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Biomedical subjects

H Behrendt

Publications and source records attributed to H Behrendt.

At least 73 records · Page 4Linked to original sources
PubMed1996

Clonal evolution of immunoglobulin heavy chain rearrangements in childhood B-precursor acute lymphoblastic leukemia after engraftment in SCID mice.

We grafted childhood B-precursor acute lymphoblastic leukemia (ALL) bone marrow (BM) cells into mice with severe combined immunodeficiency (SCID), in order to study the clonal evolution of immunoglobulin heavy chain (IgH) rearrangements in the absence of selective pressure by chemotherapy. BM cells from nine patients (six diagnosis samples and three relapse samples) were intravenously injected into SCID mice (three mice for each patient). All mice injected with cells from four patients developed a leukemia-like illness 12-40 weeks after injection. By PCR, new subclones that were the result of ongoing IgH rearrangement according to the mechanism operative in the injected cell populations (VH-replacement or VH to D-JH joining) were detected in the engrafted cell populations for all four patients. Subclones were mouse-specific, suggesting that subclone formation is a continuous process. Southern analysis after engraftment was unaltered as compared to the injected cells for one patient and revealed changes indicative of altered clonal composition for three patients. For two patients the observed changes possibly reflect the initial engraftment of a limited number of cells and occurred without changes in other parameters of the engrafted cell population, such as time needed for the development of leukemia, macroscopic organ involvement, immunophenotype and S-phase fraction. In one patient, we demonstrated the selective outgrowth of only a single cell type present at diagnosis, as characterized by IgH rearrangements. Our data show that evolution of clonal IgH rearrangements in B-precursor ALL may occur without the selective pressure of chemotherapy. Additionally, in some patients subclones present at diagnosis, as defined by IgH rearrangements, also possess different biological properties.

Animals↗
PubMed1995

Mitoxantrone is effective in treating childhood T-cell lymphoma/T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell malignancies in childhood are highly malignant diseases usually treated with intensive multidrug chemotherapy. In these regimens, anthracyclines, which are considerably cardiotoxic, are used. Mitoxantrone is structurally related to the anthracyclines, but it is considered to be less cardiotoxic. Therefore, the effectiveness of mitoxantrone in treating childhood T-cell malignancies was studied. METHODS: Fourteen newly diagnosed children with T-cell malignancies (12 T-cell non-Hodgkin's lymphoma, 2 T-cell acute lymphoblastic leukemia) initially were treated with one bolus injection of mitoxantrone, 12 mg/m2 intravenously, 1 week before standard induction therapy was begun. The effect of mitoxantrone was evaluated at Day 8, just before standard induction therapy was begun. RESULTS: Of 12 evaluable patients, 11 had significant positive responses with regard to the size of the primary tumor, the size of the involved peripheral lymph nodes, and the presence of lymphoblasts in the peripheral blood. The toxicity of mitoxantrone was mild. CONCLUSIONS: Mitoxantrone is effective in treating childhood T-cell malignancies. Its efficacy needs to be compared with the anthracyclines in a future randomized study.

Antineoplastic Agents↗
PubMed1995

Significance of lymphoblasts in cerebrospinal fluid in newly diagnosed pediatric acute lymphoblastic malignancies with bone marrow involvement: possible benefit of dexamethasone.

We analyzed retrospectively the data on 135 children treated since 1983 for acute lymphoblastic leukaemia and non-Hodgkin's lymphoma with bone marrow involvement with respect to the presence of lymphoblasts in cerebrospinal fluid (CSF) and the number of cells in CSF, both at initial diagnosis and during follow-up. Of these children 96, 11, and 28 suffered from B-progenitor, mature B cell, and T-cell malignancies respectively. In two patients initial central nervous system involvement was documented by the presence of lymphoblasts with high CSF cell counts (B+C+ patients); 19 patients had CSF lymphoblasts with normal CSF cell counts (B+C- patients); the others had no CSF blasts and normal CSF cell counts (B-C- patients). In B+C- and B-C- patients 5-year-leukaemia-free survival was 66 and 70%, respectively (i.e., not significantly different). None of the B+C- patients experienced a first relapse in the central nervous system. Differences in outcome by comparing with reports of others may be related to the use of dexamethasone instead of prednisone in almost all of our patients.

Adolescent↗
PubMed1995

A non-random chromosome abnormality found in precursor-B lineage acute lymphoblastic leukaemia: dic(9;20)(p1?3;q11).

