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A Knuth

Publications and source records attributed to A Knuth.

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

Generation of cytotoxic T-cell responses with synthetic melanoma-associated peptides in vivo: implications for tumor vaccines with melanoma-associated antigens.

Peptide epitopes derived from differentiation antigens of the melanocyte lineage have been identified in human melanomas and normal cultured melanocytes as targets for MHC-restricted cytotoxic T lymphocytes (CTL). Characterization of multiple CTL-defined antigenic determinants and the presence of corresponding precursor CTL open perspectives for the development of antigen-based vaccines. In the present study, we determined the CTL reactivity against melanoma-associated peptides derived from Melan A/MART-1, tyrosinase and gp100/Pmel17 in 10 HLA-A2+ melanoma patients and 10 healthy individuals. Then, we examined the immunological effects and toxicity of intradermal inoculation of synthetic melanoma-associated peptides. Six patients with advanced melanoma received weekly intradermal injections of 6 melanoma-associated peptides and the influenza matrix peptide as a control for 4 consecutive weeks. DTH reactions were observed in 5/6 patients at the injections sites of the tyrosinase signal peptide and of the influenza matrix peptide. No toxic side effects were observed. Changes in CTL reactivity after peptide vaccination were assessed by an MLPC assay for each peptide. Generation of peptide-specific CTL was documented against Melan A/MART-1-derived peptide epitopes, the tyrosinase signal peptide and the influenza matrix peptide after vaccination. A decreasing CTL response against the internal tyrosinase peptide was documented in 1 patient through the course of vaccination and a decrease in DTH reactions. No major tumor regressions were observed. Two patients with rapidly progressive disease before vaccination have shown disease stabilization since vaccinations started. In conclusion, our results demonstrate that peptide alone injected intradermally may generate antigen-specific DTH reactions and an increase of antigen-specific CTL reactivity.

Adult↗
PubMed1996

Amino acid substitutions at position 97 in HLA-A2 segregate cytolysis from cytokine release in MART-1/Melan-A peptide AAGIGILTV-specific cytotoxic T lymphocytes.

CD8+ T lymphocytes recognize antigenic peptides presented by major histocompatibility complex (MHC) class I molecules. Individual peptide termini appear to be fixed at the C- and N-terminal ends. In contrast, central peptide side chains residues may point in different directions and exhibit limited flexibility, dependent on the MHC class I structural variation. For instance, position 97 in HLA-A201 has been shown to shift individual peptide species into different coordinations, one oriented towards the peptide N terminus, or more towards the C-terminal end. The conformational shape of such non-anchor peptide residues may affect the affinity of MHC/peptide/TCR interaction, resulting in quantitative, or qualitative different T cell effector functions. To characterize the impact of different amino acid residues occupying position 97 in HLA-A2 on peptide binding and presentation to CTL, we generated a panel of mutated HLA-A2 molecules containing either M, K, T, V, G, Q, W, P or H at position 97. The HLA-A0201 presented melanoma-associated MART-1/Melan-A derived peptide AAGIGILTV was employed to assess the impact of such position-97 mutations on HLA-A2 in peptide binding measured in an HLA-A2 reconstitution assay and presentation to AAGIGILTV-specific polyclonal or clonal T lymphocytes as measured by cytotoxicity, or interferon (IFN)-gamma and granulocyte/ macrophage colony-stimulating factor (GM-CSF) secretion. The high-affinity AAGIGILTV peptide bound to all position-97 mutants, albeit with differential efficiencies, and elicited specific release of IFN-gamma and GM-CSF by CTL. CTL responses were triggered only by the HLA-A2 wild type, by HLA-A2-H97 (histidine position 97 mutant), and HLA-A2-W97. The HLA-A2-M97 presenting molecule elicited enhanced cytokine release and CTL effector functions by polyclonal and by clonal effector T cells. These results indicate that MHC class I-bound peptides can trigger specific cytokine release by effector T cells independently of their ability to induce cytolysis. We conclude that relatively minor changes in the MHC class I peptide binding groove, including substitutions at position 97, can affect recognition by antigen-specific T cells. Mutant MHC class I molecules, such as those described here, may act as partial peptide antagonists and could be useful for inducing T lymphocytes with qualitatively different effector functions.

