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Biomedical subjects

V Diehl

Publications and source records attributed to V Diehl.

At least 199 records · Page 11Linked to original sources
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

Phase-II trial of idarubicin, fludarabine, cytosine arabinoside, and filgrastim (Ida-FLAG) for treatment of refractory, relapsed, and secondary AML.

The current phase-II trial was initiated to assess the efficacy and toxicity of the Ida-FLAG regimen in patients with poor-risk acute myeloid leukemia (AML). Three subgroups of patients with AML were eligible for the study: (a) refractory, (b) first relapse, or (c) secondary AML (i.e., signs of trilineage myelodysplasia at diagnosis or the history of a myelodysplasia or myeloproliferative disorder). Fifty-seven fully evaluable patients were included in the study. Twenty patients received a second course of Ida-FLAG. Complete remission was achieved by 1/14 patients with refractory AML, 12/15 patients with relapsed AML, and 17/28 patients with secondary AML. The median duration of ANC <1000/microl was 17 days (10-36); of platelets <30,000/microl 23 days (9-65); of days with fever >38.0 degrees C 6 days (1-33). Thirteen patients (22.8%) died within 42 days of severe infection or hemorrhage. Overall survival at 20 weeks in the subgroups was 24% for patients with refractory, 78% for patients with relapsed, and 55% for patients with secondary AML. The toxicity of the first cycle of Ida-FLAG is moderate. The feasibility and subjective tolerance of the Ida-FLAG regimen are acceptable. There is no evidence for an increase of atypical infections. The efficacy for patients with secondary AML and especially those with first relapse of AML is good, with a high rate of complete remissions. Remission duration seems to be short. Therefore, an intensified post-remission therapy seems necessary.

Acute Disease↗
PubMed1999

Two cases of toxoplasmic encephalitis in patients with acute T-cell leukaemia and lymphoma.

Two cases of opportunistic cerebral infections in HIV-negative cancer patients due to chemotherapy induced immunosuppression are reported. A 61-year-old patient with low grade lymphoma (immunocytoma as referred to the Kiel classification) developed stereotactical biopsy proven toxoplasmic encephalitis 6 months after initiation of fludarabine treatment. The lymphoma had been diagnosed 8 years earlier and had been treated with several different regimens. In the second case, a 55-year-old patient developed neurological symptoms while in complete remission from acute T-cell leukaemia. The patient had been treated with a multidrug chemotherapy regimen including radiotherapy of the brain and intrathecal chemotherapy. When toxoplasmic encephalitis was bioptically diagnosed the patient was on maintenance chemotherapy with methotrexate and mercaptopurine for 12 months. The patients' characteristics and outcome are reported and the potential pathogenesis is discussed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

How many myeloid post-progenitor cells have to be transplanted to completely abrogate neutropenia after peripheral blood progenitor cell transplantation? Results of a computer simulation.

Although hematopoietic recovery following high-dose chemotherapy (HD-CT) and peripheral blood progenitor cell (PBPC) transplantation is rapid, there is still a 5- to 7-day period of severe neutropenia which, theoretically, might be abrogated by an additional transplantation of more differentiated myeloid post-progenitor cells (MPPC). However, both the number of MPPC required to abrogate neutropenia as well as the optimum scheduling of MPPC infusions are currently unknown. Therefore, these questions were addressed by applying a computer model of human granulopoiesis. First, model calculations simulating varying levels of chemotherapy dose intensity were performed and compared with typical clinical neutrophil recovery curves. Using this approach, the data for HD-CT without PBPC transplantation could be reproduced by assuming a reduction of stem cells, committed granulopoietic progenitors and proliferating precursors to about 0.001% of normal. PBPC-supported HD-CT was reproduced by increasing the starting values to at least 0.1%, which corresponded to about 1 to 2 x 10(5)/kg transplanted CFU-GM. Interestingly, reproduction of PBPC-supported HD-CT data could be observed for a wide range of starting values (0.1%-10% of normal), thus confirming the clinical observation that hematopoietic recovery after PBPCT cannot be improved by increasing the dose of transplanted cells over a certain threshold. Using the same simulation model, we then studied the effects of an additional MPPC transplantation. The results showed, that at least 5.7 X 10(8) MPPC/kg have to be provided in addition to the normal PBPC graft to avoid neutropenia <100/microL, and that MPPC are best transplanted on days 0 and 6 after HD-CT. Assuming a 100- to 120-fold cellular ex-vivo expansion rate and MPPC representing about 70% of total expanded cells, 5.7 X 10(8) MPPC/kg could be generated starting from 1 to 2 leukapheresis preparations with about 7 to 8 x 10(6) CD34+ PBPC/kg. Considering furthermore, that only a fraction of ex-vivo generated cells will seed and effectively produce neutrophils in-vivo, the required number of MPPC is most likely even higher and, therefore, might be difficult to be achieved clinically. However, the validity of the model results remains to be proven in appropriate clinical studies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Body weight changes with protease inhibitor treatment in undernourished HIV-infected patients.

