Life Extension Magazine®

Issue: Dec 2011

Radiation Therapy

Mechanisms of action and antiproliferative properties of Brassica oleracea juice in human breast cancer cell lines.

Cruciferous vegetables are an important source of compounds that may be useful for chemoprevention. In this study, we evaluated the antiproliferative activity of juice obtained from leaves of several varieties of Brassica oleracea on both estrogen receptor (ER)-positive (ER+; MCF-7 and BT474) and ER-negative (ER-;MDA-MB-231 and BT20) human breast cancer cell lines. The effect of juice on cell proliferation was evaluated on DNA synthesis and on cell cycle-related proteins. Juice markedly reduced DNA synthesis, evaluated by [3H]thymidine incorporation,starting from low concentrations (final concentration 5-15 mL/L), and this activity was independent of ER. All cauliflower varieties tested suppressed cell proliferation in a dose-dependent manner. Cell growth inhibition was accompanied by significant cell death at the higher juice concentrations, although no evidence of apoptosis was found. Interestingly, the juice displayed a preferential activity against breast cancer cells compared with other mammalian cell lines investigated (ECV304, VERO, Hep2, 3T3, and MCF-10A) (P < 0.01). At the molecular level, the inhibition of proliferation was associated with significantly reduced CDK6 expression and an increased level of p27 in ER+ cells but not in ER- cells, whereas a common feature in all cell lines was significantly decreased retinoblastoma protein phosphorylation. These results suggest that the edible part of Brassica oleracea contains substances that can markedly inhibit the growth of both ER+ and ER- human breast cancer cells, although through different mechanisms. These results suggest that the widely available cruciferous vegetables are potential chemopreventive agents.

J Nutr. 2005 Jun;135(6):1503-9.

Brassica vegetables and cancer prevention. Epidemiology and mechanisms.

This paper first gives an overview of the epidemiological data concerning the cancer-preventive effect of brassica vegetables, including cabbages, kale, broccoli, Brussels sprouts, and cauliflower. A protective effect of brassicas against cancer may be plausible due to their relatively high content of glucosinolates. Certain hydrolysis products of glucosinolates have shown anticarcinogenic properties. The results of six cohort studies and 74 case-control studies on the association between brassica consumption and cancer risk are summarized. The cohort studies showed inverse associations between the consumption of brassica's and risk of lung cancer, stomach cancer, all cancers taken together. Of the case-control studies 64% showed an inverse association between consumption of one or more brassica vegetables and risk of cancer at various sites. Although the measured effects might have been distorted by various types of bias, it is concluded that a high consumption of brassica vegetables is associated with a decreased risk of cancer. This association appears to be most consistent for lung, stomach, colon and rectal cancer, and least consistent for prostatic, endometrial and ovarian cancer. It is not yet possible to resolve whether associations are to be attributed to brassica vegetables per se or tovegetables in general. Further epidemiological research should separate the anticarcinogenic effect of brassica vegetables from the effect of vegetables in general. The mechanisms by which brassica vegetables might decrease the risk of cancer are reviewed in the second part of this paper. Brassicas, including all types of cabbages, broccoli, cauliflower, and Brussels sprouts, may be protective against cancer due to their glucosinolate content. Glucosinolates are usually broken down through hydrolysis catalysed by myrosinase, an enzyme that is released from damaged plant cells. Some of the hydrolysis products, viz. indoles, and isothiocyanates, are able to influence phase 1 and phase 2 biotransformation enzyme activities, thereby possibly influencing several processes related to chemical carcinogenesis, e.g. the metabolism, DNA-binding, and mutagenic activity of promutagens. Most evidence concerning anticarcinogenic effects of glucosinolate hydrolysis products and brassica vegetables has come from studies in animals. In addition, studies carried out in humans using high but still realistic human consumption levels of indoles and brassica vegetables have shown putative positive effects on health. The combination of epidemiological and experimental data provide suggestive evidence for a cancer preventive effect of a high intake of brassica vegetables.

Adv Exp Med Biol. 1999;472:159-68.

Breast cancer risk in premenopausal women is inversely associated with consumption of broccoli, a source of isothiocyanates, but is not modified by GST genotype.

The role of vegetable consumption in relation to breast cancer risk is controversial. Anticarcinogenic compounds may be present only in specific vegetables, thereby attenuating findings for total vegetable intake. Cruciferous vegetables contain precursors of isothiocyanates (ITCs), which may be chemopreventive through potent inhibition of phase I, and induction of phase II enzymes, such as glutathione S-transferases (GSTs). We investigated associations between consumption of cruciferous vegetables, sources of ITCs, and breast cancer risk, and potential modification of relations by GSTM1 and GSTT1 genotypes. Cases (n = 740) were Caucasian women with incident breast cancer identified from all major hospitals in Erie and Niagara counties. Community controls (n = 810) were frequency matched to cases by age and county. An in-depth interview including a validated FFQ was administered in person. Odds ratios (ORs) and 95% CIs were used to estimate relative risks. Consumption of cruciferous vegetables, particularly broccoli, was marginally inversely associated with breast cancer risk in premenopausal women [4th quartile OR = 0.6, 95% CI (0.40-1.01), P = 0.058]. Associations were weaker or null among postmenopausal women. No significant effects of GST genotype on risk were observed in either menopausal group. These data indicate that cruciferous vegetables may play an important role in decreasing the risk of premenopausal breast cancer.

J Nutr. 2004 May;134(5):1134-8.

Olive oil and health: summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008.

Olive oil (OO) is the most representative food of the traditional Mediterranean Diet (MedDiet). Increasing evidence suggests that monounsaturated fatty acids (MUFA) as a nutrient, OO as a food, and the MedDiet as a food pattern are associated with a decreased risk of cardiovascular disease, obesity, metabolic syndrome, type 2 diabetes and hypertension. A MedDiet rich in OO and OO per se has been shown to improve cardiovascular risk factors, such as lipid profiles, blood pressure, postprandial hyperlipidemia, endothelial dysfunction, oxidative stress, and antithrombotic profiles. Some of these beneficial effects can be attributed to the OO minor components. Therefore, the definition of the MedDiet should include OO. Phenolic compounds in OO have shown antioxidant and anti-inflammatory properties, prevent lipoperoxidation, induce favorable changes of lipid profile, improve endothelial function, and disclose antithrombotic properties. Observational studies from Mediterranean cohorts have suggested that dietary MUFA may be protective against age-related cognitive decline and Alzheimer's disease. Recent studies consistently support the concept that the OO-rich MedDiet is compatible with healthier aging and increased longevity. In countries where the population adheres to the MedDiet, such as Spain, Greece and Italy, and OO is the principal source of fat, rates of cancer incidence are lower than in northern European countries. Experimental and human cellular studies have provided new evidence on the potential protective effect of OO on cancer. Furthermore, results of case-control and cohort studies suggest that MUFA intake including OO is associated with a reduction in cancer risk (mainly breast, colorectal and prostate cancers).

