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Biomedical subjects

K H Robèrt

Publications and source records attributed to K H Robèrt.

At least 19 recordsLinked to original sources
PubMed1994

Low-dose ara-C in myelodysplastic syndromes (MDS) and acute leukemia following MDS: proposal for a predictive model.

Patients with myelodysplastic syndromes (MDS) comprise an extremely heterogeneous group. There is a need for decision models both for predicting the natural course of the disease and the outcomes of different treatment alternatives. In 102 consecutive patients with MDS or acute myelogenous leukemia (AML) following MDS, pre-treatment variables were studied in relation to the response to treatment with low-dose ara-C. Thirty patients (29%) responded with either a complete remission or a significant rise in the hemoglobin level. For the remaining 71%, the treatment was ineffective and in some cases hazardous. The factors associated with a poor response to treatment could be divided into two groups: one included low platelet counts and the presence of chromosomal aberrations, both signs of progressive MDS with a short survival, and the other comprised morphological findings, indicating ineffective hemopoiesis. Patients with platelet counts > 150 x 10(9)/l had a response rate of 55%, compared to 24% in patients with subnormal platelet counts. Logistic regression identified low bone marrow cellularity, absence of ring sideroblasts and < 2 chromosomal aberrations as predictors of a favourable response in patients with platelet counts < 150 x 10(9)/l. These factors and the platelet count were combined in a predictive model which divided patients into three groups with different probabilities of response: one favourable (38% of the patients), with a response rate of > 50%; a second, intermediate group (33% of the patients), with a response rate of 24%; and a third, unfavourable group (29% of the patients) with only 3% responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1992

In vitro suspension culture reactions to 1,25 dihydroxyvitamin D3 in relation to bone marrow morphology and prognosis in patients with myelodysplastic syndromes.

Thirty-four patients with MDS or AML following MDS were studied with regard to survival, peripheral blood values and bone marrow morphology. The effects of 1,25 dihydroxyvitamin D3 (D3) on differentiation (NBT positivity) and proliferation (3H-thymidine incorporation) were studied in suspension cultures of bone marrow cells. Twelve bone marrow donors served as controls. Normal cells showed spontaneous differentiation in vitro, but only 2/12 were induced to differentiation by D3. Myelodysplastic cells did not differentiate spontaneously, but cells from 18/34 patients differentiated after incubation with D3. Normal cells showed increased proliferation, myelodysplastic cells showed a heterogeneous response and leukemic cells reacted with decreased proliferation after D3 incubation. Poor survival was associated with low platelet counts, high percentage of bone marrow blasts (BM blast %), low spontaneous in vitro proliferation and absence of hypogranulation of myeloid cells. Platelet counts and hypogranulation retained their predictive value in a multi-variate analysis. Progression to AML was predicted by a high BM blast % and low scores for erythroid and total dysplasia. In conclusion, the pattern of in vitro proliferation showed prognostic value while the pattern of vitamin D3-induced differentiation failed to correlate to other parameters. An estimation of bone marrow dysplasia can be used to predict the development of AML. Our results add to the information about the biology of MDS and may be important for the evaluation of therapeutic trials.

Acute Disease↗
PubMed1992

A predictive model for the clinical response to low dose ara-C: a study of 102 patients with myelodysplastic syndromes or acute leukaemia.

The response to treatment with low-dose ara-C was studied in 102 consecutive patients; 79 with myelodysplastic syndrome (MDS) and 23 with acute myelogenous leukaemia (AML) following MDS. The aim was to find variables that could predict the response to treatment. All patients had clinical symptoms related to cytopenia. Peripheral blood values, bone marrow morphology histology and chromosomes were analysed before the start of treatment. The median survival of the patients was 9 months and a poor survival was predicted by advanced age, low platelet counts, the presence of pseudo-Pelger morphology and > or = 2 chromosomal aberrations. Thirty patients (29%) responded with either a complete remission or a significant increase in haemoglobin level. For the remaining 71%, the treatment was ineffective and in some cases hazardous. The factors associated with a poor response to treatment could be divided into two groups: one included low platelet counts and the presence of chromosomal aberrations, both signs of progressive MDS with a short survival, and the other comprised morphological findings, indicating ineffective haemopoiesis. Patients with platelet counts > 150 x 10(9)/l had a response rate of 55% compared to 23.5% in patients with subnormal platelet counts. Logistic regression identified low bone marrow cellularity, absence of ring sideroblasts and < 2 chromosomal aberrations as predictors of a favourable response in patients with platelet counts < 150 x 10(9)/l. These factors and the platelet count were combined in a predictive model which can divide patients into three groups with different probabilities of response: a favourable group, 38.6% of the patients, with a response rate of > 50%, an intermediate group, 32.7% of the patients, with a response rate of 24%, and an unfavourable group, 28.7% of the patients, with only 3% responses. While low-dose ara-C is an effective treatment for some patients, it is ineffective and hazardous for others. We present a model that can facilitate therapeutic decision making in two-thirds of patients with MDS and MDS-AML by identifying patients who should not be treated with low-dose ara-C as well as patients with a relatively high probability of response.

