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The influence of liver hyperthermia on hepatic arterial and portal venous blood flow to tumour and normal hepatic tissue was examined in a rabbit VX2 tumour model. Hyperthermia was delivered by 2450 MHz microwave generator to exteriorized livers in 18 rabbits. Blood flow was measured in both portal vein and hepatic artery using radioactive tracer microspheres before, during and 5 min after intense (greater than 43 degrees C) hyperthermia. During hyperthermia a decrease in total liver blood flow was composed primarily of a decrease in hepatic arterial blood flow to tumour tissue. Tumours were supplied almost exclusively by the hepatic artery and thus total tumour blood flow was significantly depressed during heating. The decreased tumour blood flow persisted after the cessation of hyperthermia and was indicative of vascular collapse in the tumour tissue. Temperature differentials in tumour compared to normal tissue ranged from 5 degrees C to 8 degrees C during hyperthermia because of the lower tumour blood flow. The portal vein exerted minimal influence on temperatures attained in the tumour tissue during hyperthermia but would have mediated normal liver tissue heat loss.

To assess the effects of dietary supplementation using two isomeric blends of conjugated linoleic acid (CLA) on immune function in healthy human volunteers.Double-blind, randomised, placebo-controlled intervention trial.A total of 55 healthy volunteers (n=20 males, n=35 females) were randomised into one of three study groups who received 3 g/day of a fatty acid blend containing a 50:50 cis-9, trans-11: trans-10, cis-12 CLA isomer blend (2 g CLA), and 80:20 cis-9, trans-11: trans-10, cis-12 (80:20) CLA isomer blend (1.76 g CLA) or linoleic acid (control, 2 g linoleic acid) for 8 weeks.Supplementation with the 80:20 CLA isomer blend significantly (Por =0.05) enhanced PHA-induced lymphocyte proliferation. CLA decreased basal interleukin (IL)-2 secretion (Por =0.01) and increased PHA-induced IL-2 and tumor necrosis factor alpha (TNF(alpha)) production (Por =0.01). However, these effects were not solely attributable to CLA as similar results were observed with linoleic acid. CLA supplementation had no significant effect on peripheral blood mononuclear cells IL-4 production, or on serum-soluble intercellular adhesion molecule-1 (sICAM-1) or plasma prostaglandin E2 (PGE2) or leukotreine B4 (LTB4) concentrations.This study shows that CLA supplementation had a minimal effect on the markers of human immune function. Furthermore, supplementation with CLA had no immunological benefit compared with linoleic acid.

Electrical bioimpedance spectroscopy is a fast and relatively easily applicable method for tissue characterization. In the frequency range up to 10 MHz, current conduction through tissue is mainly determined by tissue structure, i.e. the extra- and intra-cellular compartments and the insulating cell membranes. Therefore, changes in the extra- and intra-cellular fluid volumes are reflected in the impedance spectra. Investigations of tumours (DS sarcoma, implanted on the hind foot dorsum of rats) during treatment with localized hyperthermia (HT), photodynamic therapy (PDT) and the combination of these two components were carried out using impedance spectroscopy in the frequency range of 37 Hz to 3.7 MHz. Data collected reveal totally different, but characteristic, behaviour patterns for the three treatments. HT caused a slow increase in conductance at high frequencies (G(HF)) and in the extracellular space index (ECSI), indicating an increase in extracellular fluid volume and in total fluid content. With PDT, G(HF) increased immediately upon commencement of irradiation and was accompanied by a distinct decrease in ECSI, indicating the development of a pronounced intracellular oedema.

