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Biomedical subjects

T Langer

Publications and source records attributed to T Langer.

At least 19 recordsLinked to original sources
PubMed2007

Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: a report from the late effects surveillance system.

BACKGROUND: Cisplatin and carboplatin are both nephrotoxic and can induce, to a different degree, impairment in glomerular function and hypomagnesemia. Prospective longitudinal studies on these renal impairments are rare in children and adolescents. PROCEDURE: Six hundred and fifty one sarcoma patients were investigated prospectively for nephrotoxicity in the Late Effects Surveillance System (LESS) network (median follow-up 2 years). Median cumulative dose was 360 mg/m(2) for cisplatin, and 1,500 mg/m(2) for carboplatin. Patients not treated with any platinum derivative were used as controls. Most patients (including controls) also received ifosfamide. Renal function was tested by serum magnesium, serum creatinine, and the GFR as estimated by the Schwartz formula. We evaluated incidence, dependencies, and the course of impairments. RESULTS: There was no observed platinum-induced reduction of glomerular function over time. After cessation of antineoplastic therapy, hypomagnesemia (<0.7 mmol/L) occurred in 12.1% (95% CI: 6.8%-19.4%) of patients after cisplatin therapy, and in 15.6% (95% CI: 5.3%-32.8%) after carboplatin therapy, in comparison with 4.5% (95% CI: 2.0%-8.7%) in patients without any treatment with platinum derivatives (P = 0.008). In all groups, the frequency of hypomagnesemia decreased with ongoing follow-up, but serum magnesium remained lower in platinum treated patients throughout the study period. CONCLUSION: Nephrotoxicity after treatment with cisplatin and carboplatin was mild in our study. Further studies have to show if serum magnesium is permanently decreased in platinum treated patients and if this will result in any clinically relevant impairment.

Adolescent↗
PubMed2007

Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System.

BACKGROUND: Ifosfamide is widely used in paediatric oncology, but its use is limited by nephrotoxic side effects. The aim of this study was to evaluate the incidence and risk factors of tubulopathy, with special emphasis on the influence of age, where different findings have been published so far. PROCEDURE: Five hundred ninety three children and adolescents treated for Ewing, osteo- or soft-tissue sarcoma (median age at diagnosis: 11.7 years) were prospectively investigated for nephrotoxicity in the Late Effects Surveillance System (LESS) study. Tubulopathy was diagnosed in case of continuing hypophosphatemia and proteinuria. RESULTS: After a median follow up of 19 months, 27 patients (4.6%; 95% CI: 3.0-6.6%) had newly developed tubulopathy. This incidence was 0.4% (95% CI: 0-2.4%) in patients treated with a cumulative ifosfamide dose of < or =24 g/m2, 6.5% (95% CI: 3.6-10.7%) after 24-60 g/m2, and 8.0% (95% CI: 4.2-13.6%) after > or = 60 g/m2. In multivariate analysis, children younger than 4 years at time of diagnosis had an 8.7-fold (95% CI: 3.5-21.8) higher risk for tubulopathy than older patients. Neither carboplatin treatment nor abdominal irradiation showed any significant influence. CONCLUSION: Ifosfamide-induced nephrotoxicity was found in 4.6% of patients. Risk factors were the cumulative ifosfamide dose and young age at treatment.

Abdomen↗
PubMed2006

Integrated in silico tools for exploiting the natural products' bioactivity.

Whereas computational methods for molecular design are well established in medicinal chemistry research, their application in the field of natural products is still not exhaustively explored. This article gives a short introduction into both the potential for the application of computer-assisted approaches, such as pharmacophore modelling, virtual screening, docking, and neural networking to efficiently access the bioactive metabolites, and the requirements and limitations related to this specific field. The challenge is which selection criteria and/or multiple filtering tools to apply for a target-oriented isolation of potentially bioactive secondary metabolites. Application examples are provided where in silico tools and classical methods used by natural product scientists are used in an effort to maximize their efficacy in drug discovery. Thus, integrated computer-assisted strategies may help to process the huge amount of available structural and biological information in a reasonably short time for a straightforward search of bioactive natural products.

