Vitamin K prophylaxis and childhood cancer.
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Blood Coagulation↗
Biomedical subjects
J A Ross
Publications and source records attributed to J A Ross.
Disordered metabolic response with cancer and its management.
The metabolic changes in cancer cachexia appear to be mediated by a complex network of proinflammatory cytokines, neuroendocrine hormones, neurotransmitters, eicosanoids, and tumor-derived factors produced by the body in response to the tumor and by the tumor itself. The relative importance of these various mediator pathways in relation to either the anorexia or hypermetabolism associated with weight loss in cancer remains to be fully elucidated. Our current understanding suggests that proinflammatory mediators may indeed be a valid target for therapeutic intervention. Trials attempting to modify the inflammatory response to cancer with the hope of improving appetite and reversing catabolism and perhaps thereby improving qualityof life and survival are currently underway.
Animals↗
Prenatal epidemiology of pediatric tumors.
With the exception of a small percentage of cases attributable to hereditary cancer syndromes (eg, familial retinoblastoma) or genetic syndromes (Down syndrome), the etiology of most childhood cancers is unknown. Recent epidemiologic studies have focused on the prenatal period and have investigated potential associations with parental age, cigarette smoking, birth weight of the child, parental occupational exposures, and specific environmental exposures. The following challenges lie ahead for future epidemiologic studies of childhood cancer: 1) improvement of diagnostic classification; 2) improved methods for exposure assessment; 3) evaluation of data from molecular biology to generate biologically derived hypotheses; and 4) incorporation of markers of genetic susceptibility when feasible.
Adolescent↗
Role for CD40-CD40 ligand interactions in the immune response to solid tumours.
CD40-mediated interactions play an important role in the response to infections, transplantation, and cancer by affecting the development, activation, proliferation and differentiation of a variety of immune cells. In the current study we examined the role of CD40-mediated interactions in immune responses to bladder, pancreatic and breast carcinomas as well as melanoma cell lines using soluble human CD40L (rhCD40L) or anti-CD40 mAb in vitro. CD40 expression was readily detected in a large proportion of the cell lines and was augmented but not induced de novo by treatment with IFNgamma. Treatment of CD40-positive cell lines with rhCD40L or anti-CD40mAb enhanced cell surface expression of ICAM-1 and FAS and stimulated the production of IL-6, IL-8, GROalpha, GM-CSF and TNFalpha but not IL-4, IL-10, TGFbeta, MCP-1, RANTES, MIP-1beta, or IP-10. In addition, incubation of CD40+ tumour cell lines with immobilised rhCD40L or anti-CD40 mAb in vitro resulted in significant inhibition of proliferation and a corresponding decrease in viability. This CD40-mediated inhibition of cell growth was due, at least in part, to alterations in cell cycle and the induction of apoptosis. Transfection of CD40-negative tumour cell lines with the cDNA for CD40 conferred responsiveness to rhCD40L and anti-CD40 antibody. Finally, the presence of CD40 on the surface of carcinoma lines was found to be an important factor in the generation of tumour-specific T cell responses.
3T3 Cells↗
Biotransformation of trans-4,5-dihydroxy-4,5-dihydrobenzo[a]pyrene to benzo[a]pyrene bis-diols and DNA adducts by induced rat liver microsomes.
