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Eckhard Thiel

Publications and source records attributed to Eckhard Thiel.

At least 37 records · Page 2Linked to original sources
PubMed2006

Skewed expression of natural-killer (NK)-associated antigens on lymphoproliferations of large granular lymphocytes (LGL).

Killer-immunoglobulin-like receptors (KIR) or C-type lectin-like receptors are heterogeneously expressed on NK cells and small subsets of T cells and might provide a new diagnostic tool for LGL lymphoproliferations (LGLL). We investigated the diagnostic impact of these cell surface molecules in T- and NK-type LGLL. Using three-color flow cytometry we examined the expression patterns of KIR (CD158a/b/e/i), CD85j, lectin-like receptors (CD94, CD161, NKG2A/D) and natural cytotoxicity receptors (NKp30/44/46) in 13 patients with LGLL (10 T-, 3 NK-LGLL) and compared them to those of the corresponding lymphocyte subsets in 20 control subjects. The presence of clonal TCR-gamma rearrangements and of Epstein Barr virus- (EBV) DNA were evaluated by PCR. All patients exhibited an altered expression of NK-associated markers. KIR were either lacking (6/13) or overexpressed (7/13). CD94 expression was significantly higher in all LGLL. NKG2A expression was significantly higher in NK-LGLL. Absence or overexpression was observed for NKG2A in T-LGLL and CD161 in most T/NK-LGLL. In NK-LGLL expression of NKp30 and NKp46 was significantly decreased, whereas CD85j was overexpressed. We consistently found a skewed expression pattern of novel NK markers as a pathological feature of LGLL. These antigens should be included in the diagnostic workup of this rare disease.

Adult↗
PubMed2006

The anti-lymphoma effect of antibody-mediated immunotherapy is based on an increased degranulation of peripheral blood natural killer (NK) cells.

BACKGROUND: In patients treated with rituximab and alemtuzumab for lymphomas or CLL, antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism of action. Therefore, assessment of ADCC is mandatory to understand the complex mechanisms leading to the anti-lymphoma effects of monoclonal antibodies (mAb). Due to methodical difficulties, little is yet known about the relevant cell subpopulations and effector mechanisms leading to tumor lysis in ADCC. METHODS: We used a novel flow cytometric assay that detects CD107a as a marker for NK-cell degranulation to characterize and quantify peripheral blood natural killer (NK) cells mediating ADCC in vitro and in vivo. RESULTS: We observed specific and dose-dependent NK-cell activation after administration of rituximab and alemtuzumab. The number of degranulating NK cells was closely related to the concentration of mAb and the effector:target ratio. We were able to quantify and characterize the peripheral blood NK cells mediating ADCC. The majority of degranulating NK cells had the phenotype: CD56(dim), CD69(+), NKG2D(+), NKp30(-), NKp46(-), and CD94(-). Furthermore, we found that the CD107a assay can also visualize ADCC under clinical conditions as we observed increased numbers of NK cells degranulating in response to CD20(+) lymphoma cell lines in patients with non-Hodgkin's lymphoma treated with rituximab. CONCLUSIONS: We were able to quantify and characterize NK cells mediating ADCC with a new and feasible method. The CD107a assay may be useful for predicting treatment responses of individual patients and may help find the optimal dosage and timing for treatment with mAb.

Antibodies, Monoclonal↗
PubMed2006

The diagnostic value of cerebrospinal fluid pleocytosis and protein in the detection of lymphomatous meningitis in primary central nervous system lymphomas.

The exact rate of lymphomatous meningitis in primary central nervous system lymphomas (PCNSL) is uncertain. In this prospective multicenter study, cerebrospinal fluid (CSF) from 116 immunocompetent patients with newly diagnosed PCNSL was evaluated. Lymphoma cells were found in 18.1%, protein elevation (>45 mg/dL) in 65%, and CSF pleocytosis (>5/microL) in 36% of patients. Pleocytosis correlated with positive cytology, whereas CSF protein did not (specificity cell count vs. protein 74% vs. 34% [p<0.001], sensitivity 86% vs. 62% [p=0.18]).

Central Nervous System Neoplasms↗
PubMed2005

Lymphomas are sensitive to perforin-dependent cytotoxic pathways despite expression of PI-9 and overexpression of bcl-2.

