Search PubMed⌕ Search

Biomedical subjects

J Thaler

Publications and source records attributed to J Thaler.

At least 37 records · Page 2Linked to original sources
PubMed1999

Thrombotic microangiopathy with renal failure in two patients undergoing gemcitabine chemotherapy.

Described here are 2 patients who developed thrombotic microangiopathy of the kidneys after receiving high cumulative doses of the new anticancer drug gemcitabine. The first patient, who received gemcitabine for treatment of a carcinoma of the pancreas, required hemodialysis for 6 months. In the second case, a woman suffering from a cholangiocellular carcinoma, end-stage renal disease was irreversible. Clinical awareness, timely detection and discontinuation of gemcitabine are mandatory to prevent this rare but disastrous complication of gemcitabine therapy.

Adenocarcinoma↗
PubMed1999

Cladribine treatment of a patient with hairy cell leukemia and concomitant multiple sclerosis.

This is the first report on a patient suffering from both multiple sclerosis (MS) and hairy cell leukemia. The patient was first treated with interferon-alpha. Due to disease progression two courses of cladribine were given resulting in an improvement of the clinical course of both diseases. Interestingly, it was possible to arrest and even ameliorate the progression of MS by administering as little as 30% of the dosage recently recommended for the treatment of this disease.

Antineoplastic Agents↗
PubMed1999

Monitoring of remission status by fluorescence in situ hybridisation in chronic myeloid leukaemia patients treated with interferon-alpha.

Interferon-alpha (IFN-alpha) can be considered as treatment of choice for patients with chronic myeloid leukaemia (CML) in chronic phase. With this treatment major cytogenetic responses can be achieved in 30% to 50% of patients. Regular monitoring of cytogenetic response is essential for the therapeutic management of these patients. As conventional cytogenetics is not always successful, especially under IFN-alpha treatment, molecular cytogenetic methods have been established for the examination of interphase nuclei for the presence of the BCR-ABL fusion gene, the molecular counterpart of the Philadelphia chromosome. To demonstrate the value of these new methods we have analysed interphase nuclei from sequentially cultured bone marrow cells from 14 CML patients who were treated with IFN-alpha and whose bone marrow was investigated regularly during therapy. Dual-colour FISH with a breakpoint spanning BCR-YAC and a flanking cosmid from the ABL region was applied. When compared with conventional cytogenetics the results achieved by FISH were favourable. The most evident advantage of FISH analysis is that in case of failure of conventional cytogenetics a reliable determination of the remission status can be done. Together with other recent studies our results illustrate the advantages and limitations of the interphase FISH method for monitoring CML patients.

Adult↗
PubMed1998

Telomere length and telomerase activity predict survival in patients with B cell chronic lymphocytic leukemia.

The telomere-telomerase hypothesis states that the vast majority of human tumors have a prolonged replicative life span throughout expressing telomerase, which compensates the cell division-associated loss of telomere DNA. The use of telomere length and telomerase expression as new biological markers in cancer patients requires their correlation with disease prognosis. We, therefore, correlated the mean telomere length based on a telomere restriction fragment assay and the activity of telomerase measured with a telomeric repeat amplification protocol with clinical data and overall survival in 58 patients with B cell chronic lymphocytic leukemia (B-CLL). Telomere length showed a highly inverse correlation to telomerase activity. Patients with telomeres below 6.0 kb were associated with high telomerase activity, whereas patients with a telomere length >6.0 kb generally showed low enzyme activity (P <0.001). Patients in Binet A exhibited significantly longer telomeres and had less telomerase activity than did patients in Binet B or Binet C, where significantly shorter telomeres and higher telomerase activity were observed (P=0.031). Short telomere length and high telomerase activity were significantly associated with a shorter median survival (P=0.02 and P <0.001), and telomerase activity was the most significant prognostic factor for overall survival in B-CLL (P <0.001). Our data provide evidence that telomere length, as well telomerase activity, exerts a strong impact on the survival of B-CLL patients and that telomerase activity can be used as a new prognostic marker in this disease.

Aged↗
PubMed1998

Fluorescence in situ hybridization (FISH) on peripheral blood smears for monitoring Philadelphia chromosome-positive chronic myeloid leukemia (CML) during interferon treatment: a new strategy for remission assessment.

