Life Extension Magazine®

Issue: Apr 2010

Circulating Tumor Cells

Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes.

Chronic sleep loss as a consequence of voluntary bedtime restriction is an endemic condition in modern society. Although sleep exerts marked modulatory effects on glucose metabolism, and molecular mechanisms for the interaction between sleeping and feeding have been documented, the potential impact of recurrent sleep curtailment on the risk for diabetes and obesity has only recently been investigated. In laboratory studies of healthy young adults submitted to recurrent partial sleep restriction, marked alterations in glucose metabolism including decreased glucose tolerance and insulin sensitivity have been demonstrated. The neuroendocrine regulation of appetite was also affected as the levels of the anorexigenic hormone leptin were decreased, whereas the levels of the orexigenic factor ghrelin were increased. Importantly, these neuroendocrine abnormalities were correlated with increased hunger and appetite, which may lead to overeating and weight gain. Consistent with these laboratory findings, a growing body of epidemiological evidence supports an association between short sleep duration and the risk for obesity and diabetes. Chronic sleep loss may also be the consequence of pathological conditions such as sleep-disordered breathing. In this increasingly prevalent syndrome, a feedforward cascade of negative events generated by sleep loss, sleep fragmentation, and hypoxia are likely to exacerbate the severity of metabolic disturbances. In conclusion, chronic sleep loss, behavioral or sleep disorder related, may represent a novel risk factor for weight gain, insulin resistance, and Type 2 diabetes.

J Appl Physiol. 2005 Nov;99(5):2008-19

Suppression of immunity to influenza virus infection in the respiratory tract following sleep disturbance.

The extent to which sleep deprivation interferes with immunity in the respiratory tract to influenza virus has been assessed in mice. Mice were orally immunized with influenza virus on two occasions separated by a one week interval and challenged intranasally one week later. Some animals were deprived of sleep for a 7 h period immediately following challenge. Three days after challenge, virus clearance and virus specific antibody were determined in lungs of sleep deprived and normally sleeping mice and the results compared with unimmunized mice subjected to the same protocol. Whereas immunized, normal sleep mice achieved total virus clearance, sleep deprivation in immunized mice completely abrogated this effect such that sleep deprived animals behaved as though they had never been immunized. There was no difference in viral clearance in unimmunized mice whether sleep deprived or not, indicating that sleep deprivation did not itself have a direct effect on viral replication. The data reported here support the concept that sleep is a behavioral state which is essential for optimal immune function in the presence of a respiratory tract pathogen.

Reg Immunol. 1989 Sep-Oct;2(5):321-5

Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat.

Pineal melatonin secretion declines with aging, whereas visceral fat, plasma insulin, and plasma leptin tend to increase. We have previously demonstrated that daily melatonin administration at middle age suppressed male rat intraabdominal visceral fat, plasma leptin, and plasma insulin to youthful levels; the current study was designed to begin investigating mechanisms that mediate these responses. Melatonin (0.4 microg/ml) or vehicle was administered in the drinking water of 10-month-old male Sprague Dawley rats (18/treatment) for 12 weeks. Half (9/treatment) were then killed, and the other half were submitted to cross-over treatment for an additional 12 weeks. Twelve weeks of melatonin treatment decreased (P<0.05) body weight (BW; by 7% relative to controls), relative intraabdominal adiposity (by 16%), plasma leptin (by 33%), and plasma insulin (by 25%) while increasing (P<0.05) locomotor activity (by 19%), core body temperature (by 0.5 C), and morning plasma corticosterone (by 154%), restoring each of these parameters toward more youthful levels. Food intake and total body fat were not changed by melatonin treatment. Melatonin-treated rats that were then crossed over to control treatment for a further 12 weeks gained BW, whereas control rats that were crossed to melatonin treatment lost BW, but food intake did not change in either group. Feed efficiency (grams of BW change per g cumulative food intake), a measure of metabolic function, was negative in melatonin-treated rats and positive in control rats before cross-over (P<0.001); this relationship was reversed after cross-over (P<0.001). Thus, melatonin treatment in middle age decreased BW, intraabdominal adiposity, plasma insulin, and plasma leptin, without altering food intake or total adiposity. These results suggest that the decrease in endogenous melatonin with aging may alter metabolism and physical activity, resulting in increased BW, visceral adiposity, and associated detrimental metabolic consequences.

Endocrinology. 2000 Feb;141(2):487-97

Alterations in nocturnal serum melatonin levels in humans with growth and aging.

The available data on potential alterations in serum melatonin (MLT) levels during a human lifetime are fragmentary and inconsistent. We, therefore, measured day- and nighttime serum MLT concentrations in 367 subjects (210 males and 157 females), aged 3 days to 90 yr. Blood samples were collected between 0730 and 1000 h and between 2300 and 0100 h. Serum MLT levels were measured by RIA. The mean nighttime serum MLT concentration was low during the first 6 months of life, i.e. 27.3 +/- 5.4 (+/- SE) pg/mL (0.12 +/- 0.02 nmol/L). It then increased to a peak value at 1-3 yr of age [329.5 +/- 42.0 pg/mL; (1.43 +/- 0.18 nmol/L)], and it was considerably lower [62.5 +/- 9.0 pg/mL; (0.27 +/- 0.04 nmol/L)] in individuals aged 15-20 yr. During the following decades serum MLT declined moderately until old age (70-90 yr of age), i.e. 29.2 +/- 6.1 pg/mL (0.13 +/- 0.03 nmol/L). This biphasic MLT decline follows 2 exponential functions with different slopes (from age 1-20 yr: r = -0.56; P less than 0.001; y = 278.7 X e -0.09x; from age 20-90 yr: r = -0.44; P less than 0.001; y = 84.8 X e -0.017x). The decrease in nocturnal serum MLT in children and adolescents (1-20 yr) correlated with the increase in body weight (r = -0.54; P less than 0.001) and body surface area (r = -0.71; P less than 0.001). At a later age (20-90 yr) there was no correlation among these variables. Daytime serum MLT levels were low and no age-related alterations were found. This study revealed major age-related alterations in nocturnal serum MLT levels. The negative correlation between serum MLT and body weight in childhood and adolescence is evidence that expansion of body size is responsible for the huge MLT decrease during that period. The moderate decline at older ages must derive from other factors.

