Search Results - (Author, Cooperation:A. Eggermont)

2015-11-07

American Association for the Advancement of Science (AAAS)

0036-8075

1095-9203

Biology

Chemistry and Pharmacology

Computer Science

Medicine

Natural Sciences in General

Physics

Adult ; Aged ; Aged, 80 and over ; Animals ; Anti-Bacterial Agents/pharmacology ; Antibodies, Monoclonal/adverse effects/*therapeutic use ; Bacteroides/*immunology ; CTLA-4 Antigen/*antagonists & inhibitors/immunology ; Dysbiosis/immunology ; Fecal Microbiota Transplantation ; Female ; Gastrointestinal Microbiome/drug effects/*immunology ; Germ-Free Life/immunology ; Humans ; Immunologic Memory ; Immunotherapy ; Intestines/immunology/microbiology ; Male ; Melanoma/*therapy ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Skin Neoplasms/*therapy ; T-Lymphocytes/immunology

2018-01-05

American Association for the Advancement of Science (AAAS)

0036-8075

1095-9203

Biology

Chemistry and Pharmacology

Geosciences

Computer Science

Medicine

Natural Sciences in General

Physics

Immunology, Medicine, Diseases

1365-2044

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Summary Agreement between continuously measured oxygen consumption during quantitative closed system anaesthesia and intermittently Fick-derived calculated oxygen consumption was assessed in 11 patients undergoing simultaneous occlusion of the aorta and inferior vena cava for hypoxic treatment of pancreatic cancer. All patients were mechanically ventilated using a quantitative closed system anaesthesia machine (PhysioFlex®) and had pulmonary and radial artery catheters inserted. During the varying haemodynamic conditions that accompany this procedure, 73 paired measurements were obtained. A significant correlation between Fick-derived and closed system-derived oxygen consumption was found (r = 0.78, p = 0.006). Linear regression showed that Fick-derived measure = [(1.19 × closed system derived measure) – 72], with the overall closed circuit-derived values being higher. However, the level of agreement between the two techniques was poor. Bland–Altman analysis found that the bias was 36 ml.min−1, precision 39 ml.min−1, difference between 95% limits of agreement 153 ml.min−1. Therefore, we conclude that the two measurement techniques are not interchangeable in a clinical setting.

Electronic Resource

1365-3083

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

In this study, cultured T cells, pre-incubated with the bispecific monoclonal antibody (BiMAb) R73IgG1 × CC52IgG1 were adoptively transferred, via systemic and regional routes, to rats bearing day 10 hepatic metastases of the CC531 adenocarcinoma of the colon to investigate the role of the route of administration in tumour infiltration by these BiMAb-retargeted effector cells. The BiMAb, directed against the T-cell receptor and the tumour-associated antigen CC52, were used to crosslink CC531 tumour cells and T cells to induce tumour cell lysis. Retargeted T cells were administered via the jugular vein, hepatic artery or the portal vein. The number of BiMAb-retargeted T cells that reached the liver tumours was independent of the route of administration. There was also no difference between the number of T cells that reached the portal tracts, central veins of parenchyma of the liver, after loco-regional or systemic administration. These findings are in contrast to the interleukin (IL)-2 activated NK (A-NK) cells biodistribution studies earlier performed in the same animal model in our laboratory. Compared with A-NK cells, a lower number of BiMAb-retargeted T cells reached the tumours, irrespective of their route of administration while for A-NK cells, there was an advantage of administration via the hepatic artery.

Electronic Resource

1432-0851

Key words Interleukin-2 ; Central venous catheters ; Catheter-related infections ; Immunotherapy ; Septicaemia

Springer Online Journal Archives 1860-2000

Medicine

Abstract  A retrospective study on the incidence of catheter-related complications and catheter indwelling time (t CI) during treatment with continuous interleukin-2 (IL-2) infusion in patients with metastatic renal cell cancer, who were equipped with tunnelled central venous catheters (CVC). A group of 72 patients were treated with IL-2-based immunotherapy. Two induction treatment cycles of 35 days each were used. Treatment consisted of IL-2 as a continuous intravenous infusion (c.i.v.) with lymphokine-activated killer cells and interferon α intramuscularly. A tunnelled CVC was inserted at the start of treatment and was kept in place for the duration of the therapy or until the occurrence of complications. Out of 72 CVC, 30 (42%) functioned uneventfully for a median t CI of 64 days. In another 12 clinically uncomplicated cases (16%), catheter tips were positive in routine culture after a median t CI of 33 days. In 18 patients (25%), CVC-related infections were noted, including 8 (11%) local tunnel infections and 10 (14%) septic episodes. These complications occurred at a median t CI of 28 and 20 days respectively. In 15 (83%) of these 18 catheter infections, Staphylococcus aureus was isolated, whereas in the remaining 3 (17%) Staphylococcus epidermidis was found. Subclavian vein thrombosis was noted in 12 (17%) CVC at a median t CI of 31 days; 5 (36%) of these were diagnosed in the first 14 patients. This prompted us to administer prophylactic heparin 15 000 IU c.i.v. daily during IL-2 treatment. Thereafter the incidence of thrombosis dropped to 7 (12%) in the subsequent 58 CVC inserted (P = 0.03). In conclusion, in contrast to previous reports on the high incidence of CVC-related septicaemia and thrombosis, we observed a relatively low incidence of these complications, which we ascribe to the use of tunnelled catheters and prophylactic heparin.

