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R Schnell

Publications and source records attributed to R Schnell.

At least 37 records · Page 2Linked to original sources
PubMed2000

New aspects to event-synchronous cancellation of ECG interference: an application of the method in diaphragmatic EMG signals.

An "event-synchronous interference canceller" (ESC) for cancellation of electrocardiographic (ECG) interference in diaphragmatic electromyographic (EMGdi) signals is addressed in this paper. ESC pursues the concept of the "event synchronous adaptive interference canceller" (ESAIC), which was proposed in [1] as a specific application of the well known "adaptive noise canceller" (ANC) paradigm, but ESC uses a simple adaptive gain control (AGC) instead of the complex adaptive filter of the ANC. The proposed ESC method is evaluated using both computer simulations and real EMGdi data, and its efficiency in interference cancellation is compared to that of ESAIC. Of particular interest is the result that the ESC can replace the ESAIC providing better performance as well as a considerable reduction of computational costs.

Biomedical Engineering↗
PubMed1999

Suppressed neutrophil function as a risk factor for severe infection after cytotoxic chemotherapy in patients with acute nonlymphocytic leukemia.

Severe infections are a major problem in patients suffering from acute nonlymphocytic leukemia (ANLL) undergoing myeloablative chemotherapy. Possible factors leading to infectious complications in these patients are suppressed immune defense mechanisms existing prior to therapy, including those involving the neutrophil granulocyte department. In this study we investigated whether neutrophil function as measured by oxidative burst and phagocytosis before the start of treatment correlates with the severity of infection after therapy. Forty-four patients were included, 27 men and 17 women. Their median age was 46 years (range 20-70 years). According to the development of infectious complications the patients were assigned retrospectively to group 1 (no or only mild infections, n = 29) or to group 2 (severe infection or death due to infection, n = 15). The phagocytic activity was significantly reduced in group 2 as compared with group 1 [113.7+/-13.7 (SEM) vs 170.0+/-19.2, mean channel fluorescence; p =0.04]. In contrast, the oxidative burst as measured by FMLP stimulation was pronounced but not significantly enhanced in group 2 (24.8+/-6.1 vs 14.5+/-3.4, mean channel fluorescence). In conclusion, patients with severe infections after chemotherapy might already have preactivated neutrophils with suppressed function prior to treatment. Thus, evaluating function parameters could help to estimate the individual risk of infection for a patient with ANLL.

Adult↗
PubMed1999

Directional cloning of native PCR products with preformed sticky ends (autosticky PCR).

A novel method for the directional cloning of native PCR products was developed. Abasic sites in DNA templates make DNA polymerases stall at the site during synthesis of the complementary strand. Since the 5' ends of PCR product strands contain built-in amplification primers, abasic sites within the primers result in the formation of 5' single-stranded overhangs at the ends of the PCR product, enabling its direct ligation to a suitably cleaved cloning vector without any further modification. This "autosticky PCR" (AS-PCR) overcomes the problems caused by end sensitivity of restriction enzymes, or internal restriction sites within the amplified sequences, and enables the generation of essentially any desired 5' overhang.

Cloning, Molecular↗
PubMed1998

New drugs in the treatment of Hodgkin's disease.

In the treatment of Hodgkin's disease (HD) remission rates of 80% have been achieved with combination regimens such as COPP/ABVD; 30%-50% of these patients relapse, however, and less than 25% of those in first relapse can be cured. Although 90% of adults with advanced Hodgkin's disease (HD) achieve a complete remission with new polychemotherapy regimens such as BEACOPP, it is too early to assess how many patients ultimately can be cured. In addition, these regimens are associated with severe side effects including infertility, cardiomyopathy or second malignancies. Thus, alternative strategies for improving the outcome of patients with HD have been developed. These approaches include new cytostatic drugs and biological agents. Here, we review the most recent developments including the new vinca alkaloid vinorelbine, the anthracycline idarubicin, the nitrogen mustard bendamustine, the recently developed nucleoside analogue gemcitabine, and immunotoxins against Hodgkin/Reed-Sternberg cells. We conclude that current polychemotherapy regimens could possibly be improved by introducing new agents with a different mechanism of action such as gemcitabine. In addition, some of these new drugs including gemcitabine or vinorelbine could contribute to the reduction of toxic side effects, thus resulting in an improved quality of life for patients with HD.

Adult↗
PubMed1998

Clinical trials with an anti-CD25 ricin A-chain experimental and immunotoxin (RFT5-SMPT-dgA) in Hodgkin's lymphoma.

