Biomedical subjects
Publications and source records attributed to J Michon.
Seventy three Camitz-Littler operations combining carpal tunnel release and palmaris longus oppenens transfer provided 90.7% good long term results. A technical modification can provide pronation.
A phase II trial using interleukin-2 (IL2) and lymphokine-activated killer (LAK) cells was carried out in an attempt to treat children with end-stage neuroblastoma. Fifteen patients (median age, 7 years) were enrolled in the study. Twelve were in relapse after massive chemotherapy and autologous bone marrow transplantation (ABMT), and three had a primary refractory disease after conventional chemotherapy. IL2 was administered as an 18 x 10(6) IU/m2/d continuous infusion. One course consisted of a double 5-day treatment period separated by a 6-day break. Cytapheresis to harvest LAK progenitor cells was performed during the rest period. After a 4-day in vitro culture, LAK cells were reinjected during the second cycle of therapy. A phenotypic and functional analysis of immunologic parameters was conducted along with the therapeutic protocol. Toxicity was significant with two toxic deaths (cardiotoxicity and respiratory distress). The reinfusion of large amounts of LAK cells was clearly involved in one case, but this particularly severe toxicity has to be related to the patient's status (ie, heavy pretreatment). No significant clinical response was seen. The immunologic monitoring showed phenotypic and functional modifications in these patients before initiation of treatment and an unexpected absence of evolution of these parameters during IL2 therapy. Although the origin of these immune dysfunctions is not clear, they could be involved in the failure of IL2 therapy. Future studies of IL2 therapy in neuroblastoma should be undertaken earlier in the course of the disease.
Twenty patients with advanced malignant disease submitted to autologous bone marrow transplantation with marrow either unpurged (10 patients) or purged in vitro with mafosfamide (10 patients) after ablative chemotherapy, received simultaneously autologous peripheral blood stem cells (PBSC) collected during one to three 3 h cytapheresis procedures. The kinetics of the hematological recovery of these patients were compared to those of a group of patients suffering from similar diseases and grafted in the same institution with either unpurged marrow only (14 patients) or purged in vitro with mafosfamide (six patients). The median times to reach 10(9)/l leukocytes, 0.5 x 10(9)/l polymorphs, and 50 x 10(9)/l platelets were reduced by 10, 10, and 13 days, respectively, in patients transfused with both autologous bone marrow and peripheral blood stem cells as compared to those receiving bone marrow only. A reduction in the numbers of days spent in hospital post-transplantation (p less than 0.01), of days of fever greater than 38 degrees C (p = NS), and of platelet (p = 0.07) and of red blood cell transfusions (p less than 0.01) were also observed in the group of patients grafted with bone marrow and PBSC.
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The effects of placing activated monocytes in the presence of LAK cells was investigated. It was shown that the addition of monocytes to a preparation of rIL2-stimulated lymphocytes decreased LAK cell activity. This inhibition is enhanced in the presence of rIFN gamma. To analyze the mechanisms of inhibition, monocytes and lymphocytes were cultured separately, on opposite sides of a porous membrane which allowed the passage of molecules. Under such conditions, monocytes inhibited the activity of LAK cells to the same degree that a mixed culture does, suggesting a possible role of diffusible factor(s). Neither indomethacin nor PGE2 fully inhibited LAK cell activity, indicating that PGE2 is not the major monocyte-derived factor inhibiting LAK cell activity. It was also demonstrated that LAK cells can kill monocytes, but that IFN gamma can protect the monocyte from the toxic effect. This protective mechanism may be responsible for enhancing the inhibitory activity of monocytes.
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Beside their therapeutic effects, cytokines are involved in pathologies such as IL-6 in myeloma tumor growth and bone resorption, BCGF in the proliferation of hairy cell leukemic cells, IL-2 in the capillary leak syndrome. For biotherapy to develop, it is necessary to understand both the beneficial and the deletorious effects of cytokines.