Electronic Resource

1433-0415

Springer Online Journal Archives 1860-2000

Medicine

Im Rahmen der vorliegenden Arbeit wird besprochen, welche Art von Nachuntersuchungen in welchen Zeitabständen und über welchen Zeitraum durchgeführt werden sollten. Des weiteren werden die verschiedenen traditionellen Vorgehensweisen in Europa und in den USA verglichen.

Electronic Resource

1433-0415

Springer Online Journal Archives 1860-2000

Medicine

Die chirurgische Radikalität bei Entfernung des Primärtumors bzw. isolierter Metastasen unter Einhaltung definierter Sicherheitsabstände und der Dissektion regionärer Lymphabflußgebiete zählt ebenso zum Standardrepertoire der Tumorbehandlung wie die systemische Chemotherapie bei nicht resektablen soliden Tumoren. Während die Radikalität der Chirurgie zu Funktionsverlusten oder hoher postoperativer Morbidität führen kann, sind die alternativen konservativen Therapiemethoden in ihrem Palliativerfolg zeitlich und von dem Anteil profitierender Patienten oft limitiert. Neue chirurgisch-onkologische Behandlungsmethoden und -strategien haben in den letzten Jahren dazu geführt, daß stadienadaptierte Therapien eingesetzt werden können, die die Nachteile der Standards reduzieren und die Grenzen bisheriger Methoden entweder durch den Einsatz neuer Kombinationsschemata oder individualisierter Therapien verschieben.

Electronic Resource

1433-0415

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource

1420-908X

Springer Online Journal Archives 1860-2000

Medicine

Abstract It is well documented that the antitumor activity of tumor necrosis factor (TNF) is improved by interferons (IFN's). Bropirimine (BP) is an immune response modifier which induces IFN. Both TNF and BP have the capacity to inhibit the growth of a transplantable colon tumor (CC 531) in inbred WAG rats. In the present study their combined use was investigated in a one-week assay, with the tumor implanted under the renal capsule. The results indicate that BP, given on days 0 and 1, and 1 μg TNF on days 0, 2 and 4 act additively, leading to an almost complete inhibition of tumor growth.

Electronic Resource

1432-1238

Key words Sepsis ; Nitric oxide ; Nitric oxide synthase inhibition ; l-NAME ; Cytokines

Springer Online Journal Archives 1860-2000

Medicine

Abstract Objectives: We tested the effects of NG-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide (NO) synthesis, on plasma levels of interleukin (IL) IL-6, IL-8, tumor necrosis factor-alpha (TNFα) and nitrite/nitrate (NO2 −/NO3 −) in patients with severe septic shock. Design: Prospective clinical study. Setting: Surgical intensive care unit at a university hospital. Patients: 11 consecutive patients with severe septic shock. Interventions: Standard hemodynamic measurements were made and blood samples taken at intervals before, during, and after a 12-h infusion of l-NAME 1 mg ·kg−1·h−1 for determination of plasma IL-6, IL-8, TNFα and NO2 −/NO3 − concentration. Measurements and results: Patients with sepsis had increased plasma levels of IL-6, IL-8, TNFα, and NO2 −/NO3 − (p 〈 0.05). Plasma levels of IL-6, IL-8, and NO2 −/NO3 − were negatively correlated with systemic vascular resistance (r = −0.62, r = −0.65, and r = −0.78, respectively, all p 〈 0.05). Continuous infusion of l-NAME increased mean arterial pressure and systemic vascular resistance, with a concomitant reduction in cardiac output (all p 〈 0.01). No significant changes were seen in levels of plasma IL-6, IL-8, and NO2 −/NO3 − during the 24-h observation period. Plasma levels of TNFα were significantly reduced during l-NAME infusion compared to baseline (p 〈 0.05). Conclusions: NO plays a role in the cardiovascular derangements of human septic shock. Inhibition of NO synthesis with l-NAME does not promote excessive cytokine release in patients with severe sepsis.

