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Biomedical subjects

E Thiel

Publications and source records attributed to E Thiel.

At least 19 recordsLinked to original sources
PubMed2006

Increased chondroitin sulphate proteoglycan expression (B5 immunoreactivity) in metastases of uveal melanoma.

BACKGROUND: Metastatic uveal melanoma has a poor prognosis and limited therapeutic options. Proteoglycans are involved in tumor cell invasion and metastatic behavior. The mAbB5 stains a chondroitin sulphate proteoglycan (CSPG) on cutaneous melanoma cells. Here, we compare the B5-staining of CSPG in primaries and metastases of uveal melanoma. MATERIAL AND METHODS: Immunohistopathological staining was performed in 15 cutaneous and 39 uveal melanoma samples. A score for intracellular and surface staining was established. B5 staining was compared in primaries and metastases of uveal melanoma using Student's t-test. RESULTS: Eight of 11 (73%) uveal melanoma metastases were positive for B5-staining whereas only 5 of 28 (18%) primary uveal melanoma samples were B5-positive (P < 0.001). Nine of 15 cutaneous melanoma samples (60%) were B5-positive without significant difference between primary and metastatic lesions. Surface staining was found both on uveal melanoma metastases and cutaneous melanomas. CONCLUSIONS: CSPG was expressed significantly more often in metastases than in primaries of uveal melanoma. It potentially may be one factor associated with metastatic spread. Further studies are needed to determine its use as prognostic factor. The mAbB5 may also be a promising tool for immunotherapy due to its strong staining of CSPG on the surface of cutaneous and metastatic uveal melanoma cells.

Chondroitin Sulfate Proteoglycans↗
PubMed2006

A randomized phase II trial of gemcitabine plus treosulfan versus treosulfan alone in patients with metastatic uveal melanoma.

BACKGROUND: Several trials demonstrated efficacy of the gemcitabine/treosulfan (GeT) combination in metastatic uveal melamoma. This randomized phase II trial compared the GeT combination versus treosulfan alone (T) in this rare disease. PATIENTS AND METHODS: Chemotherapy-naive patients with proven metastatic uveal melanoma were randomly assigned to receive 1000 mg/m(2) of gemcitabine plus 3500 mg/m(2) of treosulfan (GeT) or 3500 mg/m(2) of T. Chemotherapy was administered on days 1 and 8 in both arms, cycles were repeated on day 29. Primary end point was rate of responses and disease stabilizations. RESULTS: Forty-eight patients were randomized. Seven confirmed stable diseases (SDs) and one partial remission (PR) were observed in 24 patients treated with the GeT regimen, whereas no PR and only three SDs were observed in the T arm (P = 0.08). Median progression-free survival (PFS) was 3 months (95% CI 1.1-4.9) and 2 months (95% CI 1.7-2.3) in the GeT and T arm (P = 0.008, log-rank). Six and 12 months PFS was 34.8% and 17.9% and 16.7% and 0% always favoring the GeT arm. CONCLUSIONS: This first randomized trial in metastatic uveal melanoma showed a superior PFS and a trend for a higher response/stabilization rate of the GeT combination over T.

Adult↗
PubMed2006

Low-dose liposomal amphotericin B in the prevention of invasive fungal infections in patients with prolonged neutropenia: results from a randomized, single-center trial.

BACKGROUND: We performed a prospective, randomized, open-label trial to evaluate the efficacy of low-dose liposomal amphotericin B (L-AmB) to reduce the incidence of invasive fungal infections (IFI) in patients with hematological malignancies and prolonged neutropenia (>10 days) following intensive chemotherapy. PATIENTS AND METHODS: In 219 neutropenic episodes (NE) of 132 patients randomization was performed. Patients received either 50 mg L-AmB every other day (arm A) or no systemic antifungal prophylaxis (arm B). RESULTS: In the first NE of each patient the incidence of proven or probable IFI (primary end point) was five of 75 patients (6.7%) in arm A and 20 of 57 patients (35%) in arm B (P=0.001). Invasive aspergillosis occurred less frequently in patients receiving L-AmB-prophylaxis (P=0.0057), whereas the reduction of invasive candidiasis did not reach statistical significance (P=0.0655). In all NE the incidence of IFI was five of 110 NE (4.6%) in arm A versus 22 of 109 NE (20.2%) in arm B (P<0.01). Adverse events, possibly related to L-AmB, were observed in five NE (4.6%) and L-AmB was discontinued in three NE (2.8%). No grade 3 or 4 toxicities were observed. CONCLUSIONS: Antifungal prophylaxis with low-dose L-AmB proved to be feasible and effective in our trial.

