Search

The combination of Imatinib (IM) and hydroxyurea (HU) was explored for the treatment of chronic myelogenous leukemia (CML).AfterAdditive specific inhibition of CML cells by IM/HU was detectedIM/HU combination was more potent in selectively inhibiting CML cells

There is a paucity of data on the incidence of neuroendocrine tumors (NET) outside pulmonary primaries and on treatment modalities applied to patients with NET in clinical practice. Only very little therapeutic progress has been made with respect to response and overall survival, particularly among patients with poorly differentiated, WHO grade 3 neuroendocrine carcinomas (G3-NEC). We sought to document the incidence and treatment modalities in patients with NET/NEC within a period of 2 years.We conducted a retrospective data analysis using a simple documentation file to be completed in written form or electronically, including localization, WHO grading, treatment modalities, and specific therapeutic regimens applied. Primary lung cancer was excluded. The time period to be covered was 2010 through 2012. Individual patient data such as names or age were not documented, so that no ethics committee approval was required.Ten different hospital- or practice-based institutions contributed their data. One to 35 patients were documented per institution, summing up to 149 patients with 154 tumor localizations. Midgut (n = 46), foregut (n = 42), hindgut (n = 17), lung (n = 9), bladder (n = 8), unknown primary (n = 11), and other including prostate and liver (n = 21) were documented as tumor sites. Histological gradings were G1 (n = 71), G2 (n = 27), G3 (n = 34), undifferentiated "G4" (n = 4), and not specified (n = 13). Treatment modalities were surgical resection (n = 102), chemotherapy (n = 49), somatostatin analogs (n = 39), radiotherapy (n = 22), receptor-directed radionuclide therapy (n = 12), and systemic tyrosine kinase inhibition (n = 5). Chemotherapy was given to patients not only with G3-NEC (n = 31), but also with G2 (n = 12) and G1 NET (n = 7). Somatostatin analogs as well as receptor-directed radionuclides were applied to patients throughout all gradings.NET and NEC are not very rare tumor entities, but are diagnosed with very different frequencies, possibly depending upon the alertness of pathologists and clinicians. Chemotherapy, receptor-directed radionuclide application, and somatostatin analog therapy are applied without a clear correlation to different histologic gradings. Diagnostic and therapeutic progress in the field of NETs/carcinomas is urgently needed.

The chemistry of the burrowing sponge Aka coralliphagum was investigated to identify chemically labile secondary metabolites. The HPLC-MS analysis of the two growth forms typica and incrustans revealed different metabolites. The previously unknown sulfated compounds siphonodictyals B1 to B3 (6-8), corallidictyals C (9) and D (10), and siphonodictyal G (11) were isolated, and their structures were elucidated by NMR and MS experiments. The compounds were tested in a DPPH assay, in antimicrobial assays against bacteria, yeasts, and fungi, and in antiproliferation assays using cultures of mouse fibroblasts. The biological activity was linked to the presence of the ortho-hydroquinone moiety.

The therapy of patients with relapsed or refractory indolent lymphoma relies on the development of new drug combinations. The drugs bendamustine and fludarabine have cytotoxic activity as monotherapy in indolent lymphoma and show synergism in vitro. In this study, we combined both drugs in a multicenter clinical phase I/II trial to evaluate their toxicity and efficacy. Bendamustine was given at 30 or 40 mg/m 2 /d (dose levels 1 and 2), fludarabine at 30 mg/m 2 /d, each drug on days 1 to 3. Six cycles were to be given every 4 weeks. A total of 29 patients with relapsed or refractory indolent lymphoma were included in the study. During phase I, 9 patients were treated at dose level 1 and 7 patients at dose level 2. Thirteen patients were added to the study during phase II. Fourteen patients had follicular lymphoma, 11 patients mantle cell lymphoma, 2 patients lymphoplasmocytic and 2 patients nodal marginal zone lymphoma. Median age was 62 years (range 39 – 74). All patients were in stages III or IV of their disease and had received prior chemotherapy with or without additional radioor immunotherapy. The dose limiting toxicity was hematotoxicity in all cases and occurred in 3 of 7 evaluable patients at dose level I and in 3 of 7 patients at dose level 2. One patient at dose level 2 died of sepsis in neutropenia with persistent thrombocytopenia. The study was continued at dose level 1 (phase II). Analysis of 19 evaluable patients treated at dose level 1 reveiled hematotoxicity CTC grade III in 47% and grade IV in 26%. Neutropenic fever occurred in 4 patients (21%). On an intent-to-treat basis, 45% or 32% of all patients at dose level 1 reached CR or PR, respectively. Nine of 9 patients with mantle cell lymphoma responded to therapy. The overall response rate was 77%. Eight of 15 responders relapsed after a median follow-up time of 14 months (range 2 – 43). The major complication of fludarabine in combination with bendamustine is hematotoxicity. Dose level 1 with 30 mg/m 2 /d of both drugs on days 1 to 3 was defined as the recommended dose. Despite unfavorable prognostic features (histologic subtype, stage of disease, pretreatment) response rates were good with this regimen.

