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Biomedical subjects

J Thaler

Publications and source records attributed to J Thaler.

At least 19 recordsLinked to original sources
PubMed2000

Treatment of patients with advanced chronic myelogenous leukemia with interferon-alpha-2b and continuous oral cytarabine ocfosfate (YNK01): a pilot study.

The efficacy of continuous oral cytarabine ocfosfate (YNK01) (300 mg/day) in combination with interferon alpha (IFNalpha, 5x10(6) IU/day) was evaluated in patients with advanced chronic myelogenous leukemia, who previously failed to respond to IFNalpha-based therapies. Dose escalations up to 900 mg YNK01 were allowed in patients who failed to respond. In view of our results, four patients developed a complete hematological response after YNK01 was started. Among those who initially responded to YNK01, one complete cytogenetic response was achieved 18 months later. Although the data are preliminary, this is the first study showing that continuous administration of YNK01 along with IFNalpha is effective in patients with advanced chronic myelogenous leukemia.

Adult↗
PubMed2000

Transplantation of IL-2-transduced murine bone marrow is associated with dose-dependent toxicity.

OBJECTIVE: The purpose of this study was to investigate the effects of interleukin-2 (IL-2) gene-transduced hematopoietic progenitor cells or cytotoxic function and systemic toxicity following syngeneic bone marrow transplantation. MATERIAL AND METHODS: Marrow of 5-fluorouracil pretreated donor mice were transfected with a retroviral vector containing the murine IL-2 gene and transplanted into lethally irradiated syngeneic hosts. RESULTS: Productive insertion of the IL-2 gene could be demonstrated at various intervals post-transplant without impairment of hematopoietic engraftment. Endogenously augmented IL-2 release resulted in a selective increase in CD4(+), CD8(+), and NK1.1(+) population in spleen and bone marrow, as well as significant cytolytic activity against syngeneic leukemia cells in vitro. Our results also illustrate the interdependence among the magnitude of systemic IL-2 levels, the number of IL-2-transduced cells in the transplant inoculum, and the appearance of systemic toxicity. Infusion of marrow transduced with high-titer, high-expressing IL-2 retrovirus resulted in significant morbidity and mortality in the recipients. Our studies demonstrate that mortality was secondary to severe lymphocytic infiltration of liver and lung, which was associated with increased expression of intercellular adhesion molecule-1 and vascular adhesion molecule-1. Reducing the number of IL-2-transduced cells in the bone marrow inoculum, however, resulted in significantly improved survival with no adverse events being evident during the post-transplant period. CONCLUSION: Delivery of IL-2 to the bone marrow can be achieved by transplantation of genetically modified hematopoietic cells, however, the overall feasibility is strongly influenced by the number of transduced cells in the bone marrow inocolum and/or the expression pattern of IL-2 in vivo.

Animals↗
PubMed2000

New rearrangement pattern after treatment of hairy-cell leukemia with 2-chlorodeoxyadenosine.

Leukemic hairy cells are clonally proliferating B-lymphoid cells with clonal rearrangements of genes for immunoglobulin chains. We describe a patient with a new hairy-cell clone after treatment with 2-chlorodeoxyadenosine (2-CdA). In this patient, a single course of 2-CdA resulted in good partial remission of hairy-cell leukemia, but Southern blot analysis of bone marrow biopsies and polymerase chain reaction using seminested amplifications with consensus primers revealed a new rearranged band 4 months after therapy with 2-CdA. Four years after therapy, the patient is in complete clinical remission and both bands disappeared during follow-up. The new rearranged band might have been related to prior treatment of hairy-cell leukemia with 2-CdA.

Antimetabolites, Antineoplastic↗
PubMed2000

Pentostatin (Nipent) in T-cell malignancies. Leukemia Cooperative Group and the European Organization for Research and Treatment of Cancer.