Nutr Metab Cardiovasc Dis. 2010 May;20(4):284-94.

The role of virgin olive oil components in the modulation of endothelial function.

The endothelium is involved in many of the processes related to the development of atherosclerosis, which is considered an inflammatory disease. Actually, traditional risk factors for atherosclerosis predispose to endothelial dysfunction, which is manifested as an increase in the expression of specific cytokines and adhesion molecules. There are firm evidence supporting the beneficial effects of olive oil, the most genuine component of the Mediterranean diet. Although the effects of olive oil and other oleic acid-rich dietary oils on atherosclerosis and plasma lipids are well known, the roles of minor components have been less investigated. Minor components constitute only 1-2% of virgin olive oil (VOO) and are composed of hydrocarbons, polyphenols, tocopherols, sterols, triterpenoids and other components usually found in traces. Despite their low concentration, non-fatty acid constituents may be of importance because studies comparing monounsaturated dietary oils have reported different effects on cardiovascular disease. Most of these compounds have demonstrated antioxidant, anti-inflammatory and hypolipidemic properties. In this review, we summarize current knowledge on the effects of these compounds contained in VOO on vascular dysfunction and the mechanisms by which they modulate endothelial activity. Such mechanisms involve the release of nitric oxide, eicosanoids (prostaglandins and leukotrienes) and adhesion molecules, in most cases by activation of nuclear factor kappaB by reactive oxygen species.

J Nutr Biochem. 2006 Jul;17(7):429-45.

Intake of carrots, spinach, and supplements containing vitamin A in relation to risk of breast cancer.

Intake of fruits, vegetables, vitamin A, and related compounds are associated with a decreased risk of breast cancer in some studies, but additional data are needed. To estimate intake of beta-carotene and vitamin A, the authors included nine questions on food and supplement use in a population-based case-control study of breast cancer risk conducted in Maine, Massachusetts, New Hampshire, and Wisconsin in 1988-1991. Multivariate-adjusted models were fit to data for 3,543 cases and 9,406 controls. Eating carrots or spinach more than twice weekly, compared with no intake, was associated with an odds ratio of 0.56 (95% confidence interval 0.34-0.91). Estimated intake of preformed vitamin A from all evaluated foods and supplements showed no trend or monotonic decrease in risk across categories of intake. These data do not allow us to distinguish among several potential explanations for the protective association observed between intake of carrots and spinach and risk of breast cancer. The findings are, however, consistent with a diet rich in these foods having a modest protective effect.

Cancer Epidemiol Biomarkers Prev. 1997 Nov;6(11):887-92.

The protective effects of garlic extract against acetaminophen-induced oxidative stress and glutathione depletion.

Acetaminophen, the most commonly sold over-the-counter antipyretic analgesic, is capable of causing severe and sometimes fatal hepatic damage in humans and experimental animals. The incidence of liver injury due to acetaminophen overdose, either with suicidal intent or by accident, is increasing. Garlic is among those medicinal plants famous for its different health protective effects. In this study, the protective effects of garlic extract on acute acetaminophen-induced liver injury were investigated using freshly isolated rat hepatocytes. The hepatocytes were isolated from Sprague-Dawley male rats by a two step collagenase model. Formation of Reactive Oxygen Species (ROS) and Glutathione (GSH) depletion were studied after addition of acetaminophen to cell suspensions. The effects of garlic extract on prevention of ROS formation as well as GSH depletion was investigated and compared with the effects of N-Acetyl Cysteine (NAC) as the standard treatment. Reactive oxygen species formation was assessed by a spectrofluorometry method and garlic extract was shown to be as effective as NAC in decreasing ROS formation induced by acetaminophen. Glutathione (GSH) levels of hepatocytes were determined using HPLC. Garlic extract was effective in preventing GSH depletion significantly (p < 0.05). It is concluded that garlic extract has an antioxidant effect and can protect hepatocytes from GSH depletion following NAPQI production.

Pak J Biol Sci. 2009 May 15;12(10):765-71.

The aqueous extract of Asparagus officinalis L. by-product exerts hypoglycaemic activity in streptozotocin-induced diabetic rats.

BACKGROUND: The inedible bottom part of asparagus (Asparagus officinalis L.) spears, around one-third to one-half of the total length, is always discarded as by-product. Since it still contains various bioactive substances, this by-product might have potential usage in food supplements for its therapeutic effects. In this study the hypoglycaemic effect of the aqueous extract of asparagus by-product (AEA) was evaluated in a streptozotocin (STZ)-induced diabetic rat model. RESULTS: Continuous administration of AEA for 21 days significantly decreased fasting serum glucose and triglyceride levels but markedly increased body weight and hepatic glycogen level in diabetic rats. In an oral glucose tolerance test, both the blood glucose level measured at 30, 60 and 120 min after glucose loading and the area under the glucose curve showed a significant decrease after AEA treatment. CONCLUSION: The results of this study demonstrate that AEA has hypoglycaemic and hypotriglyceridaemic functions, suggesting that it might be useful in preventing diabetic complications associated with hyperglycaemia and hyperlipidaemia.

J Sci Food Agric. 2011 Aug 30;91(11):2095-9.

The effects of essential oils and aqueous tea infusions of oregano (Origanum vulgare L. spp. hirtum), thyme (Thymus vulgaris L.) and wild thyme (Thymus serpyllum L.) on the copper-induced oxidation of human low-density lipoproteins.

In this study, the antioxidative capacity effect of essential oils and aqueous tea infusions obtained from oregano, thyme and wild thyme on the oxidation susceptibility of low-density lipoproteins (LDL) has been studied. The results indicate a dose-dependent protective effect of the tested essential oils and aqueous tea infusions on the copper-induced LDL oxidation. The protective effect of essential oils is assigned to the presence of phenolic monoterpenes, thymol and carvacrol, which are identified as the dominant compounds in these essential oils. The strong protective effect of aqueous tea infusions is proposed to be the consequence of large amounts of polyphenols, namely rosmarinic acid and flavonoids (quercetin, eriocitrin, luteolin-7-O-glucoside, apigenin-7-O-glucoside, luteolin, apigenin), with the most pronounced effect in the case of oregano. These findings may have implications for the effect of these compounds on LDL in vivo.

Int J Food Sci Nutr. 2007 Mar;58(2):87-93.

Indole-3-carbinol and 3,3'-diindolylmethane induce apoptosis in human prostate cancer cells.

Cruciferous vegetables contain glucobrassicin which, during metabolism, yields indole-3-carbinol (I3C). In a low pH environment I3C is converted into polymeric products, among which 3,3'-diindolylmethane (DIM) is the main one. The apoptotic effects of I3C and DIM were exhibited in human breast cancer cells. The objectives of this study were: (a) examination of the potential effects of I3C and DIM on the proliferation and induction of apoptosis in human prostate cancer cell lines with different p53 status; (b) to try to characterise the mechanism(s) involved in these effects. Our results indicate that both indole derivatives suppress the growth of these cells in a dose- and time-dependent manner, by inducing apoptosis. It appears that these indolic compounds may offer effective means against prostate cancer. Induction of apoptosis was p53-independent. Moreover, the indole derivatives employed did not affect the levels of bcl-2, bax and fasL.

