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Biomedical subjects

S Seeber

Publications and source records attributed to S Seeber.

At least 163 records · Page 9Linked to original sources
PubMed1995

Primary gastric non-Hodgkin's lymphoma: a clinicopathological study of 41 patients.

Pathological findings in 41 patients (male/female ratio: 1.3/1) with primary localized gastric non-Hodgkin's lymphoma (NHL) were retrospectively studied and correlated with survival. The median observation period after diagnosis was 32 (0-189) months. Nineteen patients were low-grade NHL, all but one B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) type. Twenty-two patients had primary (n = 7) or secondary (n = 15) high-grade lymphomas; Musshoff stage IE was found in 29 and IIE in 12 cases. The median age at diagnosis was 61 years (range, 26-88 years), and proliferation, measured by the number of mitosis and Ki-67 antigen positivity (MIB-1), was high or moderately high in 24 cases and low in 17 cases. Follicular lymphatic hyperplasia could be found in 25 of 34 evaluable cases, more often in low-grade than in high-grade NHL. Most of the patients were treated by resective surgery and additional ratio- or chemotherapy. Thirteen patients (31%) died (median survival: 10 months), 5 of them within 3 months after surgery owing to postoperative complications. Survival was superior, though not statistically significant, in low-grade lymphomas. Our retrospective analysis of heterogeneously treated gastric lymphomas reveals that gastric lymphomas, especially of the low-grade MALT type, often remain a localized disease with a good long-term prognosis. Our study confirms previous reports indicating that lymphomas of the MALT type represent a specific clinicopathological entity.

Adult↗
PubMed1995

Cytogenetics of twelve cases of uveal melanoma and patterns of nonrandom anomalies and isochromosome formation.

We present cytogenetic data of 12 new cases of uveal melanoma. One case showed a hypotetraploid chromosome number; the others were near-diploid. Underrepresentation or monosomy of chromosome 3 as well as multiplication of chromosomes 8, 8q, or regions of 8q was found in five cases. Both anomalies were observed in three cases. In two of these, multiplication of 8q resulted from isochromosome formation. The smallest multiplicated region seemed to be 8q23-24-->qter. Chromosome 6 anomalies were found in five cases without monosomy 3. Aberrations of chromosome 21 were seen in five cases and found to be the only cytogenetic change in two of them. These anomalies may define a subgroup of uveal melanoma. An anomaly of chromosome 1 was found in three cases. Anomalies of other chromosomes were detected in at most two cases each. Nonclonal centromeric or telomeric associations were seen in one case and different nonclonal ring chromosomes in another. Underrepresentation of chromosome 3 was seen exclusively in tumors with ciliary body involvement, while anomalies of chromosome 6 were detected only in pure choroideal melanomas. A review of the published cytogenetic data of untreated uveal melanoma supports our finding that monosomy 3 is frequently associated with multiplication of 8q but rarely with anomalies of chromosome 6, whereas the opposite is true for tumors with disomy 3, and that isochromosomes are closely associated with monosomy 3. Thus, cells with monosomy 3 seem to predispose to isochromosome formation.

Adult↗
PubMed1995

Schedule-dependent antagonism of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines in vitro.

Paclitaxel has demonstrated broad clinical activity in a variety of malignancies both alone and in combination with other chemotherapeutic agents. The in vitro cytotoxicity of paclitaxel and cisplatin alone, in combination and in sequence, were evaluated against established human gastric and ovarian carcinoma cell lines using 2-h drug exposure. The combination of cisplatin and paclitaxel was found to be additive or even synergistic when paclitaxel was given 24 h prior to cisplatin as demonstrated by isobologram analysis. However, when both drugs were given simultaneously or when cisplatin was given prior to paclitaxel, a strong antagonistic interaction was observed. This antagonism was evident for up to 72 h after a 2-h exposure to cisplatin. Pretreatment with cisplatin caused no alteration in [3H]paclitaxel uptake in HM2 gastric carcinoma cells, but resulted in decreased intracellular retention of paclitaxel. Since cisplatin treatment led to a reduction in cellular glutathione content in these cells and reduced levels of glutathione have been associated with protection against cytotoxicity of paclitaxel, cells were pretreated with L-buthionine sulfoximine (L-BSO). However, depletion of glutathione had no influence on the activity of paclitaxel. A significant accumulation of cells in S-phase was observed 24 h after cisplatin, which resolved after 48 h and resulted in a pronounced increase of G2M phase. These data demonstrate that the interactions of paclitaxel and cisplatin are highly schedule-dependent and applications of cisplatin simultaneously with or prior to paclitaxel may result in pronounced antagonism. These findings could have implications for the design of further clinical protocols.