Seven pyrrole alkaloids isolated from Agelas sponges were tested for interactions with the cellular calcium homeostasis. Brominated pyrrole alkaloids reduced voltage dependent calcium elevation in PC12 cells. Dibromosceptrin was the most potent alkaloid with a half maximal concentration of 2.8 mM followed by sceptrin (67.5 mM) and oroidin (75.8 mM). 4,5-Dibromopyrrole-2-carboxylic acid reduced calcium elevation at concentrations exceeding 30 mM but did not eliminate calcium elevation at concentrations up to 1 mM. 4-Bromopyrrole-2-carboxylic acid and pyrrole-2-carboxylic acid were not active in this respect. The aminoimidazole group appeared to have a significant effect on voltage dependent calcium elevation shown by the comparison of oroidin with 4,5-dibromopyrrole-2-carboxylic acid. The degree of bromination of the pyrrole moiety is another important factor, as was shown by the comparison of 4,5-dibromopyrrole-2-carboxylic acid with 4-bromopyrrole-2-carboxylic acid, as well as oroidin with hymenidin and dibromosceptrin with sceptrin. The previously reported feeding deterrent activity of brominated pyrrole alkaloids in Agelas sponges against predatory reef fish may partly be explained by a general interaction of these alkaloids with the cellular calcium homeostasis. The chemoreception of bromopyrrole alkaloids in sea water is shown using sensory neurons in the rhinophore of the sea slug Aplysia punctata. q 2004 Elsevier Ltd. All rights reserved.

Bortezomib (Velcade) is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination with other cytostatic agents in multiple myeloma (MM). In the present protocol, bortezomib was combined with other active substances like bendamustine and prednisone (BPV), in order to assess the efficacy and toxicity of the combination therapy in patients with relapsed or refractory MM.Between January 2005 and December 2011, 78 patients with relapsed or refractory MM were treated with bendamustine 60 (-120) mg/m(2) on days 1 and 2, bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11. The median number of prior therapies was 2 with a wide range of 1-9. Thirty-three patients had pre-existing severe thrombocytopenia and/or neutropenia (WHO grade 3 or 4).A median number of two (range 1-7) BPV treatment cycles were given to the patients. The majority of the patients (n = 54; 69 %) responded after at least one cycle of chemotherapy with 3 CR, 10 nCR, 10 VGPR and 31 PR. Median PFS and OS for patients without severe hematological toxicities due to previous treatments (n = 45) were 11 and 50 months, respectively. Outcome for these patients was significantly better than that for patients with severe hematological toxicities (grade 3 or 4, n = 33) with a PFS, and OS of 3 months (p0.05) and 5 months (p0.001), respectively. The regimen was well tolerated with few significant side effects in patients without severe hematological toxicities due to previous treatments. These results indicate that the combination of bortezomib, bendamustine and prednisone is well tolerated in patients with relapsed or refractory MM.

A. war eine der pragenden Gestalten im kulturellen Leben des deutschsprachigen Prag in der Ge neration vor der Gruppe »Jung-Prag« um Max Brod und Franz Kafka. Im Literaturverein »Concordia«, den er leitete, lasen u. a. Gerhart Hauptmann, Arthur Schnitzler und Detlev Liliencron. Bekannt geworden ist A. zu Beginn des Jahrhunderts durch seine er folgreiche Ubertragung von Calderons Komodie Zwei Eisen im Feuer (1900), die ins Repertoire des Wiener Burgtheaters aufgenommen wurde.

In this first report on the chemistry of the sponge Stylissa caribica, two known bromopyrrole metabolites and a new compound, N-methyldibromoisophakellin (1), were isolated and identified. The structure of 1 was determined using spectroscopic methods and the computer program Cocon. N-Methyldibromoisophakellin (1) was shown to be the only secondary metabolite in Stylissa caribica that, at its natural concentration, is active as a feeding deterrent against a common omnivorous reef fish.

