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Biomedical subjects

D K Hossfeld

Publications and source records attributed to D K Hossfeld.

At least 37 records · Page 2Linked to original sources
PubMed2002

Gemcitabine, vinorelbine and cisplatin combination chemotherapy in advanced non-small cell lung cancer: a phase II trial.

The purpose of this phase II trial was to investigate the efficacy and safety of a combination chemotherapy with gemcitabine, vinorelbine and cisplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Patients with NSCLC stage IIIB or IV disease received 1000 mg/m(2) gemcitabine and 25 mg/m(2) vinorelbine on days 1 and 8 and 75 mg/m(2) cisplatin on day 2, every 3 weeks. From December 1998 to May 1999, 31 patients (21 stage IV and 10 stage IIIB disease), with a median age of 59 years (range 40-72 years) were enrolled. The overall intent-to-treat response rate was 45% (95% confidence interval (CI): 27-64%) with 2 complete responders (CR) and 12 partial responders (PR), 7 patients had stable disease and 10 progressed. Median survival was 12.8 months (95% CI: 6.5-12.8+ months), median time to progression was 5.1 months (95% CI: 3.5-7.7 months), and the 1-year survival rate was 52.9% (95% CI: 36.7-76.2%). Patients with stage IIIB disease had a significantly longer overall survival than patients with stage IV disease (P=0.05). Transient World Health Organization (WHO) grade IV leucopenia, anaemia and thrombocytopenia occurred in 3 (10%), 2 (6%) and 3 (10%) patients, respectively. The predominant non-haematological toxicities were alopecia and nausea/vomiting. 15 patients (48%) had WHO grade II and III alopecia and 14 patients (45%) nausea/vomiting. The combination of gemcitabine, vinorelbine and cisplatin has demonstrated major antitumour efficacy in advanced NSCLC with a manageable toxicity profile.

Adult↗
PubMed2002

Whole-body hyperthermia (41.8 degrees C) combined with bimonthly oxaliplatin, high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer: a phase II study.

BACKGROUND: Second- and third-line treatments remain a challenge in advanced colorectal cancer. Studies of bimonthly regimens of high-dose leucovorin (LV) and 5-fluorouracil (5-FU) by continuous infusion combined with oxaliplatin (L-OHP) have shown encouraging response rates in patients not responding to a bimonthly LV/5-FU regimen. Hyperthermic enhancement of L-OHP efficiency by increased DNA adduct formation has been demonstrated in vitro. This study was designed to address feasibility, toxicity and efficacy issues of whole-body hyperthermia (WBH) as an adjunct to L-OHP/LV/5-FU in pretreated patients after progression to first- and second-line treatments with LV/5-FU by continuous infusion and irinotecan. PATIENTS AND METHODS: Forty-four patients with advanced colorectal cancer, who had progressed during or within 3 months after completion of chemotherapy with LV/5-FU 24-h infusion (LV/5-FU(24h)) (eight patients) or irinotecan combined with or after LV/5-FU(24h )(36 patients), were treated with L-OHP 85 mg/m(2), 2-h intravenous (i.v.) infusion, followed by LV 200 mg/m(2), 1-h i.v. infusion, and 5-FU 3 g/m(2), 48-h continuous infusion. Every second cycle of the biweekly regimen was combined with WBH, thus allowing a comparison of toxicity with and without WBH in the same patient. Whole-body hyperthermia was administered by a humidified radiant heat device. The target temperature of 41.8 degrees C was maintained for 60 min. L-OHP (2-h infusion) was started at a core body temperature of 39 degrees C. RESULTS: All patients could be evaluated for toxicity, and 41 patients were evaluable for response. A total of 273 L-OHP-containing regimens were administered, 130 with and 143 without WBH. Hyperthermic treatment combined with L-OHP/LV/5-FU showed no unexpected toxicities. WHO grade 3 toxicities were rare and evenly balanced between cycles given with or without WBH. One early death occurred due to sepsis and tumor lysis. The overall response rate was 20%, with two complete and six partial responses. Twenty-three patients (56%) had stable disease and nine patients (22%) progressive disease. With a median observation time of 70 weeks, the median time to progression was 21 weeks [95% confidence interval (CI) 17-25 weeks] and the median survival was 50 weeks (95% CI 39-61 weeks) from the start of therapy. CONCLUSIONS: This trial suggests some advantage of combining L-OHP/LV/5-FU with WBH. Results compare favorably with the activity of similar regimens without WBH in less extensively pretreated patients. These data support further evaluation and warrant phase III studies.