Cell Cycle↗
PubMed1995

Activity of N-benzyl-adriamycin-14-valerate (AD198), a new anthracycline derivate, in multidrug resistant human ovarian and breast carcinoma cell lines.

The new lipophilic anthracycline N-benzyl-adriamycin-14-valerate (AD198) was evaluated for its activity in comparison to doxorubicin in P-glycoprotein (Pgp)-positive and -negative cell lines. AD198 and doxorubicin showed comparable antitumor activity in the Pgp-negative breast cancer cell line MCF-7 and the Pgp-negative ovarian carcinoma cell line A2780. By contrast, AD198 was significantly more active than doxorubicin in the Pgp-positive breast cancer cell line MCF7AD (IC50 values 2.5 and 0.15 microM for 96 h continuous exposure) and the Pgp-positive ovarian carcinoma cell line A2780 DX5 (IC50 values 0.6 and 0.07 microM, respectively). Unlike doxorubicin, the activity of AD198 was not increased by concommittant application of cyclosporin A in cell line MCF7AD. Flow cytometry studies showed that, in contrast to doxorubicin, AD198 was not transported by Pgp and that verapamil did not change the intracellular pharmacokinetics of this new anthracycline. These data provide evidence that AD198 possesses high activity in human solid tumor cell lines expressing the classical multidrug resistant phenotype. Its further clinical development appears to be warranted.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Homozygous loss of the MTS1/p16 and MTS2/p15 genes in lymphoma and lymphoblastic leukaemia cell lines.

The genes MTS1/p16 and MTS2/p15 located in 9p21 encoding cyclin-dependent kinase-4 inhibitors are homozygously deleted in a number of different tumour cell lines. By PCR analysis of 30 cell lines, including 10 acute lymphoblastic leukaemia (ALL) and 20 lymphoma cell lines, we found homozygous deletions of at least one locus in 11 (37%) cell lines. MTS1-specific sequences were deleted in 70% of ALL (reaching 86% in T-cell ALL) but in none of the non-Hodgkin's lymphoma (NHL) cell lines. MTS2-specific sequences were deleted in 40% of ALL and 17% of NHL cell lines. We observed a higher frequency of MTS1 deletions in ALL than in NHL (P < 0.001) and in T-cell neoplasms compared to B-cell neoplasms (67% v 6%; P = 0.001). In ALL-derived cell lines deletions of the MTS2 gene only occurred in cases with MTS1 deletions but in NHL only in cases without MTS1 deletions.

Base Sequence↗
PubMed1995

Low specificity of cytokeratin 19 reverse transcriptase-polymerase chain reaction analyses for detection of hematogenous lung cancer dissemination.

PURPOSE: Sensitive detection of systemic tumor dissemination in lung cancer patients is important for selection of appropriate treatment modalities. Based on recent promising data that showed reverse transcriptase-polymerase chain reaction (RT-PCR) analyses for cytokeratin 19 (CK-19) expression in peripheral-blood or bone marrow samples to be a rapid and highly sensitive method for detection of hematogenous tumor dissemination in patients with breast and prostate cancer, we evaluated the specificity of this assay system in lung cancer patients and a large number of healthy controls. PATIENTS AND METHODS: We examined CK-19 mRNA expression by RT-PCR in 17 lung cancer cell lines and in peripheral-blood samples of 50 lung tumor patients and 65 healthy controls. RESULTS: Expression of CK-19 mRNA was observed in all lung cancer cell lines and in 50% of peripheral-blood samples from lung tumor patients. However, under the experimental conditions analyzed, at least 20% of the control samples were positive for CK-19 mRNA expression. CONCLUSION: Contrary to prior reports, RT-PCR may detect non-tissue-specific constitutive low-level (illegitimate) expression of CK-19 mRNA in peripheral-blood mononuclear (PBMN) cells in a significant number of healthy controls. This finding may not only hamper the use of this assay system in lung cancer patients, but also questions its proposed applicability in patients with other epithelial tumors such as breast and prostate cancer.