A comparison of cytogenetical data on acute lymphoblastic leukaemia studied at four large European centres has revealed a non-random dicentric chromosome abnormality: dic(9;20) (p1?3;q11) in 10 patients, nine of whom were children. All had early precursor-B lineage ALL, and eight children had a non-standard risk clinical presentation. The origin of the dicentric chromosome was demonstrated using a range of chromosome banding techniques. This was confirmed by FISH using paints and centromeric probes for chromosomes 9 and 20, together with a number of cosmid probes. The follow-up time of these patients is presently too short and the number of patients too few to determine the prognostic significant of this chromosome abnormality.

Adolescent↗
PubMed1995

Prolonged persistence of PCR-detectable minimal residual disease after diagnosis or first relapse predicts poor outcome in childhood B-precursor acute lymphoblastic leukemia.

The follow up of minimal residual disease (MRD) in childhood B-precursor ALL by polymerase chain reaction (PCR) may be of help for further stratification of treatment protocols, to improve outcome. However, the clinical relevance of this approach has yet to be defined. We report the retrospective follow-up of MRD in bone marrow (BM) samples from 50 childhood B-precursor ALL patients by IgH/TCR delta PCR. Twenty-two patients remained in continuous complete remission (median follow-up 61 months), and 28 experienced relapse (median follow-up 75 months). Initial regression of MRD on therapy correlated with outcome. At the end of induction therapy 2/18 (11.1%) patients from the CCR group were PCR positive vs 10/16 (62.5%) from the 'relapse' group (P = 0.005). The presence of PCR detectable MRD predicted event-free survival independent of standard clinical and cytogenetical parameters. Also subsequent to first BM relapse, a correlation between MRD regression and outcome was observed. Six of eight patients who became PCR negative in the time period between relapse and bone marrow transplantation are in CCR, whereas 7/7 patients who remained PCR positive in this time period died (P = 0.006). In approximately 70% of evaluable patients, clinical relapse was preceded by recurrence of detectable MRD at time intervals of 3-18 months earlier and the recurrence of PCR positivity after a period of negativity was always followed by overt relapse. At relapse, the combined use of IgH and TCR delta probes reduced false negativity caused by clonal evolution to approximately 10%. This study shows that the evolution of PCR detectable MRD is an independent predictor of outcome.

Adolescent↗
PubMed1995

Dicentric (9;12) in acute lymphocytic leukemia and other hematological malignancies: report from a dic(9;12) study group.

Fourteen cases of dic(9;12)(p11-13;p11-12) in early B-lineage acute lymphoblastic leukemia (ALL) and other hematological malignancies are reported with a review of the literature. Altogether 36 cases were collected for analysis: ALL at diagnosis (31 cases) or in relapse (one case), chronic myeloid leukemia in lymphoid blast crisis (two cases), T-cell lymphoblastic lymphoma (one case) and T-cell non-Hodgkin's lymphoma (one case). We report the first cases of dic(9;12) with a T-cell phenotype. Dic(9;12) occurs predominantly in B-progenitor ALL of childhood and young adults (age range, 1-47 years, median 12 years) but not of infancy. One or more adverse clinical features, age > 10 years, WBC > 100 x 10(9)/l, pre-B immunophenotype, platelets < 100 x 10(9)/l, were found in over 90% of cases. Additional structural chromosomal changes or trisomy 8 were frequently present. Nevertheless with a median follow-up of 5 years, 29/31 cases (94%) remain in first remission conferring an excellent prognosis to this leukemia. Additional cases are being sought to confirm the prognostic value of this cytogenetic aberration in various hematological malignancies.

Adolescent↗
PubMed1995

IgH/TCR delta PCR oligonucleotide liquid hybridization, a fast and sensitive assay for monitoring minimal residual disease in childhood B-precursor ALL.

