) 180–240 mg/m² 1.V. every 6–9 weeks, with metronidazole 1.5 g/m² p. o. 12 h and 1 h before BCNU and again 6 h and 24 h after BCNU. Of twenty-two evaluable patients, 9 (41%) responded with evidence of reduced tumor size on CT scan, 3 (14%) stabilized and 10 (45%) failed. Patients with no prior chemotherapy or radiotherapy, good performance. status, low grade tumors, and age 50 years had the highest response rates, although differences were not statistically significant. Median survival and duration of response have not been reached with a median follow-up time of ten months. Hematological toxicity was dose-limiting and was probably not augmented by the metronidazole. There was one death from infection that was possibly drug-related. Gastrointestinal toxicity was substantial, and was probably increased by the metronidazole.While the combination of BCNU and metronidazole were tolerable, the response rate seen was no higher than that noted for BCNU alone, and further studies using this dose-schedule are not recommended in astrocytomas.Presented at the 13th International Congress of Chemotherapy, Vienna Austria, August 1983.     

Longitudinal neurological follow-up of a group of HIV-seropositive and HIV-seronegative hemophiliacs: results from the hemophilia growth and development study

BACKGROUND: Boys and young men with hemophilia treated with factor infusions before 1985 had a substantial risk of acquiring the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome. This study was designed to assess the effects of HIV and hemophilia per se on neurological function in a large cohort of subjects with hemophilia, and to investigate the relationships between neurological disease and death during follow-up. METHODS: Three hundred thirty-three boys and young men (207 HIV seropositive and 126 HIV seronegative) were evaluated longitudinally in a multicenter, multidisciplinary study. Neurological history and examination were conducted at baseline and annually for 4 years. The relationship between neurological variables, HIV serostatus, CD4+ cell counts, and vital status at the conclusion of the study was examined using logistic regression models. RESULTS: The risks of nonhemophilia-associated muscle atrophy, behavior change, and gait disturbance increased with time in immune compromised HIV-seropositive subjects compared with HIV seronegative or immunologically stable HIV-seropositive subjects. The risk of behavior change in immune compromised HIV-seropositive hemophiliacs, for example, rose to 60% by year 4 versus 10% to 17% for the other study groups. Forty-five subjects (13.5%), all of whom were HIV seropositive, died by year 4. Subjects who died had had increased risks of hyperreflexia, nonhemophilia-associated muscle atrophy, and behavior change. CONCLUSIONS: These results indicate that immune compromised, HIV-seropositive hemophiliacs have high rates of neurological abnormalities over time and that neurological abnormalities were common among subjects who later died. By contrast, immunologically stable HIV-seropositive subjects did not differ from the HIV-seronegative participants. Hemophilia per se was associated with progressive abnormalities of gait, coordination, and motor function.     

Extradural dermoid tumours of the posterior fossa

Dermoid tumours in children usually occur in two locations: at the anterior fontanelle and on the occipital squama. An exceptional site of origin for a posterior fossa dermoid cyst is the extradural space. There are only six previous cases of this situation reported in the literature. A series of 103 subscalp and calvarial masses in children were reviewed and three children are reported with extradural dermoids of the posterior fossa, which communicated with the skin through midline occipital dermal sinuses. All three children were seen after the rapid growth or the formation of an abscess in a previously noted occipital subcutaneous mass present since birth. Although computed tomography or magnetic resonance imaging showed the dermal sinus and the intracranial tumour, these studies were unable to ascertain the intradural or extradural nature of the tumours, their exact origin only being established at operation. Histopathological study showed preclinical signs of infection in the two patients that had not yet formed an abscess. It is suggested that early neurosurgical treatment of these neoplasms should be done to prevent the development of severe intracranial infection. The previously reported simplicity of surgical removal of occipital extradural dermoids was not confirmed in this series.     