In an investigation of the antitumor effects of 2-methoxyestradiol (2-ME) in combination with other reactive oxygen generating treatments, 2-ME (0.5 microM) was found to completely inhibit cell proliferation of rat DS-sarcoma cells in vitro, with 71% of cells dying after exposure to 5 microM 2-ME. Concentration-dependent increases in ROS-formation, lipid peroxidation and mitochondrial changes were also observed, and an elevation in caspase-3 activity resulted in DNA fragmentation and apoptosis. Combination of 2-ME with hypoxanthine and xanthine oxidase enhanced in vitro cytotoxicity. In vivo, 2-ME caused a slight inhibition of tumor growth, with no tumors cured. Combination of 2-ME treatment with localized 44 degrees C hyperthermia, respiratory hyperoxia and xanthine oxidase caused a tumor growth delay with 51% of tumors cured. These results suggest that amplifying the levels of reactive oxygen species within tumor tissue with substances such as 2-ME may prove to be a promising strategy for adjuvant treatment of solid tumors.

The aim of this study was to examine the impact of anemia prevention by recombinant human erythropoietin (rHuEPO) treatment on the cytotoxicity of cyclophosphamide in solid experimental tumors. Anemia was induced using a single dose of carboplatin (50 mg/kg i.v.) resulting in a long-lasting reduction (30%) of the hemoglobin concentration. In a second group, the development of anemia was prevented by rHuEPO (1000 IU/kg) administered s.c. three times/week starting 7 days before carboplatin application. Four days after carboplatin treatment, tumors (DS-sarcoma of the rat) were implanted s.c. onto the hind food dorsum. Neither carboplatin nor rHuEPO treatment influenced tumor growth rate per se. When tumors were treated with a single dose of cyclophosphamide (60 mg/kg i.p.) 5 days after implantation, a growth delay with a subsequent regrowth of the tumors was observed. In the anemia group, the growth delay was significantly shorter compared with nonanemic controls (13.3 days versus 8.6 days). In the group where anemia was prevented by rHuEPO treatment, growth delay was comparable with that of nonanemic controls (13.3 days). These results suggest that chemotherapy-induced anemia reduces cytotoxicity of cyclophosphamide in tumors, whereas correction of anemia by rHuEPO treatment (epoetin alpha) increases the sensitivity, probably as a result of an improved oxygen supply to tumor tissue.

Tumor oxygenation is dependent on the cellular O2 consumption rate and on the O2 supply to the respiring cells. The latter is mainly determined by the convective transport via the blood and by the diffusional flux from the microvessels to the O2 consuming sites. Peculiarities of tumor tissue oxygenation can therefore mainly be attributed to characteristic structural and functional abnormalities of the tumor microcirculation (perfusion-limited O2 delivery), to a deterioration of the diffusion geometry (diffusion-limited O2 delivery), and--in some cases--to a reduced O2-carrying capacity of the blood due to tumor-associated anemia. As a result of a compromised and anisotropic microcirculation, the O2 availability to the cancer cells shows great variability, and many human malignancies reveal hypoxic tissue areas which are heterogeneously distributed within the tumor mass and which may be located next to well-perfused tumor areas (intra-tumor heterogeneity). As a rule, in most solid malignancies the tissue O2 status is poorer than in normal tissue at the site of tumor growth. Hypoxia in human tumors per se has been shown to contribute to resistance to standard radiotherapy, chemotherapy and photodynamic therapy with photosensitizing hematoporphyrins. In addition to conferring a direct resistance, hypoxia-induced inhibition of proliferation may also contribute to resistance since both modalities are primarily effective against rapidly dividing cells. Hypoxia in solid tumors, however, has further implications in the clinical setting: Recent data provide strong evidence suggesting that O2 deprived tumor cells are predisposed to a more malignant phenotype, i.e., tumor cells are more likely to be more metastatic and/or invasive. In addition, clonal heterogeneity is more pronounced in hypoxic tumors.