This study of first-line treatment in advanced-stage follicular lymphoma patients analysed the effects of MCP (mitoxantrone, chlorambucil and prednisolone) chemotherapy alone or in combination with rituximab (R-MCP) on circulating lymphoma cells (CLC) and assessed the prognostic value of a quantitative monitoring of CLC. CLC numbers were determined by quantitative polymerase chain reaction (PCR) for the t(14;18)-translocation or by allele-specific PCR for rearranged immunoglobulin heavy chain genes. We analysed blood samples from 43 patients treated in a randomized trial comparing eight cycles of MCP versus R-MCP. Clearance of CLC at the end of therapy was achieved in 21/25 patients (84%) treated with R-MCP compared with 0/18 after MCP alone (P0.0001). Aor = 2 log CLC reduction was associated with a favourable clinical response (P = 0.0004) and prolonged event-free survival (P = 0.02). In R-MCP patients, stable CLC numbers or consistently PCR-negative blood samples were associated with a continuing clinical remission whereas in two patients a relapse was preceded by aor = 2 log CLC increase. This study demonstrated that R-MCP led to a rapid and sustained eradication of CLC and aor = 2 log CLC reduction was associated with a superior quality and duration of the clinical response.

NAExplor is a software tool for converting coordinates files between the software packages AMBER, CHARMM, and XPLOR. In addition, it manages the conversion of NMR-derived distance restraints information from the MARDIGRAS program into the appropriate file formats used for input in AMBER, CHARMM, and XPLOR. Analyses of H-H distances in nucleic acid structures and calculations of torsion angles for nucleic acid backbone and riboses are also possible.

Purpose: This randomized phase III study compared bendamustine and prednisone (BP) to standard melphalan and prednisone (MP) treatment in previously untreated patients with multiple Myeloma (MM). Patients and Methods: To be included, patients had to have histologically and cytologically proven stage II with progressive diseases or stage III MM. They were randomly assigned to receive BP (n=68) or MP (n=63). The primary endpoint was the time to treatment failure (TTF). Secondary endpoints included survival, remission rate, toxicity and quality of life. Results: The overall response rate was 75% in the BP and 70% in the MP group. A significantly higher number of patients treated with BP achieved a complete remission than did patients receiving MP (32 vs. 13%; P=0.007), and the maximum response was achieved more rapidly in patients treated with BP compared to those receiving MP (6.8 vs. 8.7 cycles; P

A secondary metabolite from sponges of the genus Agelas, 4,5-dibromopyrrole-2-carboxylic acid, which is well known as feeding deterrent, was investigated for effects on the cellular calcium homeostasis in PC12 cells. 4,5-Dibromopyrrole-2-carboxylic acid did not change intracellular calcium levels if applied alone without cell depolarization. During depolarization of the cellular membrane using high potassium solution, a dose dependent reduction of intracellular calcium elevation was revealed utilizing Fura II as calcium indicator. Significant reduction was seen at concentrations higher than 30 M in a series of experiments, but in single experiments a concentration of 300 nM was still reversible effective. In the same concentration range, the onset of depolarization induced calcium elevations was significantly delayed by 4,5-dibromopyrrole-2-carboxylic acid. Dose dependent reduction and delay of depolarization evoked calcium elevations are probably due to a reduction of calcium entry via voltage operated calcium channels. One cellular mode of action of the feeding deterrent potential of 4,5-dibromopyrrole-2-carboxylic acid to fishes may be an interaction with the cellular calcium homeostasis of exposed cells. © 2005 Elsevier B.V. All rights reserved.

Six dimeric bromopyrrole alkaloids (1-6) were isolated from a Florida Keys specimen of Agelas conifera. One of the constituents was identified as a new bromopyrrole metabolite, bromosceptrin (1). The structure of 1 was established from MS spectrometry and 1D and 2D NMR spectrocopy.

A detailed analysis of the chemical constituents of a Caribbean specimen of Agelas sp. was carried out. Four brominated compounds (1-4) were isolated and one of them was identified as a new bromopyrrole metabolite, monobromoisophakellin (1). The structure of 1 was determined using spectroscopic methods. All compounds were tested for their antifeedant activity against the Caribbean reef fish Thalassoma bifasciatum in an aquarium assay.

A detailed analysis of the secondary metabolites of a specimen of Agelas sventres was carried out here for the first time. The chemistry of Agelas sponges is dominated by bromopyrrole derivatives. Besides three known bromopyrrole metabolites, a new compound, sventrin (1), was isolated and its structure identified using spectroscopic methods. Sventrin (1) was shown to be a feeding deterrent compound against a common omnivorous reef fish.

