Similar biological effects of different low doses of interferon alpha in cancer patients.
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Biomedical subjects
Publications and source records attributed to C Billard.
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This report describes a child with herpes simplex virus (HSV) encephalitis who improved dramatically while being treated with acyclovir but subsequently had neurological deterioration and died. A severe necrotizing process was present in the brain at autopsy but there were no focal areas of demyelination and poor inflammatory response. HSV was not cultured from brain biopsy during relapse or autopsy. Fourteen previous cases of relapsing herpes encephalitis are reviewed and treatment regime and mechanisms of relapse are discussed.
Hairy cell leukemia (HCL) is a pre-plasma B cell tumor which responds to interferon (IFN)-alpha therapy. In vitro, B cell growth factor (BCGF) can induce proliferation of hairy cells. We have investigated the effect of in vitro and in vivo treatments with different recombinant IFN on the capacity of hairy cells to proliferate in response to human BCGF. In vitro treatment of leukemic cells from HCL patients with recombinant IFN-alpha-2 (5/5 cases) or IFN-beta (4/5 cases) resulted in a marked inhibition of the BCGF-dependent response. This suppressive effect was obtained with IFN concentrations of 1000, 100 IU/ml, and even occasionally 10 IU/ml. In contrast, no such inhibition was observed with IFN-gamma, despite the presence of specific IFN-gamma receptors on hairy cells at densities similar to receptors for IFN-alpha/beta. The IFN-alpha-induced suppression of the proliferative response of hairy cells to BCGF was also observed in vivo in two patients within 6-12 hr after administration of single doses of IFN-alpha. When hairy cells were maintained in culture for 1 week, they recovered their capacity to be stimulated by BCGF. This reversion was also shown in vivo in hairy cells isolated 1 week after IFN administration. Since in vivo growth of hairy cells could possibly result from the autocrine secretion of BCGF, we propose that the therapeutic effect of IFN-alpha on HCL may be due in part to an inhibition of such autocrine loop.
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An aneurysm of the vein of Galen can have a varied sonographic appearance in infancy. The classical picture is a spherical posterior third ventricular mass with no internal echoes. With varying degrees of thrombosis of the aneurysm which may occur spontaneously or after surgery, the mass became hyper-echogenic. Our experience in two patients with this spectrum of echographic findings will be demonstrated and correlated with clinical findings CT scan, and angiography.
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We report the neurological, intellectual and visual outcome of 77 children with hydrocephalus of non tumoral origin. Neurological deficits and epilepsy were common, particularly in those with severe intellectual deficit and with acquired brain damages. Intellectual level prognosis was usually good, although lower than in a healthy population: 75% of children had full intellectual quotient (FIQ) higher than 70 but often, there was an heterogeneous pattern of the IQ with greater differences between verbal and performance results because of poor visual-spatial skills. Attention and syntax comprehension of language disabilities were also specifically encountered. Meningitis or toxoplasmosis secondary to hydrocephalus often resulted in a poor intelligence level but other causes did not influence intelligence level or pattern. Visual-spatial deficits, attention disorders and language disabilities did not seem related to the degree of hydrocephalus or the delay before shunting, but were especially encountered when ventricular dilatation persisted in spite of the operation. Functional amblyopias were frequent, certainly related to strabismus. Optic atrophy was rare and linked to direct compression of the optic nerves or to major and repeated episodes of intracranial hypertension.
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Results of a national survey of clinical symptomatology revelatrice of an aneurysm of Galen's ampulla are analyzed and compared with documented data. Three large groups can be distinguished as a function of age at diagnosis: the neonatal period: cardiac insufficiency; childhood: macrocrania; adolescence and adult life: various clinical symptoms and signs but fortuitous discovery not exceptional.
A national survey was conducted to assess modalities and results of therapy for aneurysm of Galen's ampulla. Analysis of date showed variations as a function of age at diagnosis. Prognosis appears to improve with increasing age of diagnosis of the lesion, but remains poor generally despite improvement in treatment methods.
We present the results of a collaborative study on the association of congenital muscular dystrophy with central nervous system anomalies revealed by CT scan investigation of 10 patients. In seven children, an abnormal hypodensity of the cerebral white matter is found; in four of these patients, this radiological anomaly is either isolated, or associated with a moderate intellectual impairment; in one case, severe mental retardation and ocular changes had occurred; in the other two cases, the muscular disease was progressing slowly, in association with microcephaly, epilepsy, and moderate mental retardation. Three children were afflicted with a severe early encephalopathy and congenital muscular dystrophy, and presented signs of cortical and subcortical atrophy on CT scan. Two of these patients corresponded to different types of cerebro-ocular dysplasia-muscular dystrophy syndromes, and the third patient of Fukuyama's congenital muscular dystrophy. These observations are discussed and compared with those reported in the literature. The authors emphasize the need to investigate possible cerebral CT scan anomalies in congenital muscular dystrophies, and to look for muscular changes in some prenatal encephalopathies.
