Single high-dose recombinant human granulocyte-macrophage colony stimulating factor: results of a phase I tolerability study.
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Biomedical subjects
Publications and source records attributed to R Obrist.
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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.
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.
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.
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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.
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.
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.
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161 oncological outpatients at Basel University hospital were anonymously questioned as to their motives for undergoing treatment methods which had not been proven efficacious. 71 patients stated that they were using unconventional remedies, principally diet and anthroposophical treatment. "Building up resistance" (87%) and "supplementary treatment" (69%) were the main reasons given. A lack of confidence in conventional medicine (6%) or failure of previous therapy (4%) was less important. In attempting to characterize users and non-users of unorthodox medical treatments in this group of patients significant differences were revealed in the patients' political and religious convictions, as well as their health consciousness. Users more often described themselves as "left-wing" or "ecologically-orientated", and more frequently experienced a strengthening of their religious faith through their illness. No differences could be determined as to age, sex, family status or attitude toward disease.
ABLETOP, a salvage regimen for relapsing Hodgkin's disease consisting of adriamycin, bleomycin and etoposide, has been evaluated in 18 patients, 16 of whom were evaluable for toxicity and 15 for response. Fourteen patients showed maximal grade II nausea and vomiting, whereas 13 patients had grade III/IV alopecia. The median leukocyte nadir was 3.1 x 10(3)/mm3. Twelve of 15 patients evaluable for response reached a complete or partial remission; 10 of 12 pretreated patients reached a remission, 5 a complete remission and 5 a partial remission, for an overall response rate of 83%. We conclude that ABLETOP is a well-tolerated effective regimen for relapsing Hodgkin's disease.
More than half of the patients relapsing with breast cancer will do so after 3 years. Disease free survival is negatively influenced by tumor size and increasing numbers of positive axillary lymph nodes. Small primaries, negative nodes and positive estrogen receptors predict long overall survival. Many additional prognostic factors exist, however, they are not yet in general use. Similarly to early relapses, patients with late relapses do better with skeletal than with visceral metastases. Women with liver metastases should therefore be treated with chemotherapy, whereas bone disease may respond for prolonged periods to hormonal manipulation.
In a group of 31 patients a port-a-cath-system for intraperitoneal chemotherapy was installed. From 23 evaluable patients 9 showed a tumor remission, but only 1 was a patient with gastrointestinal carcinoma. All others were patients with ovarial carcinoma. The median survival rate of all patients was 9 months after implantation of the intraperitoneal catheter. 50% of all patients with gastrointestinal carcinoma died within the first 6 months, only 1 of 11 patients with ovarial carcinoma died in this period.
A new technique was developed to coat Nuclepore filters with basement membrane matrix components. Using the EHS tumour as a source, a proteoglycan and laminin-containing fraction was extracted with guanidine and collagen type IV was solubilized in a second fraction by limited digestion with pepsin. When the two fractions are combined and guanidine removed by dialysis, a gel is rapidly formed. A flat-bed dialysis apparatus was devised, allowing gels to form on filters that are soaked in the mixture, thus coating them with components of the basement membrane. Such filters were used for selection of B16 melanoma cells penetrating the gels. 10 clones were isolated after three selection passages, and assayed for spontaneous metastasis in C57Bl/6 mice after intracutaneous injection. The metastasis rates were strongly increased to the lungs and to inguinal and axillary lymph nodes. Less accessible sites such as mediastinal and maxillary lymph nodes were reached only by selected cells. There was no particular preference for the haematogenous or lymphatic routes, indicating that the ability to traverse the basement membrane leads to a general increase of metastasis. The described method provides a valuable tool for isolating those subpopulations able to traverse basement membranes and to assess this capacity in new tumour samples.
Intratumor macrophage numbers are enhanced by the administration of chemotactic f-MET-LEU-PHE - antitumor antibody - conjugates. The four f-MET-peptides f-MET-LEU-PHE, f-MET-LEU-PHE-o-methylester, formyl-norleucyl-phenylalanine and formyl-methionyl-phenylalanine, all chemotactic for human monocytes, where evaluated alone and conjugated to the melanoma directed monoclonal antibody ZME 018. f-MET-LEU-PHE-o-methyl-ester is the most active peptide, whereas f-MET-LEU-PHE - ZME 018 is the most active conjugate, not only inducing a response at the lowest concentration, but also the highest migrating cell numbers.
We found that three tumor patients treated with mouse mAbs have T cells that recognize processed mouse Ig on autologous APC in a class II-restricted fashion, and we have shown that mouse mAbs directed against various cell surface molecules can be used as antigens to focus these T cells on an MHC class II-positive target of choice.
Thirty-seven patients with mediastinal Hodgkin's disease treated from 1972 to 1982 at the Division of Oncology of Basel University Hospital were analyzed retrospectively for their characteristics and the influence of various prognostic factors on survival. Deceased patients were older (35 vs. 25 years) and more often had systemic symptoms (8/22 vs. 3/15). 44% of the patients presented with mediastinal bulk disease, 66% of whom are in remission. No statistically significant influence of sex and stage was evident on the outcome. Patients treated with multimodality therapy had a significantly better survival than patients treated with radio- or chemotherapy only. No significant difference was found in survival in comparison to the population without mediastinal involvement.