J Clin Endocrinol Metab. 1988 Mar;66(3):648-52

Melatonin and sleep in aging population.

The neurohormone melatonin is released from the pineal gland in close association with the light-dark cycle. There is a temporal relationship between the nocturnal rise in melatonin secretion and the ‘opening of the sleep gate’ at night. This association, as well as the sleep promoting effect of exogenous melatonin, implicates the pineal product in the physiological regulation of sleep. Aging is associated with a significant reduction in sleep continuity and quality. A decreased production of melatonin with age is documented in a majority of studies. Diminished nocturnal melatonin secretion with severe disturbances in sleep/wake rhythm has been consistently reported in Alzheimer’s disease (AD). A recent survey on the effects of melatonin in sleep disturbances, including all age groups, failed to document significant and clinically meaningful effects of exogenous melatonin on sleep quality, efficiency and latency. However, in clinical trials involving elderly insomniacs and AD patients suffering from sleep disturbances exogenous melatonin has repeatedly been found to be effective in improving sleep. The results indicate that exogenous melatonin is more effective to promote sleep in the presence of a diminished production of endogenous melatonin. A MT1/MT2 receptor analog of melatonin (ramelteon) has recently been introduced as a new type of hypnotics with no evidence of abuse or dependence.

Exp Gerontol. 2005 Dec;40(12):911-25. Epub 2005 Sep 23

Melatonin treatment for age-related insomnia.

Older people typically exhibit poor sleep efficiency and reduced nocturnal plasma melatonin levels. The daytime administration of oral melatonin to younger people, in doses that raise their plasma melatonin levels to the nocturnal range, can accelerate sleep onset. We examined the ability of similar, physiological doses to restore nighttime melatonin levels and sleep efficiency in insomniac subjects over 50 yr old. In a double-blind, placebo-controlled study, subjects who slept normally (n = 15) or exhibited actigraphically confirmed decreases in sleep efficiency (n = 15) received, in randomized order, a placebo and three melatonin doses (0.1, 0.3, and 3.0 mg) orally 30 min before bedtime for a week. Treatments were separated by 1-wk washout periods. Sleep data were obtained by polysomnography on the last three nights of each treatment period. The physiologic melatonin dose (0.3 mg) restored sleep efficiency (P < 0.0001), acting principally in the midthird of the night; it also elevated plasma melatonin levels (P < 0.0008) to normal. The pharmacologic dose (3.0 mg), like the lowest dose (0.1 mg), also improved sleep; however, it induced hypothermia and caused plasma melatonin to remain elevated into the daylight hours. Although control subjects, like insomniacs, had low melatonin levels, their sleep was unaffected by any melatonin dose.

J Clin Endocrinol Metab. 2001 Oct;86(10):4727-30

Effects of exogenous melatonin on sleep: a meta-analysis.

Exogenous melatonin reportedly induces drowsiness and sleep, and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age. However, existing studies on the soporific efficacy of melatonin have been highly heterogeneous in regard to inclusion and exclusion criteria, measures to evaluate insomnia, doses of the medication, and routes of administration. We reviewed and analyzed (by meta-analysis) available information on effects of exogenous melatonin on sleep. A MEDLINE search (1980 to December 2003) provided English-language articles, supplemented by personal files maintained by the authors. The analysis used information derived from 17 different studies (involving 284 subjects) that satisfied inclusion criteria. Sleep onset latency, total sleep duration, and sleep efficiency were selected as the outcome measures. The study effect size was taken to be the difference between the response on placebo and the mean response on melatonin for each outcome measured. Melatonin treatment significantly reduced sleep onset latency by 4.0 min (95% CI 2.5, 5.4); increased sleep efficiency by 2.2% (95% CI 0.2, 4.2), and increased total sleep duration by 12.8 min (95% CI 2.9, 22.8). Since 15 of the 17 studies enrolled healthy subjects or people with no relevant medical condition other than insomnia, the analysis was also done including only these 15 studies. The sleep onset results were changed to 3.9 min (95% CI (2.5, 5.4)); sleep efficiency increased to 3.1% (95% CI (0.7, 5.5)); sleep duration increased to 13.7 min (95% CI (3.1, 24.3)).

Sleep Med Rev. 2005 Feb;9(1):41-50

Melatonin replacement therapy of elderly insomniacs.

Changes in sleep-wake patterns are among the hallmarks of biological aging. Previously, we reported that impaired melatonin secretion is associated with sleep disorders in old age. In this study we investigated the effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs. The study comprised a running-in, no-treatment period and four experimental periods. During the second, third and fourth periods, subjects were administered tablets for 7 consecutive days, 2 hours before desired bedtime. The tablets were either 2 mg melatonin administered as sustained-release or fast-release formulations, or an identical-looking placebo. The fifth period, which concluded the study, was a 2-month period of daily administration of 1 mg sustained-release melatonin 2 hours before desired bedtime. During each of these five experimental periods, sleep-wake patterns were monitored by wrist-worn actigraphs. Analysis of the first three 1-week periods revealed that a 1-week treatment with 2 mg sustained-release melatonin was effective for sleep maintenance (i.e. sleep efficiency and activity level) of elderly insomniacs, while sleep initiation was improved by the fast-release melatonin treatment. Sleep maintenance and initiation were further improved following the 2-month 1-mg sustained-release melatonin treatment, indicating that tolerance had not developed. After cessation of treatment, sleep quality deteriorated. Our findings suggest that for melatonin-deficient elderly insomniacs, melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep.

