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Biomedical subjects

M Schweigert

Publications and source records attributed to M Schweigert.

17 recordsLinked to original sources
PubMed2004

A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. PATIENTS AND METHODS: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. RESULTS: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses > or = 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses > or = 320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. CONCLUSIONS: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.

Camptothecin↗
PubMed2003

Differentiation of a pancreatic metastasis of a renal cell carcinoma from a primary pancreatic carcinoma by echo-enhanced power Doppler sonography.

In a 70-year-old patient who had been treated for a renal cell carcinoma, a pancreatic mass was detected on CT scan. To differentiate a pancreatic metastasis of the renal cell carcinoma from a pancreatic carcinoma, an echo-enhanced power Doppler sonography was performed. The pancreatic mass demonstrated a strong echo enhancement, proving its hypervascularization. This behaviour favoured the diagnosis of a pancreatic metastasis of the renal cell carcinoma which was confirmed by histology. The principles and the role of echo-enhanced power Doppler sonography in the differential diagnosis between a primary pancreatic carcinoma and a metastasis of a renal carcinoma in the pancreas are discussed. We conclude that this technique can provide an important contribution to the diagnosis in this special instance. However, histology is the standard in the differential diagnosis of pancreatic tumours.

Aged↗
PubMed2001

Intrinsic neurons in the duck choroid are contacted by CGRP-immunoreactive nerve fibres: evidence for a local pre-central reflex arc in the eye.

Intrinsic choroidal neurons represent peripherally displaced autonomic nerve cells supposed to work as a local integrative network similar to the enteric nervous system, to control choroidal vasculature and stromal smooth muscle. A typical feature of such intramural neuronal networks is the innervation by primary afferent collaterals expressing peptides, e.g. CGRP. The present study was aimed at determining primary afferent contacts on nitrergic intrinsic choroidal neurons (ICN) in the duck eye. In addition, a sympathetic innervation of ICN was assessed. Choroids were immunohistochemically processed for the following markers: neuronal nitric oxide synthase (nNOS), galanin (GAL), calcitonin gene-related peptide (CGRP), and tyrosine hydroxylase (TH). For evaluation, fluorescence as well as confocal laser scanning microscopy were used. For electron microscopy, immunoperoxidase staining for CGRP in combination with NADPH-diaphorase histochemistry was applied. ICN immunoreactive for nNOS or GAL spread over the entire choroid, although they were concentrated in an equatorial zone passing obliquely from naso-cranial to temporo-caudal. About 40% of ICN showed close relationships with CGRP-immunoreactive nerve fibres, originating most likely in the trigeminal ganglion, as seen in the fluorescence and confocal laserscanning microscope. These appositions could be ultrastructurally defined as both synapses and close contacts without synaptic specialization. Some ICN endowed with CGRP-positive fibres also received TH-immunoreactive boutons. CGRP-immunoreactive profiles were also detected in close relationship to choroidal non-vascular smooth muscle cells and collagen fibres connected to them. In many instances, they were intercalated between smooth muscle cells and processes of ICN forming triads. These results suggest that ICN, similar to other intramural autonomic systems integrate signals from trigeminal primary afferent collaterals. The 'sensory' terminals of these primary afferents may be located in the anterior eye segment but also within the smooth muscle stroma of the choroid itself. Thus, ocular homeostasis may be regulated via intraocular pre-central reflexes which are probably subject to sympathetic modulation.

Afferent Pathways↗
PubMed2001

The effect of increasing topotecan infusion from 30 minutes to 4 hours on the duration of exposure in cerebrospinal fluid.