Electronic Resource

1432-1335

Cyclosporin A ; Multidrug resistance ; P glycoprotein ; Chemosensitizing ; In vivo

Springer Online Journal Archives 1860-2000

Medicine

Abstract Colon tumours are intrinsically resistant to chemotherapy and most of them express the multidrug transporter P glycoprotein (Pgp). Whether this Pgp expression determines their resistance to anticancer agents in patients is not known. We report here on the reversibility of intrinsic multidrug resistance in a syngeneic, solid tumour model. CC531 is a rat colon carcinoma that expresses Pgp, as was shown with the monoclonal antibody C-219. In vitro the sensitivity to doxorubicin, daunorubicin and colchicine was enhanced by the addition of the chemosensitizers verapamil and cyclosporin A (CsA), while the sensitivity to cisplatin was not enhanced. In a daunorubicin accumulation assay verapamil and CsA enhanced the daunorbicin content of CC531 cells. In vivo CsA was injected intramuscularly for 3 consecutive days at a dose of 20 mg kg−1 day−1. This resulted in whole-blood CsA levels above 2 μmol/l, while intratumoral CsA levels amounted to 3.6 μmol/kg. In a subrenal capsule assay the maximal tolerable dose of doxorubicin (4 mg/kg) significantly reduced tumour growth. Doxorubicin at 3 mg/kg was not effective, but in combination with CsA this dose was as effective as 4 mg/kg doxorubicin. These experiments show that adequate doses of the chemosensitizing drug CsA can be obtained in vivo, resulting in increased antitumoral activity of doxorubicin in vivo. The in vitro and in vivo data together suggest that the chemosensitization by CsA is mediated by Pgp. This finding may have implications for the application of CsA and CsA-like chemosensitizers in the clinical setting.

Electronic Resource

1432-1335

Chemosensitizer ; Dexniguldipine ; Epidoxorubicin ; Multidrug resistance ; in vivo

Springer Online Journal Archives 1860-2000

Medicine

Abstract The chemosensitizing potency of dexniguldipine hydrochloride (B8509-035) on epidoxorubicin was assessed in a multidrug-resistant (MDR) tumour model, the intrinsic MDR rat colon carcinoma CC531. In vitro in the sulphorhodamine B cell-viability assay the cytotoxicity of epidoxorubicin was increased approximately 15-fold by co-incubation with 50 ng/ml dexniguldipine. In vivo concentrations of dexniguldipine 5 h after a single oral dose of 30 mg/kg were 72 (±19 SD) ng/ml in plasma and 925 (±495 SD) ng/g in tumour tissue. Levels of the metabolite of dexniguldipine, M-1, which has the same chemosensitizing potential, were 26 (±6 SD) ng/ml and 289 (±127 SD) ng/g respectively. The efficacy of treatment with 6 mg/kg epidoxorubicin applied intravenously combined with 30 mg kg−1 day−1 dexniguldipine administered orally for 3 days prior to epidoxorubicin injection was evaluated on tumours grown under the renal capsule. Dexniguldipine alone did not show antitumour effects in vivo. Dexniguldipine modestly, but consistently, potentiated the tumour-growth-inhibiting effect of epidoxorubicin, reaching statistical significance in two out of four experiments. In conclusion, these experiments show that dexniguldipine has potency as an MDR reverter in vitro and in vivo in this solid MDR tumour model.

Electronic Resource

1432-1335

Chemosensitizer ; Cyclosporin A ; Doxorubiein ; Multidrug resistance ; Toxicity

Springer Online Journal Archives 1860-2000

Medicine

Abstract the feasibility of using chemosensitizers in the circumvention of P-glycoprotein-mediated multidrug resistance has been shown in many studies. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same experimental design we investigated the side-effects of the combination treatment. During the 35-day experiment doxorubicin treatment caused dose-dependent weight loss, which was enhanced by combination treatment with CsA. The main doxorubicin-related side-effects were myelosuppression (transient leucopenia and thrombopenia) and nephrotoxicity. Damage to the kidney was severe, leading to a nephrotic syndrome and resulting in ascites, pleural effusion, hypercholesterolaemia and hypertriglyceridaemia. These toxicities were enhanced by the addition of the chemosensitizer CsA. Mild doxorubicin-related cardiomyopathy and minimal hepatotoxicity were seen on histological examination. There were no signs of enhanced toxicity of the combination treatment in tissues with known high expression levels of P-glycoprotein, like the liver, adrenal gland and large intestine. CsA had a low toxicity profile, as it only caused a transient rise in bilirubin. In conclusion, the chemosensitizer CsA enhanced the side-effects of the anticancer drug doxorubiein without altering the toxicity pattern. There was no evidence of a therapeutic gain by adding CsA to doxorubicin, compared to single-agent treatment with doxorubicin in 25%–33% higher doses, because of the enhanced toxicity of the combination treatment.