Interferon-alpha (IFN-alpha) alone or in combination with cytostatic drugs can induce major and durable cytogenetic responses in about 20 to 25% of chronic myeloid leukemia (CML) patients. Since these patients have a significant survival benefit, more frequent follow-up investigations have become clinically important but require bone marrow (BM) aspirates. The aim of our study was to evaluate interphase fluorescence in situ hybridization (IPF) on peripheral blood (PB) smears as a rapid and reliable method to quantify Ph-positive myeloid cells. IPF analysis was performed on 49 PB samples from 36 patients in the chronic phase of CML and at different stages of cytogenetic remission. IPF results of 30 PB samples were compared with those from BM aspirates simultaneously obtained from the same patients to evaluate the correlation of Ph-positive cells. Further, the hypermetaphase FISH (HMF) technique was performed on cultured BM preparations of 31 patients for comparison with IPF results on PB. An excellent correlation was observed between the IPF results obtained on PB and BM samples (r = 0.98, y = x - 0.6, p < 0.0001). The mean difference between HMF from BM, on the one hand, and IPF from PB, on the other hand, was 3.2% (SD = +/- 8.4%). Seventy percent of samples were identically classified in one of the four subgroups of cytogenetic response. Thirty percent were classified in neighbouring response groups. We conclude that FISH performed on PB is a rapid and reliable method for assessing the cytogenetic response of CML patients on IFN-alpha based therapies, allowing more frequent and less invasive follow-up investigations although it is not able entirely to replace routine analysis of BM.

Adult↗
PubMed1998

Idarubicin and intermediate-dose cytarabine for myeloid blast crisis of chronic myelogenous leukemia--results of a phase-II trial.

Sixteen patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in myeloid blast crisis were treated with cytarabine (AraC) 600 mg/m2 two times daily for 5 days and idarubicin 12 mg/m2 for 3 days. Patients achieving a second chronic phase received interferon (IFN) alpha 2b 5 mio units/day daily and AraC 20 mg/day subcutaneously 14 days every month. Study end points were remission rate and survival. Four patients (25%) entered a second chronic phase and had a median survival of 31.1 weeks (range 16.1-111 weeks). Nine patients (56%) experienced blast crisis again and had a median survival of 12.9 weeks (range 5.1-59.3 weeks). Three patients (18.8%) died of septic complications during marrow aplasia. The median overall survival was 16.1 weeks (range 2.6-111 weeks) with no significant difference between responders and nonresponding patients. We conclude that AraC/idarubicin is as effective as other intensive regimens in inducing second chronic phase in patients with myeloid blast crisis of CML. Remission duration and survival are comparable to previous results. Further studies to improve survival are required.

Adult↗
PubMed1998

Interferon-alpha for the treatment of elderly patients with chronic myeloid leukaemia.

The present retrospective analysis is based on data of 213 patients with chronic myeloid leukaemia (CML). They were treated with interferon (IFN)alpha-2C (Berofor) at daily doses of 3.5 MU subcutaneously (s.c.), alone or in combination with low-dose ara-C or hydroxyurea, according to four consecutive studies of the Austrian CML Study Group. Comparisons were made between 41 patients aged > or = 60 years and 172 younger patients. The elderly patients (median: 64 years; range: 60-73) showed similar pretreatment characteristics compared with the younger group, but included a higher percentage of Sokal Stage three (51 vs 20%). Median observation periods were similar (38 vs 39 months), whereas the duration of IFNalpha treatment was shorter in the elderly group (median 57 vs 42 weeks). The rate of overall haematological responses (73 vs 78%) and complete haematological response (44 vs 54%), was similar in both cohorts. Differences seen in partial (5 vs 12%) and complete cytogenetic response (10 vs 13%), were not statistically significant, but a tendency in favour of the younger cohort had to be noted. Summing up, in elderly patients acceptable rates of haematological and cytogentic response can be expected after treatment with IFNalpha alone or in combination with LD ara-C or HU.

Adolescent↗
PubMed1997

[Acceptance of an Ethics Committee (International Review Board)].