Amino Acid Sequence↗
PubMed1996

Recognition of human renal cell carcinoma and melanoma by HLA-A2-restricted cytotoxic T lymphocytes is mediated by shared peptide epitopes and up-regulated by interferon-gamma.

Cytotoxic T lymphocytes (CTL) have previously been isolated from peripheral blood of patients with renal cell carcinoma (RCC). The CD8-positive CTL line MZ1257-CTL-5 (CTL-5) has been shown to lyse autologous cultured RCC cells in an HLA-A2 restricted fashion. Allogeneic, HLA-A2-matched RCC and melanoma cell lines were also lysed by CTL-5, suggesting that melanoma and renal cancer share antigenic determinants. The aim of the study was to determine whether RCC and melanoma share peptide epitopes that are recognized by CTL-5 in the context of HLA-A2 molecules. Peptides were acideulated from various cell lines, separated by reversed phase high performance liquid chromatography (RP-HPLC), and assessed for their ability to reconstitute the CTL-5-defined epitope by pulsing the peptides on HLA-A2 positive antigen-processing mutant cell line CEM x 721.174.T2 (T2). Peptides eluted from allogeneic HLA-A2-matched RCC and melanoma cell lines exhibited the CTL-5-defined epitope in the same HPLC fractions as peptides derived from the autologous RCC line. Renal cancer and melanoma cells preincubated with interferon-gamma (IFN-gamma) resulted in an additional peak of reconstitution activity in both cell types. This second lytic peak was also observed when high amounts of autologous RCC cells were used for peptide preparation without IFN-gamma pretreatment, indicating that IFN-gamma increases the amount of MHC class I/peptide complexes per cell, rather than inducing a neo-epitope.

B-Lymphocytes↗
PubMed1996

Cytolytic T cell reactivity against melanoma-associated differentiation antigens in peripheral blood of melanoma patients and healthy individuals.

Antigenic peptides derived from several differentiation antigens of the melanocyte lineage were recently identified in human melanomas as targets for HLA-A2.1-restricted cytotoxic T lymphocytes (CTLs). To examine their potential role in tumour-directed immune responses in vivo, we determined CTL reactivity against seven antigenic peptides derived from the Melan A/MART-1, tyrosinase and gp100/Pmel17 antigens in the peripheral blood of 10 HLA-A2+ healthy controls and 26 HLA-A2+ melanoma patients. The influenza matrix peptide (GILGFVFTL) presented by HLA-A2.1 was used as a control peptide. CTL reactivity was assessed in a mixed lymphocyte 'peptide' culture assay. Reactivity against Melan A/MART-1-derived peptide antigens was readily detectable in both melanoma patients and controls. Reactivity directed against tyrosinase-derived peptide antigens was also detected in both melanoma patients and healthy individuals, but less frequently. A measurable response against gp100/Pmel17-derived antigens was found in 1/10 controls and in 1/26 of the melanoma patients. Reactivity against the influenza matrix peptide was common in both melanoma patients and controls. Our findings show that precursor CTLs against melanocyte differentiation antigens can be detected in peripheral blood of melanoma patients and healthy individuals. The pattern of CTL reactivity directed against melanoma-associated antigens does not seem to be altered in melanoma patients. Despite antigen-specific CTL reactivity, tumour growth was not prevented in melanoma patients and autoimmune phenomena were not detected in healthy individuals. It remains to be determined whether precursor CTLs recognizing melanocyte differentiation antigens can be activated by immunization and lead to effective tumour rejection in vivo.