Sleep. 1995 Sep;18(7):598-603

Neurobehavioural performance effects of daytime melatonin and temazepam administration.

Exogenous melatonin is a potential treatment for circadian disruption and insomnia. Hence, it is important to determine and quantify neurobehavioural performance effects associated with its use. The present study compared neurobehavioural performance following administration of melatonin and the benzodiazepine temazepam, using a within-subjects design. Following a training day, 16 healthy, young subjects (six males, 10 females; mean age +/- SEM, 21.4 +/- 6 years) participated in a 3-day protocol. After sleeping overnight in the laboratory, subjects completed a battery of tests at hourly intervals between 08:00 and 11:00 hours and at two hourly intervals between 13:00 and 17:00 hours. The neurobehavioural performance tasks included: unpredictable tracking, spatial memory, vigilance and logical reasoning. Subjective sleepiness was measured at hourly intervals using a visual analogue scale. At 12:00 h subjects were administered a capsule containing 5 mg melatonin, 10 mg temazepam or placebo, in a randomized, double-blind crossover fashion. A significant drug x time interaction was evident on the unpredictable tracking, spatial memory and vigilance tasks (P < 0.05). Greater changes in performance were evident following temazepam administration than melatonin administration, relative to placebo. Administration of melatonin or temazepam significantly elevated subjective sleepiness levels, relative to placebo (P </= 0.05). The present findings demonstrate that melatonin administration induces a smaller deficit in performance on a range of neurobehavioural tasks than temazepam. Given melatonin’s soporific and chronobiotic properties, these results suggest that melatonin may be preferable to benzodiazepines in the management of circadian and sleep disorders.

J Sleep Res. 2003 Sep;12(3):207-12

Melatonin as a major skin protectant: from free radical scavenging to DNA damage repair.

Melatonin, one of the evolutionarily most ancient, highly conserved and most pleiotropic hormones still operative in man, couples complex tissue functions to defined changes in the environment. Showing photoperiod-associated changes in its activity levels in mammals, melatonin regulates, chronobiological and reproductive systems, coat phenotype and mammary gland functions. However, this chief secretory product of the pineal gland is now recognized to also exert numerous additional functions which range from free radical scavenging and DNA repair via immunomodulation, body weight control and the promotion of wound healing to the coupling of environmental cues to circadian clock gene expression and the modulation of secondary endocrine signalling (e.g. prolactin release, oestrogen receptor-mediated signalling). Some of these activities are mediated by high-affinity membrane (MT1, MT2) or specific cytosolic (MT3/NQO2) and nuclear hormone receptors (ROR alpha), while others reflect receptor-independent antioxidant activities of melatonin. Recently, it was shown that mammalian (including human) skin and hair follicles are not only melatonin targets, but also sites of extrapineal melatonin synthesis. Therefore, we provide here an update of the relevant cutaneous effects and mechanisms of melatonin, portray melatonin as a major skin protectant and sketch how its multi-facetted functions may impact on skin biology and pathology. This is illustrated by focussing on recent findings on the role of melatonin in photodermatology and hair follicle biology. After listing a number of key open questions, we conclude by defining particularly important, clinically relevant perspectives for how melatonin may become therapeutically exploitable in cutaneous medicine.

Exp Dermatol. 2008 Sep;17(9):713-30

Melatonin in dermatology. Experimental and clinical aspects.

Melatonin (N-acetyl-5-metho-xytryptamine) is a hormone with multiple functions in humans, produced by the pineal gland and stimulated by beta-adrenergic receptors. Serum melatonin levels exhibit a circadian rhythm with low levels during the day, rise in the evening and maximum levels at night between 2 and 4 a.m. Melatonin participates in the regulation of several physiological processes such as seasonal biological rhythm, daily sleep induction, aging and modulation of immunobiological defence reactions. Furthermore, melatonin has a highly lipophilic molecular structure facilitating penetration of cell membranes and serving as an extra- and intracellular free radical scavenger. Melatonin seems to quench mainly hydroxyl radicals, the most damaging of all free radicals. Melatonin may play a role in the etiology and treatment of several dermatoses e.g. atopic eczema, psoriasis and malignant melanoma. The influence of melatonin on hair growth is another aspect. Topical application of melatonin inhibits the development of UV-erythema. Penetration through skin after topical application and oral bioavailability auxit further investigations on the pharmacokinetic and pharmacodynamic actions of melatonin.

Hautarzt. 1999 Jan;50(1):5-11

Effect of cranberry drink on bacterial adhesion in vitro and vaginal microbiota in healthy females.

INTRODUCTION/OBJECTIVE: Cranberries have been shown to produce urinary metabolites that influence uropathogen adhesion and prevent urinary tract infections. This study was designed to determine if consuming reconstituted, unsweetened cranberry drink from extract retained its bioactive properties by reducing uropathogen adhesion without adversely affecting urinary calcium, magnesium and the vaginal microflora. MATERIALS AND METHODS: A randomized crossover study was undertaken in 12 healthy women consuming reconstituted unsweetened cranberry drink, CranActin or water. The urine was collected at 4 hours and 1 week of consumption and evaluated for antiadhesive properties and urinary pH, calcium and magnesium. Vaginal swabs were collected after 1 week of treatment to assess the vaginal microbiota by DGGE. RESULTS: The resultant urine produced by subjects who consumed 500 ml reconstituted cranberry extract twice per day, significantly reduced the adherence to epithelial cells of P-fi mbriated uropathogenic Escherichia coli and showed a tendency towards significance for two E. coli strains expressing fimbriae and an Enterococcus faecalis isolate. The cranberry drink treatment did not alter urinary pH, but reduced calcium and magnesium concentrations compared to water, although not to statistical significance. The reconstituted cranberry drink had no apparent detrimental effect on the vaginal microbiota. However, consuming twice daily resulted in an apparent loss of a potential pathogen from the vagina in 42% subjects. CONCLUSIONS: The present findings suggest that reconstituted cranberry drink may retain the ability to reduce the risk of UTI by inhibiting pathogen adhesion while not detrimentally affecting urinary pH or vaginal microbiota, or the risk of calculi.