Aged↗
PubMed1991

From the Big Bang to sustainable societies.

A series of events in the history of cosmos has created the prerequisites for life on Earth. With respect to matter, the earth is a closed system. However, it receives light from the sun and emits infrared radiation into space. The difference in thermodynamic potential between these two flows has provided the physical conditions for self-organization. The transformation of lifeless matter into modern life forms, with their high degree of order and complexity, has occurred in the context of the earth's natural cycles, including the water cycle and the biochemical cycles between plants and animals. Primary production units, the cells of green plants, can use the thermodynamic potential of the energy balance in a very direct way, i.e. in photosynthesis. Plant cells are unique in their ability to synthesize more structure than is broken down elsewhere in the biosphere. The perpetuation of this process requires the recycling of wastes. However, modern industrial societies are obsessed with the supply side, ignoring the principle of matter's conservation and neglecting to plan for the entire material flow. As a result there has been an accumulation of both visible and invisible garbage (pollution), which disturbs the biosphere and reduces stocks of natural resources. Furthermore, due to complexity and delay mechanisms, we usually cannot predict time parameters for the resulting socio-economic consequences or the development of disease. To continue along this path of folly is not compatible with the maintenance of wealth, nor with the health of humans or the biosphere. Rather than address the millions of environmental problems one at a time, we need to approach them at the systemic level. It is essential to convert to human life-styles and forms of societal organization that are based on cyclic processes compatible with the earth's natural cycles. The challenge to the developed countries is not only to decrease their own emissions of pollutants but to develop the cyclic technology and life styles needed by the entire human community.

Animals↗
PubMed1990

Treatment of myelodysplastic syndromes with retinoic acid and 1 alpha-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study. The Scandinavian Myelodysplasia Group (SMG).

63 evaluable patients with myelodysplastic syndromes (MDS) and 15 with acute myelogenous leukemia (AML) were randomized between low-dose ara-C (arm A) and low dose ara-C in combination with 13-cis-retinoic acid (13-CRA) and 1 alpha-hydroxy-vitamin D3 (1 alpha D3) (arm B). 69 patients were evaluable and 18 (26.1%) responded to therapy. The addition of 13-CRA and 1 alpha D3 had no positive influence on survival of the patients, remission rates or duration of remissions. 12/27 patients in arm A and 6/29 patients in arm B progressed from MDS to AML during the course of the study (p = 0.0527). Arm B gave significantly more side-effects than arm A (p = 0.005). Therapeutic effects of 13-CRA and 1 alpha D3 on MDS is not supported by this study. However, an inhibiting effect on AML development in some MDS subgroups cannot be excluded.

Aged↗
PubMed1989

Alpha-interferon receptors in malignant B-cells from patients with chronic lymphocytic leukemia: relation to induction of 2'-5'-oligoadenylate synthetase and blast transformation.

alpha-Interferon (IFN-alpha) induces blast transformation of malignant B-cells from approximately 65% of chronic lymphocytic leukemia patients. We have shown previously that induction of blast transformation correlates with induction of 2'-5'-oligoadenylate synthetase. In this paper we address the question of whether low responsiveness to IFN-alpha is associated with a reduced expression of the IFN receptor. IFN-alpha receptor expression was studied by the binding of radioiodinated IFN-alpha to peripheral blood malignant B-cells from 20 chronic lymphocytic leukemia patients and to blood cells from 5 healthy donors. Chronic lymphocytic leukemia cells from all 20 patients displayed high affinity IFN-alpha receptors [mean Kd, 62 +/- 9 (SE) pM] ranging between 110 and 850 binding sites/cell [mean, 416 +/- 51]. Nonmalignant mononuclear blood cells showed similar binding data (411 +/- 105 binding sites/cell; Kd 66 +/- 20 pM). Receptor expression did not correlate with the degree of blast transformation or with induction of 2'-5'-oligoadenylate synthetase. We conclude that the deficiency of IFN sensitivity is localized somewhere between signal transduction from the receptor and induction of 2'-5'-oligoadenylate synthetase.

