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Biomedical subjects

R Obrist

Publications and source records attributed to R Obrist.

At least 19 recordsLinked to original sources
PubMed1992

Prolonged interferon-gamma application by subcutaneous infusion in cancer patients: differential response of serum CD14, neopterin, and monocyte HLA class I and II antigens.

This study reports on biological response modification induced by prolonged continuous subcutaneous (s.c.) infusion of recombinant interferon-gamma (rIFN-gamma) with particular attention to changes of soluble CD14. This glycoprotein with an unknown function is derived from myeloid cells carrying membrane CD14, which is the receptor for lipopolysaccharide (LPS)-LPS-binding protein (LBP) complexes. Fifteen metastatic cancer patients received weekly escalating doses of rIFN-gamma starting at either 50 or 100 micrograms/24 h and increasing up to 400 micrograms/24 h for a median duration of 6 weeks. The maximum tolerated dose was higher (200 micrograms/24 h) with the lower (50 micrograms/24 h) starting dose. Biological activity of rIFN-gamma was evaluated by weekly measurements of CD14, neopterin, and beta 2-microglobulin concentrations in serum as well as monocyte HLA class I and II antigen expression and tumor cytotoxicity. Serum IFN-gamma concentrations increased 20-fold within 4 weeks of therapy. The levels were correlated to the mean dose (r = 0.95, p less than 0.05). Among the biological markers, two patterns were observed. First, serum CD14 concentration and expression of monocyte HLA class II antigens increased significantly during the first week, and marker expression correlated with serum IFN-gamma levels (p less than 0.05); CD14 and HLA class II antigens thereafter returned to pretreatment levels within 4 weeks of therapy despite persistently elevated serum IFN-gamma concentrations. Second, serum neopterin and beta 2-microglobulin concentrations as well as monocyte HLA class I expression also increased significantly within the first week, but remained elevated thereafter without any further dose relationship.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Evidence for linkage between the swine L blood group and the loci specifying the receptors mediating adhesion of K88 Escherichia coli pilus antigens.

Brush borders or enterocytes obtained from the small intestine of 248 pedigreed pigs were tested by adhesion assay in vitro with enterotoxigenic Escherichia (E.) coli strains, each expressing one of the three K88 pilus variants K88ab, K88ac and K88ad. All pigs were classified as belonging to one of the four adhesion phenotypes: I--K88ab(-), ac(-), ad(-); II--K88ab(-), ac(-), ad(+); III--K88ab(+), ac(+), ad(-); and IV--K88ab(+), ac(+), ad(+). Serum or red cells were typed for 15 blood group systems: A-O, B, C, D, E, F, G, H, I, J, K, L, M, N and O; for 11 biochemical polymorphisms: PI1, PI2, PO1A, A1BG, GPI, PGD, TF, HPX, ADA, PGM and AMY; the polymorphism at the IGHG1 locus. Linkage analysis was performed between the alleles at the locus (loci) specifying K88 receptors able to bind one or more different serological types of K88 E. coli and alleles for markers at other loci. Linkage was demonstrated between the locus for the L blood group system and the locus (loci) for K88 E. coli receptors (Z = 3.24), adding one locus (loci) to the previously identified linkage group IV (LGIV) [L-SLB]. The maximum likelihood estimate of the recombination fraction (theta) was 0.23. No evidence was found for linkage between any of the other biochemical and immunogenetic markers and the receptor locus (loci) of K88 E. coli.

Animals↗
PubMed1991

[Emergency therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF)].

Granulocyte-macrophage colony stimulating factor (GM-CSF) has been tested for tolerability and efficacy on a compassionate need case basis in 17 patients (5 females, 12 males aged 4-72 years, median 35 years). GM-CSF was given at the rate of 3.5-32 micrograms/kg for 2-64 days as a continuous infusion for the following indications: impending rejection following bone marrow transplantation (5 patients), severe neutropenia secondary to chemotherapy in tumor patients (5), severe aplastic anemia (3), immune granulocytopenia (2) and accidental overdose with cytostatic agents (2 patients). Tolerance of GM-CSF was good in regard to doses of up to 16 micrograms/kg. Fever, myalgia and eosinophilia were the most frequent side effects. The patient treated with 32 micrograms/kg developed thrombosis of the vena cava. Efficacy is more difficult to assess in this heterogenous population, but 11 of 17 patients showed increased granulocyte counts and 3 patients clearly recovered from severe neutropenia. The role of GM-CSF in this recovery, however, cannot be proven. The results further indicate that GM-CSF cannot reverse ongoing rejection following allogenic BMT and cannot correct immune neutropenia. The value of GM-CSF therapy in patients with severe aplastic anemia and in the context of chemotherapy still needs to be defined. It is certainly indicated in patients with an accidental overdose of chemotherapeutic agents.