Adult↗
PubMed2002

Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin's disease.

BACKGROUND: An important variable affecting outcome in relapsed and refractory Hodgkin's disease (HD) is the potential of conventional salvage chemotherapy to reduce tumor volume before high-dose chemotherapy (HDCT) and autologous stem cell transplantation. Currently, the optimal salvage chemotherapy regimen for these patients is unclear. Since dexamethasone/cisplatin/cytarabine (DHAP) given at 3-4 week intervals has been shown to be very effective in patients with relapsed aggressive non-Hodgkin's lymphoma, we evaluated this regimen given at a median of 16-day intervals in patients with relapsed and refractory HD. PATIENTS AND METHODS: Patients with relapsed or refractory HD were treated with two cycles of DHAP [dexamethasone 40 mg intravenously (i.v.) day 1-4, cisplatin 100 mg/m(2) i.v. as 24-h continuous infusion day 1, and cytarabine 2 g/m(2) i.v. 12q day 2]. Granulocyte colony-stimulating factor (G-CSF) was given at a dose of 5 micro g/kg from day 4 until day 13. Patients with partial remission (PR) or complete remission (CR) after two cycles of DHAP received sequential HDCT. RESULTS: The median age of the 102 patients included was 34 years (range 21-64 years). Forty-two percent of the patients had late relapse, 29% early relapse, 12% multiple relapse and 16% primary progressive/refractory disease. The response rate (RR) after two cycles of DHAP was 89% (21% CR, 68% PR). The RRs for patients with late, early, multiple and progressive HD were 91%, 93%, 92% and 65%, respectively. Using the chi-square test for independence, remission status (relapsed HD versus progressive HD) and stage at relapse (stage I/II versus stage III/IV) were significant factors for response to DHAP. WHO grade 4 leukocytopenia and thrombocytopenia were the main toxic- ities occurring in 43% (mean duration 1.1 days, range 0-6) and 48% (mean duration 1.4 days, range 0-11) of all courses, respectively. Neither severe infections nor treatment-related deaths occurred. Peripheral blood stem cells (PBSCs) were collected after the first cycle DHAP in eight patients. The hematopoietic progenitors showed a very rapid increase from day 10 with a synchronous and impressive peak on day 12. A mean of 6.1 x 10(6)/kg CD34(+) cells were collected per apheresis. As originally recommended in the protocol, PBSCs were routinely collected during sequential HDCT in the remaining patients. CONCLUSIONS: A brief tumor-reducing program with two cycles of DHAP given in short intervals supported by G-CSF is effective and well-tolerated in patients with relapsed and refractory HD. This regimen can be used to mobilize stem cells and select those patients with chemosensitive relapse who should subsequently be treated with HDCT.

Adolescent↗
PubMed2002

Pretreatment serum levels of matrix metalloproteinase-9 and vascular endothelial growth factor in non-small-cell lung cancer.