Effective reduction of HIV replication by protease inhibitor (PI) treatment was expected to reverse some of the weight loss associated with HIV infection. Body weight changes in undernourished HIV-infected patients starting PI treatment were compared to its virologic and immunologic effects. This was designed as a retrospective study using prospectively collected weight data; the setting was the HIV outpatient department of a university hospital. Among 223 consecutive HIV-positive patients starting treatment with PI February 1996 to September 1997, 63 undernourished patients were evaluable. The main outcome measures were weight trend, calculated by linear regression of a patient's weight versus time, and its change from a 4-14-wk baseline period to the first 14 wk, and 28 wk, after treatment. In our results, weight trend remained unchanged (baseline, +0.4 +/- 4.0 kg/100 d; 14 wk, +0.7 +/- 4.1 kg/100 d, and 28 wk, +1.0 +/- 3.4 kg/100 d, n.s.). Reduction of viremia and increase in CD4 cell count were unrelated to weight trends. Treatment with PI did not result in an improved weight trend. Altered body composition with PI treatment, as observed in other studies, does not seem to result in body weight changes. Drug side effects may have counteracted any positive effects. The metabolic and nutritional impact of effective antiviral treatment merits further study.

Adult↗
PubMed1999

Retrospective assessment of quality of life and treatment outcome in patients with Hodgkin's disease from 1969 to 1994.

We determined the current quality of life (QoL) of patients with Hodgkin's disease treated at the Innsbruck University Hospital between 1969 and 1994 at a mean time of 9.1 +/- 7.0 years after their initial treatment. Further aims of our study were to assess potential differences in objective treatment outcome and QoL between patients treated with chemo-, radio- or combined modality therapy and those enrolled in randomised clinical trials or treated according to standard procedures. The QLQ-C30, a health-related and validated self-report questionnaire developed by the Study Group on Quality of Life of the European Organization for Research and Treatment of Cancer (EORTC) was mailed to a cohort of 194 survivors out of a total of 225 patients with Hodgkin's disease; 126 of them (64.9%) returned the completed questionnaire. The 5- and 10-year overall survival rates for the total group of 225 patients were 94.3% and 84.9%, respectively. Irrespective of stage, higher relapse-free survival rates were observed in patients receiving combined modality treatment (P = 0.025). Five-year relapse-free survival rates were 96.6% for patients enrolled in clinical trials and 82.8% for patients treated outside of randomised studies (P = 0.037 in univariate and P = 0.064 in multivariate analysis). Patients treated with combined modality regimens had reduced QoL scores in comparison with those treated with either radiation or chemotherapy alone, but QoL parameters did not differ between patients enrolled in clinical trials and those treated according to standard procedures. Patients with Hodgkin's disease had an excellent long-term prognosis and very high QoL scores a mean of 9.1 years after treatment of their disease. The improved relapse-free survival rates achieved by combined modality regimens must be carefully weighed against the accompanying reduced QoL, since lower relapse rates did not translate into a survival advantage.

Adolescent↗
PubMed1999

Prognostic factors for subdiaphragmatic involvement in clinical stage I-II supradiaphragmatic Hodgkin's disease: a retrospective analysis of the GHSG.