Adolescent↗
PubMed1991

Effect of cytokines and lipopolysaccharide on CD14 antigen expression in human monocytes and macrophages.

The 52 kD myeloid membrane glycoprotein CD14 represents the receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein (LBP); it is involved in LPS induced tumor necrosis factor-alpha production. Expression of CD14 increases in monocytes differentiating into macrophages, and it is reduced by rIFNg in monocytes in vitro. In the present study CD14 membrane antigen expression was investigated in cultures of human mononuclear leucocytes (PBL), in elutriated, purified monocytes, and in blood monocyte derived Teflon cultured macrophages. Cells were incubated for 15 or 45 h with rIL-1, rIL-2, rIL-3, rIL-5, rIL-6, rTNFa, rGM-CSF, rM-CSF, rTGFb1, rIFNa, lipopolysaccharide (LPS), and, as a control, rIFNg. The monoclonal antibodies Leu-M3 and MEM 18 were used for labelling of CD14 antigen by indirect immunofluorescence and FACS analysis of scatter gated monocytes or macrophages. IFNg concentrations were determined in PBL culture supernatants by ELISA. rIFNa and rIL-2 reduced CD14 in 15 and 45 h PBL cultures, an effect mediated by endogenous IFNg, since it was abolished by simultaneous addition of an anti-IFNg antibody. rIFNa and rIL-2 were ineffective in purified monocytes or macrophages. rIL-4 strongly reduced CD14 in PBL and purified monocytes after 45 h, whereas in macrophages the decrease was weak, although measurable after 15 h. The other cytokines investigated did not change CD14 antigen expression. Cycloheximide alone reduced CD14, but when added in combination with rIFNg the effect on CD14 downregulation was more pronounced. The effect of rIFNg on CD14 in PBL cultures was dose-dependently inhibited by rIL-4 and this inhibition is probably due to an IL-4 mediated blockade of IFNg secretion. LPS at a low dose increased CD14, at a high dose it produced a variable decrease of CD14 in PBL, which was probably due to LPS induced IFNg secretion. LPS strongly enhanced CD14 in 45 h cultures of purified monocytes. The results, showing that CD14 antigen expression is upregulated by LPS and downregulated by rIFNg and rIL-4, suggest that the LPS-LBP receptor is involved in the feedback response of IFNg and IL-4 to LPS stimulation.

Antibodies↗
PubMed1991

Acute and subacute toxicity of chemotactic conjugates between monoclonal antibody and fMet-Leu-Phe in humans: a phase I clinical trial.

Conjugates of the chemotactic peptide fMet-Leu-Phe (fMLP) to IgG retain chemotactic and antigen recognition function in vitro and enhance intra-tumour macrophage numbers in a guinea pig model. We report a study approved by the ethics committee on the acute toxicity of fMLP conjugates in ten consenting cancer patients with metastasizing melanoma and colon cancer. They were given increasing single doses (1-2500 micrograms) IgG-fMLP made with the anti-melanoma monoclonal antibody (mAb) 9.2.27. Clinical examinations and blood cell counts, urinalysis, electrolytes, and liver and kidney function tests before and after the infusion and weekly thereafter revealed no relevant toxicities. One patient had a herpes zooster exacerbation on day 1, which was judged to be coincidental. Peak post-infusion conjugate serum concentrations fell to unmeasurable levels within a few days. In no case was a human humoral anti-(mouse Ig) immune response detected.

Adult↗
PubMed1990

[Attitude of ambulatory oncological patients to academic medicine, their physician and nurse. Results of an anonymous survey].