BACKGROUND: The development of metastatic disease throughout the neuroaxis from primary central nervous system (CNS) tumors and non-CNS tumors suggests the cerebrospinal fluid (CSF) is an important source of exposure for chemotherapeutic agents. In non-human primates, a 4-hour, as compared to a 30-minute, topotecan (TPT) infusion prolonged TPT exposure in the CSF. PATIENT AND METHODS: We evaluated this approach in a 51-year-old woman with breast cancer metastatic to the CNS. TPT was administered at 1.5 mg/m2/day (cycle 1) and 1.0 mg/m2/day (cycles 2 and 3) as a 30-minute infusion on days 0-4, and as a 4-hour infusion on day 5. Cycles were repeated every 21 days. Plasma, lateral ventricular CSF, and lumbar CSF samples were obtained after 30-minute and 4-hour infusions, and assayed for TPT lactone and total by HPLC. A three-compartment model was used to calculate area under the plasma (AUCplasma) and lateral ventricular CSF (AUCCSF) concentation-time curves. TPT CSF penetration was calculated as the ratio of AUCCSF to AUCplasma. RESULTS: Mean +/- SD values for TPT total CSF penetration in lateral CSF after 30-minute and 4-hour infusions were 0.25 +/- 0.15 and 0.29 +/- 0.02, respectively. TPT total lumbar CSF concentration was 3-fold greater after a 4-hour as compared to a 30-minute infusion. For TPT lactone and TPT total, time > 1 ng/ml in lateral CSF was 1.8- and 1.7-fold greater, respectively, for a 4-hour as compared to a 30-minute infusion. CONCLUSIONS: Prolonging TPT infusion from 30 minute to 4 hours increases the duration of exposure in the CSF. This study demonstrates the ability to develop treatment strategies of systemically administered chemotherapy to enhance cytotoxic exposure in the CSF.

Antineoplastic Agents↗
PubMed2001

Tolerability of the cytoprotective agent amifostine in elderly patients receiving chemotherapy: a comparative study.

In order to determine if age and comorbidity influence the tolerability of the cytoprotective agent amifostine, we compared side effects related to amifostine in patients > or = 70 years (group I) with patients < 70 years (group II). We evaluated 268 consecutive administrations of amifostine (119 in group I and 149 in group II, respectively), given i.v. at a dose of 740 mg/m(2) just before platinum-, taxol- or cyclophosphamide-based chemotherapy. Transient hypotension was the most common side effect occurring in association with amifostine. Decreases in systolic blood pressure > 20 mmHg were of similar frequency in both groups (27.1 versus 28.8% of amifostine infusions in group I and II, respectively). Hypotension did not result in medical sequelae in any of the patients. The amifostine infusion was interrupted 16 times in group I and 8 times in group II, respectively, mainly due to hypotension, but could be restarted after a few minutes in all patients except for three cases in group I. Patients in group II more often suffered from nausea/vomiting than in group II (20.8 versus 10.0% in group I). Other subjective symptoms (e.g. warmed, flushed sensation, sneezing, metallic taste, mouth dryness, dizziness and sleepiness) and hypocalcemia occurred with a similar frequency in both groups. Adverse effects associated with amifostine were not observed more frequently in elderly patients than in younger ones, although more elderly patients had a comorbidity than the younger ones.

Adult↗
PubMed2000

Neuropathy under chemotherapy.

Neuropathy is a dose-limiting side effect for a number of effective chemotherapeutic agents. A better understanding of effective mechanisms will lead to novel treatment strategies that will protect neurons without decreasing therapeutic efficacy. The assessment of the efficacy and neurotoxicity of various chemotherapeutic agents is vital, for a determination of the maximum allowable dose. The introduction of chemotherapy in the 50s and 60s of the twentieth century has resulted in the development of curative therapeutic interventions for patients with several types of solid tumours and hemopoietic neoplasms. The important obstacles encountered in the use of chemotherapy have been the toxicity to the normal tissue. During the past 8 years there has come about a new level of understanding of the mechanisms through which chemotherapeutic agents work. This has opened the door to new paradigms of treatment in which molecular, genetic, and biologic therapy can be used together to increase the sensitivity of abnormal cells to treatment, and to protect the normal tissues of the body from therapy-induced side effects. The implementation of new strategies could change the way therapy is delivered over the next few years and improve the outcome especially in patients with neoplasms that are currently resistant to conventional dose therapy.

Antineoplastic Agents↗
PubMed2000

Patients with malignant lymphomas experience a higher rate of documented infections than patients with breast cancer after high-dose chemotherapy with autologous peripheral stem cell transplantation.