The work input of an institutional review board, the satisfaction or dissatisfaction of project applicants with its decisions, as well as the amount of time needed for preparatory and follow-up work for projects submitted to the board were surveyed in a questionnaire. An analysis of the status quo provided proposals for improvement, with the aim of increasing the satisfaction of all parties involved. Questionnaires were returned by 41.4% (101/244) of the specialist doctors surveyed. Of these, 42 were doctors who had submitted projects for review and whose evaluation was used for the study. The proportion of trained "clinical review doctors" was 14.3%. Analysis of work input showed that 13.5 +/- 15.2 hours were invested before submitting a project and 6.3 +/- 9.3 hours in the follow-up. Although the board's work was given a satisfactory grading with a score of 2.8 +/- 1.0, the surveyed satisfaction/importance profile showed marked deficits in many areas, primarily in organization and communication, as well as in the examination and evaluation of projects. The suggestions for improvement above all requested the introduction of a review system employing specialists from outside the institution or from other disciplines, standardization of project submission, optimization of organization and improvement in communication. In summary, the institutional review board plays an important role in clinical research. The acceptance of a review board's work, however, can only be improved when the suggestions for improvement are realized step by step. The results of this evaluation and the proposed solutions can also help other boards improve their work. At any rate, it would be desirable to take a new look in several years' time at how the proposals worked out in this study have been implemented.

Austria↗
PubMed1997

Modulation of transferrin receptor expression by dexrazoxane (ICRF-187) via activation of iron regulatory protein.

Dexrazoxane (ICRF-187) has recently been demonstrated to reduce cardiac toxicity induced by chemotherapy with anthracyclines, although the reason for this phenomenon has remained obscure thus far. In order to investigate whether ICRF-187 might exert its effects by modulating iron metabolism, we studied the drug's potential to influence the maintenance of iron homeostasis in two human cell lines. We demonstrate that ICRF-187 enhanced the binding affinity of iron regulatory protein (IRP), the central regulatory factor for posttranscriptional iron regulation, to RNA stem loop structures, called iron responsive elements (IRE), in THP-1 myelomonocytic as well as K562 erythroleukemic cells. Increased IRE/IRP interaction was paralleled by an elevation of transferrin receptor (trf-rec) mRNA levels which, according to the well-established mechanism of posttranscriptional iron regulation, was likely due to stabilisation of trf-rec mRNA by IRP. Subsequently, ICRF-187 treatment of cells increased trf-rec surface expression and enhanced cellular iron uptake. All these events, i.e. IRP activation, stabilisation of trf-rec mRNA and increased surface expression of the protein in response to ICRF-187, follow a dose-response relationship. Increased cellular uptake and sequestration of iron in response to ICRF-187 may contribute to the protective activity of ICRF-187 by reducing the iron-anthracycline complex and iron-catalysed generation of hydroxyl radicals via the Haber-Weiss reaction.

Antineoplastic Agents↗
PubMed1997

Interferon-alpha-2C and LD ara-C for the treatment of patients with CML: results of the Austrian multi-center phase II study.

Small pilot studies of patients with CML have reported on encouraging response rates after treatment with interferon-alpha (IFNalpha) in combination with low-dose cytosine arabinoside (LD ara-C). We therefore initiated a multi-center phase II trial in order to investigate the efficacy and tolerability of this combination in newly diagnosed patients with Ph-positive chronic myelogenous leukemia (CML). Eighty-four patients were treated with IFN-alpha-2c at daily subcutaneous doses of 3.5 MU and LD ara-C added subcutaneously for 10 days every month at a dose of 10 mg/m2, following an initial reduction of WBC to less than 20 x 10(9)/l with hydroxyurea (HU). Within a median observation period of 28 (5-59) months the patients received a median of 7 (1-35) IFNalpha and LD ara-C cycles. Treatment was stopped due to side effects in 16 cases (19%) and to primary or secondary treatment failure in 38 cases (45%). In 45 patients (54%) complete hematological response (CHR) was achieved; in 39 patients (46%) cytogenetic responses including 15 (18%) complete cytogenetic responses (CHR) were observed. Median duration of cytogenetic responses was 15 months. Relapses were seen in 8/15 patients (53%) with complete cytogenetic remission (CCR), in 3/6 patients (50%) with partial cytogenetic response and in 9/18 patients (50%) with minor cytogenetic response. In conclusion, the combination of IFNalpha and LD ara-C resulted in encouraging rates of hematological and cytogenetic responses in patients with CML with low to moderate toxicity.