The biotransformation of (+/-)-trans-4,5-dihydroxy-4, 5-dihydrobenzo[a]pyrene (trans-B[a]P-4,5-diol), the K-region dihydrodiol of B[a]P, by beta-naphthoflavone (BNF)-induced rat liver microsomes was studied. trans-B[a]P-4,5-diol was metabolized to six major products as characterized by NMR, MS, and UV spectroscopy, and all were identified as bis-diols: two diastereomers of trans,trans-4, 5:7,8-tetrahydroxy-4,5:7,8-tetrahydrobenzo[a]pyrene (trans, trans-B[a]P-4,5:7,8-bis-diol), two diastereomers of trans,trans-4, 5:9,10-tetrahydroxy-4,5:9,10-tetrahydrobenzo[a]pyrene (trans, trans-B[a]P-4,5:9,10-bis-diol), and two diastereomers of the somewhat unusual trans,trans-1,2:4,5-tetrahydroxy-1,2:4, 5-tetrahydrobenzo[a]pyrene (trans,trans-B[a]P-1,2:4,5-bis-diol). BNF-induced rat liver microsomes also metabolized B[a]P to the same trans-B[a]P-4,5-diol-derived bis-diols. The ability of trans-B[a]P-4, 5-diol to form DNA adducts was investigated using (32)P-postlabeling techniques specifically designed to detect stable polar DNA adducts. Four DNA adducts were detected after microsomal activation of trans-B[a]P-4,5-diol with calf thymus DNA. Further analyses indicated that each of these stable polar DNA adducts was derived from the further metabolic activation of the trans,trans-B[a]P-4,5:7, 8-bis-diols. We conclude that trans-B[a]P-4,5-diol can be metabolized to a series of B[a]P-bis-diols, and can also be metabolically activated to form stable polar DNA adducts. The trans, trans-B[a]P-4,5:7,8-bis-diols were shown to be metabolic intermediates in the formation of these DNA adducts.
Animals↗
Molecular characterization of the surface of apoptotic neutrophils: implications for functional downregulation and recognition by phagocytes.
We have used a panel of monoclonal antibodies and lectins to examine the profile of surface molecule expression on human neutrophils that have undergone spontaneous apoptosis during in vitro culture. Neutrophil apoptosis was found to be accompanied by down-regulation of the immunoglobulin superfamily members PECAM-1 (CD31), ICAM-3 (CD50), CD66acde, and CD66b and the integrin-associated proteins CD63 and urokinase plasminogen activator receptor (CD87) that may alter the potential for adhesive interactions. Cellular interactions may be further influenced by the reduction of the expression of surface carbohydrate moieties, including sialic acid. Reduced expression of FcgammaRII (CD32), complement receptor type 1 (CD35) and receptors for pro-inflammatory mediators C5a (CD88) and TNFalpha (CD120b) associated with apoptosis might limit neutrophil responsiveness to stimuli that trigger degranulation responses. Although many of the receptors we have examined are expressed at reduced levels on apoptotic neutrophils, we found that there was differential loss of certain receptors (e.g. CD16, CD15 and CD120b) and increased expression of aminopeptidase-N (CD13). Together with our previous data showing that expression of certain molecules e.g. LFA-3 (CD58) is not altered during neutrophil apoptosis, these data are suggestive of specific changes in receptor mobilisation and shedding associated with apoptosis. Although reduced expression of CD63 (azurophilic granules) and CR1 (specific granules) indicates that granule mobilisation does not accompany apoptosis, a monoclonal antibody (BOB78), that recognises a 90 kDa antigen localised in intracellular granules, defines a subpopulation of apoptotic neutrophils that exhibit nuclear degradation yet retain intact plasma membranes. BOB78 positive neutrophils were found to bind biotinylated thrombospondin, suggesting that this mAb defines surface molecular changes associated with exposure of thrombospondin binding moieties.
Animals↗
A randomised controlled trial of intravenous versus inhalational analgesia during outpatient oocyte recovery.
To compare the efficacy and acceptability of conventional intravenous sedation with patient-controlled inhalational isodesox, 57 women undergoing outpatient oocyte recovery were randomly allocated to receive isodesox by face mask, while 55 women were given intravenous fentanyl and midazolam. Women's satisfaction with pain relief, peroperative pain, clouding of memory and the surgeons' assessment of operating conditions were evaluated. Thirty-eight women in the inhalation group (67%) and 41 (75%) women in the intravenous group were 'very satisfied' with their analgesia (p = 0. 41). The mean (SD) pain score in women given isodesox was 46.8 (34. 7), while in the intravenous group it was 34.1 (21.3) (p = 0.02). Oxygen saturation levels < 94% were recorded in one woman using isodesox and in 16 (29%) women given intravenous analgesia. Despite higher pain scores, in comparison with the conventional analgesia, patient-controlled isodesox offers a safer method of pain relief with comparable satisfaction rates.
