Role, Extent, and Impact of Comorbidity on Prognosis and Survival in Advanced Metastatic Melanoma: A Review.

Increased incidence of comorbidity in advanced metastatic melanoma (AMM) is emerging as an important factor in patient prognosis, treatment, and survival. This paper reviews the impact of comorbidities on the prognosis and survival outcomes of patients diagnosed with AMM. Our search initially yielded limited results. We then broadened our search to include breast, colorectal, and prostate cancer and covered malignancies in which screening (like melanoma) is associated with the detection of early-stage disease. Most studies showed that a higher prevalence of comorbidity was associated with more advanced cancer stage. Both treatment and survival of patients were influenced by age and the extent of comorbidity. Racial differences in survival were greatest for patients with no comorbidities and less evident at higher levels of comorbidity. Comorbid conditions showed differential effects for prognosis, treatment, and survival. Limited Information in the literature demonstrates that more research is warranted with respect to comorbidities and AMM.

Short- and long-term exposure to low levels of pesticide and flavonoid mixtures modify endogenous antioxidants in tissues of rats.

The objective of this study was to determine if interaction between phytochemical mixtures and low level exposure to pesticides would modify tissue endogenous antioxidants in rats. Two experiments were conducted using dietary flavonoid (F) and oral pesticide (P) mixtures (FM, PM) on changes in the activities of superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione concentrations (GSH) in male Sprague Dawley rats (150-175 g) fed for 2 or 4 weeks the AIN 93M diet with or without equal amounts of quercetin, rutin, catechin (FM) at 1.0 mM or 5 mM/kg diet, and with/without PM fed orally at 0.1 mL/d/5d/wk (PM = chlorpyrifos, endosulfan, thiram at 25% LD(50) in oil). Our data indicate that (compared to corresponding Control groups): (i) While, 2 weeks of feeding reduced liver and small intestinal mucosal (IM) SOD activity in the PFM1 (PM+FM1) group, 4 weeks of feeding increased only liver SOD activity in PM, FM1, FM5 and PFM1 and PFM5 groups; (ii) Liver and IM GSH levels increased in PFM groups after 2 or 4 weeks of exposure; plasma GSH increased in the groups fed FM5 with or without PM; (iii) Liver GPX activity declined in both 2 and 4 week experiments in the FM and PFM groups, respectively. These data suggests that metabolic interaction between FM and PM, and duration of exposure, can modify endogenous antioxidants. Data also underscore the prooxidant properties of flavonoids.

Biosafety of flavonoids in rats: effects on copper and zinc homeostasis and interaction with low-level pesticide exposure.

Two 30-day experiments (36 male Sprague-Dawley rats each) were conducted to determine effect of administering flavonoid mixture (FM) with concomitant exposure to a pesticide mixture (PM) or FM at varied levels on changes in concentrations of zinc and copper in tissues. In experiment 1, PM = chlorpyrifos, endosulfan, and thiram at 25% LD(50) was dissolved in soybean (SB) oil and gavage-fed 0.1 mL 5 days/week; FM in SB oil was mixed in AIN-93M diet at 1.0 and 5.0 mM/kg diet and fed ad libitum. The groups were Control (CON), PM, FM1, FM5, PM+FM1, and PM+FM5. In experiment 2, FM in 1% polyethylene glycol was gavage-fed (0.5 mL/5 days/week), at increasing levels(mg/kg body weight); the groups were CON, FM5, FM25, FM50, FM100, and FM200. In experiment 1, PM plus FM increased tissue Cu as compared to the CON by: plasma, 16-37%; liver, 9-20%; kidney, 13-41%; small intestinal mucosa (IM), 41%; and small intestines (SI), 77%. In experiment 2, FM fed at higher levels decreased tissue Cu by: plasma, 22-36%; liver, 23%; kidney, 24-44%; IM, 17-26%; and SI, 58% and 77%, as compared to respective CON. Kidney zinc increased at higher concentrations of FM by 14-34%. These results indicate that flavonoids can modify copper homeostasis depending on whether they are fed in the diet or by gavage.

Micronuclei frequency in lymphocytes and antioxidants in the blood of traditional limited-resource farm workers exposed to pesticides.

Chronic low-level exposure to synthetic pesticides is implicated in many health conditions that result from the induction of oxidative stress, including cytogenetic damage. The objective of this study was to assess the risk of genotoxicity using micronuclei (MN) formation in lymphocytes and to determine changes in blood antioxidants superoxide dismutase (SOD) in erythrocytes (E) and glutathione (GSH) in E and plasma (PL) in farm workers for six months during a growing season. Blood and urine samples were collected once a month for six months (June to November 2003) from farm workers (n = 15) and urban unexposed controls (n = 10). Lymphocytes from blood were separated by density gradient centrifugation using Histopaque and cultured using the standard technique. There was no significant difference in the cytokinesis blocked proliferation index (CBPI) of lymphocytes between the farm workers and the control group, but there was a 76% increase in average MN frequency in lymphocytes of the farm worker group (P

Interaction between pesticides and essential metal copper increases the accumulation of copper in the kidneys of rats.