Amino Acid Sequence↗
PubMed1996

Tumor associated antigens in human renal cell carcinoma: MHC restricted recognition by cytotoxic T lymphocytes.

Based on previous studies in human melanoma leading to the molecular cloning of genes encoding peptide antigens recognized by MHC-restricted cytotoxic T lymphocytes (CTL) we extended our efforts to renal cancer systems established in tissue culture. In two patients we obtained stable CD8+ CTL clones with high cytolytic activity for the corresponding autologous tumor cell line in vitro. Neither autologous EBV-transformed B lymphocytes or PHA-activated PBL nor natural killer targets K562 were lysed by these CTL clones. MZ1257-RCC CTL5-30 lysed autologous tumor cells as well as normal kidney cell cultures in an HLA-A2 restricted fashion. Further specificity analysis showed cross reactivity with HLA-A2 matched renal cancer cell lines, melanoma cell lines and tumor cell lines of other origins. HLA-A2 negative target cells were not lysed. The restriction element for T cell recognition in another renal cancer system, MZ1973-RCC, appeared to be HLA-B8 as tested with CTL 5-10. Crossreactivity of CTL 5-10 was documented with one HLA-B8 positive RCC line. Tumor cell lines of other origin were not lysed by CTL 5-10. For further study of CTL-defined epitopes, peptides were extracted from tumor cell lines. Peptides from cultured cell lines were acid-eluted and fractionated by reversed phase HPLC. The peptide fractions were tested in cytotoxicity assays for their ability to reconstitute RCC epitopes by addition to the HLA-A2.1 positive antigen processing mutant cell line 721.124xCEM.T2. One HPLC peak was identified containing an epitope for the HLA-A2 restricted MZ1257-RCC CTL 5-30. These peptide epitopes were present in the autologous renal cancer cell line MZ1257-RCC as well as in an allogeneic HLA-A2 positive RCC cell line MZ1973 and melanoma cell line SK29-MEL, but were absent in peptides eluted from autologous EBV-B cells. We conclude that renal cell carcinoma may induce autologous CTL. Epitopes recognized by MHC-restricted CTL on RCC may be shared by HLA-matched allogeneic renal cancer or even tumors of other origin, such as melanoma. The current challenge is the determination of the amino acid sequences of these CTL-defined peptides as a step to further characterize the nature of these tumor associated antigens.

Antigens, Neoplasm↗
PubMed1996

Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1.

PURPOSE: To determine the most effective dose of leucovorin (folinic acid [FA]) within a weekly bolus fluorouracil (FU) schedule, we conducted a randomized multicenter trial to compare therapeutic effects and toxicity of high-dose FA versus low-dose FA combined with FU at equal doses in both treatment groups. PATIENTS AND METHODS: Patients with measurable inoperable or metastatic colorectal cancer were randomized to receive weekly FU 500 mg/m2 by intravenous (IV) bolus combined with high-dose FA 500 mg/m2 (group A) or low-dose FA 20 mg/m2 (group B) by 2-hour infusion. RESULTS: Of 291 assessable patients (group A, n = 148; group B, n = 143), we observed, in group A, complete response (CR)/partial response (PR) in 32 (21.6%), no change (NC) in 64 (43.2%), and progressive disease (PD) in 52 (35.1%); and in group B, CR/PR in 25 (17.5%), NC in 63 (44.1%), and PD in 55 (38.5%). The median response duration was 24.8 weeks in group A and 23.1 weeks in group B. Median progression-free intervals were 29.3 weeks (group A) and 30 weeks (group B). The median survival time was 55.1 weeks in group A and 54.1 weeks in group B. Overall toxicity was moderate. Mild nausea and vomiting, and stomatitis were common side effects in both groups. The incidence of World Health Organization (WHO) grade III/IV diarrhea was significantly higher in group A (40 v 23 patients). Severe side effects were observed only in a minority of patients in both arms. WHO grade IV diarrhea was observed in seven patients: four in group A and three in group B. The rate of toxicity-related adjustments of dose and schedule was comparable in both groups. CONCLUSION: High-dose FA/FU is not superior to low-dose FA/FU within a weekly treatment schedule. Response rates and survival were comparable in both treatment arms. Treatment-related toxicity was higher in group A (high-dose FA). Therefore, low-dose FA combined with weekly FU may be considered the preferred treatment for metastatic colorectal cancer.

