[Clinical experience with subcutaneous immunoglobulin administration in the treatment of primary immunodeficiencies]. / Expérience clinique de l'administration d'immunoglobulines par voie sous-cutanée dans le traitement des immunodéficiences primaires.

We report the clinical evolution of three adult patients with recurrent respiratory tract infections. Those patients had a low plasma level of IgG3 and/or a deficiency in anti polysaccharide antibodies. They all were previously treated with intravenous immunoglobulin, but their clinical status as well as their health related quality of life improved after they had switched to subcutaneous immunoglobulin administrations. The frequency of subcutaneous injections was on a weekly basis and the dosage was adjusted in order to reach the cumulative monthly dose of intravenous infusions. The tolerance of the subcutaneous route of immunoglobulin injection was recorded as excellent in all three patients.

Melanoma associated antigen (MAGE)-A3 expression in Stages I and II non-small cell lung cancer: results of a multi-center study.

OBJECTIVES: Adjuvant immunotherapy is an innovative therapeutic option that might potentially improve outcome of early-stage non-small cell lung cancer. Melanoma associated antigen (MAGE)-A3 is a promising target for immunotherapy because it is exclusively presented on the cell surface of cancer cells and might be associated with an aggressive cancer phenotype. The present study was performed to determine the rate of MAGE-A3 expression in early-stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Primary tumor samples from 204 patients with operable clinical Stages I or II NSCLC were collected between March and November 2001. Pathological Stage was determined by the local pathologist in each of the 16 participating institutions. Tissue samples were stored immediately after surgery in a RNA-stabilizing solution and were frozen at -20 degrees C. MAGE-A3 expression was analyzed by detection of MAGE-A3 transcripts using reverse-transcriptase polymerase chain reaction. RESULTS: MAGE-A3 expression was observed in 80 out of the 204 (39.2%) examined Stages I-II primary tumors. Stratification into UICC-Stages showed that 31 out of 105 (29.5%) Stage I non-small cell lung cancers and 49 out of 99 (49.5%) Stage II non-small cell lung cancers expressed MAGE-A3. In comparison to Stage I, the rate of MAGE-A3 positive tumors was significantly increased in Stage II (P=0.004; Chi-square test). CONCLUSION: The MAGE-A3 expression rate showed that a promising proportion of operable patients with early-stage non-small cell lung cancers are possible candidates for trials investigating adjuvant therapy with MAGE-A3 immunization. Currently, a phase two trial of adjuvant MAGE-A3 vaccination is in progress.

Immunisation of metastatic cancer patients with MAGE-3 protein combined with adjuvant SBAS-2: a clinical report.

Fifty-seven patients with MAGE-3-positive measurable metastatic cancer, most of them with melanoma, were vaccinated with escalating doses of a recombinant MAGE-3 protein combined with a fixed dose of the immunological adjuvant SBAS-2, which contained MPL and QS21. The immunisation schedule included 4 intramuscular (i.m.) injections at 3-week intervals. Patients whose tumour stabilised or regressed after 4 vaccinations received 2 additional vaccinations at 6-week intervals. The vaccine was generally well tolerated. Among the 33 melanoma patients who were evaluable for tumour response, we observed 2 partial responses, 2 mixed responses and 1 stabilisation. Time to progression in these 5 patients varied from 4 to 29 months. In addition, a partial response lasting 10 months was observed in 1 of the 3 metastatic bladder cancer patients included. None of the tumour responses described above involved visceral metastases. Immunological responses to the vaccine will be reported separately.

Immunotherapy with keyhole lampet hemocyanin-conjugated decapeptide vaccine in cypress pollen allergy.

BACKGROUND: Cupressaceae pollen allergy is a world-wide pollinosis but immunotherapy has rarely been tested. Immunotherapy is usually allergen-specific but new forms may be targeted towards IgE. OBJECTIVES: A randomized, double-blind, placebo-controlled trial was carried out to assess the efficacy of a vaccine made of keyhole lampet hemocyanin (KLH)-conjugated decapeptide from the Fc(epsilon4) domain of the IgE in cypress pollinosis. METHODS: Sixty patients with cypress pollen allergy were studied. They were included on a suggestive clinical history, positive skin tests and nasal challenge to cypress pollen extract. Three intramuscular injections of the vaccine (250 microg) or placebo were administered monthly with a booster injection 5 to 8 weeks later. The primary end-point criterion was the threshold dose inducing a positive nasal challenge. The secondary end-point was the symptom-medication scores measured when cypress pollen grains were over 50 grains/m3. RESULTS: Nasal challenge before treatment was non-significantly different between the placebo and vaccine groups. After treatment there was no significant difference between the two groups. Pollen counts were over 50 grains/m3 for 8 weeks during the trial. There was no significant difference in total symptom scores between the placebo and vaccine groups. The vaccine was safe. CONCLUSIONS: The KLH-conjugated decapeptide vaccine was not effective in cypress pollen allergy.

Different modes of action of high-dose immunoglobulins in rheumatoid arthritis.