Abstract 1855 Introduction: Bortezomib and bendamustine have turned out to be effective, rapid action drugs in the treatment of multiple myeloma (MM). Bortezomib is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination with other cytostatic agents in MM. Bendamustine is a bifunctional alkylating agent with low toxicity that produces both single- and double-strand breaks in DNA, and shows only partial cross resistance with other alkylating drugs. The combination of bendamustine and prednisone with bortezomib (BPV) was assessed to determine the efficacy and toxicity of this regimen in patients with relapsed or refractory MM. Methods: Between January 2005 and December 2011, 78 patients (median age 62; range 31–81 years) with relapsed or refractory MM were treated with bendamustine 60 (–120) mg/qm on day 1 and 2, bortezomib 1.3 mg/qm on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11. Cycles were repeated every 21 days until maximum response or progressive disease. Maximum response was achieved if three weeks of therapy did not further reduce myeloma protein by more than 10 %. The median number of prior therapies was 2 (range 1–9). Previous therapies included 31 × thalidomide, 10 × lenalidomide, 14 × bortezomib, 24 × autologous PBSCT, and 19 × autologous-allogeneic PBSCT. In contrast to other clinical studies, patients with pronounced pancytopenia due to stem-cell toxic pre-treatment or advanced disease were also included. Patients were divided into two groups: group A (n = 45) comprised patients with normal bone marrow function and group B (n = 33) patients with pre-existing restricted bone marrow function and pronounced pancytopenia (CTC-Criteria grade III and IV). Patients were excluded from this retrospective analysis if they had other secondary malignancies. To exclude myelodysplastic syndroma or secondary acute myeloid leukemia cytological and cytogenetic examination of bone marrow was performed in patients with pre-existent severe pancytopenia. Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR). Results: The median number of BPV-treatment cycles was 2 (1–7). 54 patients (69 %) responded after at least one cycle of chemotherapy with 3 CR, 10 nCR, 10 VGPR, and 31 PR. Nine patients had MR, 9 patient's stable disease and 6 patients underwent progression. A follow up of surviving patients at a median of 34 months revealed median PFS and OS for patients without preexisting severe haematological toxicities (group A) of 11 months and 50 months respectively. Outcome was significantly better than that of patients with pre-existing severe haematological toxicities (group B) who had a median PFS, and OS of 3 months and 5 months, respectively (p < 0.001). The regimen was well-tolerated with few significant side effects in patients without preexisting severe haematological toxicities. New cytopenias occured infrequently with thrombocytopenia grade 3 in 11 patients, grade 4 in 8 patients and neutropenia grade 3 in 7 patients. Six patients experienced a moderate new polyneuropathy (grade 2). Summary: BPV therapy was well tolerated in patients with relapsed/refractory MM, with a response rate of approximately 70 %. The high efficacy and the favourable toxicity profile of BPV warrant further evaluation in clinical trials. Disclosures: Poenisch: Mundipharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Clinical trials on different cytarabine doses for treatment of AML provide evidence of a dose response effect, but also for increase toxicity after high dose AraC (HDAC). Pharmacokinetic measurements of cytarabine-triphosphate (AraC-CTP), which is the most relevant cytotoxic metabolite of AraC, have revealed its formation in leukemic cells to be saturated with infusion rates above 250 mg/m2/h, this being significantly lower than used in HDAC schedules. Methods: Based on a pharmacological model and encouraging results of a phase II study we conducted a prospective randomized multicenter clinical trial comparing the effects of two different application modes of AraC in patients up to 60 years with untreated newly diagnosed AML. Patients were randomized to receive AraC at two different infusion rates (IR) during induction and consolidation treatment: arm A/experimental: 1 × 2 g/m2/d AraC over 8 hours (IR 250 mg/m2/h) arm B/standard: 2 × 1 g/m2/d AraC over 3 hours (IR 333 mg/m2/h). Induction and first consolidation consisted of AraC (days 1, 3, 5, 7) in combination with an anthracycline (Idarubicine 12 mg/m2 or Mitoxantrone 10 mg/m2, days 1–3). The final dosage points (AraC day 7 and anthracycline day 3) were excluded from the second consolidation. The third consolidation consisted of either allogeneic or autologous stem cell transplantation or of chemotherapy identical to second consolidation. Results: From 02/97 to 04/02 419 patients were enrolled in the study. The present analysis is based on 361 eligible and evaluable patients with a median follow up of 7 years. CR was reached in 249/361 (69%; 95%CI: 65%–74%) patients. No statistically significant differences were detected between arms A and B with regard to CR-rate (69% vs 69%) or early death rate (11% vs 8%). Hematological recovery of median white blood cell count (WBC) > 109/l and median platelets (plt) > 50 × 109/l revealed no difference between arms A and B after induction (WBC day 22 vs 22, p=0,68; plt day 25 vs 26, p=0,41) and consolidation (WBC day 28 vs 27, p=0,07; plt day 42 vs 40, p= 0,58). The event free survival (EFS) after 5 years is 0,25 ± 0,03 % for all patients with an overall survival of 0,31 ± 0,03 % after 5 years. For the purposes of analysis, the 83 transplant patients (23 allogeneic MRD, 14 allogeneic MUD and 46 autologous) were censored at time of transplant. No statistically significant difference between arms A and B in regard to EFS (0,25 ± 0,04 vs 0,25 ± 0,04, p=0,99), relapse incidence (0,63 ± 0,06 vs 0,60 ± 0,06, p=0,89), overall survival (0,32 ± 0,04 vs 0,30 ± 0,04, p=0,44) and therapy associated mortality (0,18 ± 0,04 vs 0,17 ± 0,03, p=0,95) were detectable after adjustment of prognostic factors. An analysis of risk factors by multivariate cox regression model confirmed cytogenetics at diagnosis to be the most important risk factor for CR rate (p1–4 × vs other ULN) (p=0,008) and FAB classification (FAB M0,6,7 vs FAB M1,2,4,5) (p=0,0005). EFS after 5 years shows a significant correlation to cytogenetics (p Conclusion: We conclude that the application of AraC at the presumptive saturating infusion rate of 250 mg/m2/h results in comparable remission rates, toxicity, event free survival and overall survival as compared to the standard IR with 333 mg/m2/h.