Adult↗
PubMed1996

Peripheral T-cell lymphomas respond well to vincristine, adriamycin, cyclophosphamide, prednisone and etoposide (VACPE) and have a similar outcome as high-grade B-cell lymphomas.

Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of T-cell malignancies including subentities with favourable (large cell anaplastic) or unfavourable (pleomorphic) prognosis. The clinical outcome of PTCL has been controversially discussed, but a worse prognosis than high-grade B-cell Non-Hodgkin's lymphomas (NHL) has been postulated by most authors. In this report we summarize the results of a prospective comparative study investigating the therapy outcome of 27 patients (pts) with PTCL and 55 pts. with high grade B-cell NHL and give an overview of therapy studies in PTCL. The histological subtypes were 14 pleomorphic, 8 large-cell anaplastic (Ki-1+), 2 angioimmunoblastic (AILD) and 3 other PTCL. In three patients the PTCL was associated with non-tropical sprue (11%). Nineteen patients presented with an advanced stage of disease (stage III and IV, 70%), 17 (63%) pts. had B-symptoms. The patients were treated with vincristine 2 mg d1, adriamycin 25 mg/m2 d1-3, cyclophosphamide 800 mg/m2 d1, prednisone 60 mg/m2 d1-7 and etoposide 120 mg/m2 d1-3 (VACPE). In 77% of pts. with PTCL and 84% of patients with high-grade B-cell NHL a complete remission (CR) was achieved. 75% of the complete responders with PTCL and 70% with B-NHL are still in ongoing CR. The subgroup of large-cell anaplastic attained a CR in 88%. The median observation time is 44 months (1(+)-77+). The probability of 1-, 3- and 5-year overall and disease-free survival for the T-cell group were 76%, 54%, 48% and 76%, 62%, 62%, respectively according to Kaplan-Meier. There was no significant difference regarding the remission rate, the overall-, event-free or disease-free survival compared to high-grade B-cell lymphomas. In conclusion, the VACPE regimen is an effective and feasible regimen in the management of PTCL achieving complete remissions in a large proportion of patients.

Adolescent↗
PubMed1996

Tumor escape from immune recognition: loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the short arm of chromosome 6.

Specific CD8(+) CTL recognition of melanoma requires expression of MHC class I molecules as well as melanoma-associated peptide epitopes. Human melanoma cells may escape immune recognition by a variety of means, including global or allelic down-regulation of MHC class I molecules. Stable MHC class I cell surface expression requires delivery of cytosolic peptides into the endoplasmic reticulum by the peptide transporter molecules TAP1 and TAP2, with peptides subsequently transported to the cell surface in complexes containing MHC class I heavy chain and beta2-microglobulin. We have evaluated a series of mechanisms resulting in MHC class I down-regulation in a human melanoma cell line, Mz18, typed as HLA-A2(+), A3(+), B7(+), B57(+), Cw1(+), and Cw6(+) by genomic PCR analysis. The melanoma cell line Mz18 exhibits a global down-regulation of MHC class I heavy chain transcripts; beta2-microglobulin; the proteasome subunits LMP2/7, involved in generating cytosolic peptide fragments; and the peptide transporter molecules TAP1 and TAP2, involved in peptide transport from the cytosol into the endoplasmic reticulum. IFN-gamma treatment of Mz18 melanoma cells leads to up-regulation of LMP2/7 and TAP1/2, as well as to up-regulation of HLA-B and HLA-C MHC loci alleles, but not HLA-A2 or HLA-A3. Karyotypic analysis and fluorescence in situ hybridization with chromosome 6 and MHC class I-specific probes showed complex rearrangement of one chromosome 6 involving the MHC class I locus on 6p and translocation of 6q to the long arm of chromosome 19. To evaluate the capability of melanoma Mz18 to present tumor-specific peptides to HLA-A2-restricted, melanoma-specific CTLs, we restored HLA-A2 surface expression by retroviral-mediated transfer of functional HLA-A2 cDNA. Melanoma peptides could only be presented and recognized by CTLs if the HLA-A2-transfected Mz18 cell line was first treated with IFN-gamma, thereby restoring LMP2/7 and TAP1/2 expression and function. Because several melanoma antigens recognized by T cells have been reported to be presented by HLA-A2 (MART-1/Melan-A, tyrosinase, gp100, and MAGE-3), the loss of HLA-A2 molecules may represent an important mechanism by which many melanomas evade immune recognition. These findings suggest that patients entering clinical trials for immunotherapy with melanoma vaccines should be carefully examined for tumor cell allelic MHC class I loss and whether such MHC class I antigen down-regulation can be restored by cytokines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Reduced membrane major histocompatibility complex class I density and stability in a subset of human renal cell carcinomas with low TAP and LMP expression.