Adult↗
PubMed1995

[New concepts in systemic chemotherapy].

The availability of sufficient amounts of cytokines for clinical use has opened new opportunities in the systemic treatment of malignant diseases. The two haematopoetic growth factors G-CSF and GM-CSF, used either alone or in combination with separation and retransfusion of peripheral haematopoetic progenitor cells, have allowed dose escalations of cytostatic agents for which myelosuppression is a dose-limiting toxicity. This has implications especially for the treatment of relapsed and very advanced testicular carcinomas. High-dose chemotherapy followed by autologous blood progenitor cells and haematopoetic growth factors seems to produce significantly better therapeutic results than standard-dosed chemotherapy in these situations. The immunomodulating agents IL2 and IL4 are currently undergoing clinical trials and seem to have direct cytotoxic activities, especially in renal cancer. A new, potentially promising therapeutic modality is becoming available with the ability to transfer genetic material directly into either tumour or immunomodulatory effector cells (gene therapy). The insertion of certain genes coding for the production of cytokines or surface molecules can produce systemic antitumour reactions when these genetically altered cells are reimplanted into the host. All these subjects are currently subjects of detailed investigation and may change the therapeutic options for the treatment of advanced urological malignancies.

Adjuvants, Immunologic↗
PubMed1995

Phase I/II study with paclitaxel in combination with weekly high-dose 5-fluorouracil/folinic acid in the treatment of metastatic breast cancer: an interim analysis.

Phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (5-FU/FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/II trial in outpatients: high-dose 5-FU (24-hour infusion)/FA (2-hour infusion preceding 5-FU) is given for 6 weeks (days 1, 8, 15, 22, 29, and 36), with paclitaxel (3-hour infusion) administered on days 1 and 22; 2 weeks' rest follows. Folinic acid 500 mg/m2 was administered throughout; the respective 5-FU doses for dose levels 1 through 3 were 1.5, 1.8, and 2.0 g/m2 with paclitaxel 135 mg/m2. Dose level 4 (500 mg/m2 FA, 2.0 g/m2 5-FU, and 175 mg/m2 paclitaxel) was chosen for phase II evaluation. To date, 46 patients with bidimensionally measurable disease (four each at dose levels 1, 2, and 3, and 34 at dose level 4) have been entered. The 12 patients treated at dose levels 1 through 3 were titrated to level 4 doses when phase II began; 35 patients are evaluable for response. The median age is 46 years, and the median number of metastatic sites is 2.5. Fourteen patients had received adjuvant chemotherapy, nine chemotherapy for metastasis, and 23 chemotherapy both adjuvantly and for metastasis. Of 31 anthracycline-treated patients, 27 had anthracycline-resistant disease. No dose-limiting toxicity appeared until dose level 4, when grade 3 or 4 leukopenia and diarrhea occurred in 15 and eight, respectively, of 108 cycles. Mild to moderate mucositis, hand-foot syndrome, myalgia, and nausea/vomiting occurred in 20% to 40% of cycles. One (3%) of the 35 patients had a complete response, 18 (51%) had partial responses, 14 (40%) had stable disease, and two (6%) had disease progression. Eleven (55%) of 20 evaluable patients with anthracycline-resistant disease responded (95% confidence interval, 34% to 76%). Median time to maximum response was 2 months, and the remission duration was 8+ months. Median survival time has not been reached. Paclitaxel and weekly high-dose 5-FU/FA was well tolerated and highly effective, even in patients with anthracycline-resistant metastatic breast cancer. The regimen can be administered safely to outpatients.