Cytogenetic high risk AML (abn 3q26, abn 11q23, −5/5q-, −7/7q- and complex) has a dismal prognosis with a two year overall survival (OS) below 20% even in young patients. Attempts to improve survival by intensifying consolidation chemotherapy have so far failed. In the two OSHO protocols AML 96 and AML 2002, we investigated the role of allogeneic HCT in these patients. A total of 708 patients have been entered into the two studies between 1997 and the present. The first protocol (AML 96) compared two different schedules employing identical total dosages of intermediate AraC and Idarubicin. The second protocol (AML 2002) studied the role of two different induction therapies in patients failing to reach CR after the first induction therapy. In patients with cytogenetic high risk AML, the search for a donor (either familial or, if none available, then unrelated) was initiated as soon as possible. Allogeneic HCT was scheduled either after induction or after first consolidation therapy. HCT was performed after conditioning with cytoxan and 1200 cGy total body irradiation followed by GvH-D prophylaxis with cyclosporine and methotrexate. Of the 708 patients, 138 (19,5%) had high risk cytogenetics and 77 (55,8%) of these went into remission after one or two cycles of induction chemotherapy. Of these 77 patients, 54 were alive and in CR after the first consolidation therapy and were allocated to either related (n=12) or unrelated (n=21) HCT or, if no compatible donor was available, to a two courses of chemotherapy (n=21). Median age of the patients was 36 (range 17–51) years, 46 years (range 23–59) years and 49 (range 16–60) years for patients receiving related HCT, unrelated HCT and chemotherapy respectively. Data were analysed as intention to treat.LFS at 3 years was 67 ± 14% after related and 44 ± 14 % after unrelated HCT, but decreased to 11 ± 7% in patients receiving chemotherapy. Allogeneic HCT results were significantly better than the results of chemotherapy with p-values of 0.005 and 0.002 for related vs. chemotherapy and unrelated vs. chemotherapy respectively. Major differences in relapse incidences were seen between the three groups, with the lowest RI at 3 years after related HCT 26±0.13%, followed by unrelated HCT 48±15% and by chemotherapy 89±8% (p=0.003 and p=0,0006 for chemotherapy vs. related or unrelated HCT). Transplant related mortality at 3 years was 10±9%, 14±10% and 6±6% for patients receiving HCT from related donors, from unrelated donors and chemotherapy, respectively. Conclusions: From the results observed in the two prospective, multicenter studies we conclude that consolidation with allogeneic HCT is superior to chemotherapy in younger patients with high risk cytogenetics. While no differences in TRM were seen between the three treatment arms, a lower relapse incidence after related and unrelated HCT contributed to the improved OS.

