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Biomedical subjects

C Nissen

Publications and source records attributed to C Nissen.

At least 55 records · Page 3Linked to original sources
PubMed1993

Cataract formation after bone marrow transplantation.

OBJECTIVE: To evaluate the incidence, time course, and factors associated with cataract formation in bone marrow transplant recipients. DESIGN: Prospective cohort study. SETTING: University Hospitals, Basel, Switzerland. PATIENTS: 197 patients treated with allogeneic or autologous bone marrow grafts at least 180 days before the start of the study. INTERVENTION: Three regimens for bone marrow transplant were used: 74 patients received single-dose, total-body irradiation (TBI), 90 patients received fractionated TBI, and 33 received chemotherapy alone. RESULTS: Three and one half years after single-dose TBI, 51 of the 74 patients (69%) were alive and cataracts had developed in all of these 51 patients. Cataracts developed in 18 of the 90 (20%) patients treated with fractionated TBI, with an 83% (95% CI, 63% to 100%) risk for lens opacification at 6 years. Cataracts developed in only 1 of the 33 (3%) patients treated with chemotherapy alone. Incidence of cataracts is higher and lens opacification occurs earlier after single-dose TBI than after fractionated TBI (P < 0.01). With Cox regression analysis, the use of irradiation (relative risk, 21.0), the mode of irradiation (relative risk, 7.4), and the use of steroid treatment (relative risk, 2.9) for more than 3 months after bone marrow transplantation increased the risk for cataract formation. In contrast, age, sex, and chronic graft-versus-host disease did not influence the rate of cataract development. The probability of requiring cataract surgery after 6 years was 85% (CI, 75% to 95%) for the patients treated with single-dose TBI and 20% (CI, 0% to 49%) for those prepared with fractionated irradiation. CONCLUSIONS: Patients treated with TBI, regardless of fractionation, are likely to have cataracts within 10 years, and some will need surgical repair. Long-term steroid treatment accelerates cataract formation. Preventive measures, such as lens shielding during TBI, should be considered.

Adolescent↗
PubMed1993

Levels of soluble stem cell factor in serum of patients with aplastic anemia.

Aplastic anemia (AA) is a rare bone marrow (BM) disorder characterized by an unexplained failure of hematopoietic precursors to proliferate. In vitro growth of AA BM cells can be improved by the addition of the hematopoietic growth factor SCF (stem cell factor), which suggests that deficiency of SCF may be one of the underlying causes of the disease. In this study, we measured the concentration of SCF in sera of patients with severe AA. One hundred twenty-eight serum samples from 32 patients, at diagnosis and following therapy, were analyzed. Before treatment, SCF levels varied between 0.33 and 6.1 ng/mL; no correlation between hematopoietic function and SCF serum levels was apparent. Therapy with antilymphocyte globulin (ALG) or bone marrow transplantation (BMT) did not result in a recognizable pattern of changes in SCF levels. However, serum concentration of SCF in many patients with AA was at the low range of control serum levels determined in healthy blood donors. Of 128 AA serum samples tested before and after therapy, 107 were below the mean normal value of 3.3 ng/mL, including 26 samples below the minimum normal value of 1.3 ng/mL, as estimated in 267 controls. We also found that SCF levels in peripheral blood serum correlate well with factor concentrations in the BM plasma. Clinical observations suggest that higher SCF serum levels are often associated with a better clinical status of the patients in terms of survival and transfusion requirements. The data indicate that a deficient production of soluble SCF may contribute to AA in some patients; thus, suggesting a potential therapeutic benefit of SCF in this disorder.

Adolescent↗
PubMed1993

[Polycythemia: primary or secondary? The differential diagnostic value of stem cell cultures].