Adult↗
PubMed2006

Continuous-wave solid-state dye laser.

We report the first realization of a cw solid-state dye laser. The laser medium consists of a laser dye (Rhodamine 6G) dissolved in a photopolymer. The UV-cured solution is sandwiched between two DVD substrates. The resonator design was derived from a conventional liquid solvent dye laser geometry. The laser radiation can be tuned from 565 to 615 nm by using a birefringent filter. A pump power of 2 W leads to a cw output power of more than 20 mW.

Journal Article↗
PubMed2006

Comparative analysis of hypermethylation of cell cycle control and DNA-mismatch repair genes in low-density and CD34+ bone marrow cells from patients with myelodysplastic syndrome.

Hypermethylation of CpG islands within the promoter region is one of the mechanisms by which genes are inactivated and may be one of the reason for silencing of cell cycle control or DNA-mismatch repair genes in myelodysplastic syndrome (MDS). Since the function of cell cycle control genes including the cyclin-dependent kinase inhibitors known as p15(INK4b) and p16(INK4a), as well as p14(ARF) which blocks MDM-2 (an inhibitor of p53), the retinoblastoma (RB1) protein and the mismatch repair gene MGMT is critical for hematopoietic proliferation and differentiation, we performed methylation specific polymerase chain reaction (MSP) in low-density, non-adherent bone marrow cells from 49 patients with MDS. In addition, expression of p15(INK4b) and RB1 was analysed by quantitative real-time PCR. From selected patients, we analyzed the methylation pattern of cell cycle control genes in CD34+ bone marrow cells. Thirty-nine of 49 cases (80%) had at least one of five genes methylated in our MDS samples by analysing low-density non-adherent bone marrow cells. The frequency of p15(INK4b) methylation was 34 of 49 samples (69%). The incidence of methylation of both p14(ARF) and p16(INK4a) was four of 49 (8%). RB1 gene was methylated in seven samples (14%) and each patient had RA. Interestingly, none of these genes were methylated in the purified CD34+ hematopoietic stem cells from the MDS patients. Furthermore, all our RARS patients had a methylated p15(INK4b) promoter correlating with non-detectable expression of this gene in bone marrow cells from those patients. These results indicate that hypermethylation of cell cycle control genes in MDS may occur late during the differentiation of myelodysplastic stem cells.

Adult↗
PubMed2006

Prospective trial on topotecan salvage therapy in primary CNS lymphoma.

BACKGROUND: Standard salvage therapy has not been established for recurrent primary central nervous system lymphoma (PCNSL). We report the final results of a prospective study on topotecan chemotherapy in relapsed or refractory PCNSL. PATIENTS AND METHODS: The study included 27 patients with a median age of 51 years and an ECOG performance status of 2. Fourteen patients were refractory to the last therapy, and 13 relapsed after a median period of 6.0 months. Pretreatment with up to four regimens included chemotherapy in 26 patients and whole brain irradiation in 14. A 30-min daily topotecan infusion of 1.5 mg/m(2) for 5 days was repeated every 3 weeks. RESULTS: The response rate was 33% with five complete (CR) and four partial remissions (PR). The median follow-up was 37.7 months. All complete responders had sustained remissions lasting for 9 to 28 months. The median event-free survival (EFS) was 2.0 months (9.1 months in responders), the overall survival (OAS) was 8.4 months. CTC grade 3-4 leukopenia occurred in 26% and thrombocytopenia in 11% of the patients. Eight of 12 patients alive without cerebral lymphoma > or = six months after topotecan exhibited deficits attributable to late neurotoxicity. CONCLUSION: Topotecan as monotherapy is active in relapsed and refractory PCNSL with tolerable toxicity.

Adult↗
PubMed2006

A randomized phase II trial of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small-cell lung cancer.