Food Chem Toxicol. 2003 Jun;41(6):745-52.

Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study.

OBJECTIVE: To compute the burden of cancer attributable to current and former alcohol consumption in eight European countries based on direct relative risk estimates from a cohort study. DESIGN: Combination of prospective cohort study with representative population based data on alcohol exposure. Setting Eight countries (France, Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Denmark) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. PARTICIPANTS: 109,118 men and 254,870 women, mainly aged 37-70. MAIN OUTCOME MEASURES: Hazard rate ratios expressing the relative risk of cancer incidence for former and current alcohol consumption among EPIC participants. Hazard rate ratios combined with representative information on alcoholconsumption to calculate alcohol attributable fractions of causally related cancers by country and sex. Partial alcohol attributable fractions for consumption higher than the recommended upper limit (two drinks a day for men with about 24 g alcohol, one for women with about 12 g alcohol) and the estimated total annual number of cases of alcohol attributable cancer. RESULTS: If we assume causality, among men and women, 10% (95% confidence interval 7 to 13%) and 3% (1 to 5%) of the incidence of total cancer was attributable to former and current alcohol consumption in the selected European countries. For selected cancers the figures were 44% (31 to 56%) and 25% (5 to 46%) for upper aerodigestive tract, 33% (11 to 54%) and 18% (-3 to 38%) for liver, 17% (10 to 25%) and 4% (-1 to 10%) for colorectal cancer for men and women, respectively, and 5.0% (2 to 8%) for female breast cancer. A substantial part of the alcohol attributable fraction in 2008 was associated with alcohol consumption higher than the recommended upper limit: 33,037 of 178,578 alcohol related cancer cases in men and 17,470 of 397,043 alcohol related cases in women. CONCLUSIONS: In western Europe, an important proportion of cases of cancer can be attributable to alcohol consumption, especially consumption higher than the recommended upper limits. These data support current political efforts to reduce or to abstain from alcohol consumption to reduce the incidence of cancer.

BMJ. 2011 Apr 7;342:d1584.

DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis.

Alcoholic beverage consumption is classified as a known human carcinogen, causally related to an increased risk of cancer of the upper gastrointestinal tract. The formation of acetaldehyde from ethanol metabolism seems to be the major mechanism underlying this effect. Acetaldehyde is carcinogenic in rodents and causes sister chromatid exchanges and chromosomal aberrations in human cells. The best-studied DNA adduct from acetaldehyde is N(2)-ethyl-2'-deoxyguanosine, which is increased in liver DNA obtained from ethanol-treated rodents and in white blood cells obtained from human alcohol abusers. However, the carcinogenic relevance of this adduct is unclear in view of the lack of evidence that it is mutagenic in mammalian cells. A different DNA adduct, 1,N(2)-propano-2'-deoxyguanosine (PdG), can also be formed from acetaldehyde in the presence of histones and other basic molecules. PdG has been shown to be responsible for the genotoxic and mutagenic effects of crotonaldehyde. The PdG adduct can exist in either of two forms: a ring-closed form or a ring-opened aldehyde form. Whereas the ring-closed form is mutagenic, the aldehyde form can participate in the formation of secondary lesions, including DNA-protein cross-links and DNA interstrand cross-links. The formation of these types of complex secondary DNA lesions resulting from PdG may explain many of the observed genotoxic effects of acetaldehyde described above. Repair of PdG and its associated adducts is complex, involving multiple pathways. Inherited variation in the genes encoding the proteins involved in the repair of PdG and its secondary adducts may contribute to susceptibility to alcoholic beverage-related carcinogenesis.

Alcohol. 2005 Apr;35(3):187-93.

The pathology of alcohol hangover.

Research on human subjects analyzing blood and urine samples determined biological correlates that may explain the pathology of alcohol hangover. These analyses showed that concentrations of various hormones, electrolytes, free fatty acids, triglycerides, lactate, ketone bodies, cortisol, and glucose were not significantly correlated with reported alcohol hangover severity. Also, markers of dehydration (e.g., vasopressin) were not significantly related to hangover severity. Some studies report a significant correlation between blood acetaldehyde concentration and hangover severity, but most convincing is the significant relationship between immune factors and hangover severity. The latter is supported by studies showing that hangover severity may be reduced by inhibitors of prostaglandin synthesis. Several factors do not cause alcohol hangover but can aggravate its severity. These include sleep deprivation, smoking, congeners, health status, genetics and individual differences. Future studies should more rigorously study these factors as well as biological correlates to further elucidate the pathology of alcohol hangover.

Curr Drug Abuse Rev. 2010 Jun;3(2):68-75.

Folate, methionine, and alcohol intake and risk of colorectal adenoma.

BACKGROUND: Reduced methylation of DNA may contribute to loss of the normal controls on proto-oncogene expression. In humans, hypomethylation of DNA has been observed in colorectal cancers and in their adenomatous polyp precursors. Accumulation of DNA methylation abnormalities, observed during progression of human colorectal neoplasia, may be influenced by certain dietary factors. The apparent protective effect of fresh fruits and vegetables, the major folate sources, on colorectal cancer incidence suggests that a methyl-deficient diet contributes to occurrence of this malignancy. Low dietary folate and methionine and high intake of alcohol may reduce levels of S-adenosylmethionine, which is required for DNA methylation. PURPOSE: To determine if dietary factors that may influence methyl availability are related to colorectal adenomas, we prospectively examined the association of folate, methionine, and alcohol intakes and risk of colorectal adenoma. METHODS: We assessed dietary intake for a 1-year period for women of the Nurses' Health Study, started in 1976, and for men of the Health Professionals Follow-up Study, started in 1986--using a semiquantitative food frequency questionnaire. Adenomatous polyps of the left colon or rectum were diagnosed in 564 of 15,984 women who had had an endoscopy between 1980 and 1990 and in 331 of 9,490 men who had undergone an endoscopy between 1986 and 1990. RESULTS: High dietary folate was inversely associated with risk of colorectal adenoma in women (multivariate relative risk [RR] = 0.66; 95% confidence interval [CI] = 0.46-0.95 between high and low quintiles of intake) and in men (RR = 0.63; 95% CI = 0.41-0.98) after adjusting for age, family history, indications for endoscopy, history of previous endoscopy, total energy intake, saturated fat intake, dietary fiber, and body mass index. Relative to nondrinkers, drinkers of more than 30 g of alcohol daily (about two drinks) had an elevated risk of adenoma (in women, RR = 1.84, 95% CI = 1.19-2.86; in men, RR = 1.64, 95% CI = 0.92-2.93). Methionine intake was inversely associated with risk of adenomas 1 cm or larger (RR = 0.62; 95% CI = 0.46-0.85, combining men and women). CONCLUSIONS: Folate, alcohol, and methionine could influence methyl group availability, and a methyl-deficient diet may be linked to early stages of colorectal neoplasia. A dietary pattern that increases methyl availability could reduce incidence of colorectal cancer. IMPLICATIONS: These data support efforts to increase dietary folate in segments of the population having diets with low intakes of this nutrient.