Adult↗
PubMed1994

Capacity of individual chronic lymphatic leukemia lymphocytes and leukemic blast cells for repair of O6-ethylguanine in DNA: relation to chemosensitivity in vitro and treatment outcome.

The elimination kinetics of the alkylation product O6-ethylguanine (O6eGua) from nuclear DNA were determined in individual lymphocytes or blast cells isolated from 27 patients with chronic lymphatic leukemia (CLL) and 26 patients with de novo acute myeloid leukemia (AML). A monoclonal antibody-based immunocytological assay was used for quantification of O6eGua in DNA of individual cells after pulse exposure of cells to N-ethyl-N-nitrosourea (EtNU). In cell specimens from a given patient, no major subpopulations with significantly different capacities for repair of O6eGua were observed. The time required to remove 50% of induced O6eGua residues varied interindividually between 0.5 and 8.4 h in CLL lymphocytes and between 0.8 and 6.3 h in leukemic blast cells. An inverse relationship was found between the rate of removal of O6eGua from DNA and the chemosensitivity of cells to EtNU, 1,3-bis(2-chloroethyl)-1-nitrosourea or mafosfamide in vitro. High rates of O6eGua repair and pronounced resistance to mafosfamide, 1,3-bis(2-chloroethyl)-1-nitrosourea, and EtNU in vitro were found in samples from 8 CLL patients nonresponsive to chemotherapy with alkylating agents. In AML patients treated with anthracyclines and 1-beta-D-arabinofuranosylcytosine, no relation was found between DNA repair capacity and treatment outcome. However, increased P-glycoprotein expression was observed between specimens derived from AML patients who had failed to reach complete remission (n = 12) after chemotherapy versus responsive patients (n = 14). DNA repair rate was not related to chemosensitivity to Adriamycin and 1-beta-D-arabinofuranosylcytosine in vitro, nor were cellular glutathione content, glutathione S-transferases activity, or P-glycoprotein expression.

Acute Disease↗
PubMed1994

Improved flow-cytometric detection of low P-glycoprotein expression in leukaemic blasts by histogram subtraction analysis.

Expression of the drug efflux pump P-glycoprotein (PGP) was determined by flow cytometry in human lung cancer cell lines and in leukaemic blasts derived from 60 patients with acute myeloid leukaemia (AML). Cells from the PGP-negative parent cell line H69/P and the multidrug resistant (MDR)-variant H69/LX4 could be clearly distinguished by immunostaining with the anti-PGP monoclonal antibody MRK16. In leukaemic blasts, the differences in fluorescence intensities between samples incubated with the idiotypic nonspecific (control sample) and specific antibody (test sample) were small, resulting in nondisjunct distributions. Only in a few leukaemia specimens were PGP-expressing cells detectable by simple subtraction of histograms using a threshold. Therefore, an improved histogram subtraction analysis, based on curve fitting and a statistical test, was applied to distinguish antigen-positive from antigen-negative cells. Moreover, a multiparametric staining procedure employing propidium iodide (PI) and Hoechst 33342 was used to reduce staining artefacts. By this approach, leukaemic cells with low expression of PGP were detected in 39 out of 60 cases. Subpopulations with strong PGP expression, resulting in disjunct fluorescence distributions, were not observed. Only in 5 out of 60 specimens were PGP expressing cells detected by a conventional subtraction of histograms using a threshold. Comparison of data obtained with or without the multiparametric gating procedure indicated that the increase in sensitivity was mainly due to the application of the data analysis. However, exclusion of cell debris using PI and Hoechst staining properties reduced the deviation of data from mean values. No relation between PGP expression and cell cycle position was observed in either cell lines or in leukaemic blasts.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Complications of spinal opioid therapy: myoclonus, spastic muscle tone and spinal jerking.

