Walking performance and health-related quality of life after surgical or endovascular invasive versus non-invasive treatment for intermittent claudication--a prospective randomised trial.

OBJECTIVES: Despite limited scientific evidence for the effectiveness of invasive treatment for intermittent claudication (IC), revascularisation procedures for IC are increasingly often performed in Sweden. This randomised controlled trial compares the outcome after 2 years of primary invasive (INV) versus primary non-invasive (NON) treatment strategies in unselected IC patients. MATERIALS/METHODS: Based on arterial duplex and clinical examination, IC patients were randomised to INV (endovascular and/or surgical, n = 100) or NON (n = 101). NON patients could request invasive treatment if they deteriorated during follow-up. Primary outcome was maximal walking performance (MWP) on graded treadmill test at 2 years and secondary outcomes included health-related quality of life (HRQL), assessed with Short Form (36) Health Survey (SF-36). RESULTS: MWP was not significantly (p = 0.104) improved in the INV versus the NON group. Two SF-36 physical subscales, Bodily Pain (p < 0.01) and Role Physical (p < 0.05) improved significantly more in the INV versus the NON group. There were 7% crossovers against the study protocol in the INV group. CONCLUSIONS: Although invasive treatment did not show any significant advantage regarding MWP, the HRQL improvements associated with invasive treatment tentatively suggest secondary benefits of this regimen. On the other hand, a primary non-invasive treatment strategy seems to be accepted by most IC patients.

Tumor-host wasting not explained by adrenal hyperfunction in tumor-bearing animals.

This study addressed the question of whether hypercorticism in tumor-bearing animals contributes to the wasting of body fat and lean body mass, particularly that of skeletal muscles. For this purpose, hydrocortisone-substituted nongrowing sarcoma-bearing and control C57BL/6J mice were used that were either adrenalectomized or sham-operated prior to experimentation. Adrenalectomy in itself did not alter food intake or body composition in normal animals. Tumor-bearing mice and pair-weighted control animals had elevated urinary excretion of corticosteroids compared with the urinary excretion in freely fed controls. The malignant tumor induced the well-recognized wasting in tumor-bearing animals, irrespective of the presence of the adrenal glands. Therefore, an elevated corticosteroid production did not account for the wasting of body fat, lean body mass, skeletal muscle proteins, or decreased RNA activity in quadriceps muscles from tumor-bearing animals, although such muscles were sensitive to physiologic doses of injected hydrocortisone (20 micrograms/day). Tyrosine aminotransferase (TAT) activity in liver tissue from tumor-bearing animals was higher than that induced by pharmacologic doses of hydrocortisone in normal animals. Physiologic doses of hydrocortisone induced hepatic TAT activity, but pair-weighed control animals with the same degree of hypercorticism as was found in tumor-bearing animals had normal TAT activity in liver tissue. Although hypercorticism is present in tumor-bearing animals, the results demonstrate that cancer cachexia can start and proceed independently of the adrenal glands. Therefore, adrenal hyperfunction is not the proximate cause for the development of experimental cancer cachexia induced by anorexia.

Effects of indomethacin, cytokines, and cyclosporin A on tumor growth and the subsequent development of cancer cachexia.