J Natl Cancer Inst. 1993 Jun 2;85(11):875-84.

Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women.

Low B-vitamin intake may increase risk of breast cancer through decreased DNA repair capacity. Alcohol intake increases risk for breast cancer, with evidence from prospective studies of an interaction between alcohol and folate. We explored dietary intake of folate and other B vitamins with risk of breast cancer in a cohort study of 34,387 postmenopausal women. To measure diet, we mailed a food frequency questionnaire; we estimated nutrient intakes and categorized them into four levels: <10th, 11th-30th, 31st-50th, and >50th percentiles. Through 12 years of follow-up, we identified 1,586 cases of breast cancer in the cohort at risk. We estimated relative risks (RRs) and 95% confidence intervals (CIs) through Cox regression models adjusted for age, energy, and other risk factors. Women in the lowest 10th percentile of folate intake from diet alone were at modestly increased risk of breast cancer relative to those above the 50th percentile: RR = 1.21 (95% CI = 0.91--1.61). We examined the joint association of folate intake and alcohol use on risk of breast cancer, with the reference group defined as women with high folate (>50th percentile) and no alcohol use. The RRs of breast cancer associated with low dietary folate intake were 1.08 (95% CI = 0.78--1.49) among nondrinkers, 1.33 (95% CI = 0.86--2.05) among drinkers of < or = 4 gm per day, and 1.59 (95% CI = 1.05--2.41) among drinkers of > 4 gm per day. These results suggest that the risks of postmenopausal breast cancer may be increased among women with low intakes of folate if they consume alcohol-containing beverages.

Epidemiology. 2001 Jul;12(4):420-8.

Inhibition of inflammation and carcinogenesis in the lung and colon by tocopherols.

Tocopherols, which exist in alpha, beta, gamma, and delta forms, are antioxidative nutrients also known as vitamin E. Although alpha-tocopherol (alpha-T) is the major form of vitamin E found in the blood and tissues, gamma- and delta-T have been suggested to have stronger anti-inflammatory activities. In the present study, using a tocopherol mixture that is rich in gamma-T (gamma-TmT, which contains 57%gamma-T), we demonstrated the inhibition of inflammation as well as of cancer formation and growth in the lung and colon in animal models. When given in the diet at 0.3%, gamma-TmT inhibited chemically induced lung tumorigenesis in the A/J mice as well as the growth of human lung cancer cell H1299 xenograft tumors. gamma-TmT also decreased the levels of 8-hydroxydeoxyguanosine, gamma-H2AX, and nitrotyrosine in tumors. More evident anti-inflammatory and cancer preventive activities of dietary gamma-TmT were demonstrated in mice treated with azoxymethane and dextran sulfate sodium. These results demonstrate the antioxidative, anti-inflammatory, and anticarcinogenic activities of tocopherols.

Ann N Y Acad Sci. 2010 Aug;1203:29-34.

The multifaceted therapeutic potential of benfotiamine.

Thiamine, known as vitamin B(1), plays an essential role in energy metabolism. Benfotiamine (S-benzoylthiamine O-monophoshate) is a synthetic S-acyl derivative of thiamine. Once absorbed, benfotiamine is dephosphorylated by ecto-alkaline phosphatase to lipid-soluble S-benzoylthiamine. Transketolase is an enzyme that directs the precursors of advanced glycation end products (AGEs) to pentose phosphate pathway. Benfotiamine administration increases the levels of intracellular thiamine diphosphate, a cofactor necessary for the activation transketolase, resulting in the reduction of tissue level of AGEs. The elevated level of AGEs has been implicated in the induction and progression of diabetes-associated complications. Chronic hyperglycemia accelerates the reaction between glucose and proteins leading to the formation of AGEs, which form irreversible cross-links with many macromolecules such as collagen. In diabetes, AGEs accumulate in tissues at an accelerated rate. Experimental studies have elucidated that binding of AGEs to their specific receptors (RAGE) activates mainly monocytes and endothelial cells and consequently induces various inflammatory events. Moreover, AGEs exaggerate the status of oxidative stress in diabetes that may additionally contribute to functional changes in vascular tone control observed in diabetes. The anti-AGE property of benfotiamine certainly makes it effective for the treatment of diabetic neuropathy, nephropathy and retinopathy. Interestingly, few recent studies demonstrated additional non-AGE-dependent pharmacological actions of benfotiamine. The present review critically analyzed the multifaceted therapeutic potential of benfotiamine.

Pharmacol Res. 2010 Jun;61(6):482-8.

In vivo antioxidant activity of procyanidin-rich extracts from grape seed and pine (Pinus maritima) bark in rats.

BACKGROUND: In vitro evidence exists for the potential antioxidant benefits of procyanidin-rich extracts, but in vivo studies are scarce. We have evaluated the effects of selected procyanidin-rich extracts on oxidative stress in rats in condition of prolonged consumption of these compounds and also after single administration i.e. in postprandial conditions. METHODS: Rats were fed for 8 weeks with diets supplemented with either a grape seed extract (GE), a pine bark extract (PE), or a high-degree polymerized pine bark extract (HPE). An additional study was performed in order to assess the postprandial effect of these extracts on plasma antioxidant capacity. The ferric-reducing antioxidant power (FRAP) and thiobarbituric acid-reactive substances (TBARS) were determined in plasma. For lipid peroxidation study of heart tissue, homogenates were prepared and TBARS were measured after lipid peroxidation induced by FeSO4-ascorbate. RESULTS: After 8 weeks of dietary treatment, total antioxidant capacity in plasma was significantly higher in the GE and PE groups as compared with the other two groups. Plasma TBARS concentrations and heart susceptibility to peroxidation were not significantly different between the groups. In the postprandial state, by comparing plasma antioxidant capacity 2 hours after ingestion of the different procyanidin-rich extracts (500 mg/kg body weight), we observed that FRAP values were higher in the procyanidin-rich extracts groups as compared with the control group. Moreover, plasma FRAP concentration was significantly higher in the GE group as compared with the other groups. CONCLUSION: The results of the present experiment constitute positive evidence for an in vivo antioxidant effect at the plasma level of procyanidin-containing plant extracts.

Int J Vitam Nutr Res. 2006 Jan;76(1):22-7.

Silymarin in the treatment of chronic liver diseases: past and future.