Adolescent↗
PubMed1997

Quality of life in patients with acute myelogenous leukemia in prolonged first complete remission after bone marrow transplantation (allogeneic or autologous) or chemotherapy: a cross-sectional study of the EORTC-GIMEMA AML 8A trial.

A cross-sectional study of quality of life (QOL) was performed in 98 patients in continued first complete remission (CR) for 1-7.4 years, after inclusion in the AML 8A trial which prospectively compared allogeneic bone marrow transplantation (AlloBMT), autologous BMT (ABMT) and intensive consolidation chemotherapy. Several significant differences between the three treatment groups were observed, on the basis of patient self-reports, with regard to somatic symptoms (mouth sores, cough, hair loss, headache), repeated acute medical problems, physical functioning, role functioning, leisure activities and, above all, sexual functioning. There were also significant differences for overall physical condition, and overall quality of life. For all these parameters, the ranking was uniformly AlloBMT lower than ABMT lower than chemotherapy. These differences remain significant after adjustment for time interval between CR and QOL evaluation, sex or age. These results, confirming a higher risk of permanent impairment of QOL after BMT, may have an impact on medical decisions and warrant further studies.

Adult↗
PubMed1997

Multidrug resistance in acute leukemia: a comparison of different diagnostic methods.

Accurate measurement of P-glycoprotein (P-170) expression in clinical samples still remains a controversial issue. In this study tumor cell P-170 expression was assessed in 29 patients suffering from acute leukemia (17 acute myeloid leukemia (AML) and 12 acute lymphoblastic leukemia (ALL)) using three different techniques: flow cytometry measuring rhodamine 123 (Rh123) efflux (functional level), immunocytochemistry (protein level) and RT-PCR (mRNA level). Rh123 efflux was detectable in 10/29 (34%) of all cases, in 9/17 (53%) of AML and in 1/12 (8%) of ALL samples. In AML patients a significant association of CD34 expression and P-170 activity was observed (P < 0.02). All AML patients with the FAB subtype M5 were Rh123 negative (P < 0.007). Cytospin preparations were analyzed for staining with monoclonal antibodies JSB1 and MM4.17. Eight of 16 (50%) AML and 0/9 (0%) ALL cases expressed the multidrug resistance (MDR) protein assessed by JSB1. With MM4.17 87% of AML and 50% of ALL patients were scored positive. Agreement between both antibodies was found in only 13/23 (57%) samples. Extracted RNA from 12 patients was analyzed by RT-PCR to evaluate the expression of MDR1 and multidrug resistance-associated protein (MRP) mRNA. An increased level of MDR1 mRNA was detectable in 4/7 AML and 0/5 ALL cases. MRP expression was found in 3/7 AML and 0/5 ALL patients. Comparison of Rh123 assay and immunocytochemistry revealed a very good correlation when using MoAb JSB1 (P < 0.004) but not with MM4.17 (not significant (NS)). JSB1 also showed a much better association with the PCR results (P < 0.05) than MM4.17 (NS). Finally, we compared the results of the functional Rh123 assay and RT-PCR and observed a high correlation for Rh123/MDR1 (r = 0.819, P < 0.001) but low for Rh123/MRP (r = 0.562, NS). We conclude that measurement of Rh123 efflux and immunocytochemical staining of cytospin preparations with JSB1 allows the accurate monitoring of P-170 expression in acute leukemia. The simplicity of these two MDR assays suggests their use for routine MDR screening.

Acute Disease↗
PubMed1997

T cells and natural killer cells after treatment of hairy cell leukaemia with 2-chlorodeoxyadenosine.

We report that continuous suppression of CD4+ lymphocyte subsets does not necessarily lead to an increased rate of infections more than 6 months after treatment of hairy cell leukemia (HCL) with 2-chlorodeoxyadenosine (cladribine; 2-CdA). In a retrospective analysis of 17 consecutive patients with HCL treated with 2-CdA and followed thereafter for an average of 440 days (ranging from 71 to 1,046 days), all lymphocyte subsets significantly decreased after therapy. However, natural killer (NK) cells increased to 203 cells/microliter during the following 4 months, whereas CD3+ and CD4+ T cell subsets did not reach pretreatment values even more than 1 year after 2-CdA therapy. In our study group, 5 opportunistic infections occurred during the first 2 weeks after treatment with 2-CdA, and no severe infections were registered after this early leukopenic phase. A review of the current literature revealed that at least 56 infections occurred in 158 patients repeatedly treated with 2CdA for low-grade lymphoproliferative diseases other than HCL (= 35%). In patients with HCL, the rapid increase of NK cell counts after 6 months might be responsible for reducing the risk of severe infections after the early leukopenic phase despite CD4+ cell suppression.