BACKGROUND: Staging laparotomy and splenectomy were routinely performed in patients with early-stage Hodgkin's disease (HD) qualifying for radiotherapy alone to determine the exact extent of disease. However, staging laparotomy is associated with a considerable number of side effects, warranting more sophisticated diagnostic procedures and new therapy strategies. We retrospectively analyzed patients undergoing staging laparotomy to identify pretherapy risk factors predicting the probability of abdominal disease and to define high-risk groups that might benefit from staging laparotomy and subsequent stage-adjusted treatment. PATIENTS AND METHODS: Between February 1988 and January 1993, 391 patients with CS I-II supradiaphragmatic Hodgkin's disease underwent staging laparotomy and splenectomy according to the treatment policy of the German Hodgkin's Lymphoma Study Group (GHSG) for early stages of Hodgkin's disease. Univariate and multivariate analysis of pretherapeutic clinical characteristics were performed in an attempt to predict staging laparotomy results and to identify risk groups. RESULTS: Of the 391 patients, 81 (21%) had subdiaphragmatic disease. Eighteen percent were upstaged to PS III and three percent to PS IV. By a multivariate model the following parameters were independent risk factors for positive surgical staging: left cervical involvement (P < 0.001), mediastinal involvement (P < 0.009), Karnofsky performance status (P < 0.004) and histology (P < 0.04). In our analysis gender (P < 0.08) and ESR (P < 0.06), often described as of high prognostic value, was not significant. The presence of systemic symptoms, number of involved areas and clinical stage were not associated with abdominal disease, as described in several former publications. To define high-risk groups, which comprise at least 15% of patients of the cohort and have a risk of subdiaphragmatic involvement of > 35%, combinations of only two or three of the predictive factors were analyzed. With respect to these criteria the following subgroups of patients were identified as having a high risk for subdiaphragmatic disease (> 35%): a) left cervical lymph node involvement and no mediastinal involvement (n = 98, observed risk 36%); b) no mediastinal involvement and MC/LD histology (n = 113, observed risk 40%). CONCLUSIONS: We conclude that initial clinical characteristics are predictive for occult abdominal involvement in early clinical stages of Hodgkin's disease. The impact of these risk factors on future therapeutical strategies have to be evaluated.

Adult↗
PubMed1999

An anti-CD30 single-chain Fv selected by phage display and fused to Pseudomonas exotoxin A (Ki-4(scFv)-ETA') is a potent immunotoxin against a Hodgkin-derived cell line.

The human CD30 receptor is highly overexpressed on the surface of Hodgkin Reed-Sternberg cells and has been shown to be an excellent target for selective immunotherapy using monoclonal antibody-based agents such as immunotoxins. To construct a new recombinant immunotoxin for possible clinical use in patients with Hodgkin's lymphoma, we have chosen the murine anti-CD30 hybridoma Ki-4 to generate a high-affinity Ki-4 single-chain variable fragment (scFv). Hybridoma V-genes were polymerase chain reaction-amplified, assembled, cloned and expressed as a mini-library for display on filamentous phage. Functional Ki-4 scFv were obtained by selection of binding phage on the Hodgkin lymphoma-derived, CD30-expressing cell line L540Cy. The selected recombinant Ki-4 scFv was shown to specifically bind to an overlapping epitope on the CD30 antigen with binding kinetics similar to those of the original antibody. The Ki-4 scFv was subsequently fused to a deletion mutant of Pseudomonas exotoxin A (ETA'). The resulting immunotoxin Ki-4(scFv)-ETA' specifically binds to CD30+ L540Cy cells and inhibits the protein synthesis by 50% at a concentration (IC50) of 43 pM. This recombinant immunotoxin is a promising candidate for further clinical evaluation in patients with Hodgkin's lymphoma or other CD30+ malignancies.

Bacterial Toxins↗
PubMed1999

Progressive multifocal leukoencephalopathy after autologous bone marrow transplantation and alpha-interferon immunotherapy.

A patient with a stage IV mantle cell lymphoma (according to the REAL classification) was treated with high-dose chemotherapy and autologous bone marrow transplantation. One year later while on alpha-interferon immunotherapy she suffered from progressive loss of short-term memory and reported difficulties in recognizing objects. Magnetic resonance imaging (MRI) showed a vast ring-enhancing lesion of the left postcentral parietal area. Serial stereotactic biopsies disclosed progressive multifocal leukoencephalopathy without JC-virus in the cerebrospinal fluid. Therapy with subcutaneous interleukin-2 (IL-2) every other day and intrathecal cytarabine once a week was started. After 4 weeks the patient refused further treatment. Nevertheless her condition improved over the next 8 months and MRI scans showed a marked improvement in the lesions.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Using at least 5x10(6)/kg CD34+ cells for autologous stem cell transplantation significantly reduces febrile complications and use of antibiotics after transplantation.