Cultures of hematopoietic precursor cells can be helpful in differentiating between primary polycythemia (polycythaemia vera, PV) and reactive secondary polycythemia: in PV erythroid precursors form hemoglobinized colonies in the absence of added erythropoietin (epo) (= endogenous erythroid colonies), whereas in normals and in patients with secondary polycythemia, formation of erythroid colonies is dependent on added epo. We have performed cultures of peripheral blood precursors from 132 patients with elevated hemoglobin in the presence/absence of added epo. In 48/132 patients we assumed that PV was the cause of polycythemia. In 80/132 patients no endogenous colonies appeared and the polycythemia was judged secondary. 23 PV patients were examined repeatedly. In 18 of them the first diagnosis was confirmed by subsequent cultures; in 5 cases endogenous colonies, which had been present in the first cultures, were no longer detectable. A questionnaire on the subsequent clinical course was sent to 108 treating physicians. 77 questionnaires were answered correctly and returned. In 86% of these patients, our culture diagnosis of PV was either confirmed or another myeloproliferative disorder had been found as a cause of endogenous colonies. In 14% our diagnosis of PV had been false positive. On the other hand, our diagnosis of secondary polycythemia was confirmed in 85% of the patients; its most frequent cause was cigarette smoking and chronic bronchitis and only rarely was it associated with heart or kidney disease. 5/77 patients had persistently elevated Hb without an evident cause, and in 3/77 the Hb normalized spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)

Colony-Forming Units Assay↗
PubMed1993

Cytokine serum levels during treatment with high-dose recombinant human IL-3 in a patient with severe aplastic anemia.

A 37-year-old woman with severe aplastic anemia (SAA), who had relapsed 6 years after antilymphocyte globulin therapy, was treated with intravenous recombinant human IL-3 (4 micrograms/kg/d) for 21 days. Subsequently, long-term therapy with subcutaneous rhIL-3 at the highest dose level tested so far (16 micrograms/kg/d) was initiated in order to maintain growth-factor response. Therapy was discontinued on day 73 due to progressive thrombocytopenia and increased petechial bleeding. Both treatment schedules resulted in a transient increase in leukocytes (twofold) due to an increase in monocytes, neutrophils, and eosinophils. RhIL-3 had no effect on hemoglobin values or platelet counts and only marginally improved colony formation of bone marrow CFU-GM in response to rhGM-CSF. Side effects of both treatment schedules were mild and did not exceed WHO grade II. Steady-state serum concentrations of IL-3, which are able to stimulate hematopoiesis in vitro (i.e. > 1 ng/ml), were achieved by both low- and high-dose treatment, although high-dose treatment resulted in markedly higher serum levels of IL-3. On measuring cytokine serum levels (neopterin, IL-1 beta, IL-6, sIL-2R, GM-CSF, TNF-alpha, IFN-gamma) we noticed a different cytokine pattern with both treatment modalities, resulting in a moderate induction of TNF-alpha and IFN-gamma during low-dose, intravenous treatment, whereas during subcutaneous, high-dose treatment a profound increase of IL-6, sIL-2R, and, to a lesser extent, neopterin was detected. These results in a single patient with SAA indicate that further studies on IL-3 serum levels and IL-3-induced secondary cytokines in a larger group of patients are needed to optimize growth-factor treatment and to better understand the in vivo biological activity of IL-3.

Adult↗
PubMed1993

Relapse of aplastic anaemia after immunosuppressive treatment: a report from the European Bone Marrow Transplantation Group SAA Working Party.