Several clinical trials have demonstrated that in patients with rheumatoid arthritis, high doses intravenous immunoglobulins (i.v.i.g.) are frequently leading to an improvement of the morning stiffness and the extra articular symptoms, as well as to a steroid-sparing effect. This i.v.i.g. therapy seems furthermore to have immunomodulatory activities in rheumatoid arthritis, since the clinical benefit is concomitant with a reduction in the number of CD4+ T-lymphocytes, with a significant dtop in the level of circulating immune complexes (CIC), and with an inhibition of the early phases of the B-lymphocytes activation. Due to the heterogeneic aspects of the rheumatoid arthritis pathogeny, it is to be expected that i.v.i.g. may interfere in different ways with many of the sequential processes in operation in the development of this disease. 1. IgGs may facilitate the reticulo endothelial clearance of inflammatory CICs by increasing their size as a consequence of the addition of exogeneous antibodies (Ab) which offers more IgG-Fc fragments as ligands for the monocytes/macrophages Fc-gamma III receptors. 2. i.v.i.g are known to down regulate the activation of B-lymphocytes and their differentiation in specialized Abs-secreting plasma-cells, and this process could affect the clones of B-cells producing anti-collagen II auto-antibodies and Abs with rheumatoid factor activity. 3. Some experimental data allow to suspect the responsibility of a super-Ag in certain forms of rheumatoid arthritis. I.v.i.g. preparations contain specific Abs which bind some of these super Ags, and impair their adequate presentation to T helper-cells. 4. Cytokines and specially the interleukin I (IL-1) which stimulates the collagenase activity, are pivotal elements in the perpetuation of the inflammatory connective tissue damages in rheumatoid arthritis. I.v.i.g. preparations contain soluble cytokine-receptors, as well as anti-IL-1 and IL-6 specific Abs which both act as cytokines agonists and sustain the effective antiinflammatory action of high-dose polyclonal IgGs. Although more clinical data are still needed to sustain the routine use of i.v.i.g. in rheumatoid arthritis, the efficacy of this therapy is not disputable any more in other pathologies with similar immunological disorders.

Treatment of refractory epilepsy with intravenous immunoglobulins. Results of the first double-blind/dose finding clinical study.

Sixty-one refractory epileptic patients (46 with partial epilepsy) were treated with intravenous immunoglobulins in a controlled double-blind/dose finding clinical trial; 18 (7 females, mean age 18.5 years) received placebo, while 14 (3 females, mean age 26.2 years, 2 excluded), 14 (4 females, mean age 24.6 years, 1 excluded) and 15 (5 females, mean age 24.4 years) patients received 100, 250 and 400 mg/kg per infusion of intravenous immunoglobulins, respectively. Seven perfusions were scheduled, four the 1st week, and thereafter one during the 2nd, 3rd and 6th week. The patients were followed for 6 months. An optional infusion was given at the end of the study. A comparison of the mean number of seizures per day was made between the baseline (4 weeks before the first infusion) and the 6th month after the first infusion. Patients were considered responders if they had a decrease of at least 50% in daily seizure frequency at the end of the study compared with the baseline. We did not find severe adverse events. One patient had to stop infusions for possible related side effects (vomiting). When all patients were analyzed together, we found a positive trend in favor of intravenous immunoglobulin treatment, but this was not significant (P = 0.095). There was no relationship between dose and efficacy (P = 0.31). When the largest group with partial epilepsy was analyzed separately, we noted 19 responders in the test group, compared with 2 in the placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Immune disorders after severe injury.

Septic complications are still the major cause of death in patients with severe injuries, whether due to polytrauma, large burns, or difficult surgical operations. The very high incidence of such infectious episodes in spite of the continuous development of new broad spectrum antibiotics and appropriate intensive care managements, may suggest that any kind of severe injury leads to a state of acquired immunologic deficiencies. Thus an intensive relation has been demonstrated between the extend of body burned surfaces and the neutrophil chemotaxis whose dramatic decline could originate either from an intraleukocytic defect, or from inhibitory factors released by the damaged tissues. Furthermore, any important tissular destruction has been shown to stimulate the clonal proliferation of T suppressor lymphocytes which could be considered as a physiological protective mechanism against the development of an autoimmunization towards self-structures released by the wound in the blood stream. Factors able to activate T suppressor lymphocytes after injury are multiple and among them most important are: HLA-bearing cell wall components, histamine released by tissue mast cells, soluble factors produced at the level of the wound, bacterial endotoxins, arachidonic acid metabolites, etc. Finally, it has been mentioned that this state of immune deficiency after injury may still be exacerbated by iatrogenic measured like catheters, antibiotherapy, corticotherapy, and mainly by malnutrition.

Evaluation and significance of the degree of pituitary-gonadal inhibition during intranasal administration of buserelin.