The detection of minimal residual disease (MRD) in childhood B-precursor acute lymphoblastic leukemia (ALL) by polymerase chain reaction (PCR) may turn out to be a powerful tool in the evaluation and guidance of therapy. Most previously described techniques are highly sensitive but also too laborious for application in a routine setting. Here we describe a technique based on the determination of IgH VHDJH and TCR V delta 2D delta 3 junctional regions by PCR/cycle sequencing analysis and hybridization of junctional region oligonucleotide probes in a standard liquid hybridization (LH) assay. We systematically analyzed the applicability of this simplified approach for the monitoring of MRD in a large patient group. IgH VHDJH and TCR V delta 2D delta 3 junctional regions were amplified from presentation bone marrow samples obtained from 53 childhood B-precursor ALL patients. The combined approach allowed the identification of at least one tumor marker for 49/53 (92.5%) of patients. A total of 75 oligonucleotide probes (54 DJH, 21 V delta 2D delta 3) was tested in the LH assay. Sensitivity range was 10(-2)-10(-5) and 10(-4)-10(-5) for DJH and V delta 2D delta 3 junctional region probes, respectively. A sensitivity of at least one malignant cell in 10(4) normal cells was obtained for 84.8% of evaluable patients, applying on average 1.1 IgH and 0.47 TCR delta probes per patient. Comparison to a method based on the use of initial PCR product as clone-specific probe showed that oligonucleotide LH was one log more sensitive in six of nine patients tested. The presented technique allows the monitoring of MRD with acceptable sensitivities in over 90% of childhood B-precursor ALL patients. Moreover, the technique is suitable for prospective patient studies in a routine setting as it is fast, reproducible and makes use of a standard hybridization protocol for different oligonucleotide probes.

Base Sequence↗
PubMed1994

B precursor acute lymphoblastic leukemia third complementarity-determining regions predominantly represent an unbiased recombination repertoire: leukemic transformation frequently occurs in fetal life.

To determine whether the ALL (acute lymphoblastic leukemia) CDR3 (third complementarity-determining region) repertoire represents the recombination repertoire, or shows evidence of selectional processes inherent to normal B cell differentiation or malignant transformation, we analyzed 68 ALL CDR3 regions and included 127 previously published sequences in the analyses. We found no evidence of selection prior to malignant transformation as recombination was random with 1/3 "in frame" and 2/3 "out of frame" joinings and usage of all three D reading frames was observed. D and JH gene segments were predominantly unmutated which allowed a detailed analysis of gene usage and rearrangement characteristics. JH4 and JH6 usage (both 32.2%) was significantly different (p = 0.005) from that observed in peripheral B lymphocytes. D gene family usage roughly represented D gene family size with the exception of the DXP and DA/K family which were over- and underrepresented (p = < or = 0.05), respectively. D-D fusions were found in 26.2% of CDR3 regions. If less stringent criteria were applied DIR homology was found in 40/65 sequences, suggesting the frequent involvement of DIR gene segments in human CDR3 formation. The rearranged D genes were evenly distributed over the D locus, suggesting that D recombination is a predominantly random process, independent of physical location at the locus. Also, there was no correlation between JH gene usge and physical location of the rearranged D gene segment, which excludes a major contribution of the DJH replacement recombination mechanism. In 36.1% of CDR3 regions N-nucleotides at the DJH junction were absent. This frequency is higher than observed for peripheral B lymphocytes. It is suggested that for a number of ALL the initial transformational event took place in early fetal life. We conclude that ALL CDR3 sequences show no evidence of selection prior to malignant transformation, nor of extensive changes subsequent to malignant transformation.

Age Factors↗
PubMed1994

Leukemic ophthalmopathy: a report of 21 pediatric cases.

A multicentric retrospective study on leukemic ophthalmopathy (LO) is reported. It includes 21 patients, 16 males and 5 females, with acute leukemia (AL) observed in 10 SIOP centers. LO developed in three patients at the time of diagnosis of AL; five patients were in first complete remission (three off therapy); four patients were in second or third remission; and nine were in combined relapse. Most frequent symptoms were blurred vision, photophobia, and ocular pain. Two patients with acute nonlymphoblastic leukemia died before treatment; another underwent bone marrow transplantation; one patient with B-cell acute lymphoblastic leukemia (B-ALL) treated with chemotherapy and radiotherapy died 4 months after LO; the remaining 17 children were treated according to different schedules with (10) or without (7) radiotherapy on the affected eye. Twelve patients achieved ocular remission and four of these had a second ocular relapse. Complete remission after LO treatment lasting for more than 3, 7, 24, 29 months was observed in four patients. The authors conclude that cure is possible in patients who had LO in first complete remission treated with chemotherapy and radiotherapy at high dose on the affected eye.

Acute Disease↗
PubMed1993

[Autotransplantation of the kidney. Indications and results].

Renal autotransplantation is an established but rarely used therapy in cases of renal vessel lesions, tumours of the kidney and ureter, long-distance ureter lesions, complex nephrolithiasis and retroperitoneal fibrosis. The indications and results of renal autotransplantation are discussed using three case reports and compared to the literature. In cases of central intrarenal tumours and aneurysms of the kidney, autotransplantation is indispensible in order to save the organ. For long-distance ureter lesions as well as for retroperitoneal fibrosis, autotransplantation of the kidney gives excellent results. In difficult clinical situations ileum segment interposition is an alternative treatment.