Administration, Inhalation↗
Characteristics of patients with pancreatic cancer expressing a novel cancer cachectic factor.
BACKGROUND: Recently a novel tumour-derived cachectic factor was identified in the murine MAC16 colonic adenocarcinoma model of cachexia. This factor, provisionally named proteolysis-inducing factor (PIF), was subsequently identified in the urine of weight-losing patients with cancer but not in the urine of weight-stable patients with cancer or weight-losing controls with benign disease. This study determined the nutritional characteristics of patients with pancreatic cancer who excrete PIF in the urine and investigated the relationship between PIF and the acute-phase protein response. METHODS: PIF was isolated from urine by precipitation and ultrafiltration and was then identified by Western blotting of nitrocellulose membranes using a previously developed monoclonal antibody. Full nutritional assessment of patients was undertaken at the same time as urine collection. RESULTS: PIF was detected in the urine of 80 per cent of patients (n = 55). These patients had a significantly greater total weight loss and rate of weight loss than patients whose urine did not contain PIF (median 12.5 (range 4-43) kg versus 4.5 (0-14) kg; P < 0.0002). No association was evident between the presence of PIF in patients' urine and serum C-reactive protein (CRP) concentration. Furthermore, the accelerated weight loss associated with PIF expression also appeared to be independent of the acute-phase response. Overall the presence of PIF was not associated with reduced survival, although the previously reported association between raised CRP concentration and poor prognosis was confirmed. CONCLUSION: PIF is associated with an accelerated rate of weight loss in patients with a tumour of the pancreatic head. This observation appears to be independent of the effect of an increased hepatic acute-phase protein response.
Aged↗
Randomized controlled trial of the effect of early enteral nutrition on markers of the inflammatory response in predicted severe acute pancreatitis.
BACKGROUND: Recent evidence suggests that intestinal dysfunction has a role in sustaining the systemic inflammatory response in acute pancreatitis and may be ameliorated by the introduction of enteral nutrition. This study therefore assessed the effect of early enteral nutrition on the systemic inflammatory response in patients with prognostically severe acute pancreatitis. METHODS: Patients with prognostically severe acute pancreatitis within 72 h of disease onset were randomized to receive either enteral nutrition or conventional therapy consisting of a nil-by-mouth regimen. Serum interleukin (IL) 6, soluble tumour necrosis factor receptor I (sTNFRI) and C-reactive protein (CRP) were used as markers of the inflammatory response. Intestinal function was assessed using a differential sugar permeability technique. RESULTS: Of 27 patients, 13 received enteral nutrition. A median of 21 (range 0-100) per cent of calorific requirements was delivered over the first 4 days by enteral nutrition. There were no significant complications of enteral nutrition. The introduction of enteral nutrition did not affect the serum concentrations of IL-6 (P = 0.28), sTNFRI (P = 0.53) or CRP (P = 0.62) over the first 4 days of the study. Although there were no significant differences in intestinal permeability between the two patient groups at admission (chi2 = 2.33, d.f. = 1, P = 0.13), by day 4 abnormal intestinal permeability occurred more frequently in patients receiving enteral nutrition (chi2 = 4.94, d.f. = 1, P = 0.03) CONCLUSION: Early enteral nutrition did not ameliorate the inflammatory response in patients with prognostically severe acute pancreatitis. Furthermore, it did not have a beneficial effect on intestinal permeability. Presented in part to the Pancreatic Society of Great Britain and Ireland in Leeds, UK, November 1998 and at Digestive Disease Week in Orlando, Florida, USA, May 1999
Acute Disease↗
H19 and IGF-2 allele-specific expression in hepatoblastoma.