The physiological significance of autoreactive T cells derived from normal individuals and activated in the absence of any identifiable foreign antigen by class II MHC-syngeneic molecules remains unexplained. Here we report that autoreactive T-cell clones (Tilkin et al. 1987) proliferate and are able to kill autologous or syngeneic EBV-cell lines but not autologous or syngeneic HLA-Class II-positive PHA-activated T-cell blasts. Furthermore, they are able to efficiently inhibit in vitro the differentiation of CFU-GM and BFU-E colonies, in agreement with the well-known observation that hematopoietic precursors express HLA-DR molecules (Cannistra et al. 1986). The reasons why the autoreactive clones do not recognize T-cell blasts, as well as their possible implications in regulatory mechanisms involving HLA-class II molecules are discussed.
Four children with persistent neuroblastoma after marrow ablative chemoradiotherapy and autologous bone marrow transplantation received continuous infusion of recombinant interleukin 2, 75 to 120 days after the graft. Recombinant interleukin 2 therapy did not induce any major or nonreversible toxicity, hematological toxicity in particular. One patient entered complete remission for 9 months and a second patient had a long-lasting normalization of urinary catecholamine metabolites with more than 50% regression of bone marrow metastases (8 months). In three children, recombinant interleukin 2 and a second patient entered complete remission for 9 months therapy was followed by major increase and activation of circulating natural killer cells which amounted to 80% of the circulating mononuclear cells.
Malunion of the lower extremity of the radius is frequently accompanied by a lesion of the inferior radio-ulnar joint marked by inversion of the inferior radio-ulnar index. Surgical treatment must always take this parameter into account and should attempt to correct it. The authors' preference in the treatment of malunion consists of Duparc osteotomy, in which the size of the graft is calculated in order to restore the inferior radio-ulnar index. If the correction is insufficient or in the case of moderate malunion, the authors propose the Kapandji-Sauvé operation which allows better preservation of the wrist stability.
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Active immunotherapy of cancer is based on the hyperactivation of the immune system of tumor-bearing patients. Interleukin 2 (IL2) has proven to be the most potent immunostimulant used so far. Therapeutic activity of IL2 and IL2-activated lymphocytes has been reported in the treatment of certain tumors such as metastatic melanoma and renal carcinoma. Effectiveness is related to the dose of IL2 administered to the patients, as are important toxic effects. Other cytokines, such as interferon (IFN) and tumor necrosis factor (TNF), are used for their direct effect on malignant cells, particularly those of the lymphoid lineage. The development of these new immunotherapeutic approaches will depend on the quality of their scientific bases, the clinical follow-up of the toxic effects, and the social management of the costs.
Human cloned 35S-labeled NK cells were disrupted by nitrogen cavitation, and their secretory granules were obtained by filtration through 5-micron and 3-micron membrane filters followed by Percoll density-gradient centrifugation. These granule preparations, which contained 35S-labeled chondroitin sulfate A proteoglycans, were sonicated and were analyzed for carboxypeptidase activity and tryptic serine esterase activity. A carboxypeptidase activity that digested angiotensin I to des-Leu-angiotensin I, Ile-His-Pro-Phe to Ile-His-Pro and Phe, and hippuryl-L-phenylalanine to hippuric acid and Phe was detected in the granules of these NK cells. As determined by cleavage of the tetrapeptide, the pH optimum of the carboxypeptidase was 7.0. As assessed by the cleavage of N-benzyloxycarbonyl-L-lysine thiobenzyl ester (BLTe), the granule preparations also contained a serine esterase with trypsin-like specificity that had a pH optimum of 8.5. When the isolated secretory granules were disrupted and chromatographed on columns of Sepharose CL-2B in PBS, greater than 60% of the BLTe serine esterase activity and essentially all of the carboxypeptidase activity filtered as a macromolecular complex with approximately 8% of the 35S-labeled proteoglycans. Whereas treatment with 4 M urea or nonionic detergent failed to disrupt the macromolecular complex, the serine esterase activity was dissociated from the macromolecular complex in the presence of 3 M NaCl, demonstrating an ionic interaction with the proteoglycans. No difference was observed in the disaccharide composition of the chondroitin sulfate glycosaminoglycans of the 35S-labeled proteoglycans that were complexed with the enzymes as compared to those that were not complexed. These studies indicate that the secretory granules of human NK cells contain serine esterase activity and carboxypeptidase activity, both of which have neutral pH optima, and both of which are bound to protease-resistant chondroitin sulfate proteoglycans.