Immunotoxins (ITs) consisting of a cell-binding component and a potent toxin were developed as a new class of biological anti-tumor agents to improve adjuvant therapy. Hodgkin's lymphoma (HL) has been demonstrated to be an excellent target for ITs because high concentrations of lymphocyte activation markers such as CD25 and CD30 are expressed on Hodgkin and Reed-Sternberg (H-RS). Several ITs against these antigens have shown potent antitumor effects against H-RS cells in vitro and in different HL animal models. On the basis of its superiority in preclinical models, the anti-CD25 IT RFT5-SMPT-dgA was subsequently evaluated in a phase I study in patients with refractory Hodgkin's lymphoma. The IT was constructed by linking the monoclonal antibody (Moab) RFT5 via a sterically hindered disulfide linker (SMPT) to deglycosylated ricin A-chain (dgA). All 15 patients enrolled in this trial were heavily pretreated with a mean of five different prior therapies. The IT was administered intravenously over four hours on days 1-3-5-7 for total doses per cycle of 5, 10, 15, or 20 mg/m2. Side effects were reversible and related to the vascular leak syndrome (VLS), i.e. decrease in serum albumin, edema, weight gain, hypotension, tachycardia, myalgia, and weakness. In all three patients receiving 20 mg/m2 NCI toxicity grade III was observed. Thus, 15 mg/m2 is the maximal tolerated dose (MTD) of RFT5-SMPT-dgA. 50% of the patients developed human anti-ricin A-chain antibodies (HARA) and/or human anti-mouse antibodies (HAMA). Clinical results included two partial remissions (PR), one minor response (MR), three stable disease (SD) and nine progressive disease (PD). In an extension of the phase I trial, five additional patients have been treated at the MTD.

Adult↗
PubMed1998

DIZE (dexamethasone, idarubicin, and continuous infusion of ifosfamide and etoposide): an effective and well-tolerated new regimen for patients with relapsed lymphoma.

We performed a phase II study of dexamethasone, ifosfamide, idarubicin and etoposide (DIZE) in patients with relapsed or refractory Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL). The regimen consisted of dexamethasone (20 mg i.v. days 1-4), idarubicin (8 mg/m2 i.v. days 1+2), continuous infusion (c.i.) of ifosfamide (1,000 mg/m2 days 1-4), and c.i. etoposide (60 mg/m2 days 1-4). G-CSF (5 microg/kg) was used to support neutrophil recovery from day 5. In older patients (> 60 years) the dosage of idarubicin and ifosfamide was reduced to 75% in the initial cycle. Fourty six patients (pts) were treated with a total of 131 cycles. Sixteen pts were primary resistant and 30 were relapsed. Median age was 54.3 years (range 22-75). The median number of different prior chemotherapies was 1.7 (range 1 to 5). 31/46 (67.4%) pts had advanced disease (stage III or IV); 19/46 had B symptoms. Of 43 evaluable pts the response rate was 58.1% including 11 complete remissions (CR) and 14 partial remissions (PR). Mean duration of response was 8 months (1-30+). DIZE was more effective in relapsed than in refractory high-grade NHL (74 % vs 16.6%; p < 0.001). Of four heavily pretreated pts with HL, one obtained CR and two PR (response rate 75%). Myelosuppression was generally moderate with a mean duration of leukocytopenia < 1,000/microl of 2.5 days (range 0-18) and of thrombocytopenia < 25,000/microl 1.5 days (range 0-17). One patient died of uncontrollable infection in treatment related neutropenia. No other serious toxicities apart from alopecia were observed. We conclude that DIZE is safe and effective in heavily pretreated pts with relapsed lymphoma. The continuous infusion of cytostatic drugs such as that used in the new DIZE protocol might reduce hematotoxicity.

Adult↗
PubMed1997

A phase-I study of an anti-CD25 ricin A-chain immunotoxin (RFT5-SMPT-dgA) in patients with refractory Hodgkin's lymphoma.

The anti-CD25 immunotoxin (IT), RFT5-SMPT-dgA, was used in a phase I dose escalation trial in patients with refractory Hodgkin's lymphoma. The IT was constructed by linking the monoclonal antibody RFT5 via a sterically hindered disulfide linker to deglycosylated ricin-A. All patients in this trial were heavily pretreated with a mean of 5 (range, 2 to 8) different prior therapies, including autologous bone marrow transplantation in 8 of 15. The mean age was 29 years (range, 19 to 34 years). Thirteen of 15 patients had advanced disease (stage IV) with massive tumor burdens and 6 of 15 had B symptoms. The IT was administered intravenously over 4 hours on days 1, 3, 5, and 7 for total doses per cycle of 5, 10, 15, or 20 mg/m2. Patients received one to four cycles of treatment. The peak serum concentration of intact IT varied from 0.2 to 9.7 micrograms/mL. The serum half life (T1/2) of the IT ranged from 4.0 to 10.5 hours (mean, 6.1 hours). Side effects were related to vascular leak syndrome (VLS), ie, decreases in serum albumin, edema, weight gain, hypotension, tachycardia, myalgia, and weakness. Two patients had a National Cancer Institute (NCI) grade 2 allergic reaction with generalized urticaria and mild bronchospasm. At 15 mg/m2, 1 patient experienced a grade 3 myalgia. All 3 patients receiving 20 mg/m2 experienced NCI grade 3 toxicities (edema, nausea, dyspnea or tachycardia) and 1 patient had NCI grade 4 myalgia. Thus, the maximal tolerated dose was 15 mg/m2. Seven of 15 patients made human antiricin antibodies (> or = 1.0 microgram/mL) and 6 of 15 developed human antimouse antibodies (> or = 1.0 microgram/mL). Clinical response included 2 partial remissions, 1 minor response, 3 stable diseases, and 9 progressive diseases. As has been predicted from the preclinical tests, these data seem to indicate clinical efficacy of this new IT in heavily pretreated Hodgkin's patients, thus warranting further clinical investigation.