BACKGROUND: Matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF) are two proteins involved in angiogenesis. In the present study we investigated the association of pretreatment MMP-9 and VEGF serum levels with clinicopathological parameters and outcome in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: From February 1998 to October 1999, pretreatment serum levels of MMP-9 and VEGF were analysed in 118 patients with enzyme-linked immunoassays. At diagnosis 50 patients (42%) were staged as early disease (I/II), 27 patients (23%) as locally advanced (IIIA/IIIB), and 41 patients (35%) had metastatic disease (IV). In 72 of the 118 patients tumours were resected and 46 patients received combination chemotherapy with gemcitabine and vinorelbine. RESULTS: The median survival of all 118 patients was 602 days. The 72 patients who had undergone surgery had a median survival of 972 days and the 46 patients who were treated with chemotherapy had a median survival of 298 days (P <0.001). Resected patients with stage I/II disease and an MMP-9 serum level <or=1293 ng/ml or a VEGF serum level <or=630 pg/ml had a significantly longer survival (median survival longer than 1218 days) than patients with higher serum levels (median survival 421 days) (P = 0.001 for MMP-9; P = 0.04 for VEGF). No significant difference in survival was observed in patients with resected stage III disease. Besides tumour stage, Karnofsky performance status and gender, the pretreatment serum level of MMP-9 was identified as an independent prognostic factor in a multivariate Cox regression analysis. CONCLUSIONS: Future studies may support our hypothesis that the pretreatment serum level of MMP-9 is a new powerful prognostic marker and can help to stratify NSCLC patients with stage I/II disease into low- and high-risk groups.

Adult↗
PubMed2001

Chromosomal gains and losses are uncommon in hairy cell leukemia: a study based on comparative genomic hybridization and interphase fluorescence in situ hybridization.

In contrast to other subtypes of lymphoproliferative malignancies, the genetic mechanisms underlying the pathogenesis of hairy cell leukemia (HCL) are unknown. We studied densely infiltrated splenic tissue of 14 cases of HCL for the presence of chromosomal gains and losses by comparative genomic hybridization (CGH). Chromosomal imbalances were detected in only four of the 14 cases. Chromosomal gains involved the regions 5q13-q31 (two cases) and 1p32-p36.2 (one case). A loss of the region 11q14-q22 was found in one additional patient. The imbalances affecting the regions 5q and 11q were confirmed by interphase fluorescence in situ hybridization (FISH) using PAC clone 144G9 (5q31) and YAC clones 755B11 (11q22.3-q23.1) and 801E11 (11q22.3-q23.1 spanning the ATM gene) and occurred in 61% to 75% of analyzed nuclei. The latter DNA probes and probes hybridizing to chromosomal regions, which are frequently deleted in other subtypes of non-Hodgkin lymphomas (NHL), namely 9p21/ P16(INK4A), 13q14/D13S25, and 17p13/P53 were subsequently applied to all 14 cases of HCL, but no additional abnormalities were found. We conclude that overrepresentation of chromosome 5 represents a recurrent aberration in HCL and that the commonly overrepresented region resides in 5q13-q31. Chromosomal imbalances including deletions of the tumor suppressor gene loci 9p21/P16(INK4A), 13q14/D13S25, and 17p13/P53 rarely occur in HCL in contrast to some other subtypes of B-cell NHL. The pathogenetic role of 11q/ATM alterations in HCL remains to be determined.

Chromosome Aberrations↗
PubMed2001

[Addition of hyperthermia. Heat potentiates cancer therapy].

It has been unequivocally demonstrated that hyperthermia (40-44 degrees C) has an potentiating effect on radiotherapy and chemotherapy. Technical improvements have facilitated the application of both local and whole-body hyperthermia, and have thus made this form of treatment available to large numbers of patients. Randomized phase III studies performed in patients with breast cancer, malignant melanoma and cervical cancer have convincingly confirmed the increased efficacy of the combination of radiotherapy with local or regional hyperthermia in comparison with radiotherapy alone. The effectiveness of other procedures such as the combination of radio- and chemotherapy with regional hyperthermia, regional thermochemotherapy and whole-body hyperthermia has so far been investigated mainly in phase II studies focusing on head and neck cancer, cervical and ovarian cancer, sarcoma, malignant germ cell tumors, and rectal carcinoma. However, the actual place of hyperthermia as a permanent element in a multimodal therapeutic concept has yet to be shown in prospective phase III studies.