BACKGROUND: Superiority of irinotecan/cisplatin over etoposide/cisplatin was suggested in small-cell lung cancer (SCLC). This trial investigated irinotecan/carboplatin (IP) versus etoposide/carboplatin (EP). PATIENTS AND METHODS: The interim analysis at the phase II/phase III transition point of the multicenter trial is reported. Extensive disease SCLC patients were randomized to receive carboplatin AUC 5 mg x min/ml either in combination with 50 mg/m2 of irinotecan on days 1, 8 and 15 (IP) or with etoposide 140 mg/m2 days 1-3 (EP). The primary end point was response rate and the secondary end points were toxicity and progression-free survival. RESULTS: Seventy patients were randomized. Significant differences in grade 3 and 4 thrombopenia (17% IP versus 48% EP, P = 0.01) and neutropenia (26% IP versus 51% PE, P < 0.01) were found. Grade 3 and 4 diarrhea was more frequent with IP (18%) than with EP (6%) (P = 0.133). Response rates were 67% and 59% (P = 0.24) in the IP versus EP arm, respectively. Median progression-free survival (PFS) was 9 months (95% CI 7.1-10.9) in the IP arm and 6 months (95% CI 4.1-7.9) in the EP arm (P = 0.03). CONCLUSIONS: IP is active, less toxic and appears to improve PFS. Based on the phase II results the trial has been extended to phase III to assess the impact on overall survival.

Adult↗
PubMed2006

Monitoring minimal residual disease by quantification of genomic chromosomal breakpoint sequences in acute leukemias with MLL aberrations.

An estimated 10% of acute leukemias carry mixed-lineage leukemia (MLL) fusion genes. Approximately 50 different fusion partners of the MLL gene have already been molecularly identified. These leukemias are commonly regarded as high-risk cases and are treated accordingly with intensified therapy regimens, including hematopoietic stem cell transplantation. However, a subset of patients may achieve long-term remissions with conventional therapy. Monitoring minimal residual disease (MRD) is undoubtedly of great value in clinical decision making, also in the pre- and post-transplant setting. Here, we describe a novel method for detecting MRD in leukemias with MLL aberrations. The method is based on monitoring patient-specific chromosomal breakpoint DNA sequences. This has several advantages over other methods that are based either on detecting specific RNA molecules of MLL fusion genes or on surrogate markers. An accurate and absolute quantification of the MRD level is possible. No reference to housekeeping genes is necessary and the target structure is much more stable than any mRNA fusion transcript.

Acute Disease↗
PubMed2006

Allogeneic hematopoietic cell transplantation following conditioning with 90Y-ibritumomab-tiuxetan.

Radioimmunotherapy (RIT) of relapsed lymphoma is gaining increasing importance. Especially the commercially available anti-CD20 antibody 90Y-ibritumomab tiuxetan is currently under investigation in various trials including dose escalation and autologous hematopoietic progenitor cell support. It is not clear, however, whether the implementation of this radiolabeled antibody into another treatment option for relapsed or poor risk lymphoma patients-allogeneic hematopoietic cell transplantation-interferes with or delays successful engraftment. This study reports encouraging results with 2 relapsed lymphoma patients (1 transformed marginal zone lymphoma and 1 mantle cell lymphoma) who underwent allogeneic hematopoietic cell transplantation from HLA-matched donors. The conditioning regimen consisted of Rituximab 250 mg m(-2) on days -21 and -14, 0.4 mCi kg(-1) body weight 90Y-ibritumomab tiuxetan on day -14 and fludarabine (30 mg m(-2)) plus cyclophosphamide (500 mg m(-2)) on days -7 to -3. The data demonstrate that engraftment is fast and reliable with leukocytes >1 x 10(9) L(-1) on day 12 and platelets >50 x 10(9) L(-1) on day 10. Thus, the incorporation of radioimmunotherapy into allogeneic transplant protocols combines established modalities with proven anti-lymphoma activity and, hence, offers an attractive new therapeutic option for relapsed lymphoma patients.

Adult↗
PubMed2006

A 19-year-old male with generalized seizures, unconsciousness and a deviation of gaze.

Light chain deposition disease (LCDD) is a form of monoclonal immunoglobulin deposition diseases (MIDD) which in contrast to light-chain derived (AL) amyloidosis is characterized by non-congophilic, non-fibrillary monoclonal protein deposits. Systemic organ deposits are common with the kidney being a major target organ. A clonal lymphoplasmocytic proliferation, e.g. plasmacytoma, is present in the majority of cases. Here we report on a 19-year-old male who presented with generalized seizures and an enhancing white matter lesion on MRI scans. A stereotactic brain biopsy revealed a low-grade B cell lymphoma with plasmacellular differentiation as well as lambda light chain deposits without birefringence under polarized microscopy. No systemic lymphoma manifestations or systemic light chain deposits were found, nor was a monoclonal gammopathy detectable in serum and urine. After systemic chemotherapy with three courses high-dose methotrexate the size of the lesion and the condition of the patient have remained stable for 24 months now. This is the first description of cerebral LCDD developing without systemic disease in conjunction with the diagnosis of a cerebral low-grade B cell lymphoma. We present the clinical, laboratory and radiological findings and discuss the pathogenesis of this unusual LCDD manifestation.