Tumor growth, oxygenation and radiosensitivity were investigated in a series of studies in which anemia was induced in rats either by the development of a hemorrhagic ascites or by a single dose of carboplatin, which resulted in reductions in the hemoglobin concentration of 30%. The development of both the tumor- and chemotherapy-induced forms of anemia could be prevented by the s. c. administration of recombinant human erythropoietin (rhEPO; 1000 IU/kg, 3 times per week over 14 days). Seven days before pO2 measurements, DS-sarcomas were implanted s. c. on the hind foot dorsum. With both anemia models, tumor growth did not differ between anemic animals and animals treated with rhEPO. Tumor oxygenation was measured polarographically using O2-sensitive needle electrodes and pO2 histography. In anemic animals, tumor oxygenation was poorer compared to untreated controls. The reduction could be partially reversed by rhEPO treatment, but not fully compensated. These findings suggested that rhEPO treatment can improve tumor oxygenation by increasing the O2 availability to tumor tissue. Further experiments therefore assessed the possibility of enhancing the efficacy of a single radiation dose (10 Gy) by rhEPO treatment of anemic animals. While anemic animals showed decreased radiosensitivity, prevention of anemia by rhEPO treatment resulted in a significant increase in tumor radiosensitivity, although again a full recovery to radiosensitivity levels found in non-anemic animals was not achieved.

The effects of respiratory hyperoxia (RH) and xanthine oxidase (XO) during localized hyperthermia (HT) were investigated by determining markers of oxidative damage to lipids and proteins and tumor growth. Anesthetized rats with s.c. DS-sarcomas underwent one of the following treatments: (a) localized saline-bath HT (60 min, 44 degrees C); (b) HT + RH (100% O2); and (c) HT + RH + XO (15 units/kg i.v.). Sham-treated animals served as controls. Tumors were investigated for: (a) thiobarbituric acid-reactive substance formation and protein-bound 4-hydroxynonenal, as indicators of lipid peroxidation; (b) reactive oxygen-mediated protein modifications; (c) apoptosis; and (d) tumor volume growth. Upon treatment, increases in thiobarbituric acid-reactive substances, protein-bound 4-hydroxynonenal, protein-associated carbonyl functions, and number of cells undergoing apoptosis were found in tumor tissue, together with an inhibition of tumor growth. When treatment groups were compared, effects in the group HT + RH + XO were generally most pronounced. These findings indicate that the antitumor effect of HT is at least partially mediated through the selective induction of lipid peroxidation and oxidative injury in tumor cells, leading to apoptosis. This effect was enhanced by adding RH or RH + XO, presumably due to enhanced tissue damage following an increased formation of reactive oxygen species, with higher levels of lipid peroxidation and protein oxidation.

Growth, blood flow, oxygenation, and bioenergetic status of experimental tumors were investigated in normal (control) and anemic animals after administration of recombinant human erythropoietin (rhEPO). DS sarcomas were implanted s.c. onto the hind foot dorsum of Sprague-Dawley rats. Tumor-associated anemia was induced by the development of an i.p. hemorrhagic ascites. rhEPO (1000 IU/kg) was administered s.c. three times per week over 14 days, after which it was found to have significantly increased hematocrit values in both normal and anemic animals. Tumor growth in anemic animals was slower than in normal animals, and rhEPO administration did not influence tumor growth in either group. Tumor blood flow in anemic animals was lower than in control animals and was only increased in larger tumors in animals in which anemia was prevented by prophylactic rhEPO application. Tumor oxygenation, determined using polarographic needle electrodes and oxygen partial pressure histography, was poorer in anemic animals than in normal animals. This reduction could be reversed partially, but not compensated fully by rhEPO treatment in smaller tumors (or = 1.4 ml). These changes suggest that rhEPO, by improving tumor oxygenation, may increase the efficacy of standard radiotherapy in anemic animals and may be of use in anemic tumor patients in whom the success of radiotherapy or O2-dependent chemotherapy might be limited by tumor hypoxia.

The effect of inhibiting DNA synthesis on the cellular O2 consumption rate of tumor cells (DS sarcoma) in vivo was analyzed using a photometric technique. Five days after DS-sarcoma ascites was induced in SD rats, animals were treated either with fludarabine (400 mg/kg i.p., 6 h prior to measurements) or lovastatin (3 x 20 mg/kg i.p., 24, 15, and 3 h prior to measurements), drugs that can inhibit tumor cell proliferation. In addition to cellular O2 consumption, the cell cycle distribution and the fraction of DNA-synthesizing cells in the tumor ascites were measured. Both drugs lowered DNA synthesis significantly, an effect that was more pronounced with fludarabine. The cellular O2 consumption rate following lovastatin application was significantly impaired (approximately 33%), whereas fludarabine had practically no effect on the respiration rate of tumor cells. From these data, it is concluded that a reduction in DNA synthesis does not necessarily result in a decrease in the O2 consumption rate of tumor cells in vivo.