For autologous stem cell transplantation, it is common practice to infuse at least 2 x 10(6)/kg CD34+ cells to ensure rapid engraftment. However it was recently claimed that increasing the threshold to 5 x 10(6)/kg leads to a faster platelet engraftment. To evaluate these threshold values in our patient population we undertook a retrospective analysis of 127 autologous transplants performed at our institution between 1992 and 1998. Diagnoses included Hodgkin's and non-Hodgkin's lymphoma, myeloma, acute leukaemias and solid tumours. The transplant was peripheral blood stem cells in 107 cases and CD34-selected peripheral blood stem cells in 20 cases. The median number of transplanted CD34+ cells was 3.2 x 10(6)/kg (range 0.64-25.9 x 10(6)/kg). Haematopoietic recovery to a neutrophil count >0.5 x 10(9)/l took a median of 10 (range 5-16) days from transplant. When comparing patients receiving at least 5 x 10(6)/kg and 2-5 x 10(6)/kg CD34+ cells we found a significant reduction in the median number of days with fever (1 vs 3.5 days, P = 0.0025), incidence of fever (78.8 vs 92.1%, P = 0.032) as well as duration of antibiotic treatment (7 vs 10 days, P = 0.038). This was paralleled by a faster neutrophil recovery to 0.5 x 10(9)/l (9 vs 10 days, P = 0.047). There was no significant difference in the number of platelet or red cell transfusions between the two groups. We conclude that transplantation with a stem cell dose of at least 5 x 10(6)/kg CD34+ cells reduces infectious complications and should thereby increase the safety of this type of therapy while reducing duration (and cost) of antibiotic therapy. The transplantation threshold should thus not remain at 2 x 10(6)/kg particularly in patients with a good stem cell mobilisation capacity.

Adolescent↗
PubMed1999

Successful peripheral blood stem cell mobilization with etoposide (VP-16) in patients with relapsed or resistant lymphoma who failed cyclophosphamide mobilization.

High-dose chemotherapy (HDCT) followed by autologous blood stem cell transplantation is considered the treatment of choice for patients with relapsed or resistant aggressive non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). However, several authors report failure of standard mobilization regimens in 29% to 56% of these patients making the completion of HDCT impossible and as a result, negatively influencing long-term outcome. Thus, effective new regimens for patients failing initial mobilization are needed. Here we report the results of using etoposide as a mobilizing agent in 16 patients with primary resistant or relapsed malignant lymphoma who had failed prior mobilization of peripheral blood stem cells (PBSC) with cyclophosphamide (4 g/m2) followed by G-CSF. The use of etoposide 500 mg/m2 (days 1-4) + G-CSF resulted in the successful collection of adequate numbers of PBSC with a median harvest of 3.6 x 10(6)/kg (range 2.2-12.6) CD34+ cells in all 16 patients. In 7/16 (44%) patients, the target yield of at least 2.0 x 10(6) CD34+ cells was harvested by a single apheresis and the maximum number of separations for all patients was two. No excessive toxicities appeared, allowing all patients to proceed to myeloablative chemotherapy. In addition, median peak values of circulating CD34+ cells were significantly higher after etoposide as compared to cyclophosphamide (49.2/microl vs 4.7/microl; P = 0.0004). These results indicate that etoposide + G-CSF is a highly effective mobilization regimen in patients who have failed cyclophosphamide mobilization.

Adult↗
PubMed1999

A chimeric receptor that selectively targets membrane-bound carcinoembryonic antigen (mCEA) in the presence of soluble CEA.

Chimeric T cell receptors with specificity for tumor-associated antigens are successfully used to target T cells to tumor cells. The efficacy of this approach, however, is reduced by soluble antigen that is frequently present in high serum concentrations. To overcome this situation, we constructed an anti-CEA chimeric receptor whose extracellular moiety is composed of a humanized single chain antibody fragment (scFv) derived from the anti-CEA mAb BW431/26 and the CH2/CH3 constant domains of human IgG. The intracellular moiety consists of the gamma-signaling chain of the human Fc epsilon RI receptor constituting a completely humanized chimeric receptor. After transfection, the humBW431/26 scFv-CH2CH3-gamma receptor is expressed as a homodimer on the surface of MD45 T cells. Co-incubation with CEA+ tumor cells specifically activates grafted MD45 T cells indicated by IL-2 secretion and cytolytic activity against CEA+ tumor cells. Notably, the efficacy of receptor-mediated activation is not affected by soluble CEA up to 25 micrograms/ml demonstrating the usefulness of this chimeric receptor for specific cellular activation by membrane-bound CEA even in the presence of high concentrations of CEA, as found in patients during progression of the disease.