In the treatment of chronic liver diseases adequate therapy can be chosen only in the knowledge of pathogenetic processes. In the liver diseases caused by oxidative stress (alcoholic and non-alcoholic fatty liver and steatohepatitis, drug and compound induced liver toxicity) the antioxidant drugs, like silymarin, in chronic hepatitis caused by hepatitis B and hepatitis C virus, combined peginterferon and nucleosid treatments are the primary therapy modalities to be selected. The main effects of silymarin are the membrane stabilising and antioxidant effects, it is able to help the liver cell regeneration, it can decrease the inflammatory reaction and inhibit the fibrogenesis in the liver. These results have been established by experimental and clinical trials. According to open studies, the long administration of silymarin significantly increased the survival time of patients with alcohol-induced liver cirrhosis. Recently it was demonstrated that high-dosage silibinin infusion treatment could significantly decrease the number of hepatitis C viruses after four-week application. On the basis of the results with the methods of molecular biology, silymarin is able to decrease significantly tumor cell proliferation, angiogenesis as well as insulin resistance. These results support the administration of silymarin preparations in the therapy of chronic liver diseases, especially in alcoholic and non-alcoholic steatohepatitis in current clinical practice, and as it can be awaited, also in the future. In some neoplastic diseases they could also be administered as adjuvant therapy.

Orv Hetil. 2008 Dec 21;149(51):2413-8.

Chlorophyll, chlorophyllin and related tetrapyrroles are significant inducers of mammalian phase 2 cytoprotective genes.

Plant chlorophylls and carotenoids are highly colored, conjugated polyenes that play central roles in photosynthesis. Other porphyrins (tetrapyrroles), such as cytochromes, which are structurally related to chlorophyll, participate in redox reactions in many living systems. An unexpected new property of tetrapyrroles, including tetramethyl coproporphyrin III, tetrabenzoporphine, copper chlorin e4 ethyl ester, and of carotenoids including zeaxanthin and alpha-cryptoxanthin is their ability to induce mammalian phase 2 proteins that protect cells against oxidants and electrophiles. The capacity of these compounds to induce the phase 2 response depends upon their ability or that of their metabolites to react with thiol groups, a property shared with all other classes of phase 2 inducers, which show few other structural similarities. Pseudo second-order rate constants of these inducers are correlated with their potency in inducing the phase 2 enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) in murine hepatoma cells. One of the most potent inducers was isolated from chlorophyllin, a semisynthetic water-soluble chlorophyll derivative. Although chlorophyll itself is low in inducer potency, it may nevertheless account for some of the disease-protective effects attributed to diets rich in green vegetables because it occurs in much higher concentrations in those plants than the widely studied 'phytochemicals.'

Carcinogenesis. 2005 Jul;26(7):1247-55.

Long-term calorie restriction, but not endurance exercise, lowers core body temperature in humans.

Reduction of body temperature has been proposed to contribute to the increased lifespan in calorie restricted animals and mice overexpressing the uncoupling protein-2 in hypocretin neurons. However, nothing is known regarding the long-term effects of calorie restriction (CR) with adequate nutrition on body temperature in humans. In this study, 24-hour core body temperature was measured every minute by using ingested telemetric capsules in 24 men and women (mean age 53.7 ± 9.4 yrs) consuming a CR diet for an average of 6 years, 24 age- and sex-matched sedentary (WD) and 24 body fat-matched exercise-trained (EX) volunteers, who were eating Western diets. The CR and EX groups were significantly leaner than the WD group. Energy intake was lower in the CR group (1769 ± 348 kcal/d) than in the WD (2302 ± 668 kcal/d) and EX (2798 ± 760 kcal/d) groups (P < 0.0001). Mean 24-hour, day-time and night-time core body temperatures were all significantly lower in the CR group than in the WD and EX groups (P ≤ 0.01). Long-term CR with adequate nutrition in lean and weight-stable healthy humans is associated with a sustained reduction in core body temperature, similar to that found in CR rodents and monkeys. This adaptation is likely due to CR itself, rather than to leanness, and may be involved in slowing the rate of aging.

Aging (Albany NY). 2011 Apr;3(4):374-9.

Effect of chronic caloric restriction on physiological variables related to energy metabolism in the male Fischer 344 rat.

In the present study, a number of physiological and behavioral measures that are related to metabolism were continuously monitored in 19-month-old male Fischer 344 rats that were fed ad libitum or fed a caloric restricted diet. Caloric restricted rats ate fewer meals but consumed more food during each meal and spent more time eating per meal than did rats fed ad libitum. Therefore, the timing and duration of meals as well as the total number of calories consumed may be associated with life extension. Average body temperature per day was significantly lower in restricted rats but body temperature range per day and motor activity were higher in restricted rats. Dramatic changes in respiratory quotient, indicating rapid changes in metabolic pathway and lower temperature, occurred in caloric restricted rats when carbohydrate reserves were depleted. Lower body temperature and metabolism during this time interval may result in less DNA damage, thereby increasing the survival potential of restricted rats. Nighttime feeding was found to synchronize physiological performance between ad libitum and caloric restricted rats better than daytime feeding, thereby allowing investigators to distinguish the effects of caloric restriction from those related solely to the time-of-day of feeding.

Mech Ageing Dev. 1989 May;48(2):117-33.

Effect of chronic caloric restriction on the circadian regulation of physiological and behavioral variables in old male B6C3F1 mice.

The circadian rhythms of food and water consumption, the number of feeding anddrinking episodes, oxygen consumption, carbon dioxide production, respiratory quotient, gross motor activity, and body temperature were measured in male B6C3F1 mice that were fed ad libitum (AL) or fed a caloric-restricted diet (CR). The CR regimen (60% of the normal AL consumption) was fed to mice during the daytime (5 hr after lights on). CR animals exhibited fewer feeding episodes but consumed more food per feeding bout and spent more total time feeding than AL mice. It appears that CR caused mice to change from their normal "nibbling behavior" to meal feeding. Compared to AL animals, the mean body temperature was reduced in CR animals, while the amplitude of the body temperature rhythm was increased. Spans of reduced activity, metabolism, and body temperature (torpor) occurred in CR mice for several hours immediately before feeding, during times of high fatty acid metabolism (low RQ). The acute availability of exogenous substrates (energy supplies) seemed to modulate metabolism shifting metabolic pathways to promote energy efficiency. CR was also associated with lower DNA damage, higher DNA repair, and decreased proto-oncogene expression. Most of the circadian rhythms studied seemed to be synchronized primarily to the feeding rather than the photoperiod cycle. Night-time CR feeding was found to be better than daytime feeding because the circadian rhythms for AL and AR animals were highly synchronized when this regimen was used.

Chronobiol Int. 1990;7(4):291-303.

Calorie restriction lowers body temperature in rhesus monkeys, consistent with a postulated anti-aging mechanism in rodents.