Combined Modality Therapy↗
PubMed2001

Gemcitabine and vinorelbine as first-line chemotherapy for advanced non-small cell lung cancer: a phase II trial.

The purpose of this phase II study was to investigate the efficacy and safety of gemcitabine plus vinorelbine as first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligibility criteria included cytologically or histologically confirmed NSCLC (stage IIIB or IV), no previous chemotherapy, and bidimensionally measurable disease. Patients received 1000 mg/m(2) gemcitabine and 30 mg/m(2) vinorelbine on days 1, 8 and 15 every 4 weeks up to eight courses. From December 1997 to November 1998, 70 patients (59 stage IV and 11 stage IIIB disease), with a median age of 59 years (range 38-74 years) were enrolled. The intent-to-treat response rate was 41% (95% confidence interval (CI) 30-54%) with 1 complete responder (CR) and 28 partial responders (PRs), 15 patients had stable disease (SD) and 26 progressed (PD). Median survival was 8.3 months (95% CI 6.0-9.9 months), median progression-free survival (PFS) was 4.8 months (95% CI 3.9-5.5 months), and 1-year survival rate was 33.5% (95% CI 24.0-46.8%). Patients received a total of 229 cycles. Haematological and non-haematological toxicities were moderate. Transient World Health Organization (WHO)-grade IV leucopenia and thrombocytopenia occurred in 13 (6%) and two (1%) cycles, respectively. The predominant non-haematological toxicity was local reactions of the veins in 19 (27%) patients (WHO-grade II and III). Neurotoxicity was infrequent, non-cumulative, and reversible. The combination of gemcitabine and vinorelbine has demonstrated activity in metastatic NSCLC, with response and survival rates similar to those of cisplatin-based regimens and a more favourable toxicity profile that is well tolerated in an outpatient setting.

Adult↗
PubMed2001

18FDG-PET following treatment as valid predictor for disease-free survival in Hodgkin's lymphoma.

PURPOSE: The value of 18FDG-PET to predict the outcome after therapy in Hodgkin's lymphoma was compared to morphologic staging and ESR. PATIENTS AND METHODS: A total of 50 concurrent 18FDG-PET and CT studies were performed in 37 patients with Hodgkin's lymphoma. ESR was evaluated 32 times after treatment was completed. RESULTS: Out of 39 residual masses found by CT 8 relapses could be proven. Out of 11 CT exams with CR 3 relapses occurred. CT turned out to show a sensitivity, specificity, PPV, NPV, and accuracy of 72%, 21%, 21%, 73%, and 32%, with respect to predict disease-free survival (DFS). 18FDG-PET was positive in 22 examinations with 10 recurrences in this group. Out of 28 negative 18FDG-PET 1 relapse developed 3 years later. 18FDG-PET turned out to show promising sensitivity, specificity, PPV, NPV, and accuracy of 91%, 69%, 46%, 96%, 74%, with respect to predict DFS. ESR was elevated in 12 studies of which 5 relapses could be proven, while out of 20 normal ESR-studies 3 relapses occurred. Thus, ESR turned out to show sensitivity, specificity, PPV, NPV, and accuracy of 63%, 71%, 42%, 85%, and 75%, with respect to predict DFS. In summary, only 18FDG-PET was able to predict DFS statistically significant. CONCLUSION: 18FDG-PET can be very useful in patients with residual masses after treatment.

Adolescent↗
PubMed2001

Hand-foot syndrome associated with short infusions of combination chemotherapy with gemcitabine and vinorelbine.

The hand-foot syndrome (palmar-plantar erythrodysesthesia) is a side-effect which is associated with several cytotoxic agents (e.g. 5-fluorouracil, UFT, capecitabine, cytarabine, doxorubicin, liposomal-encapsulated doxorubicin). An association with a prolonged infusion of high doses of vinorelbine has also been described. To date a hand-foot syndrome after gemcitabine or short infusions of vinorelbine has not been reported before. The patient described here had a non-small-cell lung cancer stage IIIB disease and developed a hand-foot syndrome after short infusions of standard-dose chemotherapy of a combination with gemcitabine and vinorelbine.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Implantable device for intravenous drug delivery in the rat.