Carcinoembryonic Antigen↗
PubMed1999

Initial (prefibrotic) stages of idiopathic (primary) myelofibrosis (IMF) - a clinicopathological study.

A clinicopathological follow-up study including sequential bone marrow biopsies was performed on 79 patients with idiopathic (primary) myelofibrosis (IMF) to characterize initial (prefibrotic) stages and to elucidate whether development of fibrosis was accompanied by corresponding clinical findings. For this purpose our cohort of patients was divided into two groups of which the first presented with the generally accepted signs and symptoms of IMF (group I; n = 60). Most patients of the second group (group II; n = 19) showed mild to moderate therapy-refractory anemia, minimal to slight splenomegaly and frequently thrombocytosis, but no bone marrow fibrosis at onset. Hematopoiesis was consistent with a striking hypercellularity in comparison to the age-related involution by adipose tissue, a conspicuous clustering and histotopographic dislocation of megakaryocytes, a neutrophil granulocytic proliferation and a reduction of erythropoietic islets with arrest of maturation. Most remarkable was the dysplastic cytology of megakaryocytes with a definitive deviation of differentiation resulting in bizarre forms. Follow-up examinations revealed that at later stages group II patients were not distinguishable from the first group with more advanced IMF. For this reason, these patients were regarded as presenting initial, prefibrotic IMF characterized by distinctive bone marrow features at the beginning. The prominent abnormalities of megakaryopoiesis together with the granulocytic proliferation were extremely helpful to differentiate prefibrotic IMF with accompanying thrombocythemia from essential thrombocythemia (ET). Dynamics of fiber progression were calculated by regarding increase in density per time. Speed of progression during the first year of observation proved to be significantly higher in group II patients with prefibrotic IMF in comparison to full-blown cases (group I). In conclusion, with respect to prospective clinical trials, diagnostic criteria for IMF should be re-evaluated by also taking initial, prefibrotic stages into account.

Anemia, Refractory↗
PubMed1999

Detection of a Hodgkin/Reed-Sternberg cell specific immunoglobulin gene rearrangement in the serum DNA of a patient with Hodgkin's disease.

We analysed multiple serum samples from a patient with mixed cellularity Hodgkin's disease for the Hodgkin/Reed-Sternberg cell clone-specific rearranged Ig gene sequence. The clone-specific sequence could be detected in DNA extracted from a serum sample obtained during clinical relapse but not in serum samples obtained during or after treatment following relapse.

Adult↗
PubMed1999

Bioelectrical impedance analysis in HIV-infected patients treated with triple antiretroviral treatment.

BACKGROUND: Triple antiretroviral treatment including protease inhibitors (PIs) delays the clinical progression of HIV infection and may thus reduce the risk of malnutrition. However, fat redistribution (lipodystrophy) was recognized recently as a metabolic side effect of PIs. OBJECTIVE: The study aimed to assess the effect of triple antiretroviral treatment on body composition and on the prevalence of malnutrition. DESIGN: Two cross-sectional studies, 1 in 1996 (t96; n = 247) and 1 in 1997 (t97; n = 266), were conducted in HIV-infected outpatients. Among patients who participated in both studies, 111 patients started a new antiretroviral treatment including a PI between t96 and t97 and were studied longitudinally. Total body water (TBW), intracellular water (ICW), extracellular water (ECW), and fat mass were estimated by monofrequency bioelectrical impedance analysis (BIA). RESULTS: Prevalence of malnutrition was reduced by 30-50% from t96 to t97, depending on the definition used. In the longitudinal study, TBW and the ratio between ICW and ECW increased and fat mass decreased (P < 0.001). BIA indicated a greater increase in ICW in 23 (21%) patients with clinically apparent fat redistribution than in patients without this syndrome, but estimates of fat mass changes were not significantly different. CONCLUSIONS: Triple antiretroviral treatment may protect HIV-infected patients against the development of malnutrition. Whole-body BIA data suggest an increase in appendicular body cell mass associated with improved antiretroviral treatment. However, the method is unreliable in detecting fat redistribution, and current prediction equations will need to be recalibrated for HIV-infected patients receiving highly active antiretroviral treatment.

Adult↗