C57BL/6J mice bearing a low or undifferentiated rapidly growing tumor were treated daily with either i.p. injections of the recombinant cytokines interleukin(IL)-1 alpha, IL-1 beta (21 ng/g), and tumor necrosis factor alpha (21 ng/g) or s.c. injections of cyclosporin A (60 micrograms/g) or indomethacin (1 micrograms/g). In some experiments, indomethacin was administered in the drinking water corresponding to the amount of s.c. injections. Survival and the time course of tumor growth and food and water intake were measured. The nutritional state (body composition) of the animals was registered at spontaneous death in the course of tumor disease. Indomethacin prolonged survival from 14 +/- 1 to 22 +/- 1 days in tumor-bearing mice when administered either in the drinking water or as s.c. injections. This effect, which was due to tumor growth inhibition, was equally effective irrespective of whether indomethacin was instituted on Day 1, 5, 7, or 9 following tumor implantation. Indomethacin did not inhibit tumor cell growth in vitro. Indomethacin-treated tumor-bearing mice were also less anorectic than untreated tumor-bearing mice, and their nutritional state, particularly lean body mass, was significantly improved by indomethacin at doses (1 micrograms/g) that did not influence the food intake or body composition in non-tumor-bearing mice. At spontaneous death, indomethacin-treated tumor-bearing mice had a significantly larger tumor burden when accounting for their degree of malnutrition as compared with untreated tumor bearers. Indomethacin did not decrease the elevation in hepatic concentrations of RNA seen in response to tumor progression. Adherent peritoneal macrophages from tumor-bearing mice had a lower prostaglandin E2 synthesis compared with macrophages from non-tumor-bearing controls in the basal state (1100 +/- 150 pg/10(6) cells versus 3700 +/- 922 pg/10(6) cells). Lipopolysaccharide stimulated macrophages from tumor-bearing mice to produce significantly more prostaglandin E2 in vitro compared with control macrophages (39,500 +/- 4208 pg/10(6) cells versus 12,500 +/- 4330 pg/10(6) cells).(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma protein synthesis in experimental cancer compared to paraneoplastic conditions, including monokine administration.

During tumor growth, there are characteristic alterations in the concentration and synthesis of various plasma proteins. The purpose of this study was to evaluate whether these changes are unique to a tumor-bearing state, or rather, they represent a generalized response to a paraneoplastic state mediated by the release of monokines or protein-calorie malnutrition. Plasma protein synthesis and concentrations in mice bearing a transplantable fibrosarcoma were compared to animals receiving either a terpentine abscess, Corynebacterium parvum administration, calorie-protein depletion, or administration of the recombinant-derived monokines, murine interleukin 1 alpha or human tumor necrosis factor-alpha. Tumor-bearing animals showed a significant increase in total plasma protein synthesis that was similar in magnitude to the increase seen following a terpentine abscess or after administration of interleukin 1 or tumor necrosis factor-alpha. Similarly, the pattern of protein synthesis and concentration, as determined by isoelectric focusing or sodium dodecyl sulphate-polyacrylamide gel electrophoresis, were similar, albeit not identical, among tumor-bearing animals and those receiving either a terpentine abscess, C. parvum and monokine administration. Serum amyloid P concentrations were markedly elevated in tumor-bearing animals, as they were in animals after a sterile abscess and following interleukin 1 administration, as well as to a lesser extent tumor necrosis factor-alpha administration. We can therefore conclude that the majority of changes in plasma protein concentration and synthesis seen in this tumor-bearing model are similar to those seen during an acute inflammation and can be reproduced to a large extent by the administration of the monokines, interleukin 1 alpha or tumor necrosis factor-alpha.

Effect of cyclooxygenase and nitric oxide synthase inhibitors on tumor growth in mouse tumor models with and without cancer cachexia related to prostanoids.