In a prospective multicenter phase III trial (M 39023) advanced stage follicular lymphoma (FL) patients were randomized to receive eight cycles of MCP (mitoxantrone, chlorambucil, prednisolone) chemotherapy alone or in combination with rituximab (R-MCP). This study was carried out to determine the effects of this therapy on circulating lymphoma cells (CLC) and to assess the value of CLC quantitation as a molecular marker of disease activity and as a prognostic parameter. CLC numbers were determined by real-time quantitative PCR for the t(14;18)-MBR translocation or by allele-specific PCR for rearranged immunoglobulin heavy chain genes. Quantitative PCR of a reference gene (wild type K-ras) allowed the exact quantitation of cells tested per sample and to exclude samples with insufficient DNA content (< 500,000 cells). We analyzed serial blood samples from 43 patients obtained before, during and after completion of therapy. Baseline clinical characteristics and response to therapy of the 43 patients of this study were not significantly different to all 201 FL patients of the clinical trial except for a higher complete response (CR) rate in the R-MCP group (18/25 (72%) in this study versus 52/105 (50%) in the clinical trial, p=.04). Similar to the results of the clinical study, response rate and CR rate in the present study were significantly higher in the R-MCP arm than after therapy with MCP alone (25/25 (100%) versus 13/18 (72%), p= .009, and 18/25 (72%) versus 5/18 (28%), p= .006, respectively). Clearance of CLC at the end of therapy was achieved in 21/25 patients (84%) treated with R-MCP compared to 0/18 (0%) after MCP alone (p< .0001). R-MCP patients achieved a greater reduction of CLC after completion of therapy and a greater reduction of CLC per treatment cycle than patients treated with MCP alone, even if the comparison was restricted to patients with clinical response (3.88 log and 1.18 log reduction versus 2.21 log and 0.23 log reduction, p= .001 and p< .0001). A ≥ 2 log reduction of CLC after completion of therapy was associated with a favourable clinical response (p= 0.0007) and prolonged event-free survival (p= 0.02) regardless of treatment arm. Among patients with a ≥2 log CLC reduction there was no significant difference in EFS between patients with PCR negative samples and patients with PCR positive blood samples at completion of therapy (p= 0.091). In conclusion, R-MCP led to a rapid and sustained eradication of CLC in the majority of patients. The results of serial determinations of CLC numbers showed a good correlation with the quality and duration of the clinical response. Therefore, quantitative molecular disease monitoring could help to develop individualized treatment strategies for patients with advanced stage FL.

AML patients with unfavourable cytogenetics generally have a poor outcome. Over the last decade a number of strategies to improving survival have been assessed by the East German Study Group (OSHO). Here, we analyse the results of three protocols (AML 93, AML 96 and AML 2002) for effects on outcome in younger patients ( Methods: Unfavourable cytogenetics, defined as abn 3q26, -5/5q-, -7/7q-, abn 11q23 or a multiaberrant clone were present in 20 (12,3%), 76 (20,5%) and 60 (26,3%) patients from the AML 93/96/2002 respectively. In the AML 93 protocol, therapy consisted of double induction (Idarubicin and standard dose AraC 3+7), followed by consolidation (Mitoxantron, Etoposide) and re-induction (Idarubicine + high dose AraC). In both AML 96 and AML 2002, a single course of induction therapy (intermediate dose AraC and Idarubicine 3+7) was repeated as the first consolidation for all patients achieving CR. In AML 96, patients in PR after the first induction received intermediate dose AraC and Mitoxantrone as a 2nd induction therapy. In AML 2002, both non-responders and those achieving PR were randomized between the same induction therapy or a more intensive regime (Mitoxantrone, Fludarabin and intermediate dose AraC). Results: Of all patients with unfavourable cytogenetics (n=156), 40%, 50%, and 65% achieved CR in the AML 93, 96 and 2002 studies respectively, with no statistically significant difference between the CR rates in the three studies (p=0,19). OS and EFS were analyzed both with and without censoring HCT. OS and EFS in patients censored at the time of transplant was not different between the three AML studies although intensity of chemotherapy differed widely (standard, intermediate and high dose AraC). The same analysis performed without censoring allogenic HCT revealed OS at 3 years of 10% for the AML 93, 14% for the AML 96 and 34% for the AML 2002 study (log rank p < 10 −2). EFS at 3 years was 9%, 10% and 32% in the AML 93, 96 and 2002 respectively (log rank p < 0,10−3). In AML 96, 32% of the patients with unfavourable karyotype underwent HCT, 40 % of these in CR1. In AML 2002, 60% of such patients were transplanted and 75% of them were in CR1. The interval from diagnosis to HCT decreased from median 204 (range 142–329) days in the AML 96 to median 125 (range 47–321) days in the AML 2002 (p=0,001). This decrease was associated with fewer cycles of chemotherapy prior to transplant: Patients in the AML 96 protocol received a median of 3 courses (range 2–4) and those in AML 2002 a median of 2 courses (p= 0,002). Conclusion: We conclude that intensity of induction and consolidation chemotherapy is not crucial for CR rate, OS or EFS in patients with unfavourable karyotype,. Improvement in OS and EFS was observed only using HCT as early as possible after CR1.