Suppression of MHC class I expression is thought to allow tumor cells to escape immune surveillance mediated by CD8(+) CTLs. For stable MHC class I surface expression, multiple protein interactions are required for efficient assembly of MHC class I heavy chain and beta 2-microglobulin with endogenous peptides. Peptide processing and transport into the endoplasmic reticulum involves the genes of the transporters associated with antigen processing, TAP-1 and TAP-2, and the two components of the proteasome complex, the low molecular weight proteins LMP-2 and LMP-7. We selected human renal cell carcinoma (RCC) cells derived from a tumor that is thought to be controlled by host immunity to study the MHC class I antigen presentation machinery. Eleven RCC lines established from primary tumors were investigated for the mRNA and protein expression of MHC class I, TAP, and LMP genes. In addition, membrane stability of MHC class I was determined by incubation of the RCC cell lines at low temperature and in the presence of exogenous HLA-binding peptides. Our results revealed the existence of two different phenotypes of RCC cell lines. Group I displayed temperature-stable MHC class I surface expression associated with high, and in most cases coordinated, expression of MHC class I heavy and light chain, TAP and LMP transcripts, and proteins. Group II demonstrated a marked MHC class I instability at 37 degreesC associated with low but coordinated expression of the respective transcripts and proteins. MHC class I membrane expression of group II, but not of group I RCC cells, could be stabilized by incubation with specific MHC class I binding peptides. These results suggest an important role of the genes of the antigen presentation machinery in stable and efficient MHC class I surface expression of RCC cells. However, it has still to be defined whether deficient antigen processing is one of the mechanisms of RCC cells to escape the surveillance of the immune system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

New cell lines of gastric and pancreatic cancer: distinct morphology, growth characteristics, expression of epithelial and immunoregulatory antigens.

Two new cell lines from stomach cancers and one from a pancreatic carcinoma are presented. MZ-GC-1 was established from a hepatic metastasis of a well differentiated gastric adenocarcinoma. MZ-GC-2 was derived from ascites induced by a poorly differentiated gastric adenocarcinoma. MZ-PC-1 originated from the pleural effusion of a moderately well differentiated pancreatic ductal adenocarcinoma. MZ-GC-1 cells were adherent and partially polarized, connected tightly via desmosomes. In contrast MZ-GC-2 cells consisted of slightly adherent or floating subpopulations and displayed no desmosomes. MZ-PC-1 cells were adherent and showed polarized growth, connected by apical junctional complexes. Cell doubling times were 7 days for MZ-GC-1 and 45 h for MZ-GC-2 and MZ-PC-1 cells. MZ-GC-2 and MZ-PC-1 gave rise to nude mouse tumours, resembling the original lesions. Chromosome analysis of the cell lines revealed a high range of numerical abnormalities. Each cell line had cytokeratin patterns fitting well to typical in vivo patterns. Furthermore the cell lines expressed a panel of antigens typical for gastrointestinal epithelia. Unique for MZ-PC-1 were high amounts of secreted Ca19-9. gamma-Interferon enhanced HLA-class I antigens up to twofold and induced ICAM-1 expression on each cell line. HLA-class II antigens were differentially enhanced by gamma-interferon. Due to their distinct characteristics the three tumour cell lines may be useful models in the investigation of the cell biology and immunogenicity of gastrointestinal tumours.