In 12 patients (11 girls, 1 boy) with central precocious puberty and 4 patients (3 girls, 1 boy) with idiopathic short stature treated for 1 year with a GnRH superagonist, buserelin (0.3 mg intranasally, 4 times a day), a variable degree of inhibition of sex steroid secretion and pubertal development was observed. Regression of breast or genital development required a daily dosage of buserelin greater than or equal to 34 microgram/kg. After 3, 6, 9 and 12 months of treatment, the serum oestradiol level in the girls was positively related (r = 0.69) to basal serum LH measured at the same time and to change in breast development during the previous 3 months. In contrast, LH response to GnRH was very low in all the patients and not related to the degree of oestradiol inhibition. Height velocity and bone age velocity during the year of treatment showed no significant correlation with mean oestradiol level. Bone age velocity during treatment was inversely related to bone age at onset of buserelin. These data show that 1) the pituitary gonadal suppression during intranasal administration of buserelin is variable and dose-dependent; 2) gonadotropin response to GnRH is not a sensitive indicator of incomplete pituitary suppression during buserelin treatment; and 3) bone age velocity during treatment is more reduced the more advanced bone age is at onset of treatment.

Treatment of idiopathic West and Lennox-Gastaut syndromes by intravenous administration of human polyvalent immunoglobulins.

A total of 7 patients (3-21 years old) suffering from an intractable "primary" Lennox-Gastaut syndrome (LGS) were treated with i.v. high doses of polyvalent human immunoglobulins. Of these patients 6 improved following such treatment with a decrease in fits and an improvement in the EEG. Hypotheses about the contribution of the treatment and immunopathological factors in some cases of idiopathic LGS are discussed.

[Treatment of idiopathic thrombopenic purpura with immunoglobulins]. / Le traitement du purpura thrombopénique idiopathique par les immunoglobulines.

Twelve patients presenting with idiopathic thrombocytopenic purpura were treated with injections of immunoglobulins. A lasting improvement was observed in 1 and a transient improvement in 8. Intramuscular injections appeared to be more effective than intravenous injections. The increase in the number of platelets was accompanied by a decrease of circulating immune complexes. The antigen-antibody reaction observed between the doses of immunoglobulins injected and the patients' sera suggests that immunoglobulins might act by enhancing the elimination of some antigens of infectious origin.

[Use of clobazam 20 mg in general practice]. / Utilisation du clobazam 20 mg en pratique générale.

Fifty practitioners treated 224 patients with clobazam for 4 weeks. The anxiolytic action, the tolerability, the degree of satisfaction and the dosage of clobazam were evaluated by means of a modified "Rating Scale for Anxiety" by Hamilton and self-evaluation scales. Clobazam proved to have an important anxiolytic activity together with good tolerability. The ability to concentrate was remarkably improved, which seems to confirm the specificity of the molecule (benzodiazepine-1,5). The reduction of anxiety and of anxious equivalents and the good tolerability of the product were confirmed by the judgement of satisfaction of the doctors as well as of their patients.

The therapeutic efficacy of human immunoglobulins as a function of their in vitro antibody activity toward circulating antigens in children with recurrent infections of the upper respiratory tract.

Children with recurrent infections of the upper respiratory tract were treated by injections of human immunoglobulins. Of the 58 children who were followed after treatment, the clinical outcome and the results of laboratory tests, i.e. serum protein profile and level of circulating immune complexes, were improved in 33. The improvement was significantly related to the in vitro antibody reaction of the immunoglobulin batch that was used for injections with unidentified antigens present, before treatment, in the patient's serum.

A review of the different hypothetical factors leading to materno-foetal tolerance during normal human pregnancy.

The immune situation of a women during pregnancy which permits the non-rejection of the foetal allograft can be compared to the pathological state of patients bearing malignant tumours. A good understanding of the former, therefore, could provide a better approach to the treatment of the latter. Four different kinds of hypothesis have been proposed for explaining this materno-foetal tolerance and each is briefly reviewed and criticised. Particular attention is drawn to the nature of the circulating factors which have been detected in the sera of pregnant women and which have been shown to have an in vitro immunosuppressive effect.

Detection of immune complexes in the sera of human newborns suspected of neonatal infection.

The special characteristics and relative immaturity of the immune system in human neonates favour the constitution and persistence of circulating immune complexes after any antigenic invasion so that their detection in serum during the first week of life could be of paticular interest for the early diagnosis of a neonatal infection. In this study, using a technique based on the inhibition of a latex agglutination, we detected circulating immune complexes in sixty-four neonates suspected of infection, at a significantly higher titre than in eleven newborns considered to be completely devoid of any clinical abnormalities. The level of those circulating immune complexes was related to the severity of a clinically considered as a high risk of infection. On the other hand, no significant correlation was found between the infection score and the level of fibrinogen in the blood or the percentage of nonsegmented neutrophils. Moreover, no correlation was demonstrated between each of these two classical biological tests and the level of circulating immune complexes.

[Segregation of HLA haplotypes in a family with infants having spina bifida]. / Recherche d'une segregation des haplotypes HLA dans une etude familiale d'enfants atteints de spina bifida.

The search for HLA association in spina bifida is particularly interesting since this condition can be associated with the effect of the T locus in mice. Gene and haplotype frequencies in 32 unrelated patients suffering from spina bifida were studied. Patients and families were examined clinically and radiologically. A high frequency of spina bifida occulta and other vertebral abnormalities was found suggesting genetic determinism but no evidence of linkage with HLA genes or haplotypes was found.