This study was designed to determine the incidence of relapse and factors predictive for relapse in 719 patients with severe aplastic anaemia (SAA) after immunosuppressive treatment (IS). Patients developing myelodysplasia or acute leukaemia after IS, and patients receiving a transplant, were excluded from this analysis. Response was defined as reaching complete independence from transfusions, relapse was defined as becoming again transfusion dependent. This criteria was validated by similar figures when using other 'relapse criteria' such as drop in neutrophil or platelet counts. Of 358 patients responding to IS. 74 patients relapsed after a mean time of 778 d after treatment. The actuarial incidence of relapse is 35.2% at 14 years after IS. The risk for relapse was higher in patients responding within 120 d from IS (48%) compared to patients responding between 120 and 360 d (40%) and only 20% for slow responders (> 360 d from IS) (P < 0.00001). In multivariate analysis this factor still proved significant (P < 0.0001). The mean time between diagnosis and treatment was significantly longer in patients relapsing compared to patients who did not relapse (260 v 134 d, P = 0.037). Relapse was not predicted by the severity of the disease, age, and sex. In 39 of the 74 relapsing patients a second response could be achieved. Responses after relapse were associated in univariate analysis with early response to previous IS and early occurrence of relapse. The actuarial survival of patients not relapsing is significantly better than survival of patients relapsing (79.8% v 67.1%, P = 0.0024). However, the actuarial survival of 39 relapsing patients who responded again to IS was similar to patients not relapsing (86%) and significantly better than in 35 patients not reaching a second response after relapse (49.3%, P = 0.0015). This study indicates that relapse is a relevant problem in the treatment of aplastic anaemia, and does have an impact on overall survival. Prospective studies of immunosuppressive regimens, looking at responses, should also address this problem in the future.

Adolescent↗
PubMed1993

Gender and response to antilymphocyte globulin (ALG) for severe aplastic anaemia.

We have evaluated the speed of haematological recovery in 103 severe aplastic anaemia (SAA) patients treated with antilymphocyte globulin (ALG) and followed at our institution for 3-15 years. We found that haemopoietic recovery was significantly delayed in six girls under the age of 10 years. This slow recovery in girls might be explained by their relative inability to release haemopoietic growth factors, granulocyte colony stimulating activity and burst promoting activity, compared to all other sex and age groups. This defect is not explained by disease severity at presentation and thus indicates a functional abnormality of monocytes/macrophages and T-lymphocytes in addition to the deficiency of haemopoietic stem cells. In a multivariate analysis, low factor production and low pretreatment reticulocyte counts turned out to be strong predictors of slow haemopoietic recovery. We conclude that young girls have a particular form of SAA characterized by low haemopoietic factor production and delayed recovery after ALG. They are preferential candidates for early bone marrow transplantation or, if they are not eligible, for treatment with recombinant human haemopoietic growth factors.

Adolescent↗
PubMed1993

Increased colony growth in peripheral blood cultures from patients with ALL depends on immunological subtype.

The proliferative capacity of precursor cells in bone marrow and peripheral blood of 19 patients with acute lymphoblastic leukaemia (ALL) at diagnosis was studied and results were compared with the immunophenotype of the leukaemic population. Bone marrow proliferative capacity in these patients was strongly diminished, low or absent, independent of the immunophenotype, compared with control values (p < 0.0002). In contrast, the growth pattern in peripheral blood cultures from the same patients varied widely according to the subtype of ALL: whereas in patients with undifferentiated ALL [TdT+, HLA-DR+, CD19+ or-, CD10-, (n = 4) or CD7+, CD5+, CD1-, CD4- and CD8- (n = 1)] PB had strongly reduced proliferative capacity compared with control (p < 0.05), there was excess growth of normal neutrophil and erythroid colonies in BP cultures from patients with a more mature immunophenotype of either B-[CD10+, (n = 11)] or T [CD1+, CD4+ and/or CD8+, (n = 3)] phenotype. This phenomenon was only seen in patients who had circulating lymphoblasts: If their number was low, growth was so prolific that single colonies could not be identified. In the presence of a high blast count, colony growth was less prolific--probably due to a "dilution" effect--but still higher than normal (p < 0.05). We conclude that, in relatively mature ALL of the B- and the T-cell line, the presence of circulating lymphoblasts is associated with increased PB proliferative capacity.

Adolescent↗
PubMed1993

[The pathophysiology of aplastic anemia].