Adenocarcinoma↗
PubMed1992

Cyclophosphamide-induced disturbance of gonadotropin secretion manifesting testicular damage.

UNLABELLED: Gonadal function was evaluated in 23 men (aged 14.8-28.8 years) treated in childhood with cytotoxic drugs for a solid tumour. Group 1 (N = 14) had been treated with non-alkylating drugs only, while group 2 (N = 9) received the alkylating drug cyclophosphamide in addition (range 3.8-19.5 g/m2). Median age at the start of treatment was 4.6 years (range 0.6-16.1) in group 1 and 13.9 years (range 3.7-16.9) in group 2. Data of the patients were compared with a reference group consisting of 14 normal men. Almost all patients of both groups showed normal development of puberty; 13 of the 14 men in group 1 showed normal hormonal values. In group 2, basal LH and FSH as well as the LH and FSH responses to GnRH showed higher levels compared to those of a reference group (p less than 0.001). Correlation analysis showed an evident correlation between the total dose of received cyclophosphamide and the basal FSH level (r = 0.78; p = 0.002), the FSH response to GnRH (r = 0.73; p = 0.002) and the LH response to GnRH (r = 0.67; p = 0.002). There was no correlation between the hormonal parameters and the doses of the other cytotoxic drugs. Semen analysis showed azoospermia in four boys of group 2 and in none of group 1. Two patients in group 2 had an elevated FSH response to GnRH while their semen analysis was normal. CONCLUSIONS: (1) There is a dose-response relationship between the basal FSH, the LH and FSH responses to GnRH and the dose of cyclophosphamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

[Multiple angiolipomas--analgesics therapy with doxepin].

Angiolipomas are rare benign tumours of the subcutaneous fat; they are sometimes solitary but their occurrence is more frequently multiple. Angiolipomas can be differentiated from lipomas clinically by their pronounced tenderness and histologically by their variable vascularization. The disease occurs mostly in young adults, the sites of predilection being the trunk and proximal extremities. Multiple angiolipomas have to be differentiated from other lipomatoses, especially from adiposis dolorosa (Dercum's disease). The case reported in this paper was characterized by typical clinical and histological findings. The systemic administration of acetylsalicylic acid, diclofenac, ketotifen, ranitidine, tramadol, tilidine combined with naloxone did not provide adequate pain relief. In contrast, the therapeutic efficiency of the antidepressant doxepin, which also displays antihistaminic effects, suggests a possible role of mediators in the development of pain in angiolipomas.

Biopsy↗
PubMed1992

[Neurothekeoma. A light and electron microscopy, histochemical and immunohistochemical study].

We report a 37-year-old man with neurothekeoma that developed on the tip of the nose. Histopathological examination revealed a lobulated myxoid dermal tumour. The tumour cells were spindle-shaped or bizarre configuration. In the lower part of the dermis the lesion contained abundant cells simulating glomus tumour or melanocytic naevus. Staining with S-100 protein, epithelial membrane antigen (EMA), neuron-specific enolase (NSE) and desmin were negative. The matrix of the tumour was positive for Alcian blue and periodic acid-Schiff (PAS). Electron microscopic examination showed that the lesion was composed of dendritic cells separated by abundant glassy matrix and varying amounts of collagen fibres. Some of the cells looked like fibroblasts, and others like perineurial cells. The histogenesis of the tumour is discussed with particular attention to histochemical, immunohistochemical, light and electron microscopic findings.

Adult↗
PubMed1991

Possible role of macrophages in allergic rhinitis.

Mononuclear phagocytes have been investigated in biopsies taken from the nasal mucosa and in epithelial cell samples from 22 grass-pollen-allergic subjects before season, after allergen challenge and during season by means of immunohistochemistry and electron microscopy. The cells were positive for CD68/EBM11 and HLA-DR, but failed to react with CD1 and CD23/BB10. The cells increased in number during season as well as after allergen challenge, especially in the upper part of the mucosa. Heteromorphy of macrophages, as seen by transmission electron microscopy, confirmed the presence of diverse macrophage subpopulations in the nasal mucosa of allergic subjects. Using brush sampling techniques, CD68-positive and HLA-DR-positive cells significantly increased in epithelial cell samples 4-8 h after allergen challenge, indicating a central role of these cells not only in antigen processing but also in late phase reactions of allergic rhinitis.