The potential interaction between cyclooxygenase (Cox) and NO metabolic pathways in the control of local tumor growth was evaluated. Mice bearing either a sarcoma-derived tumor (C57B1; MCG 101) or a malignant melanoma (C3H/HeN; K1735-M2) were used. These models were principally different because they demonstrate, in tumor hosts, conditions with and without cancer cachexia, seemingly related to high and low production of prostanoids, respectively. Cox inhibitors (Cox-1 and Cox-2) decreased tumor growth by 35-40% in MCG 101-bearing mice but had no such effect on melanoma-bearing mice, despite the expression of the Cox-2 protein in melanoma cells. Indomethacin reduced prostanoid production in both tumor (MCG 101) and host tissues and reduced tumor cell proliferation, mainly in vivo. Nitric oxide synthase (NOS) inhibitors (N(omega)-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine) reduced tumor growth in vivo by approximately 50% in both tumor models. Tumor growth reduction, related to NOS inhibition, was unrelated to prostanoid production and was an in vivo phenomenon in both tumor models. Specific inhibitors of inducible NOS activity, unexpectedly, had no effect in any tumor model, although inducible NOS protein was present in tumor tissues in large amounts. A combination of Cox and NOS inhibitors had no additive effect on tumor growth (MCG 101). Cox inhibition increased tumor tissue (MCG 101) expression of cNOS mRNA but had no significant effect on tumor tissue expression of the transferrin receptor, vascular endothelial growth factor, or basic fibroblast growth factor. NOS inhibition increased tumor tissue content of cNOS mRNA but showed as well a trend to increase mRNA content of the transferrin receptor and vascular endothelial growth factor. Our results suggest that NOS inhibitors can decrease the local growth of tumors that are either responsive or unresponsive to Cox inhibition. This effect may reflect cross-talk between Cox and NOS pathways within or among tumor cells, or it may represent unrelated effects on tumor and host cells. Whether NO inhibition may be used therapeutically in clinical tumors that are unresponsive to eicosanoid intervention remains to be evaluated.

Role of endogenous tumor necrosis factor alpha and interleukin 1 for experimental tumor growth and the development of cancer cachexia.

The aim of this study was to evaluate to what extent tumor necrosis factor alpha (TNF-alpha) and interleukin 1 may explain the development of experimental cancer cachexia. For this purpose, C57BL/6J mice bearing a transplantable low differentiated rapidly growing tumor were passively immunized every other day with rabbit or rat neutralizing immunoglobulins against either TNF-alpha (anti-TNF) or against an interleukin 1 receptor (anti-IL-1r). Anti-IL-1r in itself had no agonistic effect to the type I, T-cell/fibroblast IL-receptor. Tumor-bearing mice receiving either preimmune antiserum or nonimmune rat hybridoma IgG served as controls. Anti-TNF and anti-IL-1r inhibited tumor growth significantly, as measured by a lower wet and dry tumor weight at the end of 11 days of antiserum treatment (P less than 0.05). The acute phase response in tumor-bearing animals, measured as an increase in liver weight, hepatic RNA content, and increases in plasma concentrations of circulating IL-6, serum amyloid P, transferrin, complement (C3), and a decrease in plasma albumin, were unaffected by the specific antiserum treatments. Food intake, which declined significantly in pre/nonimmune injected tumor-bearing controls, was significantly improved in tumor-bearing animals immunized against TNF-alpha or the IL-1r. Whole body lipid content showed a trend to improvement in specifically immunized animals (P less than 0.07). The effects on whole body fat-free dry weight were insignificant, although numerically higher in specifically immunized tumor-bearing animals. The combination of anti-TNF and anti-IL-1r antiserum had no additive effects compared to single antiserum treatment suggesting that the two antibody treatments acted through a common mechanism. Cultured tumor cells, established from growing tumors, were sensitive to anti-TNF and anti-IL-1r, which both reduced tumor growth in vitro. This inhibitory effect by the antiserum could in part be reversed by the addition of recombinant IL-1 alpha and TNF alpha. We conclude that both TNF and IL-1 are involved in tumor growth and thus the progression of cancer cachexia. It seems as if the role of TNF and IL-1 was to promote tumor growth rather than restrict tumor growth in the present model. In this sense both TNF and IL-1 may act as tumor growth factors.

Anti-inflammatory treatment may prolong survival in undernourished patients with metastatic solid tumors.