Outcome of elderly patients with AML is usually poor. Increased incidence of high risk AML and intolerance against dose escalation are the main causes for treatment failure. Pharmacokinetic measurements indicated that intracellular Ara-CTP formation is saturated at much lower infusion rates than used in high dose AraC schedules, probably causing AraC accumulation in the plasma and increased toxicity. Therefore, the East German Study Group (OSHO) used intermediate doses of AraC delivered at the presumptive saturating infusion rate over a prolonged period of time. The same schedule was applied to younger (≤60 years of age, AML 96) and older (>60 years of age, AML 97) patients with AML. In the present evaluation, determining factors for complete remission rate and hematopoietic reconstitution were identified. Methods: All 690 patients entered in the AML 96 (n=370) and AML 97 (n=320) study of the OSHO and treated with one or two courses of induction therapy (AraC 2 g/m2 iv on day 1,3,5,7 in combination with idarubicine 12 mg/m2 day 1–3 or mitoxantrone 10 mg/m2 iv day 1 to 3) followed by 2 consolidation courses were evaluated. The following baseline variables were studied in univariate analysis for their impact on CR rate: sex (M vs. F), age (≤ 60 years vs. >60 years; continuous variable), cytogenetics at diagnosis (normal, favourable, unfavourable and others), disease classification (de novo or secondary AML), WBC (90 x 109/l), FAB-classification (M0/M1/M2/M3/M4/M5/M6/M7), LDH (≤ 2 x ULN vs. > 2 ULN) and the use of G-CSF (yes or no). Factors significant in this analysis were included in a multivariate model (logistic regression). Hematopoietic reconstitution was defined as the first of two consecutive days with leucocytes >1000/μL and platelets >50000/μL. Results: As shown in the multivariate analysis, the most important and highly significant parameter for CR rate was cytogenetics at diagnosis (p=10−11) followed by disease classification (de novo or secondary AML; p=0,001), WBC (p=0,003) and sex (p=0,018). In contrast, we could not demonstrate any significant influence of age (p=0,64), G-CSF (p=0,16) and FAB classification (p=0,38) on CR rate. Significant factors for the recovery of leukocytes were the use of G-CSF (p= 10−12), cytogenetics (p=10−4) and disease classification (de novo or secondary AML; p=0,04). AML classification (de novo or secondary AML; p=0,00002) and cytogenetics (p=0,001) but not age (p=0,17) were determinants for platelet recovery. Conclusion: Cytogenetics at diagnosis and disease type (de novo vs. secondary) were the most important determinants for CR rate using intermediate dose AraC. We could not demonstrate any influence of age on CR rate and hematological recovery.

Background: Clinical superiority of R-MCP (rituximab, mitoxantrone, chlorambucil, prednisolone) vs. MCP alone in patients with advanced stage indolent Non-Hodgkin’s-Lymphoma was demonstrated in a prospective, randomized, controlled, multicenter clinical trial (n=358). Data on resource utilization were collected alongside this clinical trial. Objective: To evaluate the health economic consequences, i.e. total cost and cost-consequences, of R-MCP vs. MCP from the perspective of a German payer (statutory sickness fund). Methods: Resource utilization data on 329 patients were collected and analyzed for the treatment phase (8 month). In addition, an interim analysis of the first 3 years of the subsequent observation period (planned: 7 years) was conducted. Data on resource utilization for initial chemotherapy, chemotherapy administration, treatment of adverse events, treatment of complications/progressive disease, subsequent chemotherapies and treatment for other reasons were collected. Several sensitivity analyses were performed to address different cost environments (e.g. treatment at university hospital vs. municipal hospital vs. private practice) and discounting scenarios. Results: Mean cost of the treatment phase in the base case analysis was EUR 35,890 for R-MCP (95%CI: EUR 33,178 – 38,602 and EUR 21,508 MCP per patient (95%CI: EUR 17,703 – 25,314). More treatment cycles were administered in the R-MCP arm (1,026 MCP, 1,237 R-MCP). Mean cost per active treatment cycle was EUR 4,932 for R-MCP (95%CI: EUR 4,512 – 5,353) and EUR 3,270 for MCP (95%CI: EUR 2,619 – 3,922). Mean (undiscounted) cost per patient in the observation period amounted to EUR 9,973 for R-MCP (95%CI: EUR 6,015 – 13,931) and EUR 15,896 for MCP (95%CI: 13,407 – 18,385). Mean observation time, after end of active treatment, was similar in both arms, 28.5 months for R-MCP, 27.5 months for MCP. Costs for treatment of adverse events, new chemotherapies and other reasons were reduced by 23%–39%, cost for treatment of progressive disease by 76% in the R-MCP arm compared to MCP alone. Extrapolating data to a full 3-year observation period results in savings of EUR 8,214 per patient with R-MCP compared to MCP alone. This compensates approx. 60% of the higher costs from the treatment phase. Clinically, R-MCP resulted in an objective response rate of 85.6% vs. 65.5% with MCP. After two years, based on Kaplan Maier estimate, event free survival for R-MCP was 69% vs. 44% for MCP alone (p< 0.001) (For more detailed clinical results see abstract by Herold et al.) Conclusion: Initial treatment costs with R-MCP were EUR 14,382 higher compared to MCP alone. However, approx. 60% of additional costs are regained during the first three years after therapy due to savings for subsequent treatments, particularly for progressive disease. Combined with the clinical superiority of R-MCP, a favorable cost-effectiveness ratio may be expected when more mature data are available.