There is considerable interest in immunotherapeutic approaches for lymphoma. The expression of proteinase inhibitor 9 (PI-9), a molecule that inactivates granzyme B, is considered an immune escape mechanism in lymphoma. Further, lymphomas frequently overexpress the antiapoptotic molecule bcl-2, which is able to inhibit perforin-dependent cytotoxic pathways. In this study, the impact of PI-9 and bcl-2 expression on the sensitivity of lymphomas to T- and natural killer (NK) cell-mediated cytotoxicity was analyzed. We found PI-9 expression in 10 of 18 lymphoma cell lines and in 9 of 14 primary lymphomas. Overexpression of bcl-2 was found in 8 of 18 cell lines and in 12 of 14 primary lymphomas. All lymphoma cells were sensitive to cytolysis by specific T cells and cytokine-activated NK cells, and no difference in sensitivity was observed with respect to PI-9 or bcl-2 expression. Cytolysis was mediated predominantly through perforin-dependent pathways despite expression of PI-9 and bcl-2. Interestingly, the majority of lymphoma cells were resistant to cytolysis by resting allogeneic NK cells. This was due to the failure of lymphomas to induce degranulation of resting NK cells. These results show that resistance to perforin-dependent pathways is not a relevant immune escape mechanism in lymphoma and therefore is unlikely to impair clinical outcome of immunotherapeutic approaches.

Cytokines↗
PubMed2005

Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD.

CD4+CD25+ regulatory T cells (Tregs) control immune responses to self- and foreign antigens and play a pivotal role in autoimmune diseases, infectious and noninfectious inflammation, and graft rejection. Since recent experimental studies have indicated that Tregs were able to ameliorate graft-versus-host disease (GvHD), we analyzed the number of infiltrating Tregs in the intestinal mucosa as one site of GvH reactivity using immunoenzymatic labeling to enumerate FOXP3+ T cells in 95 intestinal biopsies from 49 allografted patients in comparison with healthy controls and patients with infectious inflammation. While patients with cytomegalovirus (CMV)-colitis or diverticulitis showed a concomitant increase of CD8+ effectors and Tregs, acute and chronic GvHD were characterized by the complete lack of a counter-regulation indicated by a FOXP3+/CD8+ T-cell ratio identical to healthy controls. In contrast, specimens without histologic signs of GvHD demonstrated increased numbers of FOXP3+ per CD8+ T cells, indicating that the potential for Treg expansion is principally maintained in allografted patients. Our findings provide evidence that GvHD is associated with an insufficient up-regulation of Tregs in intestinal GvHD lesions. The determination of FOXP3+/CD8+ ratio can be a helpful tool to discriminate GvHD from infectious inflammation after allogeneic stem cell transplantation.

Acute Disease↗
PubMed2005

Intraocular lymphoma 2000-2005: results of a retrospective multicentre trial.

BACKGROUND: The prognosis of intraocular lymphoma (IOL) is poor, and the optimal treatment has yet to be defined. This study assesses the clinical characteristics and outcome of patients with IOL diagnosed and treated in the new millennium. METHODS: Patient data in this retrospective multicentre study were compiled by standardised questionnaires sent to seven university ophthalmology departments. All cases diagnosed with primary and secondary IOL in the past 5 years not associated with HIV infection were included. RESULTS: Twenty-two patients, 11 men and women; median age 64 (range 38-83) years, median Karnofsky performance status 90% (range 50-100%), were included. Nineteen patients had primary IOL (PIOL): 13 a newly diagnosed disease and six an ocular relapse of primary central nervous system lymphoma (PCNSL). Three patients had secondary IOL. First-line treatment for IOL included systemic chemotherapy in 13 cases, ocular radiation in six and intraocular chemotherapy in three. Complete remission was achieved in 14/20 evaluable patients, partial remission in five and stable disease in one. All patients treated with ifosfamide (IFO) or trofosfamide (TRO) (n=8) responded. Median progression-free survival (PFS) and overall survival were 10 (range 1+ to 44.5+) and 22.5 (range 1+ to 49+) months, respectively. Patients with newly diagnosed PIOL and ocular relapse of PCNSL had a median PFS of 10 (range 1+ to 44.5+) and 6 (range 2 to 6+) months, respectively. Median PFS was 12 (range 3+ to 22.5+) months after systemic and 5.5 (range 1+ to 44.5+) months after local first-line therapy. CONCLUSIONS: The prognosis of PIOL is similar to that of PCNSL without ocular involvement. Systemic therapy possibly prolongs PFS as compared with local management of (P)IOL. The high response rate to monotherapy with IFO and TRO is promising.