It is the conventional opinion that acquired aplastic anaemia is a heterogeneous disease including basically different conditions, such as idiopathic or virus induced pancytopenia, toxic-allergic marrow damage or autoimmunity. Here, an alternative concept is proposed, according to which aplastic anaemia is one disease, but multifactorial in all patients, apparent differences being due to the relative prevalence of one or the other pathological component in individual patients. Bone marrow from patients in the severe phase of aplastic anaemia does not grow in culture and is therefore not suitable for experimentation. Alternatively, bone marrow from patients who have resumed some degree of autologous bone marrow function, but still have residual signs of the disease after non-invasive therapy, offers the possibility to study pathological mechanisms in vitro. The majority of experiments presented have been done in such patients, assuming that their status of disease in some way reflects the original, more serious pretreatment condition. Three major pathophysiological components will be discussed, and it will be proposed how these factors act in concert to cause or aggravate aplasia.

Anemia, Aplastic↗
PubMed1993

Colony growth in cultures from bone marrow and peripheral blood after curative treatment for leukemia and severe aplastic anemia.

The recovery of colony-forming cell numbers after curative treatment for leukemia and severe aplastic anemia (SAA) was studied. We examined 191 patients (85 acute myeloid leukemia [AML], 48 acute lymphocytic leukemia [ALL], 32 chronic myeloid leukemia [CML], 17 SAA, and nine myelodysplastic syndrome [MDS]) who were in hematologic remission 6 months to 13 years after either curative chemotherapy (n = 69) or allogeneic bone marrow transplantation (BMT) (n = 122) by culturing their precursor cells from bone marrow (BM) (n = 548) and peripheral blood (PB) (n = 529) in methylcellulose. Thirty-six BM donors and 25 PB donors served as controls. BM colony-forming cell numbers were abnormally low in all patients (p < 0.002) irrespective of underlying disorder and type of treatment (chemotherapy or irradiation). These numbers did not normalize with time--colony-forming cells were still strongly reduced up to 10 years after therapy, whether or not the patient had received an allogeneic bone marrow graft (p < 0.002). We also compared patients who remained in stable hematologic remission with those who later relapsed (6 months to 2 years after treatment). BM colony-forming cell numbers were significantly lower in patients who subsequently relapsed (p = 0.004). In contrast to BM cultures, we found normal colony-forming capacity by PB precursors in all patients. We conclude that (1) after chemotherapy or BMT, colony-forming cell numbers of BM in culture are permanently reduced; (2) this defect is probably due to a dysfunction of the BM environment rather than to a numerical reduction of the precursor cell pool; and (3) very low colony-forming capacity may be related to relapse.

Acute Disease↗
PubMed1992

Morphology in patients with severe aplastic anemia treated with antilymphocyte globulin.

One hundred and seventeen patients with severe aplastic anemia (SAA) were treated at our institution between 1976 and 1990 with antilymphocyte globulin (ALG) therapy. Seventy-nine (68%) are alive and probability of survival at 14 years, according to Kaplan and Meier, is 62% +/- 12%. Twenty-six patients developed a late clonal complication: 11 had a myelodysplastic syndrome (MDS) and 17 had paroxysmal nocturnal hemoglobinuria (PNH); two patients had both. The cumulative risk at 10 years is 42%. The development of MDS/PNH after SAA directly affects survival. The probability of being alive at 14 years is 81% +/- 10% for patients with stable disease and 36% +/- 13% for those with clonal evolution (P = .001). To look for predictive signs, we reevaluated peripheral blood and bone marrow cytomorphology at presentation, during regeneration, and in remission. We examined the peripheral blood values for hemoglobin, reticulocytes, granulocytes, thrombocytes, mean corpuscular volume (MCV), and fetal hemoglobin, as well as bone marrow for cellularity, erythropoiesis, myelopoiesis, and megakaryopoiesis. ALG therapy induces slow and incomplete recovery. Although in "remission," ALG patients have lower hemoglobin values, higher reticulocyte counts, lower granulocyte and platelet values, and a higher MCV and fetal hemoglobin than normal controls. They retain a reduced number of megakaryocytes and a persistence of atypical monocytes in bone marrow morphology as stigmata of their disease. Patients with late clonal complications show distinct morphologic abnormalities: patients with PNH have higher MCVs, higher granulocyte and reticulocyte counts, and more dyserythropoiesis at diagnosis and a lower hemoglobin with an increased proportion of erythroblasts in the bone marrow in "remission." Patients who later developed MDS are not different from the total patient population at diagnosis. After therapy, these patients are characterized by the presence of ring sideroblasts and atypical monocytes during regeneration and by a persistent increase in MCV, a higher fetal hemoglobin, lower granulocyte values, and megakaryocytic dysplasia during "remission." Thus, routine morphologic follow-up examination of blood and bone marrow can discover patients at risk for late hematologic complications after ALG therapy.