Patterns of allele-specific expression of H19 and insulin-like growth factor-2 (IGF-2) were examined in tissue obtained from 30 children diagnosed with hepatoblastoma. All informative tumours demonstrated monoallelic expression of H19. In contrast, variable patterns of allele-specific expression of IGF-2 were seen in tumours from children of different ages.
Alleles↗
A polymorphism of the interleukin-1 beta gene influences survival in pancreatic cancer.
Pro-inflammatory cytokines contribute to the cachexia associated with pancreatic cancer and stimulate the acute phase response which has been associated with shortened survival in such patients. Polymorphisms of cytokine genes may influence their production. The present study examined the effect of a polymorphism of the interleukin (IL)-1b gene upon the inflammatory state and survival in pancreatic cancer. Genomic DNA was obtained from 64 patients with pancreatic cancer and 101 healthy controls. Using the polymerase chain reaction and subsequent TaqI restriction enzyme digestion the subject's genotype for a diallelic polymorphism of the interleukin-1b gene was established. IL-1b production by peripheral blood mononuclear cells and serum C-reactive protein (CRP) levels from patients were also examined and survival noted. Patients homozygous for allele 2 of the IL-1b gene had significantly shorter survival than other groups (P = 0.0001). These patients also exhibited higher IL-1b production (P = 0.022). Possession of allele 2 was also associated with significantly shorter survival (median 144 vs 256 days, P = 0.034) and significantly higher CRP level (P = 0.0003). The possession of a genotype resulting in increased IL-1b production was associated with shortened survival and increased serum CRP level. This may reflect the role of IL-1b in inducing an acute phase protein response and cachexia in cancer or may be related to changes in tumour phenotype.
Adult↗
Liver export protein synthetic rates are increased by oral meal feeding in weight-losing cancer patients.
We have demonstrated previously that, in the fasting state, whereas albumin synthesis is similar in cachectic cancer patients compared with controls, fibrinogen synthesis is increased. Whether synthesis of these proteins is altered after an oral meal was examined in eight weight-losing pancreatic cancer patients and six healthy controls by use of an intravenous flooding dose of [(2)H(5)]- or [(2)H(8)]phenylalanine. Cancer patients had a median weight loss of 19%, a significantly lower serum albumin concentration, and a significantly higher plasma fibrinogen concentration than controls (P < 0.005). Fasting albumin synthesis rates were similar between cancer patients and controls (median total synthesis rate 11.3 vs. 13.9 g/day, respectively) and rose on feeding by a similar degree (median 29 and 24%). The fasting fibrinogen total synthetic rate was significantly higher in cancer patients than in controls (median 3.3 vs. 1.0 g/day, P = 0.0019). In cancer patients in the fed state, fibrinogen synthetic rate rose by a median of 38% (P = 0.012), whereas in controls there was no significant change. These findings demonstrate significant upregulation by feeding of acute-phase protein synthesis in cachectic cancer patients.
Adult↗
Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer.
Eicosapentaenoic acid (EPA) has been shown to modulate aspects of the inflammatory response that may contribute to weight loss in cancer. This study aimed to evaluate the acceptability and effects of oral supplementation with high-purity EPA in weight-losing patients with advanced pancreatic cancer. Twenty-six patients were entered into the study. EPA (95% pure) was administered as free acid starting at 1 g/day; the dose was increased to 6 g/day over four weeks, and then a maintenance dose of 6 g/day was administered. Patients were assessed before EPA and at 4, 8, and 12 weeks while receiving EPA, for weight, body composition, hematologic and clinical chemistry variables, acute-phase protein response, and performance status. Overall survival was noted. Supplementation was well tolerated, with only five patients experiencing side effects possibly attributable to the EPA. Before starting EPA, all patients had been losing weight at a median rate of 2 kg/mo. In general, after EPA supplementation, weight was stable. After four weeks of EPA supplementation, patients had a median weight gain of 0.5 kg (p = 0.0009 vs. rate of weight loss at baseline), and this stabilization of weight persisted over the 12-week study period. Total body water as a percentage of body weight remained stable, as did the proportion of patients with an acute-phase protein response, patients' nutritional intake, and performance status. Overall median survival from diagnosis in this study was 203 days. This study suggests that EPA is well tolerated, may stabilize weight in cachectic pancreatic cancer patients, and should be tested as an anticachectic agent in controlled trials.