Can J Urol. 2009 Dec;16(6):4901-7

Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women.

OBJECTIVE: To determine whether recurrences of urinary tract infection can be prevented with cranberry-lingonberry juice or with Lactobacillus GG drink. Design: Open, randomised controlled 12 month follow up trial. SETTING: Health centres for university students and staff of university hospital. PARTICIPANTS: 150 women with urinary tract infection caused by Escherichia coli randomly allocated into three groups. Interventions: 50 ml of cranberry-lingonberry juice concentrate daily for six months or 100 ml of lactobacillus drink five days a week for one year, or no intervention. Main outcome measure: First recurrence of symptomatic urinary tract infection, defined as bacterial growth >/=10(5 )colony forming units/ml in a clean voided midstream urine specimen. RESULTS: The cumulative rate of first recurrence of urinary tract infection during the 12 month follow up differed significantly between the groups (P=0.048). At six months, eight (16%) women in the cranberry group, 19 (39%) in

the lactobacillus group, and 18 (36%) in the control group had had at least one recurrence. This is a 20% reduction in absolute risk in the cranberry group compared with the control group (95% confidence interval 3% to 36%, P=0.023, number needed to treat=5, 95% confidence interval 3 to 34). CONCLUSION: Regular drinking of cranberry juice but not lactobacillus seems to reduce the recurrence of urinary tract infection.

BMJ. 2001 Jun 30;322(7302):1571

Cranberry juice for the prevention of recurrent urinary tract infections: a randomized controlled trial in children.

OBJECTIVE: This study compares the effects of daily cranberry juice to those of Lactobacillus in children with recurrent urinary tract infections (UTIs). MATERIAL AND METHODS: Eighty-four girls aged between 3 and 14 years were randomized to cranberry, Lactobacillus or control in three treatment arms: G1, cranberry juice 50 ml daily (n=28); G2, 100 ml of Lactobacillus GG drink on 5 days a month (n=27); and G3, controls (n=29). The study lasted for 6 months. RESULTS: Only four subjects withdrew: 1/28 (3.5%) from G1, 1/27 (3.7%) from G2 and 2/29 (6.8%) from G3, because of poor compliance to the established protocol. There were 34 episodes of UTIs in this cohort: 5/27 (18.5%) in G1, 11/26 (42.3%) in G2 and 18/27 (48.1%) in the G3, with at least one episode of infection (p<0.05). CONCLUSION: These data suggest that daily consumption of concentrated cranberry juice can significantly prevent the recurrence of symptomatic UTIs in children.

Scand J Urol Nephrol. 2009;43(5):369-72

A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women.

PURPOSE: To determine, from a societal perspective, the effectiveness and cost effectiveness of concentrated cranberry tablets, versus cranberry juice, versus placebo used as prophylaxis against lower urinary tract infection (UTI) in adult women. MATERIALS AND METHODS: One hundred fifty sexually active women aged 21 through 72 years were randomized for one year to one of three groups of prophylaxis: placebo juice + placebo tablets versus placebo juice + cranberry tablets, versus cranberry juice + placebo tablets. Tablets were taken twice daily, juice 250 ml three times daily. Outcome measures were: (1) a >50% decrease in symptomatic UTI’s per year (symptoms + >or= 100 000 single organisms/ml) and (2) a >50% decrease in annual antibiotic consumption. Cost effectiveness was calculated as dollar cost per urinary tract infection prevented. Stochastic tree decision analytic modeling was used to identify specific clinical scenarios for cost savings. RESULTS: Both cranberry juice and cranberry tablets statistically significantly decreased the number of patients experiencing at least 1 symptomatic UTI/year (to 20% and 18% respectively) compared with placebo (to 32%) (p<0.05). The mean annual cost of prophylaxis was $624 and $1400 for cranberry tablets and juice respectively. Cost savings were greatest when patients experienced >2 symptomatic UTI’s per year (assuming 3 days antibiotic coverage) and had >2 days of missed work or required protective undergarments for urgency incontinence. Total antibiotic consumption was less annually in both treatment groups compared with placebo. Cost effectiveness ratios demonstrated cranberry tablets were twice as cost effective as organic juice for prevention. CONCLUSIONS: Cranberry tablets provided the most cost-effective prevention for UTI.

Can J Urol. 2002 Jun;9(3):1558-62

Reduction of bacteriuria and pyuria after ingestion of cranberry juice.

OBJECTIVE—To determine the effect of regular intake of cranberry juice beverage on bacteriuria and pyuria in elderly women. DESIGN—Randomized, double-blind, placebo-controlled trial. SUBJECTS—Volunteer sample of 153 elderly women (mean age, 78.5 years). INTERVENTION—Subjects were randomly assigned to consume 300 mL per day of a commercially available standard cranberry beverage or a specially prepared synthetic placebo drink that was indistinguishable in taste, appearance, and vitamin C content but lacked cranberry content. OUTCOME MEASURES—A baseline urine sample and six clean-voided study urine samples were collected at approximately 1-month intervals and tested quantitatively for bacteriuria and the presence of white blood cells. RESULTS—Subjects randomized to the cranberry beverage had odds of bacteriuria (defined as organisms numbering > or = 10(5)/mL) with pyuria that were only 42% of the odds in the control group (P = .004). Their odds of remaining bacteriuric-pyuric, given that they were bacteriuric-pyuric in the previous month, were only 27% of the odds in the control group (P = .006). CONCLUSIONS—These findings suggest that use of a cranberry beverage reduces the frequency of bacteriuria with pyuria in older women. Prevalent beliefs about the effects of cranberry juice on the urinary tract may have microbiologic justification.