Adult↗
PubMed2005

Neuropsychological function in high-risk breast cancer survivors after stem-cell supported high-dose therapy versus standard-dose chemotherapy: evaluation of long-term treatment effects.

BACKGROUND: Studies on cognitive functioning in breast cancer patients point out that a subset of women exhibit chemotherapy-related neuropsychological impairment. Thereby, high-dose therapy may elevate the risk of cognitive dysfunctions. The primary purpose of the study was to evaluate the impact of high-dose versus standard-dose chemotherapy on the late neuropsychological outcome in randomized assigned high-risk breast cancer survivors. Next to focusing prevalence, function specificity and extent of cognitive impairment, the question as to whether doses-dependent group differences occur was investigated. PATIENTS AND METHODS: Twenty-four high-dose and 23 standard-dose patients 5 years, on average, after treatment underwent a comprehensive neuropsychological assessment. In addition, 29 early-stage breast cancer patients matched for age, education and time since treatment were recruited as a comparison group. RESULTS: Global cognitive impairment was observed in 8% of high-dose versus 13% of standard-dose compared with 3% of early-stage breast cancer patients. Compared with normative data, all patient groups performed worse on one attention subtest measuring the simple reaction time (P < 0.001 in each case). By contrast, no significant between-group differences on the late neuropsychological outcome were found. CONCLUSIONS: Five years after treatment, standard-dose patients were slightly, but not significantly, more impaired in cognitive performance than high-dose patients.

Antineoplastic Agents↗
PubMed2005

Pharmacokinetics and efficacy of ifosfamide or trofosfamide in patients with intraocular lymphoma.

BACKGROUND: The prognosis of intraocular lymphoma (IOL) is poor, and the optimal treatment has not yet been defined. The study assesses ifosfamide (IFO) and trofosfamide (TRO) for treating IOL. PATIENTS AND METHODS: We prospectively evaluated the efficacy and aqueous penetration of intravenous IFO, oral TRO and their active 4-hydroxy (4-OH) metabolites in 10 patients with IOL. Doses varied from 1500 to 2000 mg/m2/day on days 1-3 for IFO and from 150 to 400 mg/day (continuous or intermittent administration) for TRO. Four patients had newly diagnosed disease, and six had relapsed after pretreatment. RESULTS: All patients responded to first treatment with IFO or TRO, and both of two patients responded to re-treatment with IFO on ocular relapse. Progression-free survival from the first treatment with IFO or TRO was > or = 6-18 months. In six of six patients, 4-OH metabolites were detected in the aqueous humor at a concentration of 0.32-1.56 microM immediately after IFO infusion with an aqueous/serum ratio of 0.19-0.54. 4-OH metabolites could be detected in one of three patients at a concentration of 7.2 microM 3-16 h after ingestion of TRO. CONCLUSIONS: IFO and TRO are active in IOL. IOL patients evidence aqueous penetration of 4-OH metabolites after intravenous administration of IFO.

Aged↗
PubMed2005

Primary central nervous system lymphomas (PCNSL): MRI response criteria revised.

The authors investigated the applicability of Macdonald response criteria to patients with primary CNS lymphoma (PCNSL). Four of 68 patients with persisting contrast-enhancing lesions after primary therapy did not receive further therapy, and none showed tumor progression after up to 54 months. Because contrast enhancement may not necessarily indicate residual, biologically active lymphoma, the authors propose a modification of the Macdonald response criteria.

Adult↗
PubMed2005

High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma.

