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Biomedical subjects

M Symann

Publications and source records attributed to M Symann.

At least 55 records · Page 3Linked to original sources
PubMed1989

Immune reconstitution after bone-marrow transplantation.

Recipients of both allogeneic and autologous BMT demonstrate clinically significant immune deficiency involving T and B lymphocytes. While quantitative aspects of the immune system generally return to normal in the first 3 to 4 months, there is a prolonged delay in the recovery of qualitative immune functions. T-cell proliferation is impaired immediately after transplantation and recovers after more than 1 year. There is a documented defect in IL-2 producing cells post-BMT, but PHA-stimulated T cells are TAC+. Therefore, addition of IL-2 in vitro may normalize the T-cell proliferation defect. NK and LAK activities normalize very early post-BMT. In the light of these data, the clinical assessment of rIL-2 administration on the immunological reconstitution of ABMT patients and as consolidative immunotherapy is being investigated.

Antibody Formation↗
PubMed1989

[Clinical and biological aspects of intensive chemotherapy with autologous bone marrow grafts in small-cell bronchial cancer].

Small cell lung cancer (SCLC) is a frequent and aggressive tumor characterized by its major sensitivity to chemotherapy since 80% of the patients respond dramatically to the treatment. Nevertheless, the majority of them eventually die from their cancer. We have addressed the effect of late intensification with autologous bone marrow transplantation on SCLC through a randomized clinical trial. This study included 101 patients, 45 of whom could be randomized to either conventional post-induction therapy or late intensification. Of the 32 patients with limited disease, patients who did not receive intensification relapsed on a median of 10 weeks compared with 35 weeks for patients who received intensification (p = 0.001). An important observation was that there was no patient disease free at 1 year in the group that did not receive intensification whereas there were patients who were free of disease up to 271 weeks in the group receiving late intensification. To improve upon these results we have developed a panel of anti-lung cancer monoclonal antibodies that we use for the detection of occult cancerous disease in the bone marrow and for the in vitro elimination of clonogenic tumor cells contaminating the marrow graft. In addition we are monitoring the immune defect induced by ABMT and its compensation by an in vitro recombinant human IL-2 perfusion. Finally we have devised a new induction and intensification chemotherapy regimens with different drugs in order to prevent multidrug resistance. These new tools are currently under investigation in the clinical setting.

Antibodies, Monoclonal↗
PubMed1989

Cholinergic enhancement of megakaryocytopoiesis and granulocytopoiesis in culture: mediation via T-lymphocytes.

Addition of carbamylcholine, a cholinergic analogue, to bone marrow cultures enhanced megakaryocytic and granulocytic growth by 60% and 42%, respectively. When carbamylcholine was added to spleen cells cultured in the presence of pokeweed mitogen, the resulting conditioned medium (PWM-SCM) increased the number of megakaryocytic and granulocytic colonies to 159% +/- 6% and 146% +/- 10%, respectively, compared to control cultures stimulated by PWM-SCM alone. To determine if this cholinergic augmentation of colony formation was direct or mediated via accessory marrow cells, cyclosporin A (CyA), a potent T-lymphocyte function inhibitor known to suppress the production of colony-stimulating activity (CSA) by spleen cell cultures, was added to marrow cultures. CyA (3 micrograms/ml) abrogated the enhancement of megakaryocytic and granulocyte-macrophage colony growth but had no effect on colony formation when added alone. To confirm the role of T-lymphocytes in the augmented proliferation of megakaryocytopoiesis and granulocytopoiesis, bone marrow cells from T-lymphocyte-deficient nude mice were cultured in the presence of carbamylcholine. No significant change was observed in the number of megakaryocyte colony-forming units (CFU-M) and committed granulocyte-macrophage colony-forming units (CFU-C) derived from the marrow of nude mice when cultured in the presence of carbamylcholine. The data suggest that carbamylcholine-induced enhancement of megakaryocytopoiesis and granulocytopoiesis in culture is indirect, requiring a T-lymphocyte population.

Animals↗
PubMed1989

Sequential dacarbazine chemotherapy followed by recombinant interleukin-2 in metastatic melanoma. A pilot multicentre phase I-II study.