JAMA. 1994 Mar 9;271(10):751-4

Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women.

OBJECTIVES: To compare the effectiveness of cranberry extract with low-dose trimethoprim in the prevention of recurrent urinary tract infections (UTIs) in older women. PATIENTS AND METHODS: One hundred and thirty-seven women with two or more antibiotic-treated UTIs in the previous 12 months were randomized to receive either 500 mg of cranberry extract or 100 mg of trimethoprim for 6 months. RESULTS: Thirty-nine of 137 participants (28%) had an antibiotic-treated UTI (25 in the cranberry group and 14 in the trimethoprim group); difference in proportions relative risk 1.616 (95% CI: 0.93, 2.79) P = 0.084. The time to first recurrence of UTI was not significantly different between the groups (P = 0.100). The median time to recurrence of UTI was 84.5 days for the cranberry group and 91 days for the trimethoprim group (U = 166, P = 0.479). There were 17/137 (12%) withdrawals from the study, 6/69 (9%) from the cranberry group and 11/68 (16%) from the trimethoprim group (P = 0.205), with a relative risk of withdrawal from the cranberry group of 0.54 (95% CI: 0.19, 1.37). CONCLUSIONS: Trimethoprim had a very limited advantage over cranberry extract in the prevention of recurrent UTIs in older women and had more adverse effects. Our findings will allow older women with recurrent UTIs to weigh up with their clinicians the inherent attractions of a cheap, natural product like cranberry extract whose use does not carry the risk of antimicrobial resistance or super-infection with Clostridium difficile or fungi.

J Antimicrob Chemother. 2009 Feb;63(2):389-95

Phytochemical, pharmacological and toxicological aspects of Hibiscus sabdariffa L.: a review.

This article reviews the reported phytochemical, pharmacological and toxicological properties of Hibiscus sabdariffa L. (English: roselle, red sorrel; Arabic: karkade), the calyces of which are used in many parts of the world to make cold and hot drinks. Nutritionally, these contain ascorbic acid (vitamin C). In folk medicine, the calyx extracts are used for the treatment of several complaints, including high blood pressure, liver diseases and fever. The pharmacological actions of the calyx extracts include strong in vitro and in vivo antioxidant activity. In rats and rabbits, the extract showed antihypercholesterolaemic, antinociceptive and antipyretic, but not antiinflammatory activities. In rat and man a strong antihypertensive action has been demonstrated. The effects of the calyx extracts on smooth muscles in vitro are variable, but they mostly inhibit the tone of the isolated muscles. In healthy men, consumption of H. sabdariffa has resulted in significant decreases in the urinary concentrations of creatinine, uric acid, citrate, tartrate, calcium, sodium, potassium and phosphate, but not oxalate. Oil extracted from the plant’s seeds has been shown to have an inhibitory effect on some bacteria and fungi in vitro. The plant extracts are characterized by a very low degree of toxicity. The LD50 of H. sabdariffa calyx extract in rats was found to be above 5,000 mg/kg. A single report has suggested that excessive doses for relatively long periods could have a deleterious effect on the testes of rats. In view of its reported nutritional and pharmacological properties and relative safety, H. sabdariffa and compounds isolated from it (for example, anthocyanins and Hibiscus protocatechuic acid) could be a source of therapeutically useful products. Copyright (c) 2005 John Wiley & Sons, Ltd.

Phytother Res. 2005 May;19(5):369-75

Screening of Thai medicinal plants for anticandidal activity.

Medicinal plants are often used in the treatment of various ailments. In this study, 23 of Thai medicinal plants were screened for their anticandidal activity against six pathogenic Candida species: C. albicans, C. glabrata, C. guilliermondii, C. krusei, C. parapsilosis and C. tropicalis. The methanol extract of Hibiscus sabdariffa L. fruit, Trigonostemon reidioides (Kurz) Craib root, Usnea siamensis Vain whole plant, Boesenbergia rotunda (L.) Mansf. rhizome, and Albizia myriophylla Benth. stem showed anticandidal activity against one or more species of Candida. Among them, A. myriophylla Benth. showed broad anticandidal activity. The susceptibility tests of A. myriophylla Benth. extract, in terms of minimal inhibitory concentrations (MIC) and minimal fungicidal concentration (MFC), were performed by the broth microdilution techniques as described by the Clinical Laboratory Standard Institute. MICs of A. myriophylla Benth. extract to all Candida species was ranged 100-500 mug ml(-1). The killing activity of A. myriophylla Benth. extract was fast acting against all Candida tested; the reduction in the number of CFU ml(-1) was >3 log(10) units (99.9%) in 2 h. This study indicates that A. myriophylla Benth. extract has considerable anticandidal activity, deserving further investigation for clinical applications for the treatment of candidiasis.

Mycoses. 2008 Jul;51(4):308-12

Pharmacokinetics of anthocyanidin-3-glycosides following consumption of Hibiscus sabdariffa L. extract.