Eicosanoids may be important factors for tumor cell proliferation, metastatic formation, and development of cancer cachexia. The present study has evaluated the effect of anti-inflammatory treatment on tumor progression in clinical cancer. Patients (n = 135) with insidious or overt malnutrition due to generalized malignancy (various kinds of solid tumors) and an expected survival of more than 6 months were randomized by a computer-based algorithm to receive placebo, prednisolone (10 mg twice daily), or indomethacin (50 mg twice daily) p.o. until death. Patient groups were stratified in the randomization procedure for sex, tumor type, stage, nutritional state, and previous tumor treatment, and biochemical, physiological, and some functional variables (Karnowsky index, fatigue and pain score). A majority of these variables was then registered during the follow-up. Indomethacin and prednisolone treatment maintained Karnowsky index, while placebo-treated patients experienced a decreased index. Indomethacin-treated patients suffered less pain and consumed less additional analgetics compared to the other patient groups. Indomethacin prolonged mean survival compared to placebo-treated patients from 250 +/- 28 days to 510 +/- 28 days (P < 0.05). Survival analysis on observations from all patients treated with either indomethacin or prednisolone demonstrated a significantly prolonged survival by anti-inflammatory treatment compared to placebo treatment (log rank, P < 0.03). The results suggest that not only may prostaglandin synthesis inhibition offer palliative support to patients with solid advanced cancer, but it may also impact on pathways that ultimately determine outcome.

Replication of microchannel structures in WC-Co feedstock using elastomeric replica moulds by hot embossing process.

Hot embossing is a net shaping process that is able to produce the micro-components of polymers with intrinsic and complex shapes at lower cost compared with machining and injection moulding. However, the emboss of hard metals, such as WC-Co, is more challenging due to their high thermal conductivity and ease of agglomeration. Thus, a WC-Co alloy mixed with a wax-based binder feedstock was selected. The formed feedstock exhibited pseudo-plastic flow and was successfully embossed (green part). Here, we developed a novel process that is used to replicate polymer microfluidic chips while simultaneously reducing the channel surface roughness of the mould insert, yielding optical-grade (less than 100 nm surface roughness) channels and reservoirs. This paper concerns the replication of metallic microfluidic mould inserts in WC-Co and the parameters associated with feedstock formation via a hot embossing process. A suitable formulation for micro-powder hot embossing has been established and characterised by thermogravimetric analyses and measurements of mixing torques to verify and quantify the homogeneity of the proposed feedstocks. The relative density of the samples increased with processing temperature, and almost fully dense materials were obtained. In this work, the effects of the sintering temperature on the physical properties were systematically analysed. The evolution of the metal surface morphology during the hot embossing process was also investigated. The results indicate that the feedstock can be used to manufacture micro-fluidic die mould cavities with a low roughness, proper dimensions and good shape retention. The shrinkage of the sintered part was approximately 19-24% compared with that of the brown part.

The effect of indomethacin on food and water intake, motor activity and survival in tumour-bearing rats.

This investigation has addressed the question whether food and water intake, motor activity and tumour growth are influenced by indomethacin in experimental cancer. Growing rats implanted with a methylcholanthrene-induced sarcoma were studied in metabolic cages connected to a computer. Food intake, water consumption and motor activity were continuously recorded over 30 days following tumour implantation. Treated tumour-bearing animals received indomethacin 1.0 mg/kg per day in drinking water. Food intake declined early in untreated tumour-bearing animals, but water intake was not affected. Motor activity decreased in untreated tumour-bearing animals from days 16-17 onward. Indomethacin treatment prolonged survival and 40% of these tumour-bearers were 'complete responders'. In some animals tumour growth was only marginally affected, but survival was still significantly improved ('partial responders'). Food intake was significantly improved in complete responders. Thus this positive effect seen in complete responders was secondary to less active tumour growth. Motor activity was also significantly higher in responders compared with non-responders.

Expression of interleukin-6 in tumor-bearing mice with cytokine dependent cachexia.