The experimental design of studies using small laboratory animals may require repeated venous access for the application of drugs or diagnostics. An appropriate device should provide quick intravenous access without causing severe handling stress to the animals or the necessity of anaesthesia. In addition, the system should be suitable for repeated injections over several weeks. A silicone catheter is connected to an intravenous indwelling cannula with fixation wings. A closure stopper with injection port completes this system. The device is fixed subcutaneously on the back of the animal and the catheter is inserted into the jugular vein. The device is easily and quickly assembled and is more economic than commercial systems. It is easily implanted and allows repeated intravenous injections for several weeks without anaesthesia or restraint of the animals. The method allows repeated intravenous drug delivery over a couple of weeks in small animals.

Animals↗
PubMed2001

Effects of vascular endothelial and platelet-derived growth factor receptor inhibitors on long-term cultures from normal human bone marrow.

Endothelial cells and fibroblasts are important constituents of the haemopoietic microenvironment. Growth and function of these cells are controlled by a variety of cytokines, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). We analysed the effects of novel tyrosine kinase inhibitors targeting the VEGF and PDGF receptors (compounds SU5614 and SU5768) on the performance of long-term cultures from normal human bone marrow. In developing cultures, the inhibitors induced a dose-dependent reduction in stromal fibroblasts, macrophages and endothelial cells with a concomitant decrease in blood cell production and an increase in fat cells. For SU5614, the concentration inhibiting stroma formation by 50% (IC50) was 123nM, and the IC50 for haemopoietic colony forming cell output was 186 nM. For SU5768, the respective values were 871 nM and 331 nM. Changes in stroma composition and inhibition of haemopoietic cell production were also demonstrable after delayed addition of the inhibitors to established cultures. By contrast, haemopoietic colony formation in clonogenic agar cultures was unimpaired (IC50 not reached at 100 microM). Immunofluorescence studies and time course analyses suggested that the primary effect of the inhibitors was interference with the proliferation and function of fibroblasts and endothelial cells which in turn resulted in decreased haemopoiesis and increased adipogenesis. This was associated with decreased levels in conditioned media of granulocyte-macrophage colony-stimulating factor, interleukin-6 and leptin. VEGF and PDGF may play a hitherto underestimated role in the control of blood cell formation. VEGF/PDGF receptor inhibitors may have therapeutic potential in stroma diseases such as myelofibrosis. Since they weaken the stimulatory signals provided by the microenvironment, they may also be of value in the treatment of leukaemia and other neoplastic bone marrow diseases.

Adipocytes↗
PubMed2000

Detection of t(11;18)(q21;q21) by interphase fluorescence in situ hybridization using API2 and MLT specific probes.

The translocation of chromosome 11, long arm, region 2, band 1, to chromosome 18, long arm, region 2, band 1 (t(11;18)(q21;q21)) represents a recurrent chromosomal abnormality in extranodal marginal zone B-cell lymphoma (MZBCL) of mucosa-associated lymphoid tissue (MALT) type and leads to a fusion of the apoptosis inhibitor-2 (API2) gene on chromosome 11 and the MALT lymphoma-associated translocation (MLT) gene on chromosome 18. A 2-color fluorescence in situ hybridization (FISH) assay, which can be used for the detection of t(11;18) in interphase nuclei and metaphase chromosomes on fresh and archival tumor tissue, was developed. The P1 artificial chromosome (PAC) clone located immediately telomeric to the MLT gene and the PAC clone spanning the API2 gene were differentially labeled and used to visualize the derivative chromosome 11 resulting from t(11;18), as evident by the overlapping or juxtaposed red and green fluorescent signals. The assay was applied to interphase nuclei of 20 cases with nonmalignant conditions and 122 B-cell non-Hodgkin's lymphomas (NHLs). The latter group comprised 20 cases of nodal follicle center cell lymphoma and diffuse large B-cell NHL, 10 cases of gastric diffuse large B-cell lymphoma, 10 cases of hairy cell leukemia, and 82 cases of MZBCL (41 extranodal from various locations, 19 nodal, and 22 splenic MZBCL) including 35 cases with an abnormal karyotype, 2 of which revealed t(11;18). By interphase FISH, t(11;18) was detected in 8 gastrointestinal low-grade MALT-type lymphomas including the 2 cytogenetically t(11;18)(+) cases. In the 8 t(11;18)(+) cases, the FISH results were confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) using API2 and MLT specific primers. Our results indicate that t(11;18)(q21;q21) specifically characterizes a subgroup of low-grade MZBCL of the MALT-type and that the FISH assay described here is a highly specific and rapid test for the detection of this translocation.