The attitude of ambulatory cancer patients at the Division of Oncology, Dept. of Internal Medicine, of the Basel University Hospital towards official medicine, its therapeutic modalities as well as doctors and nurses was analysed. 33% of the patients answered an anonymous questionnaire containing 55 questions, which was distributed at their first visit during 1987. Four fifths showed a positive attitude towards official medicine overall. Two thirds of the patients believed to have profited from surgery, radiotherapy and chemotherapy alike. Side effects of chemotherapy were classed as barely tolerable by one third, as tolerable by two thirds of the patients. Nearly 80% would accept another surgical, radiotherapeutical or cytostatic treatment. 44% of all patients used therapies of unknown efficacy, and these patients suffered more from side effects than non-users, but no differences existed in regard to other parameters. The medical oncologist was felt to be the closest person caring for the patient, followed by the partner, the family practitioner, the oncology nurse and the community nurse. Most important for the patients are firm technical skills--significantly more than emotional support. 97% of the patients asked for thorough information on all aspects of their disease, good or bad.

Communication↗
PubMed1990

Recombinant interferon gamma up-regulates in vivo and down-regulates in vitro monocyte CD14 antigen expression in cancer patients.

The expression of the monocyte membrane glycoprotein CD14 was measured and related to the serum interferon gamma (IFN gamma) concentration in thirteen patients with disseminated cancer during treatment with human recombinant interferon gamma (rIFN gamma). The drug was administered by continuous subcutaneous infusion using an escalating dose schedule, starting at 50 micrograms/day or 100 micrograms/day and increasing weekly up to 600 micrograms/day, if tolerated. Treatment was continued at a mean maximal tolerated dose of 200 micrograms/day for a median duration of 43 days. Serum IFN gamma concentration and monocyte CD14 antigen expression (immunofluorescence with the monoclonal antibody LeuM3 and fluorescence-activated cell sorting analysis) were determined weekly. The serum IFN gamma concentration was positively correlated with the rIFN gamma dose (P less than 0.05). Therapy induced a dose-dependent enhancement of CD14 antigen expression. The increase in mean CD14 fluorescence intensity was on average 60% after 3 weeks of treatment at a mean dose of 220 micrograms rIFN gamma/day and was reversed after withdrawal of therapy. Patients with a rapidly rising serum IFN gamma concentration (starting dose 100 micrograms/day) showed a smaller increment in CD14 fluorescence intensity than those with slowly rising serum IFN gamma levels (starting dose 50 micrograms/day). Since rIFN gamma is known to down-regulate CD14 antigen expression in vitro, monocytes from patients off therapy and from healthy volunteers were cultured with this cytokine. A similar decrease of CD14 fluorescence was observed in both groups. In patients several factors, such as IFN gamma concentration, duration of drug effect and type of serum, were evaluated and could not explain the discrepant in vivo and in vitro findings. In conclusion, the monocyte marker CD14 was found to be differentially regulated by rIFN gamma in vivo and in vitro. In vivo, secondary mediators, induced by rIFN gamma and acting on a constantly renewed cell population, may contribute to the enhanced CD14 expression.

Adult↗
PubMed1990

Effectiveness and low toxicity of hepatic artery infusion with fluorouracil and mitomycin for metastatic colorectal cancer confined to the liver. The Swiss Group for Clinical and Epidemiological Cancer Research (SAKK).

The usefulness of hepatic artery infusion (HAI) with floxuridine is limited by the severe biliary and hepatic toxicity of floxuridine. This prompted the SAKK to evaluate the effectiveness, toxicity and feasibility of HAI with fluorouracil (FU) and mitomycin (MMC) administered by an external portable pump. Of 28 patients treated, partial responses were obtained in 14 (50%, 95% confidence interval: 30% to 70%) and stabilization in 11 (39%, 21% to 60%), for a median duration of 12.6+ months. Median survival was 19.5+ months. Grade I-II toxicity (WHO) consisted of nausea (46%), leucopenia (32%) thrombocytopenia (21%) and abdominal discomfort (25%). Two patients developed gastro-duodenal ulcers and two others grade III leucopenia. No life-threatening side effects, especially no sclerosing cholangitis or chemical hepatitis, were observed. In conclusion, HAI with FU and MMC is a valid alternative to floxuridine HAI in metastatic colorectal cancer confined to the liver.

Adult↗
PubMed1990

Improved tolerance of interferon alpha-2a by continuous subcutaneous infusion.