Within this phase II trial of the European Organization for Research and Treatment of Cancer, we have investigated the safety and efficacy of pentostatin (Nipent; SuperGen, San Ramon, CA) in refractory lymphoid malignancies. Pentostatin was administered at a dosage of 4 mg/m2 every week for the first 3 weeks, then every 14 days, followed by maintenance therapy of 4 mg/m2 monthly for a maximum of 6 months. We have previously reported the results in T- and B-cell prolymphocytic leukemia, B-cell chronic lymphocytic leukemia, and hairy cell leukemia This report focuses on the outcome in T-cell malignancies: T-cell chronic lymphocytic leukemia, Sézary syndrome, mycosis fungoides, and T-zone lymphoma. Of 92 patients with these diagnoses enrolled, 76 were evaluable for response and toxicity, ie, 25 of 28 with T-cell chronic lymphocytic leukemia, 21 of 26 with Sézary syndrome, 22 of 26 with mycosis fungoides, and eight of 12 with T-zone lymphoma. All patients had progressive and advanced disease. Sixteen patients (21%) died during the first 9 weeks of treatment: 12 of progressive disease, two of infectious complications thought to be unrelated to treatment, one of myocardial infarction, and one of renal failure related to administration of intravenous contrast. Major toxicity (grades 3 and 4) included infection in 10.5% of patients, nausea/vomiting in 5%, and hepatotoxicity in 3%. One patient (1.3%) achieved a complete remission and 15 (19.7%) a partial remission. Better results were achieved in patients with Sézary syndrome or mycosis fungoides (complete remission + partial remission = 33.4% and 22.7%, respectively) than in patients with T-cell chronic lymphocytic leukemia (8%) or T-zone lymphoma (25%). We conclude that pentostatin is active in low-grade T-cell malignancies. Toxicities are mild to moderate at the dose schedule administered. Severe hematologic toxicity has not been observed. The efficacy at the present dose level is moderate. A higher dose might be necessary for some T-cell malignancies.

Adult↗
PubMed1999

T-cell subsets in schizophrenia: a comparison between drug-naive first episode patients and chronic schizophrenic patients.

T-cell subsets (CD3+, CD4+, CD8+, NK-cells) and the CD4+/CD8+ ratio were measured in 56 schizophrenic patients admitted to hospital with an acute psychosis. Thirty-five patients with chronic schizophrenia and 21 drug-naive first episode schizophrenic patients were compared with 16 healthy controls. T-cell subsets were quantified in the acute state of the illness (day 0), after 7 days of treatment and at the time of discharge. In the acute state, schizophrenic patients showed higher CD3+ and CD4+ cells (p = 0.05) and a higher CD4/CD8 ratio (p = 0.02) than healthy controls, while NK-cells were lower (p = 0.05). In first episode patients, all T-cell alterations normalized during treatment. In the chronic group the ratio remained high, whereas the initially low number of NK-cells normalized over time. These findings, supporting immune system dysregulation in schizophrenia, are discussed in relation to psychopathology, the stage of illness and effects of medication.

Acute Disease↗
PubMed1999

Expression of LFA-1 identifies different prognostic subgroups in patients with advanced follicle center lymphoma (FCL).

In a retrospective immunohistochemical study based on 27 patients with stage IV follicle center lymphoma (FCL) the expression of CD44standard (CD44s), LFA-1 (CD11a, CD18), VLA-4 (CD49d, CD29) and ICAM-1 (CD54) was analysed on lymphoma cells in bone marrow infiltrates. The results were correlated to clinical data and overall survival. Our data demonstrate that the expression of LFA-1 on lymphoma cells is predictive for the prognosis of patients with advanced FCL. In detail, patients exhibiting weak to moderate expression (+/++) of CD11 and CD18 showed a significantly shorter median survival (51 months and 33 months, respectively) than did those presenting with strong expression ( ) of the LFA-1 adhesion molecule (P = 0.04 and P = 0.0051, respectively). Furthermore, multivariate analysis identified CD18 as a new independent prognostic factor in patients with advanced FCL. Our findings emphasize the relevance of adhesion molecules for the pathology of FCL and give further support for their impact on clinical course and overall survival.

Adult↗
PubMed1999

Detection and quantitation of genetically marked acute myeloid leukemia by competitive polymerase chain reaction after autologous bone marrow transplantation: a preclinical model for minimal residual disease.

Preclinical models and methods aimed at detecting and quantitating minimal residual disease (MRD) after autologous bone marrow transplantation (BMT) for acute myeloid leukemia (AML) could facilitate assessment of innovative therapeutic strategies for their antileukemic potential. Among the various techniques exploited to identify MRD, polymerase chain reaction (PCR) proved to be a valuable tool in instances in which clonogeneic markers are involved during the evolution of disease. In human AML, however, detection of MRD by PCR is limited to a minority of subgroups, as clonospecific markers are absent or presently unknown. Although gene labeling has proved to be efficient in detecting marker-devoid leukemia cells in preclinical models, detection and quantitation by PCR have not yet been considered. We therefore developed an experimental model in which detection and quantitation of genetically marked murine AML cells are based on a highly sensitive two-step nested PCR and competitive PCR protocol, respectively. We further demonstrated its applicability to a murine syngeneic BMT model that was designed to monitor minimal numbers of gene-tagged AML cells at various time intervals after transplantation. Our results showed that detection and quantitation could reproducibly be achieved at levels as low as one in 10(6) and 10(5) cells, respectively.