Rituximab proved to be effective in relapsed and refractory indolent NHL as a single agent and generated impressive results in phase II studies in combination with chemotherapy. In a prospective randomized trial we compared the efficacy and toxicity of rituximab (375 mg/m² d 1) plus MCP-chemotherapy ( mitoxantrone 8 mg/m² d 3 + 4, chlorambucile 3 x 3 mg/m² d 3 – 7, prednisolone 25 mg/m² d 3 – 7 ) given every 28 days for a total of 8 cycles versus MCP (d 1 – 5) x 8 cycles alone in advanced indolent NHL and MCL. Efficacy endpoints included overall and complete response rates, event free survival, progression free survival, overall survival and toxicity. For response assessment classical definitions have been used. Between 10/98 and 09/03 we randomized 358 patients (pts) with advanced stage follicular lymphoma (FL) (grade 1 + 2), lymphoplasmacytic lymphoma and MCL to either R-MCP or MCP. The study arms are well balanced for all demographic factors. 201/358 pts (56%) had FL. Both regimens were well tolerated with a low incidence of serious adverse events. The overall response rate (RR) and the complete response rate (CR) for all pts was 85,5% and 42% in the R-MCP arm versus 65,5% and 20% in the MCP arm (p

Treatment of elderly patients (pts) with AML requires a sensitive balance between efficacy and toxicity. In the AML97 study all pts with AML > 60 years (y) were registered and, according to their clinical status, treated in curative, palliative or supportive intention. From a total of 520 pts enrolled, 375 (72%) pts were allocated to the curative, 112 (22%) to the palliative and 33 (6%) to the supportive part of the protocol. Patient characteristics between the 3 groups differed in respect to age, but not in regard to the distribution de novo and secondary AML. Median age of the pts was 66 y (range 60–80 y), 75 y (range 64–90 y) and 76 y (range 63–97 y) for the curative, palliative and supportive protocol respectively. Curative treatment consisted of one (in case of PR after the first chemotherapy of two) courses of induction therapy (AraC 2 g/m2 iv on day (d) 1,3,5,7 in combination with mitoxantrone 10 mg/m2 iv d 1-3) followed by two consolidation courses (AraC 240 mg/m2 iv d 1-5 combined with mitoxantrone 10 mg/m2 iv d 1-2). Palliative treatment included idarubicin 10 mg po d 1 in combination with thioguanine 40 mg po d 1-5, or AraC 80 mg sc d 1-5 or etoposide 100mg po d 1-5. In the supportive arm transfusions were applied. CR was obtained in 75% (95 CI: 68–82%) of pts with de novo AML and in 61% (95 CI: 50–70%) of pts with secondary AML in the curative arm with an early death rate of 12 % (95CI: 7–17%) and 19% (95 CI: 12–24%) respectively. Cytogenetic risk factors at diagnosis were the most important prognostic factor for CR (p Median survival was 54 d and only 12 d for pts treated with palliative chemotherapy and supportive therapy respectively. We conclude, that the curative protocol is able to induce high CR in pts with AML > 60 y with low mortality and CR are not different to those of pts < 60 y, if cytogenetics are taking into account. Despite high CR rate, OS remains low and consolidation therapy need to be improved. Transplant protocols with reduced intensity conditioning are currently tested in these patients. Treatment results in the palliative arm are disappointing and confirm the need to develop novel therapeutic strategies.

Previous studies have determined that Caribbean reef sponges of the genus Agelas are chemically defended from fish predation by brominated pyrrole alkaloids, and that the compounds responsible for this defense have been elucidated for one species, Agelas clathrodes. In this study, we expand our understanding of chemical defense in this common sponge genus to include the characterization of defensive metabolites in the tissues of Agelas wiedenmayeri and Agelas conifera. Bioassay-directed isolation of defensive metabolites was undertaken using fish feeding assays carried out in laboratory aquaria and in the field. Agelas wiedenmayeri contained the same two major metabolites as Agelas clathrodes, 4,5-dibromopyrrole-2-carboxylic acid (1), and oroidin (2), in addition to a small amount of bromoageliferin (7). The two major metabolites were present at higher concentrations in samples of Agelas wiedenmayeri than in Agelas clathrodes, and their relative concentrations were reversed, with Agelas wiedenmayeri on average containing more 4,5-dibromopyrrole-2-carboxylic acid (1) (2.0 mg/mL) than oroidin (2) (0.8 mg/mL). Agelas conifera contained a mixture of dimeric bromopyrrole alkaloids dominated by sceptrin (3), with