Fifteen patients with progressing melanomas, hypernephromas or B-cell malignancies were treated in a phase I study with Interferon (IFN) alpha-2a by continuous subcutaneous infusion. With the help of a syringe driver pump daily doses of 12-15 MU resulting in median weekly doses of 90 MU could be safely given with little side effects. Flu-like symptoms and side effects from the gastrointestinal tract were mainly of grade 1 or 2 only. The major dose limiting but reversible toxicity was leukopenia. Five patients developed local inflammatory reactions at the infusion site. The pharmacokinetic data demonstrate that by this route of administration median serum levels of 54 IU/ml (range 9.6-192.0 IU/ml) (EIA-F-assay) can be achieved. Antibody formation was observed in 4 patients. - One out of 9 patients evaluable for tumor response demonstrated a partial tumor regression and 4 patients had a stabilisation of their disease. In comparison to intermittent i.m. or s.c. schedules, this novel route of administration by continuous subcutaneous infusion results in significant serum concentrations, biological activity and little clinical side effects. This may facilitate in the future the combination of IFN alpha-2a with other biological response modifiers like interleukin-2 or tumor necrosis factor.

Adult↗
PubMed1990

[Prostate cancer with an unusual course].

The case of a 60 years old patient with peritoneal carcinomatosis of a tumor with small cell histology is reviewed. At presentation, biopsy of a rectal palpatory finding revealed a small cell carcinoma, infiltrating the mucosa. A laparotomy was done, which showed a grotesque peritoneal carcinomatosis of the same histology with masses retro- and infraperitoneally and in the pelvis. Clinically and histologically a probable epithelial peritoneal mesothelioma was diagnosed. The patient survived half a year only. Autopsy and post-mortem work-up demonstrated the presence of a small cell prostatic cancer, positive for both prostate specific antigen and acid phosphatase. A discussion of diagnostic procedures and differential diagnoses is given.

Biomarkers, Tumor↗
PubMed1990

[Cytokines in the clinic].

Recombinant cytokines are available for clinical evaluation since several years. They are expected to have novel effects with fewer side effects than conventional cytostatics. Until now interferon alpha has been registered for Kaposi's sarcoma and hairy cell leukemia. Further indications will follow. Hemopoietic growth factors will have a major impact, as no doubt exists about their effectiveness, but their indications need to be defined more thoroughly. Many substances like interleukin 2, tumor necrosis factor and interleukin 1 are currently at a purely experimental stage.

Biological Factors↗
PubMed1979

[Immune profile in patients with Hodgkin's disease in long-term remission after cytostatic chemotherapy].

13 patients in complete and prolonged remission after treatment with cytostatic chemotherapy for disseminated Hodgkin's disease have been investigated for immune competence by a total of 27 immunological parameters. 11 patients had abnormal values for lymphocyte populations, lymphocyte function and skin tests. The immune profile described is suitable for long-term evaluation of patients under immunosuppressive therapy.

Adolescent↗
PubMed1979

Vindesine. A clinical trial with special reference to neurological side effects.

A good tumoricidal activity of vindesine (VDS) has been reported in a variety of animal tumors and in human leukemias and lymphomas. We treated 22 patients who had received no prior chemotherapy and were suffering from a variety of malignant neoplasms with 0.5 mg/m2 to 3.0 mg/m2 VDS i. v. once or three times at weekly intervals and recorded the clinical, hematologic, and especially, neurological side effects. Clinically we observed fatigue in nine patients, paresthesias in seven, myalgias in three, vertigo and diarrhea in two, and skin pains, tinnitus, gastric pains, alopecia, and tremor in one patient each. There was no obvious dose-action relationship. Paravenous injection caused cellulitis similar to that seen with vincristine. No side effects were apparent in liver (SGPT) and renal (creatinine) function tests. Hematologically there was a clear trend toward leukopenia with higher doses of DVA and a mean increase in the thrombocyte count by 51 X 10(3)/mm3 was found (sign test: P greater than 0.05). The hemoglobin level did not change. Clinical neurological examination and monitoring by electroneurography revealed no changes in tensiometer performance, motor and sensory nerve conduction velocity, motor or sensory nerve action potential amplitudes, or H-reflex responses. There was dose-related diminution of the proprioceptive reflexes, especially in the lower extremities. Even with as little as 2.0 mg/m2 VDS i. v. at weekly intervals for 3 weeks Achilles and patellar tendon reflexes were diminished or absent in all patients.

Action Potentials↗