Many studies of caloric restriction (CR) in rodents and lower animals indicate that this nutritional manipulation retards aging processes, as evidenced by increased longevity, reduced pathology, and maintenance of physiological function in a more youthful state. The anti-aging effects of CR are believed to relate, at least in part, to changes in energy metabolism. We are attempting to determine whether similar effects occur in response to CR in nonhuman primates. Core (rectal) body temperature decreased progressively with age from 2 to 30 years in rhesus monkeys fed ad lib (controls) and is reduced by approximately 0.5 degrees C in age-matched monkeys subjected to 6 years of a 30% reduction in caloric intake. A short-term (1 month) 30% restriction of 2.5-year-old monkeys lowered subcutaneous body temperature by 1.0 degrees C. Indirect calorimetry showed that 24-hr energy expenditure was reduced by approximately 24% during short-term CR. The temporal association between reduced body temperature and energy expenditure suggests that reductions in body temperature relate to the induction of an energyconservation mechanism during CR. These reductions in body temperature and energy expenditure are consistent with findings in rodent studies in which aging rate was retarded by CR, now strengthening the possibility that CR may exert beneficial effects in primates analogous to those observed in rodents.

Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4159-64.

Caloric restriction, the traditional Okinawan diet, and healthy aging: the diet of the world's longest-lived people and its potential impact on morbidity and life span.

Long-term caloric restriction (CR) is a robust means of reducing age-related diseases and extending life span in multiple species, but the effects in humans are unknown. The low caloric intake, long life expectancy, and the high prevalence of centenarians in Okinawa have been used as an argument to support the CR hypothesis in humans. However, no long-term, epidemiologic analysis has been conducted on traditional dietary patterns, energy balance, and potential CR phenotypes for the specific cohort of Okinawans who are purported to have had a calorically restricted diet. Nor has this cohort's subsequent mortality experience been rigorously studied. Therefore, we investigated six decades of archived population data on the elderly cohort of Okinawans (aged 65-plus) for evidence of CR. Analyses included traditional diet composition, energy intake, energy expenditure, anthropometry, plasma DHEA, mortality from age-related diseases, and current survival patterns. Findings include low caloric intake and negative energy balance at younger ages, little weight gain with age, life-long low BMI, relatively high plasma DHEA levels at older ages, low risk for mortality from age-related diseases, and survival patterns consistent with extended mean and maximum life span. This study lends epidemiologic support for phenotypic benefits of CR in humans and is consistent with the well-known literature on animals with regard to CR phenotypes and healthy aging.

Ann N Y Acad Sci. 2007 Oct;1114:434-55.

Circulating androgens in women: exercise-induced changes.

Physical exercise is known to strongly stimulate the endocrine system in both sexes. Among these hormones, androgens (e.g. testosterone, androstenedione, dehydroepiandrosterone) play key roles in the reproductive system, muscle growth and the prevention of bone loss. In female athletes, excessive physical exercise may lead to disorders, including delay in the onset of puberty, amenorrhoea and premature osteoporosis. The free and total fractions of circulating androgens vary in response to acute and chronic exercise/training (depending on the type), but the physiological role of these changes is not completely understood. Although it is commonly accepted that only the free fraction of steroids has a biological action, this hypothesis has recently been challenged. Indeed, a change in the total fraction of androgen concentration may have a significant impact on cells (inducing genomic or non-genomic signalling). The purpose of this review, therefore, is to visit the exercise-induced changes in androgen concentrations and emphasize their potential effects on female physiology. Despite some discrepancies in the published studies (generally due to differences in the types and intensities of the exercises studied, in the hormonal status of the group of women investigated and in the methods for androgen determination), exercise is globally able to induce an increase in circulating androgens. This can be observed after both resistance and endurance acute exercises. For chronic exercise/training, the picture is definitely less clear and there are even circumstances where exercise leads to a decrease of circulating androgens. We suggest that those changes have significant impact on female physiology and physical performance.

Sports Med. 2011 Jan 1;41(1):1-15.

Exercise alleviates Parkinsonism: clinical and laboratory evidence.

The present review examines the putative benefits for individuals afflicted with Parkinsonism, whether in the clinical setting or in the animal laboratory, accruing from different exercise regimes. The tendency for patients with Parkinson's disease (PD) to express either normal or reduced exercise capacity appears regulated by factors such as fatigue, quality-of-life and disorder severity. The associations between physical exercise and risk for PD, the effects of exercise on idiopathic Parkinsonism and quality-of-life, the effects of exercise on animal laboratory models of Parkinsonism and dopamine (DA) loss following neurotoxic insults, and the effects of exercise on the DA precursor, L-Dopa, efficacy are examined. It would appear to be case that in view of the particular responsiveness of the dopaminergic neurons to exercise, the principle of 'use it or lose' may be of special applicability among PD patients.

Acta Neurol Scand. 2011 Feb;123(2):73-84.

Physical activity for health: What kind? How much? How intense? On top of what?

Physical activity improves health. Different types of activity promote different types of physiologic changes and different health outcomes. A curvilinear reduction in risk occurs for a variety of diseases and conditions across volume of activity, with the steepest gradient at the lowest end of the activity scale. Some activity is better than none, and more is better than some. Even light-intensity activity appears to provide benefit and is preferable to sitting still. When increasing physical activity toward a desired level, small and well-spaced increments will reduce the incidence of adverse events and improve adherence. Prior research on the relationship between activity and health has focused on the value of moderate to vigorous activity on top of an indefinite and shifting baseline. Given emerging evidence that light activities have health benefits and with advances in tools for measuring activities of all intensities, it may be time to shift to zero activity as the conceptual starting point for study.

Annu Rev Public Health. 2011 Apr 21;32:349-65.

Exercise like a hunter-gatherer: a prescription for organic physical fitness.

A large proportion of the health woes beleaguering modern cultures are because of daily physical activity patterns that are profoundly different from those for which we are genetically adapted. The ancestral natural environment in which our current genome was forged via natural selection called for a large amount of daily energy expenditure on a variety of physical movements. Our genes that were selected for in this arduous and demanding natural milieu enabled our ancestors to survive and thrive, leading to a very vigorous lifestyle. This abrupt (by evolutionary time frames) change from a very physically demanding lifestyle in natural outdoor settings to an inactive indoor lifestyle is at the origin of many of the widespread chronic diseases that are endemic in our modern society. The logical answer is to replicate the native human activity pattern to the extent that this is achievable and practical. Recommendations for exercise mode, duration, intensity, and frequency are outlined with a focus on simulating the routine physical activities of our ancient hunter-gatherer ancestors whose genome we still largely share today. In a typical inactive person, this type of daily physical activity will optimize gene expression and help to confer the robust health that was enjoyed by hunter-gatherers in the wild.

Prog Cardiovasc Dis. 2011 May-Jun;53(6):471-9.

Fructose, exercise, and health.