The influence of underlying disease on documented infections has rarely been addressed in patients treated with high-dose chemotherapy (HDCT) and subsequent autologous peripheral blood stem cell transplantation (PBSCT). Because autografting has been used most frequently for malignant lymphomas and breast cancer, we analyzed in a retrospective study the data of 100 consecutive adult patients with either malignant lymphomas (group A, n = 50) or breast cancer (group B, n = 50) treated with HDCT at a single institution. The number of autografted CD34+ cells was not statistically different in either group. In this paper, we show for the first time that there is a significant difference in clinically or microbiologically documented infections in these groups of patients: documented infections occurred in 30% of malignant lymphoma patients but only in 4% of breast cancer patients (P=0.001). Of all isolated microorganisms, 78% were gram-positive. Because most of the documented infections were due to staphylococci, further studies should prospectively evaluate preventive measures to reduce the high incidence of these infections. This is especially important for lymphoma patients, who can be regarded as a high-risk group concerning gram-positive bacteremia.

Adult↗
PubMed2000

Further evidence for oxidant-induced vascular endothelial growth factor up-regulation in the bronchoalveolar lavage fluid of lung cancer patients undergoing radio-chemotherapy.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent inducer of physiological and neoplastic blood vessel growth. Moreover, in vitro studies have demonstrated that VEGF can be up-regulated by conditions associated with the generation of free radicals and reactive oxygen species. In a previous study we reported on strongly increased VEGF concentrations in the bronchoalveolar lavage fluid (BALF) of patients with lung cancer under therapy. In this study we aimed to reveal whether this increase was due to the therapy-associated intrapulmonary oxidative burden. PATIENTS AND METHODS: A total of 103 BALF samples from 94 patients with lung cancer (82 patients with non-small-cell lung cancer, 12 patients with small-cell lung cancer) were studied at different times before, during or after cancer treatment. VEGF levels in the lavage fluid and ratios of oxidised methionine in proteins of epithelial lining fluid (ELF) were determined. RESULTS: As reported previously, strongly increased VEGF levels in the ELF were observed in patients undergoing chemotherapy when radiotherapy had been administered before. Increased levels of oxidised methionine indicated that these patients suffered from severe pulmonary oxidative stress that was significantly less in patients undergoing only chemotherapy. Similarly, VEGF concentrations in the ELF were significantly elevated in cancer patients at the time of diagnosis, but the oxidised methionine levels did not reveal significant oxidant/antioxidant imbalances in these patients. CONCLUSION: Systemic chemotherapy is associated with oxidative stress in vivo, which is more pronounced if patients are additionally treated with radiation. VEGF levels in the ELF are increased by this condition as well as by the activity of the tumour itself.

Adult↗
PubMed1999

Increased levels of vascular endothelial growth factor in bronchoalveolar lavage of patients with bronchial carcinoma effect of tumour activity and oxidative stress due to radio-chemotherapy?

BACKGROUND: Vascular endothelial growth factor (VEGF) plays a crucial role in physiological and neoplastic angiogenesis. Moreover, VEGF has been found to be upregulated by conditions associated with the generation of free radicals and reactive oxygen intermediates. In patients with cancer, studies to evaluate VEGF as a measure of tumour activity were carried out. We tested the hypothesis that VEGF is additionally affected by oxidative stress due to anticancer therapy. Moreover, the suitability of epidermal growth factor (EGF) to estimate tumour activity was studied. PATIENTS AND METHODS: 60 patients with non-small cell lung cancer (NSCLC) covering different therapy progress and modalities underwent bronchoalveolar lavage. VEGF-, EGF-, albumin- and total protein-concentrations in bronchoalveolar lavage fluid (BALF) and VEGF-levels in blood plasma were studied. RESULTS: BALF VEGF-levels were increased in patients with advanced NSCLC before and in anticancer therapy. In patients who had received radiotherapy to the lung prior to chemotherapy, VEGF concentrations were noticeably higher than under sole chemotherapy. Pulmonary endothelial hyperpermeability was found in patients with recently diagnosed tumours and patients undergoing anti-cancer therapy. Evaluation of EGF-levels in BALF revealed no significant influence of tumour activity or cancer therapy on this parameter. CONCLUSION: BALF-levels of VEGF are affected by tumour activity and oxidative stress due to anticancer therapy.