Adenocarcinoma↗
Elevated levels of soluble tumor necrosis factor receptors are associated with increased mortality rates in patients who undergo operation for ruptured abdominal aortic aneurysm.
PURPOSE: Elevated levels of soluble tumor necrosis factor receptors (sTNF-Rs) are associated with multiple organ failure and increased mortality rates in critically ill patients. Paradoxically, experimental data suggest exogenous sTNF-Rs may improve outcome in patients who undergo elective abdominal aortic aneurysm (AAA) repair. This study examines, for the first time, changes in sTNF-R levels during repair of ruptured and nonruptured AAA. METHODS: Sixteen patients who underwent surgical procedures for ruptured AAA and 10 patients who underwent surgical procedures for nonruptured AAA were studied. Levels of sTNF-Rs p55 and p75 were measured before the operation and immediately before and 5 minutes, 6 hours, and 24 hours after aortic clamp release. RESULTS: When compared with nonruptured AAA, levels of sTNF-R p55 were significantly higher in ruptured AAA 5 minutes (P <.02) and 24 hours after aortic clamp release (P <.05). Levels of sTNF-R p75 were significantly higher in ruptured AAA before (P <.05), during (P <.001), and after the surgical procedure (P <.01). Six hours after aortic clamp release, sTNF-R p75 levels were significantly higher in nonsurvivors of ruptured AAA when compared with survivors (P <.05) and patients who underwent surgical procedures for nonruptured AAA (P <.01). CONCLUSION: Ruptured AAA repair is associated with increased sTNF-R expression. Furthermore, elevated levels of sTNF-R p75 are associated with increased postoperative mortality rates.
Aged↗
Metabolic response to feeding in weight-losing pancreatic cancer patients and its modulation by a fish-oil-enriched nutritional supplement.
Weight-losing patients with advanced cancer often fail to gain weight with conventional nutritional support. This suboptimal response might be explained, in part, by an increased metabolic response to feeding. It has been suggested that eicosapentaenoic acid (EPA) can modify beneficially the metabolic response to cancer. The aim of the present study was to examine the metabolic response to feeding in cancer and the effects of an EPA-enriched oral food supplement on this response. A total of 16 weight-losing, non-diabetic patients with unresectable pancreatic adenocarcinoma and six healthy, weight-stable controls were studied by indirect calorimetry in the fasting and fed states. Body composition was estimated by bioimpedence analysis. Cancer patients were then given a fish-oil-enriched nutritional supplement providing 2 g of EPA and 2550 kJ daily, and underwent repeat metabolic study after 3 weeks of such supplementation. At baseline, resting energy expenditure whether expressed per kg body weight, lean body mass or body cell mass was significantly greater in the cancer patients compared with controls. Fat oxidation was significantly higher in the fasting state in cancer patients [median 1.26 g.kg(-1).min(-1) (interquartile range 0.95-1.38)] than in controls [0.76 g.kg(-1). min(-1) (0.62-0.92); P<0.05]. Over the 4 h feeding period, changes in insulin and glucose concentrations in cancer patients suggested relative glucose intolerance. In response to oral meal feeding, the percentage change in the area under the curve of energy expenditure was significantly lower in the cancer patients [median 7.9% (interquartile range 3.4-9.0)] than in controls [12.6% (9.9-15.1); P<0.01]. After 3 weeks of the EPA-enriched supplement, the body weight of the cancer patients had increased and the energy expenditure in response to feeding had risen significantly [9.6% (6. 3-12.4)], such that it was no different from baseline healthy control values. Similarly, fasting fat oxidation fell to 1.02 g. kg(-1).min(-1) (0.8-1.18), again no longer significantly different from baseline healthy control values. While weight-losing patients with advanced pancreatic cancer have an increased resting energy expenditure and increased fat oxidation, the energy cost of feeding is, in fact, reduced. Provision of a fish-oil-enriched nutritional supplement results in some normalization of the metabolic response in both the fasted and fed states, in association with an improvement in nutritional status.