This study was made in order to define risk factors for patients requiring spinal opioid therapy developing painful spastic muscle tone together with myoclonus and spinal jerking (MSJ). The case histories of 75 patients, all receiving morphine spinally, were retrospectively analysed and, of these, 10 suffered from the MSJ syndrome. The following were taken as evaluation criteria: age, sex, performance status, duration and dosage of previous systemic and current spinal morphine therapy, concomitant analgesic and co-analgesic medication, pretreatment of the dorsal column and neurological dysfunction due to damage either of the nerval plexus or of the medulla spinalis. As a result, high spinal morphine doses in conjunction with pathological changes within the spine were shown to be risk factors for this syndrome. Changing from spinal to systemic morphine application or reduction of spinal doses together with the addition of systemic morphine led to complete recovery from MSJ. As underlying mechanism, an imbalance between the activity of spinal and central opioid receptors and/or toxic morphine effects on the medulla spinalis are discussed. In conclusion, great care should be taken when applying morphine to the spine in patients with neurological dysfunction due to an apparent pathology of the medulla spinalis, especially if large amounts of morphine are likely to be required. Some systemic application of morphine might reduce the risk of patients developing MSJ syndrome.

Administration, Oral↗
PubMed1994

Repair of O6-alkylguanines in the nuclear DNA of human lymphocytes and leukaemic cells: analysis at the single-cell level.

Inter-individual and cell-cell variability of repair of O6-alkylguanines (O6-AlkGua) in nuclear DNA was studied at the single-cell level in peripheral lymphocytes from healthy donors and in leukaemic cells isolated from patients with chronic lymphatic leukaemia (CLL) or acute myeloid leukaemia (AML). Cells were pulse exposed to N-ethyl- or N-(n-)butyl-N-nitrosourea in vitro, and O6-AlkGua residues in DNA were quantified using an anti-(O6-AlkGua) monoclonal antibody and electronically intensified fluorescence. The kinetics of O6-AlkGua elimination revealed considerable inter-individual differences in O6-ethylguanine (O6-EtGua) half-life (t1/2) values in DNA, ranging from 1.5 to 4.5 h (five AML patients), from 0.8 to 2.8 h (five CLL patients) and from 1.2 to 7.3 h (five healthy donors). The elimination from DNA of equimolar amounts of O6-butylguanine was generally 3-5 times slower in comparison with O6-EtGua. The t1/2 values of individual samples varied in parallel for both DNA alkylation products. Upon preincubation with O6-benzylguanine, the activity of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AT) in both lymphocytes and leukaemic blasts was reduced to < or = 1%. However, while the rate of O6-EtGua elimination from DNA was decelerated it was not abolished, suggesting the possible involvement of additional repair systems that might be co-regulated with AT. Within individual samples, no major cell subpopulations were observed whose repair kinetics would differ significantly from the remaining cells.

Alkylating Agents↗
PubMed1994

Weekly high-dose 5-fluorouracil and folinic acid as salvage treatment in advanced gastric cancer.

BACKGROUND: A weekly schedule of a 24-h high-dose 5-FU infusion in combination with folinic acid was investigated as salvage therapy in patients with advanced gastric cancer. PATIENTS AND METHODS: Seventeen patients with progressive disease after chemotherapy were treated with a weekly schedule of 500 mg folinic acid/sqm by i.v. 2-h infusion followed by an i.v. 24-h infusion of 2.6 g 5-FU/sqm times six. Fourteen of the 17 patients (82%) had been pretreated in regimens which included 5-FU/folinic acid i.v. bolus. RESULTS: Toxicity was mild, with diarrhea, mucositis and nausea; WHO grade III/IV diarrhea was observed in only two patients. Three patients achieved partial remissions (18%; 95% confidence interval: 0%-38%) and 7 patients stable disease (41%; 95% confidence interval: 17%-64%). Their median survival time was five months (range 1.5-10 months) after the onset of salvage therapy. CONCLUSIONS: This schedule of weekly 24-h infusions of high-dose 5-FU and folinic acid is effective, even in patients pretreated with or resistant to regimens including 5-FU/folinic acid i.v. bolus. Based on these data, it appears that this schedule of high-dose 5-FU/folinic acid in first-line combination chemotherapy merits investigation.