2',5'-Oligoadenylate Synthetase↗
PubMed1989

Effects of retinoic acid, 1,25-dihydroxyvitamin D3, cytosine arabinoside and alpha-interferon on bone marrow cells from patients with myelodysplastic syndromes.

Bone marrow cells from 15 patients with myelodysplastic syndromes and 2 with acute myeloid leukemia were incubated in vitro with all-trans-retinoic acid (RA), 1,25-dihydroxy vitamin D3 (D3), cytosine arabinoside (ara-C) and alpha-interferon (IFN). 3H-thymidine incorporation (3H-TdR), differentiation and clonal growth were studied. D3 was found to be the most effective inducer of differentiation and differentiation was correlated with a decreased 3H-TdR. Differentiation with one of the inducers was significantly correlated to differentiation with any of the other inducers. Patterns of differentiation and spontaneous and D3-induced 3H-TdR were used to divide the patients into 3 different groups. In the first group, 5 patients with extremely low spontaneous 3H-TdR and differentiation in combination with a slightly increased 3H-TdR after induction differed from all other patients by a higher percentage of bone marrow blast and a more pronounced pancytopenia. The two other groups had a high spontaneous 3H-TdR but differed with respect to the D3-induced differentiation which was absent in one group (n = 6) and present in the other (n = 5). The two groups showed no difference in the clinical features.

Bone Marrow↗
PubMed1989

Management of non-Hodgkin lymphoma in adults in Scandinavia, United Kingdom, and The Netherlands. Report from the European School of Oncology intercity meeting at Huddinge Hospital, 3rd June, 1988.

Current treatment strategies in northern Europe of non-Hodgkin lymphoma are presented. High-grade malignant lymphomas have been treated with doxorubicin-containing polychemotherapy in various modes. The advantage of six-drug regimens over CHOP-like therapy is as yet not proven. Patients with the ability to tolerate the calculated dose have good prognosis. High-dose therapy and bone marrow transplantation should be considered in poor-risk patients with lymphoblastic lymphomas in first remission, patients with all high-grade histologies in partial remission after first-line therapy and patients with relapse that are still responsive to therapy. Preliminary results from autologous bone marrow transplantation in follicular lymphoma are also encouraging. Chlorambucil induces multiple remissions in follicular lymphoma, with a median duration of the 1st, 2nd and 3rd remission being the same. The watch and wait strategy seems justified initially in most asymptomatic generalized low-grade malignant lymphomas. Systemic therapy is required in aggressive stage II-IV lymphomas. A meticulous investigation is needed for stage I patients before giving local treatment only. Immune phenotyping is of great value for diagnosis and staging. Liver, but not bone marrow involvement seems to be an adverse prognostic factor. Follicular lymphoma is an example of a dynamic tumour with gradual cellular changes associated with new and more malignant clinical signs.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Induction of proliferation and blast transformation by interferon in human malignant and non-malignant lymph node B cells.

The influence of interferon (IFN) on cellular proliferation, blast transformation, and differentiation was studied in lymph node cells from 17 patients with B-cell lymphomas, one patient with T-cell lymphoma, and eight patients with enlarged, non-malignant lymph nodes. The effects of IFN on lymph node cells were compared with effects on mononuclear blood cells from chronic lymphocytic leukemia (CLL) patients and healthy donors. Natural IFN-alpha (nIFN-alpha) induced a proliferative response in cells from seven of 17 of the B-cell lymphomas, in two of eight of the non-malignant lymph nodes, and in lymphoid blood cells from two of 32 CLL patients. With few exceptions, the proliferating cells were B cells and the data suggest that IFN acts directly on the B cells. Proliferation was not induced with IFN in cells from the T-cell lymphoma or in mononuclear blood cells from 13 healthy donors. nIFN-alpha induced blast transformation in cells from ten of 14 of the B-cell lymphomas and in four of seven of the non-malignant lymph nodes. Also beta- and gamma-IFN were shown to induce proliferation and blast transformation in lymph node cells from some patients. No major effect on the expression of various differentiation markers could be observed following culture in the presence of nIFN-alpha. We conclude that IFNs can induce proliferation and blast transformation in malignant and non-malignant B cells from lymph nodes.

Adult↗
PubMed1988

Therapeutic effects of low-dose cytosine arabinoside, alpha-interferon, 1 alpha-hydroxyvitamin D3 and retinoic acid in acute leukemia and myelodysplastic syndromes.