The occurrence of differential heating and differential thermal sensitivity between malignant tumors and normal tissues is thought to be due to limited heat dissipation and energy depletion in many solid tumors which in turn results from an inadequately functioning tumor microcirculation (Jain and Ward-Hartley 1984; Song 1984, 1991; Vaupel and Kallinowski 1987; Reinhold 1988; Vaupel et al. 1988a; Vaupel 1990). As a consequence of the latter pathophysiological condition, supply and drainage function are restricted in many solid tumors or, at least, in some tumor areas, thus creating a hostile metabolic microenvironment characterized by tissue hypoxia, acidosis, and energy depletion. Thermal sensitivity has been shown to depend greatly on tumor pH, and on energy and nutritional status of the tumors treated. Although no conclusive evidence is so far available concerning the ranking of these pivotal factors, there is no doubt that the rate and homogeneity of blood perfusion plays a paramount role in determining the metabolic and energy status.

A novel device consisting of an infrared-A (= ultrared-A) radiation source equipped with a water filter in the radiation path is described which allows for the therapeutic heating of superficial experimental and human tumors. Preliminary studies with agar phantoms showed that heating in the presence of the water-cuvette avoids intolerable overheating in the very superficial layers. This effect can be further enhanced by surface cooling with room air such that a stratification of the temperature distribution can be achieved. In subsequent experiments, temperature distributions were recorded in the x-, y- and z-axis of superficial rodent tumors. The results obtained confirm those from the phantom experiments, showing that therapeutically relevant temperatures (Tor = 42 degrees C) could be achieved through the tumor mass to a depth of approximately 1.2 cm. Temperature homogeneity is comparable to that seen in superficial tumors undergoing water-bath hyperthermia. This novel technique has proved to be reliable, is well-tolerated, is easy to apply, and is easily accessible to a larger number of potential users for the local heating of superficial malignancies.

In selective internal radiation (SIR) therapy of hepatic metastases, tumor vasculature is preferentially embolized with high-energy beta-emitting yttrium-90-labeled microspheres. To enable accurate estimation of the resultant absorbed radiation doses to tissues, an intraoperative beta detection probe is used to scan the liver surface. The validity of the response of this probe to Y-90 and its clinical application were assessed with a phantom containing varying activities and with biopsy samples obtained from patients being treated with SIR therapy. A linear relationship was found between the probe counts taken from the biopsy samples and the calculated tissue radiation doses from the specific activities of each sample. This relationship was repeated with probe counts determined against a water phantom containing various activities of Y-90. The probe was shown to respond minimally to bremsstrahlung. The use of the probe in measuring tissue radiation doses at laparotomy provides the opportunity to control dose administration during SIR therapy. In this way, subtherapeutic exposure of normal tissue can be assured while tumor tissue receives maximal radiation levels.

There are no reliable data documenting the tolerance of the human liver to ionizing radiation from a continuous Yttrium-90 source. As Yttrium-90 incorporated into microspheres is being used to treat patients with liver cancer, it is imperative that the tolerance of the human liver to this form of radiation damage be determined. Four patients with metastatic liver cancer were treated with Yttrium-90 to deliver radiation doses above that considered tolerable when given by conventional external sources. Patients were monitored with serial estimations of liver function tests and between 7 and 9 months after treatment liver biopsies were performed. Histological examination of the liver biopsies confirmed only minimal changes in the normal liver parenchyma. These data indicate that the human liver may tolerate relatively large radiation doses when delivered by Yttrium-90 microspheres embedded in the liver parenchyma as a number of discrete point sources.