Computer-Aided Design↗
PubMed2006

Prospective longitudinal evaluation of doxorubicin-induced cardiomyopathy in sarcoma patients: a report of the late effects surveillance system (LESS).

BACKGROUND: Prospective longitudinal examinations of anthracycline-induced cardiomyopathy in a homogeneous cohort are rare in pediatric oncology. We herein report the results of observations on the frequency of cardiomyopathy in doxorubicin-treated sarcoma patients in Germany, Austria, and Switzerland. PROCEDURE: The Late Effects Surveillance System (LESS) prospectively collects longitudinal data on late sequelae of antineoplastic therapy in Ewing-, soft tissue-, and osteosarcoma patients treated within the therapy trial protocols of the German Society of Pediatric Oncology and Hematology. Two hundred sixty-five relapse-free patients who had received doxorubicin for the treatment within the EICESS-92/EURO-E.W.I.N.G.-99, COSS-96, and CWS-96 therapy trials were serially examined by echocardiography. The analyzed population consisted of 142 males and 123 females. Their mean age at the end of therapy was 13 +/- 5 years. The mean follow-up time was 34 +/- 12 months. The mean cumulative doxorubicin dose was 290 +/- 91 mg/m(2). RESULTS: In this cohort, the total cumulative incidence of doxorubicin-induced cardiomyopathy was 7.5%. Four patients (1.5%) suffered from a symptomatic cardiomyopathy and 16 (6%) from a subclinical cardiomyopathy. Cardiomyopathy manifested in 11 cases already under antineoplastic therapy and in the remaining nine cases at a median of 26 days (range: 17-174 days) after stopping antineoplastic therapy. Univariate and multivariable analysis did not confirm any of the known risk factors for developing anthracycline-induced cardiomyopathy in our patient group within the described time interval. CONCLUSIONS: After a mean follow-up of 34 +/- 12 months, cumulative incidence of doxorubicin-induced cardiomyopathy in our pediatric sarcoma patients was at the lower end of that reported by other groups.

Adolescent↗
PubMed2006

Strategies for efficient lead structure discovery from natural products.

This investigation aims to evaluate strategies for an efficient selection of bioactive compounds from the multitude and biodiversity of the plant kingdom. Statistics prove natural products (NPs) as a source leading most consistently to successful development of new drugs. However, there are several reasons why the interest in finding bioactive NPs has generally declined at several major pharmaceutical companies. Their substantial argument is that the research in this field is time-consuming, highly complex and ineffective. A more rational and economic search for new lead structures from nature must therefore be a priority in order to overcome these problems. In this paper, different strategies are described to exploit the molecular diversity of bioactive secondary metabolites, namely classical pharmacognostic approaches and computational methods. The latter include various data mining tools, like virtual screening filtering experiments using pharmacophore models, docking studies, and neural networks, which help to establish a relationship between chemical structure and biological activity. The strengths and weaknesses of these methods will be shown in this review. Focusing on selected targets within the arachidonic acid cascade (phospholipase A(2), 5-lipoxygenase, cyclooxygenase-1 and -2), several studies of successful discoveries in the field of anti-inflammatory NPs were scrutinized for the applied strategies. Both the compilation of relevant published data and recent studies supported by our own research clearly demonstrate the benefits of the synergistic effect of a hybridization of these strategies for an effective drug discovery from natural ingredients.

Anti-Inflammatory Agents↗
PubMed2005

Comparison of epirubicin and doxorubicin cardiotoxicity in children and adolescents treated within the German Cooperative Soft Tissue Sarcoma Study (CWS).

PURPOSE: Up to now, cardiotoxicity of epirubicin has been studied almost exclusively in adult cancer patients. The aim of this study was to investigate epirubicin in children and adolescents, in comparison with doxorubicin. METHODS: About 172 soft tissue sarcoma patients (mean age at diagnosis: 8.3 years), treated with epirubicin (median cumulative dose: 450 mg/m2) or doxorubicin (median cumulative dose: 240 mg/m2) within the high-risk group of the CWS-96 study, were examined in a prospective multicentre study. Heart function was analysed by echocardiography, measuring left-ventricular fractional shortening (FS). The median follow up was 27.7 months. RESULTS: Incidence of clinically manifest cardiomyopathy was 0% (0/60; 95% CI: 0-6.0%) in patients treated with epirubicin, and 0.9% (1/108; 95% CI: 0-5.1%) in patients treated with doxorubicin. A further three patients showed subclinical cardiomyopathy. There was no difference in FS between the two treatment arms. CONCLUSIONS: Cardiotoxicity was low in our study. For the short term, cardiotoxicity seems to be only a minor problem in patients treated with epirubicin as applied in this cohort.