Adult↗
PubMed1997

A phase-II study with idarubicin, ifosfamide and VP-16 (IIVP-16) in patients with refractory or relapsed aggressive and high grade non-Hodgkin's lymphoma.

We report a phase-II study of idarubicin, ifosphamide and etoposide (IIVP-16) in heavily pretreated patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. The IIVP-16 regimen consisted of idarubicin (10 mg/m2 i.v. days 1 + 2 or days 1 + 8), ifosfamide (1000 mg/m2 i.v. days 1-5) and VP-16 (150 mg/m2 i.v. days 103). 40 patients were enrolled. Of 38 evaluable patients, 26 had centroblastic subtype, followed by lymphoblastic (6), immunoblastic (2), and other entities (4). 18 patients were primary resistant; 14 patients had early relapse (CR less than 12 months) and 8 patients late relapse (CR longer than 12 months). The median number of different prior chemotherapy regimens was 2 (range 1 to 6). 20 patients had received additional radiotherapy. The response-rate was 47.4% including 8 CR (21.1%) and 10 PR (26.3%). IIVP-16 was more effective in patients with relapsed disease when compared with patients with primary resistant disease (response rate 65% vs. 27.8%, p < 0.025). Leukopenia and thrombocytopenia were the major toxicities occurring in 73/107 (68.2%) and 57/107 (53.3%) of cycles (WHO grade IV). IIVP-16 is an effective regimen particularly in patients with unfavorable relapsed NHL.

Adult↗
PubMed1997

Idarubicin: a brief overview on pharmacology and clinical use.

Idarubicin exhibits features rendering this drug unique among anthracyclines. The higher lipophilicity leads to faster accumulation in the nuclei, superior DNA-binding capacity and consequently greater cytotoxicity compared to daunorubicin. A major advantage over this reference drug is its ability to overcome MDR at least partially. Its major metabolite idarubicinol is as active as the parent compound and crosses the blood-brain barrier. Furthermore, idarubicin can be administered orally reaching sufficient plasma levels. Compared to other anthracyclines, the risk of cardiotoxicity as the main side effect for this group of drugs is reduced with idarubicin, when administered in a therapeutical dose. Thus, IDA has become an important drug in the treatment of acute leukemias and its potency in lymphomas, plasmocytomas and other solid tumors such as breast cancer is currently under investigation in several clinical studies.

Animals↗
PubMed1997

The emerging role of immunotoxins in leukemia and lymphoma.

Despite important advances in conventional cancer therapy, there is still a strong need for new approaches in order to reduce cancer death rates, which have not been drastically influenced in the past ten years. Since minimal residual disease is regarded as the major cause for relapses of malignant diseases, immunotherapeutic strategies utilizing monoclonal antibodies (MoAbs) or their conjugates to target 'dormant' tumor cells have increasingly attracted scientific interest. Immunotoxins (ITs) constructed by chemically linking plant or bacterial toxins to a MoAb can selectively kill their target cells when internalized after binding to specific cell surface receptors. Many different ITs against various blood-borne as well as solid malignancies have been successfully tested in vitro and in animal models. Chemically linked ITs and recombinant fusion toxins generated by using DNA technologies are currently being evaluated for their antitumor activity in several clinical phase I/II/III trials. While serious side effects are rare, there are still many problems to be solved, such as the immunogenicity of the toxin and/or antibody moiety or the poor capacity of ITs to penetrate large solid tumors. At the moment only heavily pretreated patients with massive tumor burden are admitted to early clinical studies, so that even minor responses after IT treatment are encouraging. However, minimal residual disease is expected to be most amenable to IT therapy.

Animals↗
PubMed1997

A phase I/II study of idarubicin, dexamethasone and interferon-alpha (I-Dexa) in patients with relapsed or refractory multiple myeloma.