Incubation of human lymphocytes with recombinant interleukin-2 (rIL-2) results in the generation of lymphokine-activated killer (LAK) cells capable of lysing a wide variety of tumor cells. The present study was undertaken to examine the effect of recombinant gamma interferon (rIFN-gamma) on LAK cell cytotoxicity generated from different peripheral blood mononuclear cell (PBMC) subpopulations. When unseparated PBMC were stimulated by rIL-2 and rIFN-gamma, the latter induced a transient enhancement after 2 days followed by a suppression of LAK cell cytotoxicity at day 6. Enhancement of LAK cell cytotoxicity was moderate and inconstant, whereas the inhibition was strong and observed with all the donors tested. This suppression was not associated with a decrease in the [3H]thymidine uptake. PBMC depleted of adherent cells were more sensitive to the stimulation by rIL-2 and the induced cytotoxicity was not modified by rIFN-gamma. Monocyte-enriched plastic-adherent cells, when incubated with rIL-2 and rIFN-gamma, became cytotoxic after 2-3 days of culture and inhibited LAK cell activity after 5-6 days. Collectively, our results suggest that rIFN-gamma affects LAK cell cytotoxicity through the activation of plastic-adherent, monocyte-rich, cells which modulate natural killer cells, first in a positive, then in a negative way.
Thirty dissections were performed on adult non embalmed cadavers, after vascular injection with MICROFIL or Methylene blue. In contrast to the classical descriptions of a single dorsal metacarpal artery, this study shows the existence of a vascular network with 1 or 2 vessels running over or under the deep aponeurosis. Direct cutaneous arteries provide blood supply to the kite flap when the only dorsal metacarpal vessel of the first web space is in a deep situation. The main source of blood supply to the kite flap is described in each anatomical variation of the dorsal network.
Nine children with poor prognosis neuroblastoma have been treated by continuous infusion of IL-2 and autologous LAK cells, as described previously by West et al. in adult patients. Six patients were in relapse after high-dose chemotherapy and autologous BMT and three presented with primary refractory disease after conventional therapy. Although patients were very young (median age 6 years; average weight 17 kg), infusion of IL-2, cytapheresis and reinjection of LAK cells appeared feasible with the usual and transient complications observed with IL-2. Haematological toxicity, although reversible, was more important than usually described and due to the presence of bone-marrow metastases in 8 of the 9 patients. Life-threatening toxicity was observed in only one of the admission centres and was probably due to the rapid reinjection of a very large number of activated cells. Two patients presenting with very active disease after high-dose chemotherapy and autologous or allogeneic BMT received IL-2 alone, at 120 days and at 90 days after the graft. The reactivation of grade-II GVHD was the major complication in the patient treated after an allograft, whereas no BMT-related toxicity was observed in the patient treated after the autologous BMT. Immunological modifications induced by IL-2 were very different between these patients. As expected, a preferential outgrowth of NK cells with both NK and LAK activity was observed in the patient treated just after the autograft. In contrast, in the patient treated after an allograft and in the 9 patients in relapse, T lymphocytes remained the major mononuclear cell population with a very large excess of CD8+ T cells. All patients progressed after the first induction cycle with the exception of the only patient treated after autologous BMT who reached a very good partial remission with disappearance of the local tumor and bone metastases. Although very preliminary, these data clearly show that the efficacy of IL-2 largely depends on the patient's immunological status with the optimal effect being observed when IL-2 is given in the first few months following an autograft.