Adolescent↗
PubMed2005

Cisplatin-induced ototoxicity in osteosarcoma patients: a report from the late effects surveillance system.

The aim of this study was to analyze cisplatin-induced ototoxicity in a recent study trial. Seventy-four patients who had received cisplatin for the treatment of osteosarcoma (median cumulative dose: 360 mg/m2) were investigated prospectively for ototoxicity in a multicenter trial. Hearing function was tested by audiometry. We evaluated the incidence and dependencies of hearing loss. After cessation of therapy, 51% of the patients showed a hearing loss of >20 dB in the frequency range of 4-8 kHz. Only in one patient a hearing loss was found at 2 kHz, and in none at 1 kHz. At a cumulative cisplatin dose of < or = 240 mg/m2, almost no ototoxicity was found. Incidence and magnitude of hearing loss increased significantly with a higher cumulative dose. Furthermore, hearing thresholds were significantly poorer in children <12 years. A further follow-up investigation showed only a marginal change in hearing function. We conclude that ototoxicity is moderate in our group of patients and probably irreversible.

Adolescent↗
PubMed2005

Why drugs fail--a study on side effects in new chemical entities.

Over 90% of the market withdrawals were caused by drug toxicity. Hepatotoxicity and cardiovascular toxicity proved to be the major causes for two out of three market withdrawals in the respective time period. In clinical phases I-III 43% of drug development project terminations were due to insufficient efficacy of the investigated compound. The second important issue, which caused one third of the projects to be closed, was toxicity. ADME parameters and economic and other reasons played a minor role. The results of our study indicate that compared with previous studies on this subject, no major improvements have been achieved in the last decade.

Drug-Related Side Effects and Adverse Reactions↗
PubMed2005

Application of the in combo screening approach for the discovery of non-alkaloid acetylcholinesterase inhibitors from Cichorium intybus.

Because of the direct correlation of cholinergic deficit and the severity of dementia, Alzheimer's disease is preferentially treated with acetylcholinesterase (AChE) inhibitors to supplement the acetylcholine level. In this study we focused on non-alkaloid AChE inhibitors from natural sources in order to discover new lead structures. In the course of in vitro extract screening of Tyrolean plants using an enzyme assay with Ellman's reagent, the dichloromethane extract of chicory roots (Cichorium intybus L.) showed a pronounced inhibitory effect on AChE. At a concentration of 1 mg extract/ml an inhibition of 70% was measured. Based on a 3D multi-conformational molecular-structure database consisting of secondary metabolites from C. intybus known from the relevant literature, virtual screening filtering experiments were conducted using both a feature-based pharmacophore model and a docking procedure. Some low molecular weight sesquiterpenoids exhibited distinct interactions with the pharmacophore model. In order to verify the applicability of this computer-aided strategy, an activity-guided fractionation of the chicory root extract was performed, which resulted in the isolation of two sesquiterpene lactones, 8-deoxylactucin and lactucopicrin, showing significant and dose-dependent inhibitory activity on AChE (IC(50) of 308.1 microM [CI(95) 243.9 - 405.3 microM] and 150.3 microM [CI(95) 100.8 - 188.1 microM], respectively). The two isolates were correctly predicted within the virtual screening process which corroborates the potential of the computer-assisted in combo screening approach for the discovery of the anti-cholinesterase compounds from C. intybus.

Acetylcholinesterase↗
PubMed2004

[Bioartificial materials in urology].