Antigen-Presenting Cells↗
PubMed1991

High survival rate in advanced-stage B-cell lymphomas and leukemias without CNS involvement with a short intensive polychemotherapy: results from the French Pediatric Oncology Society of a randomized trial of 216 children.

From April 1984 to December 1987, the French Pediatric Oncology Society (SFOP) organized a randomized trial for advanced-stage B-cell lymphoma without CNS involvement to study the possibility of reducing the length of treatment to 4 months. After receiving the same three intensive six-drug induction courses based on high-dose fractionated cyclophosphamide, high-dose methotrexate (HD MTX), and cytarabine in continuous infusion, patients were evaluated for remission. Those who achieved complete remission (CR) were randomized between a long arm (five additional courses with two additional drugs; 16 weeks of treatment) and a short arm (two additional courses; 5 weeks). For patients in partial remission (PR), intensification of treatment was indicated. Two hundred sixteen patients were registered: 15 stage II nasopharyngeal and extensive facial tumors, 167 stage III, and 34 stage IV, 20 of the latter having more than 25% blast cells in bone marrow. The primary sites of involvement were abdomen in 172, head and neck in 30, thorax in two, and other sites in 12. One hundred sixty-seven patients are alive in first CR with a minimum follow-up of 18 months; four are lost to follow-up. Eight patients died from initial treatment failure, 14 died from toxicity or deaths unrelated to tumor or treatment, and 27 relapsed. The event-free survival (EFS), with a median follow-up of 38 months, is 78% (SE 3) for all the patients, 73% (SE 11) for the stage II patients, 80% (SE 3) for the stage III patients, and 68% (SE 8) for the stage IV and acute lymphoblastic leukemia (ALL) patients. One hundred sixty-six patients were randomized: 82 in the short arm and 84 in the long arm. EFS is, respectively, 89% and 87%. Statistical analysis confirms equivalence of both treatment arms with regard to EFS. Moreover, morbidity was lower in the short arm. This study confirms the high survival rate obtained in the previous LMB 0281 study without radiotherapy or debulking surgery and demonstrates the effectiveness of short treatment.

Adolescent↗
PubMed1990

Bone marrow relapse occurring as first relapse in children with acute lymphoblastic leukemia.

In a retrospective review which covered the whole Dutch childhood population of approximately 3 million children we studied the prognosis in 164 children with acute lymphoblastic leukemia (ALL) who were initially treated between 1973 and 1983, and who had an isolated bone marrow relapse occurring as first relapse. Until their first relapse, the patients were initially treated according to standard protocols, while treatment for relapse was heterogeneous, and not intensive. Second complete remission (CR) was attained by 78% of the patients. The median duration of second CR was 9 months, the median survival 13 months. Multivariate analysis showed that the duration of the first CR was the most significant variable with regard to prognosis. None of the patients who developed their bone marrow relapse during initial treatment, i.e., within 24 months from diagnosis, survived. Among the 73 patients who relapsed after cessation of the initial treatment there were 19 long-term disease-free survivors, 14 of whom had not developed subsequent relapses after 48(+)-125 + months. From this study we conclude that treatment in children with first bone marrow relapse has to be intensified.

Adolescent↗
PubMed1990

Levels of itraconazole in skin blister fluid after a single oral dose and during repetitive administration.

Oral itraconazole is effective in the treatment of mycoses. To measure its concentrations in the tissue, levels of total and non-protein-bound itraconazole were determined in serum, suction-induced blister fluid, and cantharides-induced blister fluid. Six healthy subjects received 200 mg as a single dose, followed by 100 mg/day for 10 days. Itraconazole binding in suction-induced blister fluid (99.54%) and cantharides-induced blister fluid (99.77%) was calculated from plasma protein binding (99.8%). The single-dose study showed the drug levels in blister fluid to increase more slowly than those in serum. The terminal half-life of itraconazole in serum was 22.5 +/- 3.2 hours. Suction- and cantharides-induced blister fluid levels declined in parallel. After the final dose, itraconazole penetration into cantharides-induced blister fluid was only 70%. Moreover, trough levels of unbound itraconazole in suction- and cantharides-induced blister fluid were 0.239 +/- 0.115 and 0.334 +/- 0.101 ng/ml and thus were significantly lower than free itraconazole levels in serum (0.422 +/- 0.125 ng/ml). Thus a distribution equilibrium between serum and blister fluids was not obtained. Free drug concentrations in suction- and cantharides-induced blister fluid were far lower than the minimal inhibitory concentration values for Candida ssp. and dermatophytes.

Administration, Oral↗