Adult↗
PubMed1992

Stem cell factor stimulates the in vitro growth of bone marrow cells from aplastic anemia patients.

Aplastic anemia (AA) is a rare human bone marrow disorder of unknown etiology manifested by a strongly impaired growth of hematopoietic precursors. In this study, we examined the ability of recombinant human stem cell factor (SCF) to stimulate proliferation in vitro of bone marrow cells from 15 AA patients. All patients had been previously treated with antilymphocyte globulin (ALG). SCF, in combination with erythropoietin (Epo), interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF), increased the number of hematopoietic colonies formed in a semisolid medium by AA marrows. Maximal colony numbers reached 30% of the numbers observed with normal bone marrow cells. Proliferation of AA cells cultured in a liquid medium containing SCF together with Epo, IL-3, GM-CSF, and G-CSF approached 70% of the control level, as measured by 3H-thymidine incorporation. The effect of the combination of SCF with the other growth factors was more than 10 times stronger than that of the growth factors alone. The most marked effect of SCF was on the generation of erythroid colonies by precursor cells. The results demonstrate synergism between CSF and other hematopoietic growth factors, resulting in the most efficient stimulation of the in vitro growth of AA bone marrow cells described to date. Use of SCF, either alone or in combination with other factors, may be of potential value in treatment of AA.

Adolescent↗
PubMed1992

Recombinant human granulocyte-macrophage colony-stimulating factor accelerates neutrophil and monocyte recovery after allogeneic T-cell-depleted bone marrow transplantation.

In a prospective randomized study, five European transplant centers compared recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; mammalian glycosylated) with placebo. rhGM-CSF was administered in a dose of 8 micrograms glycoprotein (5.5 micrograms protein)/kg/d, as a continuous intravenous (IV) infusion for 14 days, starting 3 hours after bone marrow infusion. Fifty-seven patients entered and completed the study. Median age of the recipients was 34 years (range, 17 to 51 y). All donors were HLA-identical, MLC-nonreactive siblings. Marrow grafts were depleted of T lymphocytes either by counterflow centrifugation (n = 42) or by immunological methods (n = 15). Twenty-nine patients received rhGM-CSF and 28 patients placebo. The leukocyte count and the absolute neutrophil count were significantly higher in the rhGM-CSF-treated group from day +9 to day +14 after bone marrow transplantation (BMT). This was also true for the monocyte count from day +12 to day +21. Early neutrophil (greater than 0.1 and greater than 0.3 x 10(9)/L) and early leukocyte (greater than 0.3 and greater than 0.5 x 10(9)/L) recovery was significantly faster for the patients given GM-CSF. The incidences of graft-versus-host disease (GVHD) and transplant-related mortality were not different in both groups. However, the number of bronchopneumonias was significantly lower in the rhGM-CSF-treated group (P = .03). Long-term follow-up showed a trend to better overall disease-free survival at 2 years and a trend to a lower relapse risk in patients treated with rhGM-CSF. This study shows that rhGM-CSF significantly increases neutrophil and monocyte counts during periods of 6 to 10 days in the second and third week after BMT. This shortened period until myeloid cell recovery after transplantation resulted in a decreased number of pneumonias, without an increase in incidence of GVHD or relapse.