62 evaluable patients with myelodysplastic syndromes (MDS) or acute leukemia were treated with different combinations of low dose ara-C, alpha-interferon (IFN), 1 alpha-hydroxyvitamin D3 (vit D3) and retinoic acid. The aim was to study the efficacy and toxicity of each combination. The overall rate was 44%. Of these, 50% responded favorably to the combination of IFN, vit D3 and retinoic acid (IDR), which was comparable to the response rate of 43% for low-dose ara-C. The results of the IDR treatment may be explained by additive or synergistic effects between the separate drugs in the combination. Ara-C and IDR treatment was generally well-tolerated but interferon gave more side effects than any other drug used in the study. Evaluation of the full combination of ara-C, IFN, vit D3 and retinoic acid was not possible because of toxicity. Marrow hypoplasia was infrequent (5/27 patients) in cases responding favorably to treatment. Complete remissions were not longer than partial remissions or significant responses.

Actuarial Analysis↗
PubMed1988

Influence of interferon-alpha on the expression of cellular oncogenes in primary chronic lymphocytic leukemia cells.

The influence of interferon-alpha 2 (IFN-alpha 2) on the mRNA levels of cellular proto-oncogenes was studied in malignant cells from patients with chronic lymphocytic leukemia (CLL). These cells can be induced to blast transform, differentiate and, in some cases, proliferate upon exposure to IFN. Treatment with IFN-alpha enhanced the levels of c-myc mRNA in malignant cells from the patients, whereas the levels of c-myb mRNA decreased, as measured by slot blot hybridizations. In cells from some patients, an enhanced expression of c-fos and k-ras was observed following exposure to IFN-alpha. No major effect on the expression of c-raf or of enolase was observed in any of the patients following exposure to IFN-alpha, whereas the levels of beta 2-microglobulin mRNA increased. In contrast to the observed effects on oncogene expression in CLL cells, IFN had no major effect on the expression of any of the tested oncogenes in lymphocytes from healthy donors or in B-cells from three neoplastic cell lines (380, FL18, RS). We conclude that IFN-alpha can enhance or repress the expression of several oncogenes in nondividing primary malignant cells from patients with leukemia. We also show that the response of malignant cells from patients to IFN-alpha is different than that seen with neoplastic cell lines which represent a similar stage of B-cell differentiation.

B-Lymphocytes↗
PubMed1987

Role of chromosomal abnormalities in chronic lymphocytic leukemia.

Chromosomal aberrations occur in both B-CLL and T-CLL. The polyclonal B-cell mitogens, in particular Epstein-Barr virus and lipopolysaccharide from E. coli, have been used successfully to reveal chromosomal abnormalities in 40-60% of patients with B-CLL, while T-cell mitogens have shown chromosomal aberrations in T-CLL. The most common clonal chromosomal aberration in B-CLL is an extra chromosome 12, alone or together with other abnormalities. Other common aberrations are 14q+, structural aberrations on 6, 11, 12 and 13. Proto-oncogenes are frequently located close to breakpoints. The proto-oncogene c-K-ras is located on chromosome 12 and an abnormal transcript has recently been implicated in a subset of B-CLL-patients. An extra chromosome 12 as well as multiple chromosomal abnormalities in B-CLL appear to predict a less favourable prognosis. T-CLL is in most patients characterized by an inv(14), an extra 8q and structural abnormalities in chromosome 7. The genes for the specific T-cell receptor as well as the immunoglobulin heavy chain are located on these chromosomes. Chromosomal aberrations appear to have pathogenetic importance in both B-CLL and T-CLL.

Chromosome Aberrations↗
PubMed1986

Bone marrow mononuclear cell thymidine uptake in chronic B-lymphocytic leukaemia. Relation to prognosis.

The uptake of tritium-labelled thymidine in bone marrow mononuclear cells from 22 untreated patients with Rai stage 0-II chronic B-lymphocytic leukaemia was analysed in 4-d in vitro cultures. The thymidine uptakes showed a great interindividual variability; the counts per min ranged from 1100 to 80 000 (mean 26 360 +/- 21 800 cpm). Bone marrow cells from patients who needed treatment within 1 yr from diagnosis had a lower thymidine uptake than those from patients who were untreated for more than 2 yr (7 820 +/- 7 420 and 34 300 +/- 23 200 cpm, respectively, p less than 0.001). Patients with low uptake cells had poorer prognosis than those with high uptake cells, both regarding survival (5-yr probability: 0.6 and 1.0, respectively; p less than 0.03) and therapy-free survival (5-yr probability: 0.36 and 1.0, respectively; p less than 0.02).

Adult↗