Between April 1988 and August 1989, 30 melanoma patients were entered in a multicentre Phase II study of dacarbazine (DTIC) 850 mg/m2 i.v. bolus on day 1, and recombinant interleukin-2 (rIL-2) (Cetus) 18 x 10(6) IU/m2/day i.v. continuous infusion on days 4-9. Six treatment cycles were given: the first two at an interval of 13 days, and further cycles at intervals of 20 days. Twenty patients are currently evaluable for toxicity and 18 for response. Two of these patients presented with metastatic intraocular melanoma. Median age was 48 years (range 18-83), and median Karnofsky index was 100 (range 80-100). Four patients had received prior radiotherapy and one had received prior immunotherapy. Seventeen patients received two cycles of treatment and nine patients received three or more cycles. Four patients responded (22%): two complete remissions and two partial remissions. Stable disease was seen in six patients (33%). Responses occurred in the lung, skin, spleen and lymph nodes. Seventy-five percent of the patients received the full dose of rIL-2 during cycle 1, whilst only 2 out of 9 (22%) received the planned dose on the third cycle. Rebound lymphocytosis of 5.3 x 10(3)/L (range 1.2-18.1) occurred 24-48 h after rIL-2, but was not predictive for response. Currently, there is no evidence that pretreatment with DTIC impacts negatively on the rIL-2-stimulated lymphocyte proliferation. The toxicity profile of this treatment regimen did not differ significantly from that already described for similar regimens of rIL-2. However, in this interim analysis, there was a trend for a higher percentage of patients (25%) to experience severe weight gain (greater than 10%). This study shows that this treatment regimen is active in metastatic melanoma, with acceptable toxicity. Further research will focus on using other chemotherapeutic agents and/or other biological response modifiers (e.g. interferons, tumour necrosis factor) in combination with rIL-2.

Adolescent↗
PubMed1988

Cytolytic response of human T cells against allogeneic small cell lung carcinoma treated with interferon gamma.

Human lymphocytes stimulated in vitro by allogeneic small cell lung carcinoma cell lines did not show any significant cytolytic activity against the stimulator tumor cells. However, a high level of lysis was observed when both stimulator and target small cell lung carcinoma cells were pretreated with interferon gamma, which increased considerably the expression of major histocompatibility class I molecules by these cells. The demonstration that small cell lung carcinoma cells can be lysed by cytolytic T lymphocytes, suggests that it will be feasible to study the autologous T cell response of patients against this tumor.

Carcinoma, Small Cell↗
PubMed1988

Monoclonal antibodies for the in vitro detection of small cell lung cancer metastases in human bone marrow.

Three rat monoclonal antibodies were selected for the immunodetection of small cell lung cancer metastases in bone marrow and other hematologic samples. By membrane immunofluorescence, they define three distinct surface antigens here termed lung cancer-associated antigens or LCAs. The latter are widely expressed on small cell lung cancer and non-small cell lung cancer cells/cell lines, but not detectable on a variety of normal and transformed bone marrow, blood and lymphoid cells. Anti-LCA1 (IgM) is similar to the many anti-lacto-N-fucopentaose III IgM antibodies rasied against human tumors. In contrast, anti-LCA2 (IgG2b) and anti-LCA3 (IgG2a) define surface proteins of 29, 32, 41 and 98 kilodaltons, respectively, that have not been reported earlier. These three reagents have immunodiagnostic potential, since in combination they label all 49 lung cancer cell lines tested. Their ability to detect lung cancer metastases in patient's bone marrow samples is documented in an accompanying paper.

Animals↗
PubMed1988

Immunodetection of small cell lung cancer metastases in bone marrow using three monoclonal antibodies.

Detection of bone marrow metastases by indirect immunofluorescence methods was investigated using three monoclonal antibodies (MoAbs) raised against small cell lung cancer (SCLC). These antibodies, designated anti-LCA1, -LCA2 and -LCA3, recognize three different antigens on the surface of SCLC cells. Eighty-four bone marrow samples from 74 different patients were studied. Whereas tumor cells were found in 32 (38%) by MoAb staining, only 10 (12%) were positively identified using conventional morphological methods. Nine out of the morphologically positive specimens showed reactivity with at least two monoclonal antibodies. Among the 32 samples proven positive by immunofluorescence, an important antigenic variability was noted. Anti-LCA1 recognized tumor cells in 62%, anti-LCA2 and anti-LCA3 in 53%. Due to the recognition of bone marrow involvement by fluorescence methods in 26% of the 34 patients classified as limited disease, a new subgroup of limited disease patients was defined whose prognosis remains undetermined. Our results confirm the utility of immunodetection in the diagnosis of SCLC bone marrow metastases and emphasize the advantage of using a panel of MoAbs with different antigenic specificities. Further study is needed to determine the prognostic significance of bone marrow involvement established by immunodetection.

Antibodies, Monoclonal↗
PubMed1988

Detection of small cell lung cancer bone marrow metastases by immunofluorescence.