Electronic Resource

1432-1335

Cyclosporin A ; Growth promotion ; Metastasis ; Multidrug resistance

Springer Online Journal Archives 1860-2000

Medicine

Abstract The immunosuppressive drug cyclosporin A has been evaluated recently in phase II trials in cancer therapy as a reverter of P-glycoprotein-mediated multidrug resistance. As an immunosuppressive agent, cyclosporin A potentially can enhance tumour growth. We investigated this potency of cyclosporin A in the weakly immunogenic CC531 colon adenocarcinoma model, using the same dose that had previously been shown to intensify the antitumour activity of doxorubicin in vivo. In vitro cyclosporin A caused no growth acceleration and only in high doses was growth inhibition of CC531 cells observed. In vivo no evidence of growth enhancement was found in short-term assays but, after 4 weeks, rats treated with cyclosporin A had a significantly higher tumour load, mainly consisting of locoregional metastases. These experiments in the CC531 tumour model show that cyclosporin A, used as a reverter of multidrug resistance, may produce short-term improvement of antitumour activity but may also induce enhancement of tumour metastasis.

Electronic Resource

1569-8041

cytokine ; immunotherapy ; melanoma ; vasospasm

Springer Online Journal Archives 1860-2000

Medicine

Abstract The cytokine interferon-alpha (IFN-α) is increasingly prescribed fora number of indications, especially viral hepatitis and several malignancies.Two patients are described who developed Raynaud's syndrome during treatmentwith IFN-α as adjuvant therapy for high-risk melanoma. With a review ofthe available literature the symptomatology, possible pathophysiologicmechanisms and treatment options are discussed.

Electronic Resource

0935-6304

Gas chromatography ; Mass spectrometry ; L-Phenylalanine mustard ; Melphalan ; Chemistry ; Analytical Chemistry and Spectroscopy

Wiley InterScience Backfile Collection 1832-2000

Chemistry and Pharmacology

4 Ill.

Electronic Resource

1573-8280

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource

1573-8280

interleukin-2 ; alpha-interferon ; lymphokine activated killer phenomenon (LAK) ; renal cancer ; melanoma ; solid tumors

Springer Online Journal Archives 1860-2000

Medicine

Abstract Between October 1987 and October 1989 we have treated 110 patients with advanced solid tumors with recombinant interleukin-2 (rIL2) based immunotherapy. In renal cell cancer we have studied rIL2 alone, rIL2 combined with rIL2 activated lymphocytes (LAK), and in an ongoing study rIL2 and LAK and alpha-interferon (αIFN). There is suggestive evidence of increasingly good results in these consecutive studies. In melanoma the combination of rIL2 and chemotherapy was investigated, followed by an ongoing study of rIL2 and αIFN. In these studies rIL2 has been administered as a continuous intravenous infusion of 18 x 106 International Units/m2/day for 5 days (18 x 106 IU = 3 x 106 Cetus Units = 6.9 Biological Response Modifiers Program (BRMP) Units). Patients with non-small cell lung cancer are entered in a phase I-II study of rIL2 and αIFN. The rIL2 administration differs from the above mentioned schedule in that rIL2 is given at a maximum dose of 6 x 106 IU/m2/day for 28 days on an outpatient basis. In a phase I study we have searched for the maximum tolerated dose of a daily time 4 schedule of rIL2. In the second part of this study a daily time 4 schedule, every week for 4 weeks is being investigated. Finally, we are investigating the safety and efficacy of local regional administration of rIL2 in patients with head and neck cancer, mesothelioma, and liver metastasis of colorectal cancer.

Electronic Resource

0730-2312

melanoma ; TNFα ; isolation perfusion ; melphalan ; interferon-γ ; Life and Medical Sciences ; Cell & Developmental Biology

Wiley InterScience Backfile Collection 1832-2000

Biology

Chemistry and Pharmacology

Medicine

Recombinant tumor necrosis factor-alpha (rTNFα) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNFα is hampered by severe systemic side-effects. The maximum tolerated dose range from 350 to 500 mg/m2, which is at least 10-fold less than the efficient dose in animals. Isolation perfusion of the limbs (ILP) allows the delivery of high dose rTNFα in a closed system with acceptable side-effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNFα with chemotherapy, with interferon-y, and with hydperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response, compared with 52% after ILP with melphalan alone. Release of nanograms levels of TNFα in the systemic circulation was evident but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this prtocol is due to a dual targeting: rTNFα activates and electively lyses the tumor endothelial cells while melphalan is mainly cytoxic to the tumor cells. ILP with rTNFα appears to be a useful model for studying the biochemotherapy of cancer in man.

2 Ill.

Electronic Resource

0935-6304

Capillary electrophoresis ; TNF-α ; Cytokines ; Chemistry ; Analytical Chemistry and Spectroscopy

Wiley InterScience Backfile Collection 1832-2000

Chemistry and Pharmacology

5 Ill.

Electronic Resource