Pharmacokinetic parameters of several dietary anthocyanins following consumption of Hibiscus sabdariffa L. extract were determined in 6 healthy volunteers. Subjects were given a single oral dose of 150 mL of Hibiscus sabdariffa L. extract yielding 62.6 mg of cyanidin-3-sambubioside, 81.6 mg of delphindin-3-sambubioside, and 147.4 mg of total anthocyanins (calculated as cyanidin equivalents). Within 7 hours, the urinary excretion of cyanidin-3-sambubioside, delphinidin-3-sambubioside, and total anthocyanins (ie, the sum of all quantifiable anthocyanidin glycosides) was 0.016%, 0.021%, and 0.018% of the administered doses, respectively. Maximum excretion rates were determined at 1.5 to 2.0 hours after intake. The dose-normalized plasma area under the curve estimates were 0.076, 0.032, and 0.050 ng x h/mL/mg for cyanidin-3-sambubioside, delphinidin-3-sambubioside, and total anthocyanins, respectively. The dose-normalized C(max) estimates were 0.036, 0.015, and 0.023 ng/mL/mg in the same sequence. They were reached each at 1.5 hours (median) after intake. The geometric means of t1/2 were 2.18, 3.34, and 2.63 hours for cyanidin-3-sambubioside, delphinidin-3-sambubioside, and total anthocyanins, respectively. The urinary excretion of intact anthocyanins was fast and appeared to be monoexponential. To evaluate the contribution of anthocyanins to the health-protecting effects of Hibiscus sabdariffa L. extract, it will be necessary to perform further studies on both the intact glycosides and their in vivo metabolites or conjugates in human plasma and urine.

J Clin Pharmacol. 2005 Feb;45(2):203-10

Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: meta-analysis of quality-adjusted survival.

BACKGROUND: Adjuvant tamoxifen for early breast cancer provides an improvement in relapse-free (RFS) and overall survival (OS), especially for older women. We carried out a meta-analysis to find out whether the benefit of adding chemotherapy to tamoxifen outweighs its costs in terms of toxic effects for postmenopausal patients. METHODS: The meta-analysis of quality-adjusted survival was based on data from 3,920 patients aged 50 years or older with node-positive breast cancer randomly assigned in nine trials that compared combination chemotherapy plus tamoxifen with tamoxifen alone. The nine trials were included in the worldwide overview conducted by the early breast cancer trialists’ collaborative group (EBCTCG). The quality-adjusted time without symptoms or toxicity (Q-TWiST) method was used to provide treatment comparisons incorporating differences in quality of life associated with subjective toxic effects of treatment and symptoms of disease relapse. FINDINGS: Within 7 years of follow-up the modest benefit of increased RFS and OS for patients who received chemotherapy just balanced the costs in terms of acute toxic side-effects. Chemotherapy-treated patients gained an average of 5.4 months of RFS and 2 months of OS (neither statistically significant), but had to receive cytotoxic treatment for between 2 and 24 months to achieve these gains. No values of preference weights for time spent undergoing chemotherapy and time after relapse gave significantly more Q-TWiST with chemotherapy plus tamoxifen than with tamoxifen alone. INTERPRETATION: Within 7 years of follow-up, adjuvant chemoendocrine therapy did not provide more quality-adjusted survival time than tamoxifen alone for women aged 50 years or older with node-positive breast cancer. Better selection and administration of chemotherapy regimen, different scheduling of chemotherapy and tamoxifen, and appropriate use of patient and tumour characteristics may increase the therapeutic advantage of the combination.

Lancet. 1996 Apr 20;347(9008):1066-71

HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials.

BACKGROUND: Adjuvant chemotherapy with anthracyclines improves disease-free and overall survival compared with non-anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer. The role of HER2 status as a marker of anthracycline responsiveness has been explored by subset analyses within randomized clinical trials, with inconsistent results. We performed a pooled analysis of the interaction between HER2 status and the efficacy of adjuvant anthracyclines based on the published subset data. METHODS: We searched literature databases to identify randomized trials that compared anthracycline-based with non-anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer and reported efficacy data according to HER2 status. Log hazard ratios (HRs) for disease-free and overall survival were pooled across the studies according to HER2 status by inverse variance weighting. A pooled test for treatment by HER2 status interaction was performed by weighted linear meta-regression. All statistical tests were two-sided. RESULTS: Eight studies (with 6564 randomly assigned patients, of whom 5,354 had HER2 status information available) were eligible for this analysis. In HER2-positive disease (n = 1536 patients), anthracyclines were superior to non-anthracycline-based regimens in terms of disease-free (pooled HR of relapse = 0.71; 95% confidence interval [CI] = 0.61 to 0.83; P < .001) and overall (pooled HR of death from any cause = 0.73; 95% CI = 0.62 to 0.85; P < .001) survival. In HER2-negative disease (n = 3818 patients), anthracyclines did not improve disease-free (HR = 1.00; 95% CI = 0.90 to 1.11; P = .75) or overall (HR = 1.03; 95% CI = 0.92 to 1.16; P = .60) survival. The test for treatment by HER2 status interaction yielded statistically significant results: for disease-free survival, the chi-square statistic for interaction was 13.7 (P < .001), and for overall survival, it was 12.6 (P < .001). CONCLUSIONS: The added benefits of adjuvant chemotherapy with anthracyclines appear to be confined to women who have HER2 overexpressed or amplified breast tumors.

Natl Cancer Inst. 2008 Jan 2;100(1):14-20

Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.