It is well known that small cell lung cancer (SCLC) has a high propensity to metastasize to the bone marrow and that such involvement has a prognostic significance. A more accurate detection of these bone marrow metastases is thus mandatory. In this study, we analysed the results of the detection of these metastases using an indirect immunofluorescence test. For this purpose, 3 anti-SCLC rat monoclonal antibodies (MoAbs) specific for 3 different antigens (LCA1, LCA2, LCA3) have been utilized to examine 59 bone marrow samples from patients at time of diagnosis and 20 samples from chemotherapy treated patients. Eight patients had bone marrow clearly involved by morphological analysis. They all had fluorescent cells recognized at immunodetection with at least 2 MoAbs positive for 7 out of the 8 samples. Fifteen samples, negative by morphological analysis, were proven positive by immunofluorescence. In 12 cases, involvement was detected only by 1 MoAb (6 anti-LCA1, 2 anti-LCA2, 4 anti-LCA3). A correlation was found between the number of samples proven positive by morphological analysis and the number of positive MoAbs for these samples (p less than 0.005). Among the bone marrow samples provided by the 32 limited disease patients, LCA positive cells were detected in 9 (28%) compared to 14 out of the 27 (52%) samples from extensive disease patients (p less than 0.05). We concluded that the indirect immunofluorescence with a panel of MoAbs increases the rate of detection of bone marrow SCLC metastases.

Antibodies, Monoclonal↗
PubMed1988

Detection of small cell lung cancer bone marrow metastases by tumor stem cell assay.

Detection of small cell lung cancer (SCLC) bone marrow (BM) metastases has a prognostic implication in itself and a therapeutic interest in the setting of autologous bone marrow transplantation. In a prospective study involving 68 bone marrow samples, we compared SCLC detection results obtained using a tumor stem cell assay and those obtained using conventional morphology by light microscopy. In agar, tumoral cells were stimulated either by Salmon's conditioned medium or by epidermal growth factor (EGF). Tumoral clonogeneic cells were detected in 11 cases, although 7 of these were considered negative when investigated by light microscopy. On the contrary, metastases were detected by morphology in 8 instances where no growing colonies were revealed by tumor stem cell assay. The choice of stimulating factor did not seem critical since the number of colonies was similar in all the cases. We conclude that the tumor stem cell assay is useful in the detection of small cell lung cancer bone marrow metastases, particularly in cases where these metastases have failed to be recognized through light microscopy investigation. However, the sensitivity of this assay is low and should be complemented by other techniques such as immunodetection.

Bone Marrow Cells↗
PubMed1988

Concentration of bone marrow progenitor cells by separation on a Percoll gradient using the Haemonetics model 30.

To perform an optimal ex vivo bone marrow purge, it is necessary to concentrate the bone marrow progenitor cells and to eliminate both the red blood cells and the polymorphonuclear leucocytes. To achieve this goal which cannot be accomplished by using the Haemonetics model 30 alone, we used the Haemonetics model 30 and a density gradient together in a two-step procedure. In the first step we obtained the buffy coat from original bone marrow grafts and in the second we reintroduced these buffy coats into the Haemonetics bowl followed by Percoll, adjusted to 1.079 g/ml, at 5 ml/min in order to recover the light density mononuclear cells. After this second step, the mean volume of the marrow and the RBC and nucleated cell contaminations were reduced to 9%, 0.96% and 16% of their original values the unseparated bone marrow, respectively. This was far better than the values obtained after the first step (volume: 19%; RBC: 10%; nucleated cells: 54%). The CFU-GM recoveries after the first and second steps were 71% and 70% of the original samples, respectively. The entire procedure lasted between 75 and 150 min. At this time, 17 of the 24 patients whose bone marrow was separated using Percoll gradient in the Haemonetics bowl have been grafted. Thirteen of these 17 patients had an evaluable haematological recovery which was complete and rapid for all but one patient with acute myeloid leukaemia. These results demonstrate that the introduction of a density gradient into the Haemonetics model 30 bowl is possible and effective. The reduction in total volume and cell number permits ex vivo purging, without decreasing the grafting capability.

Bone Marrow↗
PubMed1988

Identification of a light density murine megakaryocyte progenitor (LD-CFU-M).