Aged↗
Glutathione S-transferase polymorphisms in children with myeloid leukemia: a Children's Cancer Group study.
GSTM1 and GSTT1 are polymorphic genes. Absence of enzyme activity is due to homozygous inherited deletion of the gene, reducing detoxification of carcinogens such as epoxides and alkylating agents and potentially increasing cancer risk. We hypothesized that GST null genotype would increase risk of acute myeloid leukemia and myelodysplasia (AML/MDS) in children. DNA was extracted from bone marrow slides of 292 AML/MDS patients. PCR amplification was used to assign GSTM1 and GSTT1 genotypes for cases and controls. Given that the frequency of the null genotype varies by ethnicity and that the majority of the cases were Caucasian, analyses were restricted to 232 white (non-Hispanic) cases and 153 Caucasian non cancer controls. The frequency of GSTM1 null was significantly increased in AML/MDS cases compared with controls [64 versus 47%; odds ratio (OR), 2.0 [95% confidence interval (CI), 1.3-3.1]; P = 0.001], whereas the frequency of GSTT1 null genotype in AML/MDS cases was not statistically different from controls. AML comprises biologically distinct subtypes, and a test for homogeneity revealed a statistically significant difference among subtypes (P = 0.04; df, 8) for GSTM1 only. In particular, there was an increased frequency of GSTM1 null genotypes in French-American-British groups M3 [82%; n = 22; OR, 5.1 (95% CI, 1.6-21.3)] and M4 [72%; n = 53; OR, 2.9 (95% CI, 1.4-6.0)]. We conclude that the GSTM1 null genotype is a significant risk factor for childhood AML, particularly French-American-British groups M3 and M4. This may indicate an important role for exogenous carcinogens in the etiology of childhood AML.
Child↗
Population density and risk of childhood acute lymphoblastic leukaemia.
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Europe↗
Genomic imprinting of H19 and insulin-like growth factor-2 in pediatric germ cell tumors.
BACKGROUND: Insulin-like growth factor-2 (IGF2) and H19 are reciprocally imprinted genes on chromosome 11; IGF2 is expressed paternally and H19 is expressed maternally. Loss of imprinting (LOI) at both H19 and IGF2 has been reported in seven fully informative adult testicular germ cell tumors (GCTs) and may contribute to germ cell carcinogenesis. METHODS: Genomic DNA from 61 pediatric GCTs was amplified by polymerase chain reaction (PCR) and screened for heterozygosity at both IGF2 and H19 using either ApaI or RsaI, respectively. If heterozygous, polyadenylated RNA was isolated and reversed-transcribed into cDNA. cDNA then was amplified by PCR and the products were digested with restriction enzymes to evaluate GCT expression of IGF2 and H19. RESULTS: Eleven pediatric GCTs were fully informative for H19 and IGF2, including 5 ovarian GCTs, 2 testicular GCTs, and 4 extragonadal GCTs. Consistent with prior studies, both testicular GCTs showed LOI at both H19 and IGF2. In contrast, three of the five ovarian GCTs had LOI at both IGF2 and H19; one had LOI at IGF2 only, and one retained imprinting at both loci. Only one of the four extragonadal GCTs had LOI at IGF2 whereas three of the four had LOI at H19. CONCLUSIONS: These data suggest that LOI at H19 and IGF2 also may be common in pediatric testicular GCTs. However, ovarian and extragonadal pediatric GCTs showed variable patterns of LOI that may indicate differences in the timing of carcinogenesis in germ cells at these sites.
Adolescent↗