Adult↗
PubMed2005

Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia.

Adult patients with acute lymphoblastic leukemia (ALL) who are stratified into the standard-risk (SR) group due to the absence of adverse prognostic factors relapse in 40% to 55% of the cases. To identify complementary markers suitable for further treatment stratification in SR ALL, we evaluated the predictive value of minimal residual disease (MRD) and prospectively monitored MRD in 196 strictly defined SR ALL patients at up to 9 time points in the first year of treatment by quantitative polymerase chain reaction (PCR). Frequency of MRD positivity decreased from 88% during early induction to 13% at week 52. MRD was predictive for relapse at various follow-up time points. Combined MRD information from different time points allowed definition of 3 risk groups (P < .001): 10% of patients with a rapid MRD decline to lower than 10(-4) or below detection limit at day 11 and day 24 were classified as low risk and had a 3-year relapse rate (RR) of 0%. A subset of 23% with an MRD of 10(-4) or higher until week 16 formed the high-risk group, with a 3-year RR of 94% (95% confidence interval [CI] 83%-100%). The remaining patients whose RR was 47% (31%-63%) represented the intermediate-risk group. Thus, MRD quantification during treatment identified prognostic subgroups within the otherwise homogeneous SR ALL population who may benefit from individualized treatment.

Adolescent↗
PubMed2005

CD10- pre-B acute lymphoblastic leukemia (ALL) is a distinct high-risk subgroup of adult ALL associated with a high frequency of MLL aberrations: results of the German Multicenter Trials for Adult ALL (GMALL).

Immunophenotyping disclosed CD10 negativity in 70 of 2408 cases of B-lineage acute lymphoblastic leukemia (ALL), although other criteria followed classification of pre-B ALL (eg, cytoplasmic immunoglobulin positivity). These blasts showed high myeloid antigen expression (60% CD65 positivity) and reacted with antibody 7.1 in 95% of the cases. MLL-AF4 fusion transcripts or an 11q23/MLL rearrangement or both were evident in 46 of 56 samples (82%). Although 83% of the patients achieved complete remission, the remission duration remained remarkably low: 141 days for MLL rearrangement-positive and 245 days for MLL rearrangement-negative CD10(-) pre-B ALL. Thus, the overall survival probability 3 years after diagnosis was 0.34 +/- 0.20 SE in MLL-rearrangement-negative versus 0.12 +/- 0.06 SE in MLL rearrangement-positive CD10- pre-B ALL. Our data identify CD10- cytoplasmic immunoglobulin-positive pre-B ALL as a rare (2.2%) but distinct immuno-subtype of adult ALL that is characterized by a high MLL rearrangement rate and a worse outcome.

Adolescent↗
PubMed2005

Retrospective study of prognostic factors in non-Hodgkin lymphoma secondarily involving the central nervous system.

The aim of this retrospective single-center study was to analyze the clinical characteristics and outcome of non-Hodgkin lymphoma (NHL) patients with central nervous system (CNS) involvement and to identify prognostic factors for survival. We searched our hospital records for NHL patients diagnosed with CNS involvement from 1982 to 2004, and 43 patients were identified. The median age was 63 years (range 23-88) and the median Karnofsky performance status was 55% (range 10-90). Treatment of CNS lymphoma included intrathecal chemotherapy in 33 patients (77%), systemic chemotherapy in 25 (58%), and radiotherapy in 16 (37%). Twenty-six patients showed a CNS response. The median survival after CNS manifestation was 5 months (range 2 days-82.5+months). Nine patients achieved long-term survival. Low lactate dehydrogenase (LDH) at CNS manifestation and a CNS response to therapy were favorable independent prognostic factors for survival in multivariate analysis (p = 0.051 and p < 0.0005, respectively), whereas a young age at initial diagnosis, initial CNS involvement, an initially normal LDH, and high-dose chemotherapy for CNS involvement were significant in univariate analysis. In conclusion, long-term survival can be achieved in patients with secondary CNS lymphoma. LDH at CNS manifestation and a CNS response to therapy were significantly associated with survival.