Acute Disease↗
PubMed1999

Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9.

Sonic hedgehog (Shh) specifies the identity of both motor neurons (MNs) and interneurons with morphogen-like activity. Here, we present evidence that the homeodomain factor HB9 is critical for distinguishing MN and interneuron identity in the mouse. Presumptive MN progenitors and postmitotic MNs express HB9, whereas interneurons never express this factor. This pattern resembles a composite of the avian homologs MNR2 and HB9. In mice lacking Hb9, the genetic profile of MNs is significantly altered, particularly by upregulation of Chx10, a gene normally restricted to a class of ventral interneurons. This aberrant gene expression is accompanied by topological disorganization of motor columns, loss of the phrenic and abducens nerves, and intercostal nerve pathfinding defects. Thus, MNs actively suppress interneuron genetic programs to establish their identity.

Animals↗
PubMed1999

Pentostatin in T-cell malignancies--a phase II trial of the EORTC. Leukemia Cooperative Group.

PURPOSE: Within this phase II EORTC trial, we have investigated the safety and efficacy of pentostatin in lymphoid malignancies. We have previously reported the results in T- and B-cell prolymphocytic leukemia, B-cell chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia. This report focuses on the outcome in T-cell malignancies: T-CLL, Sézary syndrome (Sézary), mycosis fungoides (MF) and T-zone lymphoma (TZL). PATIENTS AND METHODS: Of the 92 patients with these diagnoses enrolled, 76 were evaluable for response and toxicity, i.e., 25 of 28 with T-CLL, 21 of 26 with Sézary, 22 of 26 with MF, and 8 of 12 with TZL. All patients had progressive and advanced disease. Pentostatin was administered at a dosage of 4 mg/m2 every week for the first 3 weeks, then 4 mg/m2 every 14 days for another 6 weeks, followed by maintenance therapy of 4 mg/m2 monthly for a maximum of 6 months. RESULTS: Response rates (complete and partial responses) in patients with Sézary (n = 22) or MF (n = 21) were 33% and 23%, respectively, and in patients with T-CLL (n = 21) or TZL (n = 8) 8% and 25%, respectively. Sixteen (21%) patients died during the first ten weeks of treatment: twelve of progressive disease, two of infectious complications with progressive disease, one of myocard infarction and one of renal failure related to administration of i.v. contrast. Major toxicity (grade 3-4) included infection in 11% of patients, nausea/vomiting in 4%, diarrhea in 3%. Hematologic toxicity was mild to non-existent. CONCLUSIONS: We conclude that pentostatin is active in Sézary and MF but showed marginal activity in T-CLL or TZL. Toxicities are mild to moderate at the dose schedule administered. Due to its relatively specific lympholytic effect and its favorable toxicity spectrum, pentostatin might be especially useful for the palliative treatment of T-cell malignancies.

Adult↗
PubMed1999

Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice.

In most mammals the pancreas develops from the foregut endoderm as ventral and dorsal buds. These buds fuse and develop into a complex organ composed of endocrine, exocrine and ductal components. This developmental process depends upon an integrated network of transcription factors. Gene targeting experiments have revealed critical roles for Pdx1, Isl1, Pax4, Pax6 and Nkx2-2 (refs 3,4,5,6,7, 8,9,10). The homeobox gene HLXB9 (encoding HB9) is prominently expressed in adult human pancreas, although its role in pancreas development and function is unknown. To facilitate its study, we isolated the mouse HLXB9 orthologue, Hlxb9. During mouse development, the dorsal and ventral pancreatic buds and mature beta-cells in the islets of Langerhans express Hlxb9. In mice homologous for a null mutation of Hlxb9, the dorsal lobe of the pancreas fails to develop. The remnant Hlxb9-/- pancreas has small islets of Langerhans with reduced numbers of insulin-producing beta-cells. Hlxb9-/- beta-cells express low levels of the glucose transporter Glut2 and homeodomain factor Nkx 6-1. Thus, Hlxb9 is key to normal pancreas development and function.

Animals↗
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↗