To improve the outcome for patients with relapsed or refractory multiple myeloma (MM), we combined idarubicin (Ida), dexamethasone and interferon (IFN) in a new regimen, 'I-Dexa'. Here we report our results of a phase I/II study using the I-Dexa protocol in an outpatient setting. A total of 31 patients were enrolled. Most patients were heavily pretreated with a median of two different chemotherapy regimen (range, 1-4). All but four patients had advanced disease (stage III). The dose of Ida was escalated to define the maximal tolerated dose (MTD) in this regimen. Four patients were treated with 5 mg/m2 and 27 patients with 7.5 mg/m2 Ida (day 1, i.v.). Dexamethasone was given at a fixed dose of 20 mg per os daily on days 2-5 and 11-14. Treatment was repeated at day 21 and consisted of up to six cycles. Patients who achieved a response or stable disease received IFN maintenance. IFN was administered three times weekly at a dose of 3 x 10(6) U/day s.c. until relapse. At the time of evaluation, 125 courses of I-Dexa were analyzed. The MTD of Ida in this regimen was 7.5 mg/m2. Hematological toxicity was mild including 5% leukocytopenia, 3% thrombocytopenia and 1% anemia (WHO grade III) at dose level 2. The MTD was defined by nonhematological toxicities including two WHO grade IV infections and one renal failure. The overall response rate including stable disease was 62.5% (PR: nine patients, 37.5%). So far, nine patients have been treated with IFN maintenance therapy with a median duration of 7 months (range, 1-16). In conclusion, I-Dexa can be given safely in an outpatient setting and is effective for the treatment of relapsed and refractory MM.

Adult↗
PubMed1996

Potent anti-tumor effects of an anti-CD24 ricin A-chain immunotoxin in vitro and in a disseminated human Burkitt's lymphoma model in SCID mice.

A new anti-CD24 immunotoxin (IT), SWA11.dgA, was constructed by coupling the MAb SWA11 via the bivalent linker SMPT to deglycosylated ricin A-chain (dgA). The effects of SWA11.dgA were evaluated in vitro against the B-precursor leukemia cell line REH, the non-B-non-T acute lymphoblastic leukemia cell line NALM-6 and the Burkitt's lymphoma cell lines BL-2 and BL-38. Binding of SWA11 to the CD24 antigen was assessed by flow cytometry demonstrating high affinity of the MAb for all cell lines tested. SWA11.dgA inhibited the protein synthesis of BL-38, NALM-6, REH and BL-2 cells by 50% at concentrations (IC50) of 4.0 x 10(-11) M, 6.0 x 10(-11) M, 8.0 x 10(-11) M and 3.0 x 10(-9) M, respectively. SWA11.dgA was subsequently used for the treatment of disseminated human BL-38 Burkitt's lymphoma in a newly developed SCID mouse model. The mean survival time (MST) of BL-38-bearing SCID mice was extended from 23 days in untreated controls to more than 230 days when 6 microg SWA11.dgA was applied intraperitoneally one day after tumor challenge. All of the animals achieved continuous complete remissions. SCID mice treated with SWA11.dgA 4 days after tumor cell challenge or a reduced dose of SWA11.dgA (67%) also had a significantly extended MST (45.0 and 51.4 days, respectively, as compared to 22.7 and 23.1 days in the controls). We conclude that SWA11.dgA might be of potential use for the treatment of lymphoma in man.

Animals↗
PubMed1996

Hodgkin's disease. Future treatment strategies: fact or fiction?

Many new approaches involving biological agents have given promising results in experimental HD models. Clinical trials with immunotoxins, IL-2, Bi-Moabs or radioimmunoconjugates have demonstrated some clinical efficacy in patients with advanced refractory HD. Although it looks very unlikely to cure patients with larger tumour masses by either of these approaches, it might be feasible to treat bulky disease by conventional therapy first and then administer biological drugs to kill residual H-RS cells. Future phase-III trials will have to prove a possible superior effect of this combined immuno-/chemotherapy. In the meantime, the search for the most promising approach continues.

Antibodies, Anti-Idiotypic↗
PubMed1996

Development of immunotoxins for potential clinical use in Hodgkin's disease.

During the last decade, immunotoxins (ITs) consisting of a cell-binding moiety and a potent toxin were developed as a new class of biological anti-tumor agents. Hodgkin's disease has shown to be one of the best targets for immunotoxins, as lymphocyte activation markers such as CD25 and CD30 are expressed on Hodgkin and Reed-Sternberg (H-RS)-cells in large numbers. Several immunotoxins against these antigens, which are expressed physiologically only on a small subset of activated hematopoietic cells have demonstrated potent anti-tumor effects both, in vitro and in animal models. Here we summarize the experimental and recent clinical data of using ITs in Hodgkin's disease.

Clinical Trials as Topic↗