BACKGROUND: Doxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug. A large-scale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an estimated 7% of patients developed doxorubicin-related congestive heart failure (CHF) after a cumulative dose of 550 mg/m(2). To assess whether this estimate is reflective of the incidence in the broader clinical oncology setting, the authors evaluated data from three prospective studies to determine both the incidence of doxorubicin-related CHF and the accumulated dose of doxorubicin at which CHF occurs. METHODS: A group of 630 patients who were randomized to a doxorubicin-plus-placebo arm of three Phase III studies, two studies in patients with breast carcinoma and one study in patients with small cell lung carcinoma, were included in the analysis. RESULTS: Thirty-two of 630 patients had a diagnosis of CHF. Analysis indicated that an estimated cumulative 26% of patients would experience doxorubicin-related CHF at a cumulative dose of 550 mg/m(2). Age appeared to be an important risk factor for doxorubicin-related CHF after a cumulative dose of 400 mg/m(2), with older patients (age > 65 years) showing a greater incidence of CHF compared with younger patients (age < or = 65 years). In addition, > 50% of the patients who experienced doxorubicin-related CHF had a reduction < 30% in left ventricular ejection fraction (LVEF) while they were on study. CONCLUSIONS: Doxorubicin-related CHF occurs with greater frequency and at a lower cumulative dose than previously reported. These findings further indicate that LVEF is not an accurate predictor of CHF in patients who receive doxorubicin.

Cancer. 2003 Jun 1;97(11):2869-79

HER-2 gene amplification can be acquired as breast cancer progresses.

Amplification and overexpression of the HER-2 oncogene in breast cancer is felt to be stable over the course of disease and concordant between primary tumor and metastases. Therefore, patients with HER-2-negative primary tumors rarely will receive anti-Her-2 antibody (trastuzumab, Herceptin) therapy. A very sensitive blood test was used to capture circulating tumor cells (CTCs) and evaluate their HER-2 gene status by fluorescence in situ hybridization. The HER-2 status of the primary tumor and corresponding CTCs in 31 patients showed 97% agreement, with no false positives. In 10 patients with HER-2-positive tumors, the HER-2/chromosome enumerator probe 17 ratio in each tumor was about twice that of the corresponding CTCs (mean 6.64 +/- 2.72 vs. 2.8 +/- 0.6). Hence, the ratio of the CTCs is a reliable surrogate marker for the expected high ratio in the primary tumor. Her-2 protein expression of 10 CTCs was sufficient to make a definitive diagnosis of the HER-2 gene status of the whole population of CTCs in 19 patients with recurrent breast cancer. Nine of 24 breast cancer patients whose primary tumor was HER-2-negative each acquired HER-2 gene amplification in their CTCs during cancer progression, i.e., 37.5% (95% confidence interval of 18.8-59.4%). Four of the 9 patients were treated with Herceptin-containing therapy. One had a complete response and 2 had a partial response.

Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9393-8

HER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients.

PURPOSE: Early metastasis in node-negative breast cancer indicates that breast cancer cells obviously can bypass the lymph nodes and disseminate directly hematogenous to distant organs. For this purpose, we evaluated the prognostic value of blood-borne, HER2-positive circulating tumor cells (CTC) in the peripheral blood from 42 breast cancer patients with a median follow-up of 95 months. EXPERIMENTAL DESIGN: Cells were isolated by the patented combined buoyant density gradient and immunomagnetic separation procedure and analyzed by immunocytochemistry. RESULTS: We detected one to eight CTCs in the peripheral blood of 17 of 35 patients (48.6%) presenting no overt metastasis. As a positive control, 7 of 7 (100%) patients with metastatic disease presented positive. Healthy persons and patients (n = 32) operated for nonmalignant diseases presented negative for CTCs. The presence and frequency of HER2-positive CTCs correlated with a significantly decreased disease-free survival (P < 0.005) and overall survival (P < 0.05). Interestingly, in 12 patients with HER2-positive CTCs, the primary tumor was negative for HER2 as assessed by immunohistochemical score and fluorescence in situ hybridization. CONCLUSIONS: This study provides some evidence of a prognostic effect of HER2-positive CTCs in stage I to III breast cancer. Future studies have to determine the outcome of patients treated with HER2-targeting therapies with respect to HER2-positive CTC levels because it is not unlikely that high levels of HER2-positive CTCs reflect the activity of the tumor and may predict response to trastuzumab.

Clin Cancer Res. 2006 Mar 15;12(6):1715-20

Prognostic value of circulating prostate cells in patients with a rising PSA after radical prostatectomy.

BACKGROUND: To predict poor outcome in patients with a biochemical recurrence (rising PSA) after radical prostatectomy (RP), urologists rely primarily on Gleason score, PSA doubling time, and time from surgery to biochemical (i.e., PSA) recurrence. In the present study, we assess the value of RT-PCR detection circulating prostate cells in blood of patients with a rising PSA. METHODS: RNA from blood samples was obtained from 55 patients with a rising PSA and from 45 patients without evidence of biochemical failure (PSA < 0.1 ng/ml). Both groups were matched for age, Gleason score, pT stage, and interval between radical prostatectomy and PCR testing. RESULTS: PSA positive cells were detected in 1/45 (2%) patients without a PSA recurrence and 19/55 (34%) patients with a PSA recurrence. In the rising PSA group, mean PSA doubling time was significantly shorter in patients with positive RT-PCR (5 months) than in patients with negative RT-PCR (16 months; P = 0.001). An earlier onset of recurrence was also detected in patients with a positive RT-PCR (31 months for positive RT-PCR vs. 50 months for negative RT-PCR) but this result did not achieve statistical significance (P = 0.102). Salvage radiation therapy was administered in 15 patients. Three of the five patients with a positive RT-PCR progressed during radiotherapy whereas 7 of the 10 patients with a negative RT-PCR obtained a complete response and none have progressed. CONCLUSIONS: These preliminary results suggest that RT-PCR detection of prostate cells in blood of patients after RP correlates with rapidly progressing biochemical failure after RP.

Prostate. 2003 Aug 1;56(3):163-70

Prognostic significance of reverse transcriptase polymerase chain reaction for prostate-specific antigen in metastatic prostate cancer: a nested study within CALGB 9583.