The large daily energy intake common among athletes can be associated with a large daily intake of fructose, a simple sugar that has been linked to metabolic disorders. Fructose commonly is found in foods and beverages as a natural component (e.g., in fruits) or as an added ingredient (as sucrose or high fructose corn syrup [HFCS]). A growing body of research suggests that excessive intake of fructose (e.g., >50 g.d(-1)) may be linked to development of the metabolic syndrome (obesity, dyslipidemia, hypertension, insulin resistance, proinflammatory state, prothrombosis). The rapid metabolism of fructose in the liver and resultant drop in hepatic adenosine triphosphate (ATP) levels have been linked with mitochondrial and endothelial dysfunction, alterations that could predispose to obesity, diabetes, and hypertension. However, for athletes, a positive aspect of fructose metabolism is that, in combination with other simple sugars, fructose stimulates rapid fluid and solute absorption in the small intestine and helps increase exogenous carbohydrate oxidation during exercise, an important response for improving exercise performance. Although additional research is required to clarify the possible health-related implications of long-term intake of large amounts of dietary fructose among athletes, regular exercise training and consequent high daily energy expenditure may protect athletes from the negative metabolic responses associated with chronically high dietary fructose intake.

Curr Sports Med Rep. 2010 Jul-Aug;9(4):253-8.

Organ-sparing radiation therapy for head and neck cancer.

To improve locoregional tumor control and survival in patients with locally advanced head and neck cancer (HNC), therapy is intensified using altered fractionation radiation therapy or concomitant chemotherapy. However, intensification of therapy has been associated with increased acute and late toxic effects. The application of advanced radiation techniques, such as 3D conformal radiation therapy and intensity-modulated radiation therapy, is expected to improve the therapeutic index of radiation therapy for HNC by limiting the dose to critical organs and possibly increasing locoregional tumor control. To date, Review articles have covered the prevention and treatment of radiation-induced xerostomia and dysphagia, but few articles have discussed the prevention of hearing loss, brain necrosis, cranial nerve palsy and osteoradionecrosis of the mandible, which are all potential complications of radiation therapy for HNC. This Review describes the efforts to prevent therapy-related complications by presenting the state of the art evidence regarding advanced radiation therapy technology as an organ-sparing approach.

Nat Rev Clin Oncol. 2011 Jul 26.

Clinical implications of radio-necrosis to the head and neck surgeon.

Radiation necrosis is one of the most serious complications in the treatment of malignancies of the head and neck. As radiotherapy becomes more frequently used as a primary modality and in combination with chemotherapy and surgery, the head and neck surgeon needs to be able to prevent and recognize the often subtle signs and symptoms of radiation necrosis. The symptoms of necrosis can mimic the recurrence of cancer, which presents a diagnostic dilemma, because aggressive surgical biopsy may worsen necrosis and contribute to the formation of a fistula. This review provides a brief discussion of the diagnostic and treatment options for osteoradionecrosis and chondroradionecrosis in the head and neck.

Curr Opin Otolaryngol Head Neck Surg. 2003 Apr;11(2):103-6.

Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years.

PURPOSE: To estimate the risk of ischemic stroke in patients irradiated for head and neck tumors.PATIENTS AND METHODS: The incidence of ischemic stroke was determined in 367 patients with head and neck tumors (162 larynx carcinomas, 114 pleomorphic adenomas, and 91 parotid carcinomas) who had been treated with local radiotherapy (RT) at an age younger than 60 years. Relative risk (RR) of ischemic stroke was determined by comparison with population rates from a stroke-incidence register, adjusted for sex and age. Other risk factors for stroke (hypertension, smoking, hypercholesterolemia, diabetes mellitus [DM]) were registered. The median follow-up time after RT was 7.7 years (3,011 person-years of follow-up). RESULTS: Fourteen cases of stroke occurred (expected, 2.5; RR, 5.6; 95% confidence interval [CI], 3.1 to 9.4): eight in patients with laryngeal carcinoma (expected,1.56; RR, 5.1; 95% CI, 2.2 to 10.1), four in pleomorphic adenoma patients (expected, 0.71; RR, 5.7; 95% CI, 1.5 to 14.5), and two in parotid carcinoma patients (expected, 0.24; RR, 8.5, 95% CI, 1.0 to 30.6). Five of six strokes in patients irradiated for a parotid tumor occurred at the ipsilateral side. Analysis of other risk factors for cerebrovascular disease showed hypertension and DM to cause an increase of the RR after RT. After more than 10 years' follow-up, the RR was 10.1 (95% CI, 4.4 to 20.0). The 15-year cumulative risk of stroke after RT on the neck was 12.0% (95% CI, 6.5% to 21.4%). CONCLUSION: This is the first study to demonstrate an increased risk of stroke after RT on the neck. During medical follow-up, preventive measures should be taken to reduce the impact of the risk factors for cerebrovascular disease, to decrease stroke in these patients.

J Clin Oncol. 2002 Jan 1;20(1):282-8.

Coronary artery disease mortality in patients treated for Hodgkin's disease.

The authors conducted a follow-up study of the association between mediastinal irradiation, chemotherapy, and mortality from coronary artery disease in 4665 patients treated for Hodgkin's disease. Study subjects were followed after the diagnosis of Hodgkin's disease until death or the closing date of the study. The average duration of follow-up was 7 years; 2415 patients died, and 124 cases of coronary artery disease were identified from death certificates, including 68 cases of acute myocardial infarction. The age-adjusted relative risks (RR) of death with any coronary artery disease after mediastinal irradiation and after chemotherapy were 1.87 (95% confidence interval [CI], 0.92 to 3.80) and 1.28 (CI, 0.77 to 2.15), respectively. A significantly increased risk of death in the subcategory myocardial infarction was observed after mediastinal irradiation (RR, 2.56; CI, 1.11 to 5.93) but not after chemotherapy (RR, 0.97; CI, 0.53 to 1.77). These results support the hypothesis that radiation therapy to the mediastinum increases the risk of coronary artery disease.

Cancer. 1992 Mar 1;69(5):1241-7.

Long-term complications associated with breast-conservation surgery and radiotherapy.

BACKGROUND: Breast-conservation surgery plus radiotherapy has become the standard of care for early-stage breast cancer; we evaluated its long-term complications. METHODS: We selected patients treated with surgery and radiotherapy between January 1990 and December 1992 (an era in which standard radiation dosages were used) with follow-up for at least 1 year. Patients were prospectively monitored for treatment-related complications. Median follow-up time was 89 months. RESULTS: A total of 294 patients met the selection criteria. Grade 2 or higher late complications were identified in 29 patients and included arm edema in 13 patients, breast skin fibrosis in 12, decreased range of motion in 4, pneumonitis in 2, neuropathy in 2, fat necrosis in 1, and rib fracture in 1. Arm edema was more common after lumpectomy plus axillary node dissection than after lumpectomy alone. Arm edema occurred in 18% of patients who underwent surgery plus irradiation of the lymph nodes and 10% who underwent surgery without nodal irradiation.CONCLUSIONS: Breast-conservation surgery plus radiotherapy was associated with grade 2 or higher complications in only 9.9% of patients. Half of these complications were attributable to axillary dissection, it is hoped that lower complication rates can be achieved with sentinel lymph node biopsy. Breast-conservation surgery and radiotherapy is associated with grade 2 or greater complications in only 9.9% of patients. Nearly half of these complications are attributable to axillary dissection.