Increased production of IL-6 in tumor-bearing mice occured in a variety of host-tissues including tumor tissue. Elevated IL-6 transcription in tumor-bearing mice occured in the tumor, liver, kidney and the small intestine, and was associated with increased concentration in the circulation of bioactive IL-6 of normal size (almost-equal-to 20 000 kDa) in addition with two larger but biologically inactive serum fractions containing immune-reactive IL-6. These inactive complexes were not explained by circulating inhibitor(s). The occurrence of differently sized tumor and host-tissue IL-6 mRNAs were dependent on the subcellular location (nuclear, ribosomal, cytoplasm). the tissue type and the kind of cellular stimulation. In tumor-tissue, IL-6 was produced to the highest concentration in tumor cells, followed by inflammatory and endothelial cells respectively, but IL-6 did not seem to represent an autocrine growth factor loop as earlier reported by us for both IL-1alpha and TNFalpha in the present tumor model. In contrast, evidence supported that IL-6 acted as a paracrinic factor in this model stimulated by some other host-derived factor(s).

Effects related to indomethacin prolonged survival and decreased tumor-growth in a mouse-tumor model with cytokine dependent cancer cachexia.

Tumor-bearing mice with two different locally growing malignant tumors (epithelial like, MCG 101; malignant melanoma, K1735-M2) were used to evaluate the putative role of prostaglandins for survival and local tumor growth in experimental cancer. Daily systemic injections of indomethacin (1 mu g/g bw) were used to block prostaglandin production in normal and T-cell deficient tumor-bearing nude mice. Tumor progression was determined by measurements of tumor weight, DNA-synthesis, cell cycle kinetics in vivo and in vitro (flow cytometry), tumor tissue concentrations of polyamines (putrescine, spermidine, spermine) and tumor tissue gene expression of growth regulating factors (IL-1 alpha, IL-6, TNF alpha, A,B-PDGF, EGF, VEGF, bFGF, TGF beta(3), angiogenin and transferrin receptor). Tumor tissue content of von Willebrandt factor VIII was estimated by immunohistochemistry. Indomethacin had no effect on survival, host nutritional state or local tumor growth in mice bearing the malignant melanoma with low PGE(2) production. In contrast, indomethacin prolonged survival, improved cachexia and decreased tumor growth in mice bearing the MCG 101 tumor with hundredfold higher prostaglandin tumor production, leading to elevated liver and muscle tissue as well as plasma concentrations of PGE(2). Indomethacin inhibited almost completely the high tumor PGE(2) production in MCG tumors, leading to prolonged potential doubling time for tumor growth in vivo, and a trend to decreased tumor tissue concentration of polyamines (spermidine). Indomethacin had no inhibitory effect on tumor cell proliferation in vitro, although PGE(2) production was decreased by 75%. The effect of indomethacin in vivo was independent of T-cells and was observed with similar magnitude irrespective of the number of MCG cells (10(4)-10(6)) implanted or the site of implantation (s.c., i.p., liver, lung, skeletal muscles). Tumor growth inhibition by indomethacin was not intrinsically transferable by tumor cells from indomethacin treated tumor-animals. Tumor expression of mRNA for several growth regulating factors were either increased (IL-6, TNF alpha, GM-CSF, TGF beta(3)) unchanged (EGF, VEGF, PDGF A,B, IL-1 alpha, transferrin receptor) or decreased (b-FGF and angiogenin) (p<0.05) by indomethacin treatment of MCG mice. Decreased tumor content of von Willebrandt factor VIII in combination with an attenuated tumor vasculature were associated with decreased tumor growth (p<0.05). Our results confirm that high tumor production of prostaglandins was related to reduced survival. Tumor prostaglandins probably promote local tumor growth by stimulation of tumor surrounding cells to produce growth factor(s) for tumor angiogenesis including tumor and matrix cell proliferation unrelated to immune cells.

The secretion of cholecystokinin in the gallstone patient before and after removal of a functioning gallbladder.