Adult↗
PubMed1994

Bcr-abl-positive and -negative clonogenic cells in CML patients undergoing long-term interferon treatment.

Bone marrow (BM) and peripheral blood cell (PBC) samples of 11 Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) patients in long-lasting hematologic remission induced by interferon (IFN) treatment were examined for the presence of leukemic hematopoietic precursor cells. Southern blot analysis revealed residual leukemic cells in BM samples of four patients, whereas seven patients showed no aberrant bands. Reverse transcription polymerase chain reaction (RT-PCR), however, amplified bcr-abl-specific cDNA in unfractionated BM or PBC samples in all 11 patients. The patients demonstrating bcr rearrangements in Southern blots had either a mosaic pattern (three patients) of bcr-abl-negative and positive colony-forming precursors (CFU-GEMM, BFU-E, CFU-GM, CFU-Mega), or all colonies were derived from leukemic precursors (one patient). However, in soft agar cultures of four patients without aberrant bands in Southern blots, only colonies without amplifiable bcr-abl transcripts were detectable. In another patient, few bcr-abl-positive colonies were found after 44 months of treatment, but not after 53 and 56 months of therapy. In these patients, therefore, residual disease detectable by PCR analysis of unfractionated cell samples does not appear to reside in the colony-forming cell compartment. The prognostic implications of these observations and the nature of the remaining bcr-abl-positive cells within unfractionated cell samples remain to be determined.

Adult↗
PubMed1994

Structural analysis of the deoxycytidine kinase gene in patients with acute myeloid leukemia and resistance to cytosine arabinoside.

Deficiency of deoxycytidine kinase (dCK) activity represents one possible cause of resistance to cytosine arabinoside (ara-C). Mutations of the dCK gene have recently been shown to be responsible for dCK deficiency and increased resistance in vitro. In order to define the relevance of this mechanism in vivo, we analyzed the dCK gene in 16 adult patients with relapsed/refractory acute myeloid leukemia (AML) and clinical resistance to standard-dose and/or high-dose ara-C. Southern blot analysis using genomic DNA from peripheral blood or bone marrow samples containing > or = 70% leukemic blasts and agarose gel electrophoresis of cDNA obtained by RT-PCR did not reveal gross rearrangements of the dCK gene. Sequencing of the dCK coding region showed point mutations in seven patients. Besides two silent mutations (or RFLPs) in codon 42 and 86, base pair mutations resulting in amino acid replacements were found in five patients affecting codon 20, 93, 98, 99, and 154, respectively. dCK cDNA clones from three patients with > or = 50% of sequenced clones revealing the specific base pair alteration were bacterially expressed in E. coli and analyzed for dCK activity. Normal enzyme activity was found in two patients (codon 20 and 98), and a complete loss of activity in one patient (codon 99). We conclude that structural alteration of the coding region of the dCK gene represents one possible mechanism for ara-C resistance in vivo, but, considering the frequency of this event, other mechanisms may play a more important role for clinical resistance to ara-C in patients with AML.

Adult↗
PubMed1994

[Surgery of locally advanced non-small-cell bronchial cancer after intensive preoperative chemo-/radiotherapy].

From March 1991 to June 1993 50 patients with local advanced NSCLC (mediastinoscopy obligatory) have been entered into an ongoing trial with preoperative chemotherapy and simultaneous chemo-/radiotherapy, followed by re-mediastinoscopy and surgery. Clinical response rates after chemotherapy amounted to 66.8% after chemo/radiotherapy 77.5%, no severe toxicity was observed. 36 patients ultimately underwent operation, 29 with a curative, 5 with a palliative resection and 2 with an explorative thoracotomy. Pathological complete remission rates of the primary tumor were found in 11 (32.3%), R0-resection in 18 (52.9%) and R1-resection in 5 (14.7%) cases. Sterilisation rates of mediastinal nodes were found in 86.3% of N2 tumors and 66.6% of N3 tumors. Median survival time ranged between 21 months for stage III a and 16 months for III b disease. This intensive preoperative neoadjuvant treatment is tolerable and effective, the requirements for a randomised comparative trial was met.

Adult↗