Adult↗
PubMed1999

Preliminary report of mortality among workers compensated for work-related asthma.

BACKGROUND: Although fatalities due to asthma have been reported among subjects with occupational asthma (OA) associated with re-exposure, groups of subjects with work-related asthma have not been systematically followed up for mortality. During a review of compensation claims for asthma in Ontario, we identified 3 respiratory deaths among subjects previously compensated for OA for whom their surviving spouses received death benefits. This suspected "cluster" prompted us to undertake an investigation to examine mortality pattern among workers compensated for work-related asthma. METHODS: Subjects receiving compensation for OA or aggravation of asthma (AA) between 1980 and 1993, and a comparison sample of workers with claims for musculoskeletal injuries during the same period were identified from the Ontario Workers' Compensation Board. We also identified another comparison group of non-compensated asthmatic patients seen at a hospital clinic during the same period. The files of those with work-related asthma were reviewed to determine if OA or AA was adequately documented. Mortality was ascertained by linkage with the Mortality Database at the Ontario Cancer Registry through 1996. We compared the mortality of the three groups with that expected in the general population of Ontario using SMRs, and directly by proportional-hazards regression. RESULTS: The study included 3,070 subjects: 1,112 with work-related OA/AA with adequate documentation, 1,556 with work-related injuries, and 402 patients with non-work-related asthma. Of the 66 deaths identified, only 2 deaths were due to asthma, both in the work-related asthma group: one from the index cluster and one not previously identified. A second index death was coded as dying from COPD not elsewhere classified (ICD9 496), while the third index death also died of asthma but there was not sufficient information documenting OA to include the subject in the analyses. As compared with the general population, there were fewer deaths than expected from most causes, except for deaths among the work-related asthma claimants and the nonwork-related asthma patients from respiratory diseases (SMRs 1.3 and 5.9, respectively; 0.5 among injury claimants), all chronic obstructive lung disease (ICD9 490-496; SMRs 2.3 and 7.7, respectively), and asthma (SMRs 18.2 and 0, respectively). In direct comparison of the work-related asthma claimants with the injury claimants, the risk of death appeared elevated from respiratory disease (RR 2.6) and ischemic heart disease (IHD) (RR 2.8) but the confidence intervals included unity. CONCLUSIONS: This preliminary report raises the possibility that serious outcomes, including excess deaths from respiratory disease, in particular asthma, may occur among those with work-related asthma even in the absence of re-exposure. However, the findings are inconclusive given that the number of deaths was small and we identified only one new asthma death in addition to the index cluster. We also observed for the first time that deaths due to circulatory disease, particularly IHD, may also be increased among such workers; this needs to be confirmed elsewhere.

Adult↗
PubMed1999

Eosinophilia during fludarabine treatment of chronic lymphocytic leukemia.

Although eosinophilia has been reported as a side effect of purine analogues, there is no report on fludarabine-induced eosinophilia in chronic lymphocytic leukemia (CLL). During chemotherapy with fludarabine and cyclophosphamide, we observed two cases of significant eosinophilia. A 67-year-old patient with CLL developed bone marrow and peripheral blood eosinophilia up to 7.9x10(9)/l, the highest eosinophil count ever reported during treatment with a purine analogue. The eosinophilia persisted for 33 days. Another patient developed bone marrow eosinophilia without eosinophilia in the peripheral blood. These are the first documented cases of fludarabine-induced eosinophilia in CLL, and this side effect may conceivably be more common than previously recognized.

Aged↗
PubMed1999

Prolonged infusion of gemcitabine in stage IV breast cancer: a phase I study.