The influence of regional liver hyperthermia in conjunction with systemic doxorubicin administration was examined in a rabbit VX2 tumour model. Hyperthermia was delivered by 2450MHz microwave generator to the exteriorised livers of the rabbits to provide a thermal dose equivalent of 43 degrees C for 30 minutes. Animals receiving doxorubicin infusion were treated with a total of 1.2 mg/kg over a 3 day protocol through an ear vein. Rabbits were divided into 4 groups; a no treatment control, hyperthermia alone, doxorubicin alone and hyperthermia immediately preceded by doxorubicin. The tumour mass, 10 days post treatment was significantly (P less than 0.0001) reduced in all treatment groups. However, the mean tumour mass in the combination treatment group was also significantly lower than both treatments alone (P less than 0.001). This increased response was not accompanied by any signs of increased systemic or local toxicity associated with any treatment.

Ten patients with liver metastases from primary tumors in the colorectum were treated with selective internal radiation (SIR) therapy. This involved the embolisation of yttrium-90-containing microspheres into the hepatic artery at the time of laparotomy. The microspheres were concentrated in the microvasculature of the tumour nodules by the concurrent administration of angiotensin II. The radiation dose being delivered to liver parenchyma was measured at the time of operation by use of an intraoperative radiation detection probe. All nine patients in whom the preoperative carcinoembryonic antigen (CEA) level was elevated experienced a decrease in CEA levels posttreatment. Intraoperative dosimetry confirmed the poor correlation between total radioactivity used and radiation dose received by normal liver parenchyma.

Auranofin in the mucosal fluid inhibited the active Na+-dependent absorption of taurocholic acid by everted sacs of rat ileum. It did not however, affect the passive uptake of taurocholic acid by sacs of mid-intestine. The inhibition by auranofin of active bile acid absorption could result from its previously demonstrated ability to inhibit Na+, K+-ATPase activity. A reduction in the reabsorption of bile acids by the ileum may contribute to the diarrhoea experienced by some patients taking auranofin.

Auranofin (AF) a new antiarthritic gold compound effective when administered orally, frequently causes diarrhea with abnormal stool electrolyte content. Studies were designed to determine the mechanism of the diarrhea caused by AF. In perfused canine Thiry-Vella loops, AF caused significant elevations in effluent volume, osmolarity, and sodium concentration and a significant decrease in potassium concentration. In mucosal homogenates of rat small bowel, AF inhibited sodium, potassium ATPase in a concentration dependent manner. AF did not alter canine colonic smooth muscle activity in vitro. We suggest that AF induced diarrhea results from interruption of normal water and electrolyte absorption by inhibition of enterocyte sodium, potassium ATPase activity.

Auranofin in the mucosal fluid caused a dose-dependent inhibition of fluid and Na+ absorption by everted sacs of rat colon. Serosal auranofin was without effect. (Na+ + K+)ATPase activity of homogenates of mucosal scrapes of rat colon was inhibited by auranofin in a dose-related manner, while Mg2+-ATPase activity was little affected. These actions of the drug on colonic transport mechanisms could contribute to the diarrhoea associated with auranofin therapy.

The importance of training low vision-patients to use low vision aids is discussed. The team approach is emphasized and the advantages of the additional expertise considered. Specific procedures and techniques are are recommended to enhance the chances for success of the training program and it is concluded that training is an important aspect of follow-up care which should be made an intergral part of low vision care.

Mucosal auranofin (AF) caused a concentration dependent inhibition of fluid, Na+, glycine and galactose transport by everted sacs of rat small intestine (IC50 = 2 X 10(-4) M). Inhibition of nutrient absorption was not due to reduced fluid uptake since a similar reduction in fluid uptake induced by a mucosal osmotic load failed to alter glycine transport. Inhibitory effects of AF were not observed when metabolism was reduced, suggesting that carrier mediated entry processes were unaltered. AF inhibited Na+, K+-ATPase activity in isolated enterocytes (IC50 = 2 X 10(-4) M), without affecting Mg2+-dependent ATPase activity. Our studies suggest that the actions of AF on small intestinal absorption may result from inhibition of the Na+ pump.