Effects on the buoyant density of rabbit platelets of ADP and agents that increase the concentration of cyclic AMP

Rabbit platelets were aggregated by adenosine diphosphate (ADP), allowed to deaggregate and then separated into density subpopulations by centrifugation through discontinuous Stractan density gradients. Although ADP causes little or no release of the contents of the amine storage granules of rabbit platelets, ADP caused a decrease in platelet density as compared with control platelets subjected to the same procedures except for exposure to ADP. The density change persisted for at least four hours. The apparent size of platelets stimulated with ADP increased initially, but returned to control values during a one-hour period. A similar decrease in platelet density was observed with an albumin density gradient. Under conditions in which aggregation did not occur in response to ADP with ethylenediaminetetraacetic acid (EDTA) in the medium, little or no decrease in platelet density was observed. Agglutination with polylysine did not change platelet density. Thus, not only agents such as thrombin and plasmin that cause the release of the contents of the platelet granules decrease platelet density, but ADP also has this effect. Platelets would be exposed to all of these stimuli during thromboembolic processes, and their effect on platelets may account for the decrease in platelet density observed previously in experiments with rabbits with indwelling aortic catheters. Agents that increase the concentration of cyclic AMP (cAMP) in platelets (PGE1, adenosine, dibutyryl cAMP, forskolin, and papaverine) also decreased platelet density. This effect persisted when the platelets were washed and resuspended in fresh medium and was also demonstrable in plasma. Platelet size was gradually increased by prostaglandin E1 (PGE1) which maintains platelets in a disc shape and does not cause the release of granule contents, indicating that the decrease in platelet density caused by PGE1 may be attributable to platelet swelling.     

Abnormal clonogenic potential of T cells from multiple myeloma patients

Peripheral blood lymphocytes (PBLs) from multiple myeloma patients are defective in both proportion and absolute numbers of OKT4+ cells and have a normal proportion but reduced absolute number of OKT8+ cells. To assess the functional capabilities of the T cells in myeloma patients, we cloned the T cells in PBLs using limiting dilution conditions in which 100% of OKT4+ and OKT8+ T cells in normal PBLs are able to form a clone. In contrast, the OKT8+ cells from PBLs of five of seven multiple myeloma patients were severely compromised in their clonogenic potential; only 7% to 25% of OKT8+ T cells appeared to give rise to a clone. Clonogenic potential of the OKT4+ cells in patients was more nearly normal. Analysis of two multiple myeloma patients with abnormally low numbers of T cells in PBLs revealed the existence of abnormalities in the progenitors of T cell clones. In both patients, two to three times as many T cell clones were observed as would have been expected based on the number of PBLs cultured at limiting dilution, indicating that OKT4-8- cells in PBLs are capable of giving rise to OKT4+ and, at lower frequency, to OKT8+ clonal progeny in vitro. We conclude that purely quantitative assessment of T cell subsets should be interpreted with caution, since proportionately normal numbers of OKT8+ cells in patient PBLs are seriously compromised in their ability to give rise to clonal progeny in vitro, and since there appears to be a OKT4-8- population of T cells in PBLs that are committed to become OKT4+ or OKT8+ T cells, but are unable to do so in vivo.     

APPLICATION OF PROGNOSTIC SCORING SYSTEMS IN DIFFERENTIATED THYROID CARCINOMA

Background : Total thyroidectomy is widely practised in Australasia for papillary and follicular thyroid carcinoma. Data from large overseas series have demonstrated that patients with these cancers may be separated into risk groups based on clinicopathological prognostic factors. Furthermore, evidence suggests that low-risk patients may be safely treated with less than total thyroidectomy. The aim of the present paper was to determine what proportion of our patients with papillary and follicular thyroid cancer were in the low-risk group in order to select candidates for less aggressive treatment. Methods : A prospectively documented series of 175 previously untreated patients with papillary and follicular thyroid carcinoma, treated principally by total thyroidectomy over a 10-year period, was divided into risk groups using the Mayo Clinic, Lahey Clinic and Memorial Hospital prognostic scoring systems. Complication rates for 103 patients treated by total thyroidectomy were also studied and reported. Results : Women outnumbered men by 2.3:1. There were 128 papillary carcinomas (73%) and 47 follicular cancers (27%). These tumours were < 4 cm in diameter in 81% of patients, and 41% of patients were 40 years of age or younger. Low-risk patients accounted for 75, 81 and 45% of the study group, respectively, when the three prognostic scoring systems were applied to our patient population. The rates for recurrent laryngeal nerve palsy and permanent hypoparathyroidism for patients having total thyroidectomy were 1 and 1.9%, respectively. In the low-risk group there were no permanent complications. Conclusion : Most patients treated at Royal Prince Alfred Hospital during the past 10 years were low-risk patients who may have been eligible for less aggressive surgical treatment.