The scope of our research is the development of polymer-based bioabsorbable stents for urologic applications and in vitro testing of tissue reactions of cultured ureteral and urethral segments induced by implanted polymer stent prototypes. For these purposes a tissue cultivation model was developed using selected techniques of tissue engineering. Essential advantages of degradable over nondegradable urethral stents are elimination of the adverse extraction of epithelialized stents and the potential for recovery of organ-specific functionality. Moreover, the biocompatibility of a degradable urethral stent could potentially reduce the risk of restenosis due to hyperplasia and could be used, even repeatedly, for the treatment of a number of subvesical obstructions. For the treatment of tumor-induced strictures, application of degradable polymer stents coated with cytostatic drugs may be possible. The mechanical effect of the drug-loaded stent as a "place holder" could be complemented by adjuvant or palliative approaches such as local chemotherapy. We have developed and tested in vitro a degradable urethral stent incorporated with the model drug methotrexate for local drug delivery (LDD) by diffusion and during stent degradation.

Absorbable Implants↗
PubMed2004

Doppler studies evaluating the effect of a physical therapy screening protocol on vertebral artery blood flow.

General and isolated cervical positional tests are used to screen for potential vertebro-basilar insufficiency (VBI). There is limited research evaluating vertebral artery blood flow in these positions to justify the rationale of progressive mechanical stress occurring to the arteries. The purpose of the study was to determine vertebral artery blood flow in six cervical positions used in clinical practice. A comprehensive cervical assessment was conducted on 22 men and women (mean age 35) with no known vascular pathology. Vertebral artery peak systolic (PS), end diastolic (ED) flow rates and resistive index (RI) were measured using duplex colour Doppler sonography (sampling at C3-C5) in neutral, rotation, extension, combined rotation-extension, combined rotation-extension-traction, deKelyn's position and a C1-C2 pre-manipulative hold. Results showed there was a significant decrease in PS and ED in the contra-lateral artery during the pre-manipulative hold, and a decrease in ED in the contra-lateral artery during rotation. There was no effect of age, gender or mobility restriction on these blood flow changes. The pre-manipulative hold had the greatest response with 34% of the arteries demonstrating a complete cessation of ED flow. In conclusion the pre-manipulative hold and rotation created the greatest mechanical stress to the contra-lateral vertebral artery. These two positions may be useful screening positions to identify individuals at risk for VBI due to inadequate collateral blood flow.

Adult↗
PubMed2004

Asymmetric multiplex-polymerase chain reaction - a high throughput method for detection and sequencing genomic fusion sites in t(4;11).

Chromosomal translocations are a characteristic feature of leukaemia and other malignant diseases. As clonal markers, they can be applied to identify and quantify the number of malignant cells by polymerase chain reaction (PCR) methods. The translocation t(4;11) is present in >60% of infant leukaemia. In order to facilitate the sequencing of chromosomal breakpoints, we developed an optimized set of 30 PCR primers and a new approach, designated as asymmetric multiplex PCR (am-PCR). Due to the high number of primers, small breakpoint-spanning DNA fragments are obtained in one nested multiplex PCR reaction. All PCR products contain an identical binding site for the initiation of direct sequencing. By using am-PCR, the translocation t(4;11) was examined in bone marrow and blood samples from children with acute leukaemia. Compared with previously described methods for the determination of genomic breakpoints, am-PCR may be advantageous with regard to its simplicity and rapidity. Breakpoint-spanning sequences were also evaluated with regard to their applicability as unique clonal markers to design primers and probes for minimal residual disease quantification by real-time PCR. This approach can easily be adapted to other chromosomal translocations in malignant diseases for the detection and analysis of clone-specific DNA markers.

Chromosome Breakage↗
PubMed2004

Hearing function in soft tissue sarcoma patients after treatment with carboplatin: a report from the Late Effects Surveillance System.

The aim of this study was to analyse carboplatin-induced ototoxicity in a recent study trial. Twenty patients who had received carboplatin for the treatment of soft tissue sarcoma were investigated prospectively for ototoxicity in a multi-centre trial. Hearing function was tested by audiometry. All patients but one were treated with a cumulative dose of 1500 mg/m(2), the remaining with 500 mg/m(2). We evaluated the incidence and dependencies of hearing loss, and compared hearing thresholds to those of an untreated control group (n=60). Hearing thresholds in the carboplatin treated group were only marginally poorer compared with those of the control group. After carboplatin therapy no patient (0%; 95%-KI: 0-17%) had a hearing loss >20 dB. Hearing thresholds were not dependent on age, sex or cranial irradiation. We conclude that ototoxicity after carboplatin was low in our group of patients.