Adenocarcinoma↗
PubMed1995

Cytogenetic characterization of three human and three rat medullary thyroid carcinoma cell lines.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of the thyroid C-cells. MTC may arise as a sporadic tumor or as a component of one of three autosomal dominant familial cancer syndromes, MEN 2A, MEN 2B, or familial MTC. Recent studies have identified mutations of the RET proto-oncogene in the proximal long arm of chromosome 10, which are thought to be causative for these syndromes. To facilitate the search for other genes involved in the development of MTC, we characterized cytogenetically three human MTC cell lines and three rat MTC cell lines. The human cell lines studied were TT and RO-H85-1, previously reported, and an uncharacterized cell line, MZ-CRC-1, derived from a malignant pleural effusion from a patient with metastatic MTC. The rat MTC cell lines characterized were CA-77, 6-23C6, and 44-2. Cytogenetic abnormalities present in the human and rat cell lines were compared with 13 reported cytogenetic studies of human MTC tumors and three other cytogenetically analyzed MTC cell lines. The human 9q/rat 3 and human 3p/rat 15 chromosomes were affected in six of the comparable cell lines and tumors. These findings suggest human chromosome regions 9q and 3p may contain genes involved in the pathogenesis of MTC.

Animals↗
PubMed1995

Recombinant human granulocyte-macrophage colony-stimulating factor after combined chemotherapy in high-grade non-Hodgkin's lymphoma--a randomised pilot study.

High-grade non-Hodgkin's lymphomas (NHL) can potentially be cured with combination chemotherapy, although the optimum schedules still have to be defined. Clinical trials with intensive chemotherapy are predominantly limited by myelosuppression. Here, haematopoetic growth factors open up the possibility of reducing chemotherapy-associated toxicities. In this randomised pilot study, we investigated the effects of a recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) following combined chemotherapy with vincristine, doxorubicin, cyclophosphamide, prednisone and etoposide (VACPE). A total of 35 patients with high-grade NHLs were randomised to receive either rhGM-CSF or placebo during the first two chemotherapy cycles and rhGM-CSF for all following cycles. rhGM-CSF was administered at a dosage of 5 micrograms/kg for 10 days or until neutrophils were > 1/nl following chemotherapy. The analyses revealed a significant reduction of neutropenia and duration of neutropenia in the rhGM-CSF group. Adverse events were rare and generally mild apart from one anaphylactoid reaction. No effects of rhGM-CSF were observed concerning the platelet nadir or duration of thrombocytopenia. The benefit of rhGM-CSF for response induction and survival via rhGM-CSF-supported dose intensification remains to be determined.

Adolescent↗
PubMed1995

Treatment of advanced pancreatic cancer with 5-fluorouracil, folinic acid and interferon alpha-2A: results of a phase II trial.