Ann Surg Oncol. 2002 Jul;9(6):543-9.

Risk of lymphoedema following the treatment of breast cancer.

The incidence of lymphoedema was studied in 200 patients following a variety of treatments for operable breast cancer. Lymphoedema was assessed in two ways: subjective (patient plus observer impression) and objective (physical measurement). Arm volume measurement 15 cm above the lateral epicondyle was the most accurate method of assessing differences in size of the operated and normal arm. Arm circumference measurements were inaccurate. Subjective lymphoedema was present in 14% cent whereas objective lymphoedema (a difference in limb volume greater than 200 ml) was present in 25.5%. Independent risk factors contributing towards the development of subjective late lymphoedema were the extent of axillary surgery (P less than 0.05), axillary radiotherapy (P less than 0.001) and pathological nodal status (P less than 0.10). The risk of developing late lymphoedema was unrelated to age, menopausal status, handedness, early lymphoedema, surgical and radiotherapeutic complications, total dose of radiation, time interval since presentation, drug therapy, surgery to the breast, radiotherapy to the breast and tumour T stage. The incidence of subjective late lymphoedema was similar after axillary radiotherapy alone (8.3%), axillary sampling plus radiotherapy (9.1%) and axillary clearance alone (7.4%). The incidence after axillary clearance plus radiotherapy was significantly greater (38.3%, P less than 0.001). Axillary radiotherapy should be avoided in patients who have had a total axillary clearance.

Br J Surg. 1986 Jul;73(7):580-4.

Radiation-induced coronary artery disease.

Radiation-induced heart disease must be considered in any patient with cardiac symptomatology who had prior mediastinal irradiation. Radiation can affect all the structures in the heart, including the pericardium, the myocardium, the valves and the conduction system. In addition to these pathologies, coronary artery disease following mediastinal radiotherapy is the most actual cardiac pathology as it may cause cardiac emergencies requiring interventional cardiological or surgical interventions. Case A 36-year-old man was admitted to the clinic with unstable angina pectoris of one month duration. The patient had no coronary artery disease risk factor. The history of the patient revealed that he had mediastinal radiotherapy due to Hodgkin's disease at 10-year of age. Coronary arteriography showed total occlusion of the left anterior descending artery and 70% stenosis of the proximal right coronary artery. Both arteries are dilated with placement of two stents. Control coronary arteriography at the end of the first year showed patency of both stents and the patient is free of symptoms. Previous radiotherapy to the mediastinum should be considered as a risk factor for the development of premature coronary artery disease. Percutaneous transluminal coronary angioplasty with stent placement or surgical revascularization are the preferred methods of treatment. Preoperative assessment of internal thoracic arteries should be considered prior to surgery. As the radiation therapy is currently the standard treatment for a number of mediastinal malignancies, routine screening of these patients and optimal cardiac prevention during radiotherapy are the only ways to minimize the incidence of radiation-induced heart disease.

Z Kardiol. 2003 Aug;92(8):682-5.

Complications of axillary lymph node dissection for carcinoma of the breast: a report based on a patient survey.

BACKGROUND: Axillary lymph node dissection is commonly performed as part of the primary management of breast carcinoma. Its value in patient management, however, has recently been questioned. Few studies exist that document long term complications. METHODS: Four hundred thirty-two patients with Stage I or II breast carcinoma who were free of recurrence 2-5 years after surgery were identified. A cross-sectional survey was conducted to determine the prevalence of long term symptoms and complications as perceived by the patient, and patient and treatment factors that may have predicted complications were determined. Three hundred thirty of the 432 (76%) completed a mailed, self-administered questionnaire. In addition, the medical records of the 330 patients were reviewed. Patient and treatment factors were analyzed with logistic regression. RESULTS: Numbness was reported by 35% of patients at the time of the survey. Pain was noted in 30%, arm swelling in 15%, and limitation of arm movement in 8%. Eight percent reported episodes of infection or inflammation at some point since the diagnosis of breast carcinoma. The majority of symptoms were mild and interfered minimally with daily activities. Younger age (P=0.001) was associated with more frequent reporting of pain. Numbness was more common in younger patients (P=0.004) as well as in those with a history of smoking (P=0.012). There was a positive association of limitation of arm motion with adjuvant tamoxifen therapy (P=0.016). Arm swelling was associated with both younger age (P=0.004) and greater body surface area (P=0.008). Radiation therapy was associated with a higher frequency of infection or inflammation in the arm and/or breast (P=0.001). CONCLUSIONS: Mild symptoms, especially pain and numbness, are common 2-5 years after axillary lymph node dissection. The frequency of inflammation or infection in patients treated with radiation to the breast or chest wall after an axillary lymph node dissection may be greater than previously appreciated. Severe complications or symptoms that have a major impact on daily activities are uncommon. These findings should help health care providers and their patients with breast carcinoma weigh the pros and cons of axillary lymph node dissection.

Cancer. 1998 Oct 1;83(7):1362-8.

Are deaths within 1 month of cancer-directed surgery attributed to cancer?

BACKGROUND: Cancer mortality should include not only deaths from cancer but also deaths from cancer treatment. By convention, deaths within 30 days of a surgical procedure are considered treatment-related deaths in the calculation of operative mortality-that is, the chance of dying from surgery. How cause of death is attributed in patients who die within 1 month of cancer-directed surgery is unknown. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program data from 1994 through 1998 were used to examine the cause of death in patients diagnosed with one of 19 common solid tumors who had died within 1 month of diagnosis and had also received cancer-directed surgery. We determined the proportion of deaths not attributed to the cancer and the magnitude of the undercount in cancer-specific mortality. RESULTS: Among 4,135 patients with only one cancer who died within 1 month of diagnosis and cancer-directed surgery, the proportion of deaths not attributed to the coded cancer was 41% (1,714/4,135), ranging from 13% (1/8) for cervical cancer to 81% (13/16) for laryngeal cancer. Selected intermediate values include 25% (14/56) for esophageal cancer, 34% (177/525) for lung cancer, 42% (719/1695) for colorectal cancer, 59% (110/186) for breast cancer, and 75% (80/106) for prostate cancer. Restricting the analysis to deaths following specific major procedures (e.g., esophagectomy, pneumonectomy, colectomy) had little effect on the findings. If all deaths within 1 month of cancer-directed surgery were attributed to cancer, cancer mortality would rise about 1%. CONCLUSION: Some deaths that are conventionally attributed to surgery are not being attributed to the cancer for which the surgery was performed. Although the estimated effect of this misclassification on overall cancer mortality is modest, it may be indicative of more widespread confusion about how to code treatment-related deaths of patients with cancer.

J Natl Cancer Inst. 2002 Jul 17;94(14):1066-70.