BACKGROUND: The dose of high-dose methotrexate (HDMTX) in elderly patients often has to be reduced, resulting in a loss of treatment efficacy. We evaluated HDMTX-related toxicity with special regard to age distribution in patients with primary central nervous system lymphoma (PCNSL) in a phase IV multicenter trial. PATIENTS AND METHODS: One hundred and fifty-four patients (median age 61 years; 89 patients >60 years old, 21 patients >70 years old) received 619 HDMTX cycles. Toxicity was evaluated prospectively using the WHO classification. Unless a reduced dose was required after calculating a decreased glomerular filtration rate (GFR), the patients received 4 g/m(2) HDMTX followed by leucovorin rescue. RESULTS: Toxicity was generally mild with toxicities of WHO grade > or =3 usually <10%. The differences in the incidence and severity of toxicity were not statistically significant between patients >60 years and < or =60 years old. The same was true for therapy termination owing to MTX toxicity and for delayed serum MTX clearance. Dose reduction significantly differed between patients < or =60 years and those >60 years old (18% versus 44%; P = 0.001). CONCLUSIONS: HDMTX is a safe treatment for PCNSL patients regardless of age, with adherence to dose reduction determined by calculating the GFR before each treatment cycle.

Adult↗
PubMed2005

CD56dimCD16neg cells are responsible for natural cytotoxicity against tumor targets.

The activation of natural killer (NK) cells leads to degranulation and secretion of cytotoxic granula. During this process, the lytic granule membrane protein CD107a becomes detectable at the cell surface. Based on this phenomenon, we have analyzed by a novel flow cytometry-based assay, the number and phenotype of NK cells responding to tumor targets. Using human leukemia and lymphoma cell lines, we observed a close correlation between CD107a surface expression and target cell lysis, indicating that NK cell cytotoxicity can be assessed by this method. The number of degranulating NK cells was closely related to the ratio of effector and target cells and showed a maximum at a ratio of 1:1. Moreover, we were able to show that the population of CD56(dim)/CD16(neg) NK cells is primarily responsible for the cytotoxic activity against tumor targets whereas neither CD56(dim)/CD16(pos) nor CD56(bright) NK cells degranulated in response to the cell lines. Our results indicate that the CD107a assay represents a promising new method for the quantification and characterization of cells exhibiting natural cytotoxicity.

Antigens, CD↗
PubMed2005

Wilms' tumour gene 1 (WT1) in human neoplasia.

The transcription factor Wilms' tumour gene 1 (WT1) is important as a prognostic marker as well as in the detection and monitoring of minimal residual disease in leukaemia and myelodysplastic syndromes. Evidence has accumulated over the past decade to show that WT1 is a key molecule for tumour proliferation in a large number of human neoplasms most prominent in acute leukaemias, making it a suitable target for therapeutic strategies. Based on animal results, showing safety and efficacy of immunization with WT1 peptides and protein, early clinical trials in leukaemia have recently been initiated. The First International Conference on WT1 in Human Neoplasia was held in Berlin, March 11--12, 2004. This report reviews the current knowledge on the role of WT1 in tumour promotion and as a diagnostic and therapeutic target, and summarizes the data presented and discussed in this meeting.

Animals↗
PubMed2005

Molecular heterogeneity of sporadic adult Burkitt-type leukemia/lymphoma as revealed by PCR and cytogenetics: correlation with morphology, immunology and clinical features.

Chromosomal translocations involving the MYC oncogene are a hallmark of Burkitt lymphoma but they are only found in a varying frequency in mature Burkitt-type acute lymphoblastic leukemia (B-ALL). We have investigated samples of 56 sporadic Burkitt leukemia/lymphoma patients for the translocations t(8;14)(q24;q32), t(2;8)(p11;q24) and t(8;22)(q24;q11). Long PCR was used for detecting the immunoglobulin heavy chain (IgH) translocation and cytogenetics and/or fluorescence in situ hybridization for detecting the 'variant' MYC translocations. A total of 29 samples (51.8%) were t(8;14)-positive by long PCR. Approximately one-third had a chromosomal breakpoint in the IgH joining region while the others had breakpoints in the IgH switch regions. Among them were two cases with a previously unreported MYC translocation into the IgE switch region. Long PCR was more reliable compared to conventional cytogenetics for detecting the t(8;14). Epstein-Barr virus was detected in high copy number in two (3.6%) t(8;14)-positive cases by real-time quantitative PCR. Human herpesvirus 8 was not detected in any case by nested PCR. A typical L3 or L3-compatible cytomorphology was highly predictive (>80%) but not specific of a MYC translocation. A total of 34 patients were treated according to the GMALL B-ALL therapy protocols and there was no significant difference in overall survival between patients with or without t(8;14).

Adolescent↗