Gemcitabine is an effective agent in the treatment of metastatic breast cancer. The phosphorylation of gemcitabine into the active gemcitabine triphosphate (dFdCTP) is catalyzed by deoxycytidine kinase. This enzyme is saturated at plasma concentrations achieved after an infusion over 30 min. Therefore accumulation of higher intracellular dFdCTP concentrations, which may result in an enhanced antineoplastic activity, cannot be achieved by higher dosage, but only by prolonged infusion time. The objectives of this phase I trial were to determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of gemcitabine given as a 6 h i.v. infusion. Patients with metastatic breast cancer were treated with gemcitabine as a 6 h infusion on days 1, 8 and 15 every 4 weeks. The starting dose was 200 mg/m2 with an interindividual escalation in 50 mg/m2 increments. Sixteen patients received 196 doses through three dose levels. All patients were assessable for toxicity, 13 assessable for response. The MTD was 250 mg/m2. DLT was observed at 300 mg/m2 consisting of a reversible elevation of transaminases WHO grade 3 in two patients and cutaneous toxicity grade 3 in one patient. Most common non-hematologic toxicities were mild to moderate and rapidly reversible elevation of liver enzymes in all patients, nausea and vomiting (four patients grade 2, five patients grade 3), and mild alopecia. Hematologic toxicity was mild with neutropenia WHO grade 3 and 4 in only one patient each, and no grade 3 thrombocytopenia. One patient achieved a complete remission and another patient a partial response, for an overall response rate of 15% (two of 13). In addition, seven patients (54%) had stable disease and four (31%) failed to respond to the treatment. We conclude gemcitabine 250 mg/m2 days 1, 8 and 15 every 4 weeks can be safely administered as 6 h infusion. Toxicity, especially myelosuppression, is surprisingly mild. Based on this result a phase II study with 250 mg/m2 administered over 6 h was initiated to determine the efficacy.

Adolescent↗
PubMed1994

Does saline "correct" the abnormal mass balance in metabolic alkalosis associated with chloride depletion in the rat?

An elevated plasma pH and bicarbonate are the clinical hallmarks of metabolic alkalosis. Nevertheless, to fully define its pathophysiology, one needs a quantitative interpretation of events in 3 areas - the ECF, ICF, and urine. Accordingly, our purpose was to study mass balance in Cl--depletion metabolic alkalosis with normal initial balance for Na+ and K+. In the 20 h following the "exchange" of Cl- (loss, 2455 mumol) and HCO(3-) (gain, 2455 mumol), only 334 mumol HCO(3-) remained in the ECF and 337 mumol were excreted. The remaining 1784 mumol disappeared primarily via titration because 3051 mueq of endogenous anions were produced and excreted largely with K+. Accordingly, metabolic alkalosis was associated with a deficit rather than a surplus of HCO(3-). To reflect the shift of H+ into cells driven by the exit of K+, the cumulative deficit of Cl- was replaced as KCl or NaCl. The fall in plasma [HCO(3-)] was larger in the KCl group (13.2 vs. 9.4 mmol/L); it was largely due to H+ exit from cells; in contrast, disappearance of HCO(3-) from the ECF was due to new endogenous acid production in the NaCl group. Thus, there was an overall deficit of HCO(3-) in metabolic alkalosis associated with KCl depletion (extracellular alkalosis and intracellular acidosis); processes in the ICF were not corrected by NaCl.

Alkalosis↗
PubMedDate not supplied

Disseminated mucormycosis caused by Absidia corymbifera leading to cerebral vasculitis.

An 18-year-old woman was admitted to hospital because of subcutaneous hematoma and fever of unknown origin. Acute myeloid leukemia was diagnosed and empirical antimicrobial treatment and induction chemotherapy were started. After initial defervescence, fever relapsed 2 days after the onset of neutropenia. The CT scan of the lung was consistent with an invasive fungal infection. Treatment with amphotericin B was started and antimicrobial treatment was continued with liposomal amphotericin B because of an increase in creatinine later. The fever persisted and the patient suddenly developed progressive neurological symptoms. CT scan of the head suggested cerebral infarction and angiography of the extra- and intracranial arteries showed signs of vasculitis. Six days after the onset of neurological symptoms cerebral death was diagnosed. Autopsy revealed non-septate, irregularly branched hyphae in various histologic sections including brain. Absidia corymbifera could be isolated from lung tissue confirming the diagnosis of disseminated mucormycosis. In this case, angiographic findings suggested severe cerebral vasculitis which was in fact caused by thromboembolic dissemination of fungal hyphae. This case underlines the fact that cerebral symptoms in febrile neutropenic patients are highly indicative for fungal infections of the brain.

Absidia↗