Adolescent↗
PubMed1992

Human serum stimulates the production of G-CSF, IL-1, IL-6 and IL-8 by human peripheral blood leucocytes.

Human serum induces human peripheral blood leucocytes (PBL) to release an activity stimulating neutrophil colony formation (G-CSA) from human bone marrow cells. By titrating individual growth factors and using specific neutralizing antibodies we showed that: human serum contains very low levels of G-CSF which are by themselves insufficient to stimulate myeloid colony formation in primary human bone marrow cultures and cannot account for the serum releaser activity; that although no detectable levels of IL-1, IL-2, IL-3, IL-4, IL-6 or IL-8 are found in the serum, anti IL-1 antibodies partially block the release of G-CSA when added early during PBL incubation; that PBL incubated in the absence of serum for 2 d produce small amounts of IL-1, IL-6, IL-8 and G-CSF and this is increased 6-16 fold in the presence of human serum; and that the neutrophil colony-stimulating activity released by PBL incubated with human serum is G-CSF.

Biological Assay↗
PubMed1992

Suspected distinct activation pathways of human lymphocytes induced by antilymphocyte globulin and anti-CD3 monoclonal antibody result in different secretion of hematopoietic colony-stimulating activities.

We evaluated the activation sequence of peripheral blood lymphocytes from healthy donors using different mitogens, including antilymphocyte globulin (ALG), anti-CD3 monoclonal antibody (OKT3), and phytohemagglutinin (PHA). Blood mononuclear cells stimulated by ALG, OKT3 and PHA incorporated 3H-thymidine in the same way. When enriched T cells were tested in the presence of interleukin-1 alpha (0 to 100 U/ml, incorporation of 3H-thymidine was greater in those cells stimulated by ALG than by PHA. OKT3 did not activate enriched T cells. Thymidine incorporation was reduced to less than 50% of maximum concentrations by the addition of 10(-7) mol/1,25-dihydroxyvitamin D3 (vit D3) in PHA- or OKT3-activated cells. However, the inhibitory effect of vit D3 was not apparent in ALG-activated cells. Production of granulocyte-macrophage colony-stimulating factor and interleukin-3 by lymphocytes upon activation was consistently higher when cells were treated with ALG or PHA than with OKT3. Taken together, the data indicate that there appear to be distinct functional mechanisms between ALG- and OKT3-induced lymphocyte activation that lead to characteristic immunohematologic events.

Antibodies, Monoclonal↗
PubMed1991

[Health status and late complications following allogeneic bone marrow transplantation. A review].

Better results following bone marrow transplantation (BMT) have increased the number of patients in longterm follow-up. Health status and late effects are therefore of increasing interest. We discuss here the incidence and follow-up of late complications after allogenic BMT. Any conditioning regimen including TBI in postpubertal women introduces a postmenopausal status. In contrast, normal function is found after BMT without irradiation. In men, there is usually permanent azoospermia after TBI but not following chemotherapy alone. Thyroid dysfunction after BMT with TBI has been reported in about 40% of patients. In most of them compensated hypothyroidism with elevated TSH is found. BMT with TBI induces growth retardation in children. Decreased growth hormone levels are observed and substitution can induce normal height development. Interstitial pneumonitis (IP) is a major cause of death. It occurs on average three months after BMT but late onset IP's are increasingly reported. Cataracts are common after BMT. The risk of cataracts in patients given single dose TBI attains 80-100% after four years. Under treatment with cyclophosphamide alone, the risk of lens opacification is less than 20%. So far, patients treated with fractionated TBI have not developed more cataracts than those treated with chemotherapy alone. Impaired renal function is common early post-transplant. Risk factors include cyclosporine (CSA) nephrotoxic antibiotics and antifungal drugs. So far, few secondary malignancies have been reported in humans after BMT. However, actual observation time is still too short for final evaluation. Prevention or treatment is instituted for common complications. It is expected that other types of tissue damage will be recognized.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