Caspases↗
PubMed2000

Analysis of the P53, RB/D13S25, and P16 tumor suppressor genes in marginal zone B-cell lymphoma: An interphase fluorescence in situ hybridization study.

The genetic mechanisms underlying the genesis, disease progression, and high-grade transformation of marginal zone B-cell lymphoma (MZBCL) are poorly understood. We analyzed 33 cases of histologically and immunophenotypically well-characterized MZBCL (12 extranodal, 11 nodal, and 10 splenic MZBCL; 27 at primary diagnosis and six during the course of disease) by dual-color interphase fluorescence in situ hybridization (FISH) for deletions of tumor suppressor genes. We investigated loci known to play a role in the genesis or disease progression of other subtypes of lymphoid malignancies, namely the P53 gene (17p13), the retinoblastoma gene (RB, 13q14), the D13S25 locus (13q14), and the P16(INK4A) gene (9p21). Heterozygous deletions of P53 were detected in three out of the 33 cases, including two splenic and one extranodal MZBCL. One of these patients was analyzed at primary diagnosis and two during the course of disease. Heterozygous deletions of the RB gene (nodal MZBCL) and D13S25 (splenic MZBCL) were found in one case each. P16 deletions were not detected in any of our cases. We conclude that deletions of the analyzed tumor suppressor genes are relatively rare in MZBCL, which contrasts with the findings in some other subtypes of NHL.

Aged↗
PubMed2000

In vitro differentiation of endothelial cells from AC133-positive progenitor cells.

Recent findings support the hypothesis that the CD34(+)-cell population in bone marrow and peripheral blood contains hematopoietic and endothelial progenitor and stem cells. In this study, we report that human AC133(+) cells from granulocyte colony-stimulating factor-mobilized peripheral blood have the capacity to differentiate into endothelial cells (ECs). When cultured in the presence of vascular endothelial growth factor (VEGF) and the novel cytokine stem cell growth factor (SCGF), AC133(+) progenitors generate both adherent and proliferating nonadherent cells. Phenotypic analysis of the cells within the adherent population reveals that the majority display endothelial features, including the expression of KDR, Tie-2, Ulex europaeus agglutinin-1, and von Willebrand factor. Electron microscopic studies of these cells show structures compatible with Weibel-Palade bodies that are found exclusively in vascular endothelium. AC133-derived nonadherent cells give rise to both hematopoietic and endothelial colonies in semisolid medium. On transfer to fresh liquid culture with VEGF and SCGF, nonadherent cells again produce an adherent and a nonadherent population. In mice with severe combined immunodeficiency, AC133-derived cells form new blood vessels in vivo when injected subcutaneously together with A549 lung cancer cells. These data indicate that the AC133(+)-cell population consists of progenitor and stem cells not only with hematopoietic potential but also with the capacity to differentiate into ECs. Whether these hematopoietic and endothelial progenitors develop from a common precursor, the hemangioblast will be studied at the single-cell level.

Animals↗