Adolescent↗
PubMed2002

Extramedullary blast crisis of chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation mimicking aggressive, translocation t(14;18)-positive B-cell lymphoma.

We report the case of a 42-year-old male patient who was diagnosed with a large tumor of the right thoracic aperture 30 months after unrelated hematopoietic stem cell transplantation (HSCT) for accelerated phase of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Biopsy revealed an immature lymphoid neoplasia with blastic tumor cell morphology and immunoreactivity for CD34, CD79a, CD43, and CD30 as well as slight positivity for TdT and CD20. Bcr-Abl rearrangement was found in interphase tumor cell nuclei by fluorescence in situ hybridization (FISH). Furthermore, a translocation t(14;18)(q32;q21) was amplified by polymerase chain reaction (PCR). Bone marrow (BM) examination showed regular hematopoiesis including a negative FISH analysis for Bcr-Abl and complete donor chimerism. Nested PCR from peripheral blood (PB), but not conventional PCR, was positive for the b3a2 Bcr-Abl transcript. Neither radiation nor intensive chemotherapy was capable of achieving a tumor remission, and the patient died from progressive disease 6 months later. Postmortem examinations showed a shift of immunophenotype with appearance of myeloperoxidase-positive tumor cells and loss of lymphoid antigens. In addition, there were characteristic cytogenetic findings of multiple Ph chromosomes and a clonal loss of P53 tumor suppressor gene. The latter was already deleted before HSCT. We conclude that lymphoid neoplasia occurring in our patient should be interpreted as an extramedullary, very immature blast crisis of CML expressing lymphoid differentiation markers rather than a true de novo NHL.

Adult↗
PubMed2002

Multicentre analysis of anthracycline-induced cardiotoxicity in children following treatment according to the nephroblastoma studies SIOP No.9/GPOH and SIOP 93-01/GPOH.

BACKGROUND: To study cardiac function and the incidence of anthracycline-induced cardiotoxicity in children following treatment according to the nephroblastoma studies SIOP No.9/GPOH and SIOP 93-01/GPOH. PROCEDURE: Analysis of clinical status, echocardiography, and ECG findings prior to administration of anthracyclines (median cumulative doxorubicin dose: 250 mg/m(2) [range: 90-411 mg/m(2)] and after a median posttherapeutic interval of 2.9 years [range: 0-10.2 years]. Data on cardiac function before and/or after therapy could be obtained of 186 patients. RESULTS: Posttherapy left ventricular fractional shortening was reduced in 4/157 (2.5%) patients. Out of the 4 children, 2 had clinically reduced tolerance to exercise and received anticongestive therapy. Abnormal ECG findings that were not detectable prior to therapy were found in 7/124 (5.6%) children. CONCLUSIONS: The incidence of abnormal findings is low in our study group in comparison to data from the literature and might be due to the comparably short posttherapeutic interval.

Adolescent↗
PubMed2002

Evidence that the novobiocin-sensitive ATP-binding site of the heat shock protein 90 (hsp90) is necessary for its autophosphorylation.

The 90kDa heat shock protein (Hsp90) is one of the most abundant protein and essential for all eukaryotic cells. Many proteins require the interaction with Hsp90 for proper function. Upon heat stress the expression level of Hsp90 is even enhanced. It is assumed, that under these conditions Hsp90 is required to protect other proteins from aggregation. One property of Hsp90 is its ability to undergo autophosphorylation. The N-terminal domain of Hsp90 has been shown to contain an unusual ATP-binding site. A well-known inhibitor of Hsp90 function is geldanamycin binding to the N-terminal ATP-binding site with high affinity. Recently it was shown that Hsp90 possesses a second ATP-binding site in the C-terminal region, which can be competed with novobiocin. Autophosphorylation of Hsp90 was analysed by incubation with gamma(32)P-ATP. Addition of geldanamycin did not interfere with the capability for autophosphorylation, while novobiocin indeed did. These results suggest that the C-terminal ATP-binding site is required for autophosphorylation of Hsp90.

Adenosine Triphosphate↗