Male Sprague-Dawley rats, weighing 175-200 g, six per group were fed AIN 93M diet (CON) or diets containing 500 mg Ca (LCa), 7 mg Zn (LZn), 2 mg Cu (LCu), 60 mg Zn (HZn), or 12 mg Cu (HCu) per kilogram of diet in the following combinations: control (CON), LCa+LZn (LC+Z), LCa+LZn+LCu (LC+Z+C), or HZn+HCu (HZ+C) without or with a pesticides mixture (PM); Endosulfan, Thiram, and Acephate were added to the diets at 25% of LD50/kg. Rats were fed for 2 wk (small intestinal changes) or 4 wk (tissues changes). Plasma Zn was 47% lower than CON in the experimental groups. Plasma Cu and ceruloplasmin concomitantly decreased in the LC+Z+C group and increased with the addition of PM. Kidney Cu was 40% lower in LC+Z+C group, than CON and increased by 31% with PM; in the HZ+C+PM group, kidney Cu was 38% higher than the HZ+C group. Mucosal and small intestines Ca declined by 47% in all experimental groups; PM increased Zn in the LC+Z+C and HZ+C groups; PM further decreased intestinal and mucosal Cu retention in the LC+Z+C and HZ+C groups. Data suggest that low levels of PM in the diet can induce Cu accumulation in the kidney when dietary Zn and Cu are low or high.

Pesticides and essential minerals modify endogenous antioxidants and cytochrome P450 in tissues of rats.

Two experiments were conducted in male Sprague Dawley (SD) rats (175-200 g) to determine changes in the activities of endogenous antioxidants superoxide dismutase (SOD), glutathione peroxidase (GPX), cytochrome P450 (ethoxyresorufin deethylase; EROD) and concentrations of glutathione (GSH) in the blood, liver, and small intestinal mucosa (IM). In both experiments, six rats/group were fed diets based on the AIN-93M diet (Control) or the same modified to contain either 500 mg calcium (Low Ca), 7 mg Zn (Low Zn): 2 mg copper (Low Cu), 60 mg zinc (High Zn) or 12 mg copper (High Cu) in the following combination: Control, LCa/LZn, LCa/LZn/LCu, or HZn/HCu, with and without a pesticide mixture containing acephate, endosulfan, and thiram at 25% LD50 for four or two weeks. Pesticides decreased feed intake and weight gain in all groups by 28%. Erythrocyte SOD was higher than control in the HZn/HCu group and in the LCa/LZn/LCu and HZn/HCu groups with pesticide (P#0.05). Plasma GPX declined by more than 55% in all the groups with and without pesticides compared to the control. The LCa/LZn/LCu and HZn/HCu diets with and without pesticides reduced GPX in the IM by up to 88%, 40%, and 74%, respectively, than the control. Plasma GSH was about 20% higher than the control in most groups with and without pesticides in the diet. Liver and IM GSH were higher than the control in the HZn/HCu group, whereas IM GSH concentrations were lower than the control in the LCa/LZn and LCa/LZn/LCu groups (P#0.05). All three experimental diets with and without pesticides had a significant effect on liver EROD activity (P#0.05). The results indicate that endogenous antioxidants and EROD were independently modified by dietary zinc and copper levels and pesticides.

Exposure to low doses of endosulfan and chlorpyrifos modifies endogenous antioxidants in tissues of rats.

Two experiments were conducted in male SD rats (225-250 g) to determine changes in the activities of endogenous antioxidants superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and concentrations of glutathione (GSH) in tissues after exposure to low doses of endosulfan and chlorpyrifos using a whole body exposure technique. In both experiments, 6 rats/group were exposed 3 hr/day, 5 days/week for 30 days to: 0 (control), 5, 10, 20, 40 and 60% of LD50 of either pesticide in 50% ethanol; actual concentrations were: endosulfan = 0, 0.5, 1.0, 2.0, 4.0, 6.0 mg/250 g body weight; chlorpyrifos = 0, 1.9, 3.8, 7.6, 15.2, and 22.8 mg/250 g body weight. Endosulfan decreased erythrocyte SOD by 21% in all groups and chlorpyrifos increased SOD by 18% in groups 40 and 60. Liver SOD was 12%-20% lower after endosulfan exposure; lung SOD was altered: endosulfan decreased activity by 21% and 51% and chlorpyrifos by 58 and 75% in the 40 and 60 groups, respectively (P < or = 0.05). Both pesticides increased plasma GPX activity at lower levels and reduced it by 26% and 19% in groups 40 and 60, respectively (P < or = 0.05). Liver GPX increased in the 60 group and lung GPX declined between 20% and 38% after endosulfan exposure. GSH in the liver and lung: endosulfan reduced GSH by about 30% at lower levels and increased by 41% or 70% at higher levels; chlorpyrifos decreased GSH by 28-40% in 20 and 60 groups, respectively (P < or = 0.05). Exposure to low, increasing levels of endosulfan and chlorpyrifos can differentially modify endogenous antioxidants SOD, GPX and GSH, which may lead to the development of oxidative stress in some tissues.