Adult↗
PubMed2005

Ifosfamide/liposomal daunorubicin is a well tolerated and active first-line chemotherapy regimen in advanced soft tissue sarcoma: results of a phase II study.

BACKGROUND: The anthracycline/ifosfamide combination is the most effective chemotherapy in soft tissue sarcoma. To improve the tolerability and potential efficacy of this combination, the authors combined a moderate dose of continuous infusion ifosfamide with liposomal daunorubicin (L-Dauno). METHODS: In a single-arm, Phase II study, 40 patients with a median age of 57 years (range, 19-78 years) were enrolled. Of these, 35 patients were treated with first-line chemotherapy. The treatment regimen was comprised of ifosfamide at a dose of 5 g/m(2) over 24 hours and L-Dauno at a dose of 100 mg/m(2) every 4 weeks with granulocyte-colony-stimulating factor support. RESULTS: Eleven (31%) of 35 anthracycline/ifosfamide-naive patients achieved a partial/complete response, 6 patients (17%) had stable disease, and 13 patients (37%) had disease progression. Three patients were not evaluable, and there were two intermittent deaths. The median time to disease progression was 6 months, the median overall survival was 14 months, and the median time to treatment failure was 15 months. Toxicity was tolerable. CONCLUSIONS: The combination of Ifosfamide and L-Dauno was found to be a highly active chemotherapy regimen for first-line treatment of soft tissue sarcoma. Therefore, we believe randomized studies with this regimen are warranted.

Adult↗
PubMed2005

Improved outcome in central nervous system aspergillosis, using voriconazole treatment.

The mortality of central nervous system (CNS) aspergillosis approaches 100%, requiring improved therapies. Voriconazole gives superior efficacy and survival in invasive aspergillosis, compared with amphotericin B. Also, in contrast to other antifungal drugs, voriconazole penetrates well into the CNS. We evaluated, retrospectively, the outcome and survival of 81 patients who were treated with voriconazole for definite (n = 48) or probable (n = 33) CNS aspergillosis. Complete and partial responses were recorded in 35% of patients and varied by the underlying disease group: hematologic malignancies (54%), other underlying conditions (50%), chronic immunosuppression (45%), solid organ transplantation (36%), and hematopoietic stem cell transplantation (16%). Thirty-one percent of patients survived CNS aspergillosis for a median observation time of 390 days. There were 31 patients who underwent neurosurgical procedures, including craniotomy/abscess resection (n = 14), abscess drainage (n = 12), ventricular shunt (n = 4), and Ommaya-reservoir (n = 1). Multifactorial analysis revealed that neurosurgery was associated with improved survival (P = .02). Patients who underwent hematopoietic stem cell transplantation had a poorer survival (P = .02), but 7 (22%) of 32 survived for a median of 203 days. We conclude from this large cohort of patients that voriconazole treatment together with neurosurgical management, whenever feasible, is currently the best approach to treat patients with CNS aspergillosis.

Adult↗
PubMed2005

Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma.

Standardized guidelines for the baseline evaluation and response assessment of primary CNS lymphoma (PCNSL) are critical to ensure comparability among clinical trials for newly diagnosed patients. The relative rarity of this tumor precludes rapid completion of large-scale phase III trials and, therefore, our reliance on the results of well-designed phase II trials is critical. To formulate this recommendation, an international group of experts representing hematologic oncology, medical oncology, neuro-oncology, neurology, radiation oncology, neurosurgery, and ophthalmology met to review current standards of reporting and to formulate a consensus opinion regarding minimum baseline evaluation and common standards for assessing response to therapy. The response guidelines were based on the results of neuroimaging, corticosteroid use, ophthalmologic examination, and CSF cytology. A critical issue that requires additional study is the optimal method to assess the neurocognitive impact of therapy and address the quality of life of PCNSL survivors. We hope that these guidelines will improve communication among investigators and comparability among clinical trials in a way that will allow us to develop better therapies for patients.