Antineoplastic Agents↗
PubMed1997

The safety profile of low-dose cladribine in refractory rheumatoid arthritis. A pilot trial.

Cladribine (2-chlorodeoxyadenosine, 2-CdA) is a newer purine analog with specific toxicity to lymphocytes. As lymphocytes play a major role in rheumatoid arthritis (RA), we assessed the safety profile of low-dose 2-CdA in patients who were refractory to more than three disease-modifying drugs. Five patients were given a subcutaneous dosage of 0.05 mg/kg 2-CdA weekly over a period of 8 weeks. Of the lymphocyte subsets, both T and B cells decreased below the normal range, whereas natural killer cells remained stable. These changes were the only side-effects noted during treatment and 4 weeks afterwards. In one patient a pacemaker was implanted for reasons unlikely to be related to 2-CdA administration. We conclude that even low-dose 2-CdA (0.05 mg/kg) can decrease T and B cell populations in patients with refractory RA, but other side-effects are unlikely. For assessing the possible clinical efficacy of low-dose 2-CdA further studies are warranted.

Aged↗
PubMed1997

Cytokine priming of the granulocyte respiratory burst in myelodysplastic syndromes.

Increased susceptibility to infections in patients with myelodysplastic syndromes (MDS) is thought to be due to neutropenia as well as functional abnormalities of neutrophils. In the present study we examined the effect of two different stimulants (fMLP, PMA) and three cytokines (alphaTNF, G-CSF and GM-CSF), both singly and in combination on granulocyte (RB) in 25 MDS patients compared to seven healthy controls. Single fMLP and PMA-stimulation showed similar results for both groups. Preincubation with cytokines enhanced fMLP-stimulated RB in most MDS patients and controls, but in patients to a significantly lesser extent when compared to the control group (p < or = 0,05). Combinations of alphaTNF + GM-CSF and alphaTNF + G-CSF were highly synergistic in priming fMLP-stimulated burst in both groups. But again, as with the single cytokine priming this effect was markedly reduced in MDS patients compared to controls (p < or = 0,05). A specific priming defect for one of the cytokines or a cytokine combination could not be demonstrated. Serum alphaTNF levels were measured in 18 and neutrophil alkaline phosphatase (NAP) index in 23 patients. Results did not correlate with variations of the RB in MDS patients. We conclude that reduced alphaTNF, GM-CSF and G-CSF priming of granulocyte RB is a frequent finding in MDS and may contribute to the enhanced susceptibility to bacterial infections.

Adult↗
PubMed1996

Different CD44 splicing patterns define prognostic subgroups in multiple myeloma.

CD44 variant isoforms (CD44v) are generated by alternative splicing of the nuclear RNA resulting in the expression of additional protein domains in the extracellular region of the CD44 standard molecule (CD44s). In multiple myeloma (MM), CD44 mediates binding of tumor cells to stroma and regulates interleukin-6 production. To evaluate the role of CD44v isoforms in MM, CD44v expression was analyzed by immunohistochemical staining of 64 bone marrow biopsies from 38 MM patients. Expression of variant isoforms containing the 9v domain was observed in 36% of cases and was associated with an advanced stage (P < .02; n = 61), a progressive disease (P < .001; n = 61), and a shorter overall survival (P < .02; n = 36). In contrast, 3v, 4v, 6v, or 10v isoforms were detected only in a small percentage of the patients. To analyze the exon composition in RNA-transcripts, reverse transcriptase polymerase chain reaction analyses followed by Southern hybridization with exon-specific probes were performed in fluorescence-activated cell sorted myeloma plasma cells. Tumors expressing the 9v domain showed complex, 9v-containing transcripts in combinations with the 3v, 7v, 8v, and 10v exons. Identical transcripts were detected in several myeloma cell lines and in a Ki-1 B-immunoblastic lymphoma. Similar to high-grade non-Hodgkin's lymphoma and gastric and renal cell carcinoma, overexpression of 9v-containing isoforms in MM is related to an unfavorable clinical presentation and represents a new prognostic parameter.

Adult↗