Cholecystectomy will not always relieve the abdominal symptoms of the patient with gallstones. The functional effects of gallbladder removal in a patient with a patent cystic duct are not known in detail. Studies of the function of the gallbladder and pancreas have suggested feedback mechanisms for the release of cholecystokinin (CCK). A disturbed regulation of CCK release after cholecystectomy might induce pancreaticobiliary and gastrointestinal dysfunctions. In our study the concentrations of CCK in plasma were measured in 17 patients with gallstones. The measurements were taken with gallbladders opacified at cholecystography and with patent cystic ducts at the operation, in the fasting state, and during stimulation before and 17 weeks after the cholecystectomy. The CCK assay used measures sulfated CCK-8, CCK-22, and CCK-33 with equimolar potency but neither nonsulfated CCK nor any gastrins. Emtobil (containing peanut oil and sorbitol) was used for peroral stimulation of the CCK release. The basal concentration of CCK was 4 pmol/L and rose five times during a "test meal." No significant differences were seen in fasting or stimulated concentrations of plasma CCK before and after the cholecystectomy. Thus cholecystectomy in gallstone patients with functioning gallbladders does not seem to influence the regulation of CCK release.

Multicenter clinical experience with large core soft tissue biopsy without vacuum assistance.

The increasing interest in accurate pretreatment diagnosis of solid tumours by morphology, immunohistochemistry, genetics and molecular biology requires clinicians to obtain undamaged large core biopsies. Simultaneously, medical imaging and surgery give priority to minimal tissue injury, affordable technology and optimal patient compliance. A new large core soft tissue biopsy device has been developed to meet the above criteria. After intensive preclinical testing, 30 patients gave informed consent and 26 underwent the new diagnostic biopsy procedure. The sample was studied by morphology, immunohistochemistry and, where indicated, by molecular biology. Successful diagnosis was considered when in line with clinical follow-up and, as for all malignant lesions, when confirmed by open biopsy or surgery. No difficulties in the technique were encountered in 25 patients. In one patient the procedure was prematurely stopped because of anxiety. In all other 25 procedures a complete diagnosis was reached with regard to morphology, immunohistochemistry and molecular biology. A number of radiologists suggested some automation of the technique. This new large core soft tissue biopsy system performs well in the clinical context without injury to the breast parenchyma or artefacts in the harvested tissue specimen. The system meets almost all of the proposed technical and financial requirements. Automation is underway.

[Psychological aspects observed during function rehabilitation of coronary patients]. / Aspects psychologiques observés au cours de la réadaptation fonctionnelle des coronariens

The authors have studied the influence of rehabilitation on the anxiety of 93 patients with myocardial infarction. The index of anxiety was measured objectively, as were the various primary factors. The change in these various factors has been favourable one in those patients who have had the benefit of complete rehabilitation. There seems to be a correlations between this change and the quality of rehabiltation as judged by the results of the exercise test which is undertaken at the end of it. Other psychological factors were also studied: the patient's estimate of his anxiety, of the rehabilitation, and of his own relationship to his illness, the factors which finally released his from the anxiety, and the features taken as a while.

Imaging of polypoid endoluminal growing bile duct tumors.

We reviewed the radiological documents and protocols of 196 cases of bile duct tumors examined over a period of 12 years: 20 of them (10.2%) presented with a polypoid endoluminal growth. The aim of this study was to provide a better knowledge about the radiological features of this less frequent kind of tumor. In these 20 cases, the correct diagnosis of bile duct lesion was provided in 100% by E.R.C.P., P.T.C., U.S. as well as C.T., and in 42% by arteriography. The correct diagnosis of tumor was made by E.R.C.P. in 86%, by P.T.C. in 88%, by U.S. in 61%, by C.T. in 63%, and by arteriography in 25%. A correct diagnosis of tumor could be reached in all cases by combination of several examination techniques. The anatomopathological diagnosis was: bile duct adenocarcinoma (7 cases), adenocarcinoma of the ampulla of Vater (4), villous adenoma of Vater's ampulla (2), cystadenoma (1), cystadenocarcinoma (1), hepatocellular carcinoma (1), apudoma (1), and metastases (3).