Alveolar II pulmonary tumor cells (A549 cells) maintained in continuous tridimensional organotypic culture were used to test the effects of recombinant human interferons -alpha 2, -beta and -gamma on growth inhibition and survival of the tumor nodules. The organotypic culture method has several advantages: the three-dimensional structures of the cells as well as some cell differentiation are maintained and the extremely low traumatizing culture conditions offer injured cells the maximum chance of survival. A continuous treatment lasting 65 days (three weekly interferon changes) with 10, 10(2), 10(3) and 10(4) U/ml doses of the three interferons led to growth inhibition and necrosis only in the presence of the two highest doses (10(3) and 10(4) U/ml) of IFN-alpha 2 and -gamma. IFN-beta had no inhibitory effect. Some nodules, especially at the lower dose levels (10(2) U/ml), showed enhanced growth in presence of the three types of interferons. After stopping the treatments, all the necrotic and disintegrating nodules resumed growth. Growth of the recovered nodules was followed in the absence of interferon for another period of 70 days. The growth rate of IFN-beta and -gamma-treated nodules was similar to that of the controls, but was slowed down for the regenerated IFN-alpha 2-treated nodules. Hence, in A549 organotypic cancer nodules and under our experimental conditions, only high doses of IFN-alpha 2 and -gamma appeared to have a partial cytolytic, but finally no tumoricidal action; IFN-beta was inactive. At the lower doses growth stimulation was found during the treatments with the three interferons.
Interferons (IFNs) initiate their effects by interacting with specific high-affinity cell surface receptors, but little is known about the physiology of IFN receptor interaction in vivo. Treatment of patients suffering from hairy cell leukemia (HCL) with human recombinant alpha IFN results in significant tumor regression, with clinical improvement in a high percentage of cases. To investigate a possible relevance of binding parameters as response markers, IFN receptor interaction on tumor cells responsive to IFN in vivo was studied. Binding of human alpha 2 IFN to circulating hairy cells was analyzed before and during IFN therapy in ten patients selected on the basis of high numbers of peripheral hairy cells. Binding experiments were carried out on Ficoll-Paque fractionated peripheral cell samples containing a majority of hairy cells. All patients reacted to recombinant alpha IFN treatment with a striking decrease in binding capacity within 12 hours after the first injection. As demonstrated by using a monoclonal antibody able to recognize alpha 2 IFN bound to its receptor, this decreased binding capacity was not due to blocking by circulating IFN but rather to a decrease in receptor number. This receptor "down-regulation" was partially reversible after the first IFN injection. However, upon prolonged IFN therapy, all patients displayed a stable state of decreased receptor expression. Down-regulation of IFN receptors can be regarded as a response marker to IFN treatment. This response marker, however, was not correlated with the clinical response within the first months of IFN therapy.
Seventeen patients with hairy cell leukemia (HCL) were treated with low doses of recombinant alpha interferon (IFN) for over 4 months. Marked improvement was observed in peripheral blood and bone marrow in 15 of 17 patients. Comparison of pretreatment values and hemograms obtained after 4 months of treatment showed a marked decrease in circulating hairy cells (P less than .01), a decrease in the number of lymphocytes (P less than .01), a rise in the number of platelets (P less than .05), granulocytes (P less than .05), and monocytes (P less than .01), and a rise in the hemoglobin level (P less than .01). Transient reduction in the number of granulocytes was noted during the first month. Correction of thrombocytopenia often appeared within 2 months and usually preceded improvement of anemia, monocytopenia, and neutropenia. Bone marrow biopsy specimens were taken before treatment and 2, 4, and 7 months after its initiation. The volumes occupied by hairy cells, cells of the myeloid lines, and adipocytes were studied by stereological analysis of semithin sections. Decrease in the volume occupied by hairy cells was seen after 4 months of treatment (P less than .01), and the volume continued to decrease at the seventh month (P less than .05). Hairy cells were no longer detected on bone marrow biopsies of 4 of 17 patients by the fourth month and in 3 of 8 additional patients by the seventh month. A rise in the volume occupied by normal myeloid cells was visible by the second month of treatment (P less than .01). Nevertheless, the volume occupied by granulocytes remained lower than in the normal controls (P less than .01). After an initial increase during the first 2 months of treatment (P less than .01), the overall cellularity remained unchanged at 4 months and decreased significantly (P less than .05) at 7 months. Except for biopsies at 2 months, mean cellularity was below that of control biopsies (P less than .01).
The present study was undertaken to verify the effect of ventricular dilatation on cerebral blood flow by a non invasive Doppler technique in infants with hydrocephalus. The measurement of pulsatile flow in cerebral arteries is also a valuable parameter for determination of optimal timing of corrective intervention.
Two cases of abnormal movements (hemichorea and ballismus) resulting from craniopharyngiomas are reported and discussed. They highlight the infiltrative nature of these tumors. Tumoral causes of extrapyramidal signs are rare but should be kept in mind.
The growth properties of fibroblasts from the thoracic skin of patients with mammary cancers were compared to those of fibroblastic cultures from patients with benign lesions or having undergone surgery for non-neoplastic diseases. As expected, an inverse correlation was found between the doubling potential of fibroblasts in vitro and the donor's age for cells from patients with benign lesions; however no correlation, was found with cultures from cancer patients. Moreover, the latter group responded in an abnormal way to three biological parameters: anchorage dependence, colony formation on monolayers of normal human epithelial cells and saturation densities in overcrowded culture conditions. Skin fibroblasts from one patient with a benign lesion, whose mother had developed a breast cancer, displayed all the abnormal growth properties. Periodic controls of this patient resulted in the early detection of a carcinoma 3 years after the first operation for a benign microcystic lesion. Finally, we found that multiple subcultivations in overcrowded culture conditions cause the selection of a fibroblastic cell subset with greater growth potential which, in the cell strain tested, could invade foreign tissue in vitro.
A case of herpes zoster acute meningo-encephalitis is reported. It is characterized by a profuse intra-cerebral hemorrhage on CT scan and a favorable outcome after treatment with acyclovir. The serological basis for the diagnosis, the mechanism of the encephalitis (viral invasion or immuno-allergic type of reaction), and the origin of the hemorrhagic lesion are discussed. The effectiveness of acyclovir in treating the extention of the infection to the nervous system in patients suffering from varicella-zoster is also discussed.