Central Nervous System Neoplasms↗
PubMed2005

Peptide vaccination after repeated resection of metastases can induce a prolonged relapse-free interval in melanoma patients.

This pilot study was carried out to gain a first insight into the effects of peptide vaccination in melanoma patients in the high-risk adjuvant disease setting. From the adjuvant peptide vaccination studies carried out in our institution since 1998, we identified all melanoma patients with a history of at least 3 completely resected metastases during the year preceding enrollment into the trial and describe the clinical and immunologic observations. Out of a total of 44 patients with resected cutaneous melanoma entered into adjuvant peptide vaccination trials, 9 patients were identified with more than 3 metastases in the year before vaccination. After initiation of vaccination, 2 patients remained relapse-free for 27 and 42+ months, 2 patients experienced single or several initial relapses and subsequent relapse-free intervals of 18 and 65+ months, whereas 5 patients progressed. In both patients with relapse after prolonged relapse-free intervals, the relapses were initially confined to the small intestine and could be resected. Induction or boosting of functional tyrosinase peptide-specific T cells was noted in 6 of 8 patients, including all 4 patients with prolonged relapse-free intervals. In conclusion, adjuvant peptide vaccination was associated with cessation of recurrences in 4 of 9 patients, of whom all 4 had an immunologic response to the vaccine.

Adjuvants, Immunologic↗
PubMed2005

Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group.

PURPOSE: To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell CNS lymphoma (TPCNSL). PATIENTS AND METHODS: A retrospective series of patients with TPCNSL was compiled from twelve cancer centers in seven countries. RESULTS: We identified 45 patients with a median age of 60 years (range, 3 to 84 years). Twenty (44%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Twenty-six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Serum lactate dehydrogenase was elevated in 7 (32%) of 22 patients, and CSF protein was elevated in 19 of 24 patients (79%) with available data. The median disease-specific survival (DSS) was 25 months (95% CI, 11 to 38 months). The 2- and 5-year DSS were 51% (95% CI, 35% to 66%) and 17% (95% CI, 6% to 34%), respectively. Univariate and multivariate analyses were conducted for age (</= 60 v > 60 years), PS (0 or 1 v 2, 3, or 4), involvement of deep structures of the CNS (no v yes), and methotrexate (MTX) use in the primary treatment (yes v no). Only PS and MTX use were significantly associated with better outcome with hazard ratios of 0.2 (95% CI, 0.1 to 0.4) and 0.4 (95% CI, 0.2 to 0.8), respectively. CONCLUSION: This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of B cell PCNSL. PS 0 or 1 and administration of MTX are associated with better survival.

Adolescent↗
PubMed2005

T cell responses against tumor associated antigens and prognosis in colorectal cancer patients.

INTRODUCTION: Spontaneous T cell responses against specific tumor-associated antigens (TAA) are frequently detected in peripheral blood of tumor patients of various histiotypes. However, little is known about whether these circulating, spontaneously occurring, TAA-reactive T cells influence the clinical course of disease. METHODS: Fifty-four HLA-A2 positive colorectal cancer patients had been analyzed for the presence of T cell responses against epitopes derived from the TAA Ep-CAM, her-2/neu, and CEA either by ELISPOT assay or by intracellular cytokine staining. Then, Kaplan-Meier survival analysis was performed comparing T-cell-responders and T-cell-non-responders. For comparison, a group of T-cell-non-responders was compiled stringently matched to T-cell-responders based on clinical criteria and also analyzed for survival. RESULTS: Sixteen out of 54 patients had a detectable T cell response against at least one of the three tested TAA. Two out of 21 patients (9.5%) with limited stage of disease (UICC I and II) and 14 out of 33 patients (42.4%) with advanced disease (UICC III and IV) were T cell response positive. Comparing all T-cell-responders (n = 16) and all T-cell-non-responders (n = 38), no survival difference was found. In an attempt to reduce the influence of confounding clinical factors, we then compared 16 responders and 16 non-responders in a matched group survival analysis; and again no survival difference was found (p = 0.7). CONCLUSION: In summary, we found no evidence that spontaneous peripheral T cell responses against HLA-A2-binding epitopes of CEA, her-2/neu and Ep-CAM are a strong prognostic factor for survival.

Journal Article↗