Murine bone marrow cells were separated on discontinuous Percoll gradients and assayed for their ability to give rise to megakaryocyte colonies. Ninety-one percent of the megakaryocyte progenitors (CFU-M) sedimented at densities between 1.070 and 1.080 g/mL. Six percent of CFU-M were found at densities between 1.060 and 1.070 g/mL, 2% between 1.050 and 1.060 g/mL, whereas less than 1% had a density either lower than 1.050 g/mL or higher than 1.080 g/mL. The number of doublings and endomitoses achieved by progenitors of density classes higher than 1.050 g/mL were similar. However, colonies derived from CFU-M of densities less than 1.050 g/mL (LD-CFU-M) had a higher probability of polyploidization and a lower probability of cell division in vitro. The inverse correlation found between the number of cells per colony and their DNA content was invariate regardless of the density class of the progenitors. The heterogeneity of the ploidy of cells within colonies increased continuously with increasing cell numbers per colony. The study if a short-period exposure of LD-CFU-M to acute thrombocytopenia could modify the ploidy of their progeny, mice were given rabbit antimouse platelet serum while control animals received normal rabbit serum. Twenty-four hours after injection, marrow was cultured. After a five-day culture period, no change in the number of colonies, doublings, ploidy, and heterogeneity of ploidy were observed between control and thrombocytopenic animals. The data suggests that LD-CFU-M are a distinct category of CFU-M, perhaps more mature than the common CFU-M.

Acute Disease↗
PubMed1987

Late intensification chemotherapy with autologous bone marrow transplantation in selected small-cell carcinoma of the lung: a randomized study.

A multicentric randomized prospective trial was conducted to test whether late intensification chemotherapy would increase the remission rate, the relapse-free survival, and the survival of small-cell lung cancer patients responding to induction chemotherapy. Autologous bone marrow transplantation was used as support to reduce the duration of the aplasia induced by very high-dose chemotherapy. As induction chemotherapy, 101 patients received, during a period of 5 months, a total dosage of 120 mg/m2 methotrexate, 4.5 mg/m2 vincristine, 1,800 mg/m2 cyclophosphamide, 180 mg/m2 doxorubicin, 160 mg/m2 cisplatin, 750 mg/m2 VP-16-213, and 30 Gy prophylactic cranial irradiation. Forty-five patients, selected for their sensitivity to this induction treatment, were randomized to a last cycle of chemotherapy that combined cyclophosphamide, BCNU, and VP-16-213 either at a conventional dosage of 750 mg/m2 intravenously (IV), 60 mg/m2 IV, and 600 mg/m2 orally or alternatively at a very high dosage of 6 g/m2 IV, 300 mg/m2 IV, and 500 mg/m2 IV, respectively. In the late intensification group, the complete remission rate increased from 39% before randomization to 79% after high-dose chemotherapy. Median relapse-free survivals after randomization for intensified and control chemotherapy groups were 28 and 10 weeks, respectively (P = .002). Median overall survival after induction therapy was 68 weeks for the intensified group compared with 55 weeks for the conventional therapy group (P = .13). Four patients died during intensification. Patients in both groups relapsed at the primary site. It can thus be concluded that late intensification chemotherapy for sensitive small-cell lung cancer increases the complete remission rate and resulted in a statistically significant increase in the relapse-free survival. However, since relapse occurred at the primary site and toxicity was high, overall survival was not significantly improved.

Adult↗
PubMed1986

Cytogenetic investigations in childhood chronic myelocytic leukemia.

Cytogenetic studies were performed on 25 chronic myelogenous leukemia patients aged between 6 mo and 19 yr. Of these, 14 presented with the adult form and 11 with the juvenile form of the disease. In patients with the adult type, 12 of 14 had a Ph chromosome and additional anomalies appearing during blastic transformation. In patients with the juvenile form, 6 of 11 had a monosomy 7 and a short survival time (median 10 mo). Salient features of these patients, as well as a survey of the pertinent literature on the subject, are presented in this paper.

Adolescent↗
PubMed1986

A phase I study of vinblastine tryptophan ester.

Vinblastine tryptophan ester (VTrpE) is a new vinca alkaloid derivative that achieves antitumor activity in a large variety of animal models. In this phase I study the drug was given as an i.v. injection over 5 min, once a week or once every 2 weeks. Twenty patients with advanced cancer were entered in this trial. The doses ranged from 2.5 mg/m2 to 35 mg/m2. Myelosuppression is the dose-limiting toxicity, with the risk of leukopenia being more serious than that of thrombocytopenia, but the myelosuppression is always reversible. Neurotoxicity, well documented when other vinca alkaloid derivatives are used, is insignificant. Two cases of disease stabilization have been observed in patients with non-small cell lung cancer. For VTrpE, a dose schedule of 30 mg/m2 per week may be recommended for phase II studies in non-small cell lung cancer.

Adult↗