Interferon alpha-2a (IFN-alpha) and folinic acid (FA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. A phase II study was initiated to evaluate the effect of a combination of 5-FU/FA/IFN-alpha in patients with advanced pancreatic cancer. Sixty previously untreated patients with advanced adenocarcinoma of the pancreas were treated with 500 mg m-2 FU via an intravenous bolus 1 h after the initiation of a 2 h infusion of 500 mg m-2 FA. Before starting the FA infusion, 6 million units (MU) of IFN-alpha was administered subcutaneously. The treatment was repeated once a week. Of 57 evaluable patients, eight (14%) had a partial response (PR), eight (14%) a minor response (MR) and 28 (49%) no change of disease (NC). Thirteen patients (23%) had progressive disease (PD). The median survival time was 10 months for all patients, 22 months for patients with partial remission and 5 months for patients with progressive disease. Many patients with tumour-related pain whose tumours were affected in terms of PR, MR, NC were free of pain during treatment with this regimen (22/36 patients). The common toxicities observed were fever (56%), nausea (37%) and diarrhoea (33%). These data suggest that biochemical modulation of 5-FU with FA and IFN-alpha has some positive effects in the treatment of pancreatic cancer of moderate toxicity.

Adenocarcinoma↗
PubMed1995

Vincristine, doxorubicin, cyclophosphamide, prednisone and etoposide (VACPE) in high-grade non-Hodgkin's lymphoma--a multicenter phase II study.

BACKGROUND: Patients with high-grade non-Hodgkin's lymphoma (NHL) can potentially be cured by intensive chemotherapy. However, many patients still die of their disease, which underscores the need to define patient groups with different long-term prognoses and for more effective and possibly risk-adapted treatment approaches. PATIENTS AND METHODS: In this phase II study we investigated the feasibility and efficacy of a polychemotherapy consisting of 2 mg vincristine (V) on day 1, 25 mg/m2 doxorubicin (A) days 1-3, 800 mg cyclophosphamide (C) day 1, 60 mg/m2 prednisone (P) days 1-7 and 120 mg/m2 etoposide (E) days 1-3. This cycle (VACPE) was repeated on day 22 for up to 5 cycles in stages I-III and 6 cycles in stage IV, respectively, followed by consolidating radiotherapy in 38/73 patients. A total of 75 patients with high-grade NHLs according to the Kiel classification were eligible, and 73 patients are evaluable for response. The predominant histological subtypes were centroblastic, pleomorphic T-cell and large-cell anaplastic lymphomas, 60% of the patients presented with stage III/IV, 55% with a poor performance status (ECOG > or = 2), 53% with B symptoms and 60% with a LDH level >200 U/l. RESULTS: 57/73 patients achieved CR (78%), and the overall response rate (CR-PR) was 95%. The median observation time is 40 months (10+-74+). The 1-, 3- and 5-year overall survivals for the entire VACPE group were 79%, 64% and 61%, respectively. Forty-one patients are in ongoing CR with a continuous complete remission rate (CCR) of 67%. Fourteen of the 16 patients who relapsed (88%) did so within the first 24 months. The predicted 1-, 3- and 5-year DFS for those patients who achieved CR is 83%, 67% and 67%, respectively. The early mortality was 3/73 (4.1%). In patients with reduced performance status the overall survival (OS) (ECOG > or = 2) was significantly reduced, with a predicted 1-, 3- and 5-year survival of 62%, 49% and 49% versus 100%, 84% and 77% in patients with favorable performance status, respectively (p = 0.001). The predicted overall survival in stages III/IV is worse than in early stages with a 1-, 3- and 5-year probability of 73%, 52% and 52% versus 90%, 86% and 78%, respectively (p = 0.02). Comparison of patient groups with cumulative risk factors shows a significant decrease in overall survival. Especially in patients with 0-2 risk factors versus those presenting with >2 risk factors, there is a significantly better 3- and 5-year survival (p = 0.002). In contrast to overall survival, there were no differences between the listed risk groups concerning the disease-free survival of complete responders. CONCLUSION: In conclusion, the VACPE regime is feasible and effective in high-grade NHLs and may also be administered on an outpatient basis. Despite encouraging data, however, a prospective randomized trial is warranted to define a possible superiority to standard CHOP. However, this regimen may be the basis for further randomized and risk adapted innovative approaches for high-grade NHLs.

Adolescent↗