PURPOSE: To determine whether reverse transcriptase polymerase chain reaction (RT-PCR) to detect circulating prostate-specific antigen (PSA)-positive cells is a prognostic factor for survival in hormone refractory prostate cancer and to validate the prognostic importance of this test in relation to other known prognostic factors. PATIENTS AND METHODS: A single centralized laboratory received and analyzed whole blood for RT-PCR for PSA for a subset of patients enrolled on two Cancer and Leukemia Group B (CALGB) randomized trials (CALGB 9583 and CALGB 9480). Using 9583, a prognostic model was developed and an independent data set (CALGB 9480) was used to validate the fitted model. RESULTS: Of 162 patients in 9,583, 91 (56%) patients were negative for RT-PCR for PSA and 71 (44%) patients were positive. The median survival time was 21 months (95% confidence interval [CI], 18 to 27 months) for RT-PCR-negative patients compared with 11 months (95% CI, 8 to 15 months) for RT-PCR-positive patients (P < or =.001). In multivariable analysis, the hazard ratio (HR) for death was 1.7 (95% CI, 1.2 to 2.4; P =.006) for positive RT-PCR patients compared with negative RT-PCR patients. A fitted model that incorporated RT-PCR for PSA and other factors was used to classify patients from 9,480 into one of two risk groups: low or high. We observed good agreement between the observed and predicted survival probabilities for the two risk groups. CONCLUSION: RT-PCR to detect PSA-positive circulating cells is confirmed to be a significant prognostic factor of survival in patients with hormone refractory prostate cancer. This model could be used to stratify patients in randomized phase III trials.

J Clin Oncol. 2003 Feb 1;21(3):490-5

Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer.

PURPOSE: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. EXPERIMENTAL DESIGN: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We estimated the probability of survival over time by the Kaplan-Meier method. The concordance probability estimate was used to gauge the discriminatory strength of the informative prognostic factors. RESULTS: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. CONCLUSIONS: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.

Clin Cancer Res. 2007 Dec 1;13(23):7053-8

Circulating tumor cells versus imaging—predicting overall survival in metastatic breast cancer.

PURPOSE: The presence of >or=5 circulating tumor cells (CTC) in 7.5 mL blood from patients with measurable metastatic breast cancer before and/or after initiation of therapy is associated with shorter progression-free and overall survival. In this report, we compared the use of CTCs to radiology for prediction of overall survival. EXPERIMENTAL DESIGN: One hundred thirty-eight metastatic breast cancer patients had imaging studies done before and a median of 10 weeks after the initiation of therapy. All scans were centrally reviewed by two independent radiologists using WHO criteria to determine radiologic response. CTC counts were determined approximately 4 weeks after initiation of therapy. Specimens were analyzed at one of seven laboratories and reviewed by a central laboratory. RESULTS: Interreader variability for radiologic responses and CTC counts were 15.2% and 0.7%, respectively. The median overall survival of 13 (9%) patients with radiologic nonprogression and >or=5 CTCs was significantly shorter than that of the 83 (60%) patients with radiologic nonprogression and <5 CTCs (15.3 versus 26.9 months; P=0.0389). The median overall survival of the 20 (14%) patients with radiologic progression and <5 CTCs was significantly longer than the 22 (16%) patients with >or=5 CTCs that showed progression by radiology (19.9 versus 6.4 months; P=0.0039). CONCLUSIONS: Assessment of CTCs is an earlier, more reproducible indication of disease status than current imaging methods. CTCs may be a superior surrogate end point, as they are highly reproducible and correlate better with overall survival than do changes determined by traditional radiology.

Clin Cancer Res. 2006 Nov 1;12(21):6403-9

Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival.

PURPOSE: We reported previously that >or=5 circulating tumor cells (CTC) in 7.5 mL blood at baseline and at first follow-up in 177 patients with metastatic breast cancer (MBC) were associated with poor clinical outcome. In this study, additional follow-up data and CTC levels at subsequent follow-up visits were evaluated. EXPERIMENTAL DESIGN: CTCs were enumerated in 177 MBC patients before the initiation of a new course of therapy (baseline) and 3 to 5, 6 to 8, 9 to 14, and 15 to 20 weeks after the initiation of therapy. Progression-free survival (PFS) and overall survival (OS) times were calculated from the dates of each follow-up blood draw. Kaplan-Meier plots and survival analyses were done using a threshold of >or=5 CTCs/7.5 mL at each blood draw. RESULTS: Median PFS times for patients with <5 CTC from each of the five blood draw time points were 7.0, 6.1, 5.6, 7.0, and 6.0 months, respectively. For patients with >or=5 CTC, median PFS from these same time points was significantly shorter: 2.7, 1.3, 1.4, 3.0, and 3.6 months, respectively. Median OS for patients with <5 CTC from the five blood draw time points was all >18.5 months. For patients with >or=5 CTC, median OS from these same time points was significantly shorter: 10.9, 6.3, 6.3, 6.6, and 6.7 months, respectively. Median PFS and OS times at baseline and up to 9 to 14 weeks after the initiation of therapy were statistically significantly different. CONCLUSIONS: Detection of elevated CTCs at any time during therapy is an accurate indication of subsequent rapid disease progression and mortality for MBC patients.

Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4218-24

Breast cancer-specific mRNA transcripts presence in peripheral blood after adjuvant chemotherapy predicts poor survival among high-risk breast cancer patients treated with high-dose chemotherapy with peripheral blood stem cell support.

PURPOSE: To study the prognostic significance of the presence of breast cancer-specific mRNA transcripts in peripheral blood (PB), defined by serial analysis of gene expression, in high-risk breast cancer (HRBC) patients undergoing high-dose chemotherapy after receiving adjuvant chemotherapy. METHODS: From 1994 to 2000, 84 HRBC patients (median age, 44 years; > 10 nodes; 74%) received adjuvant chemotherapy (fluorouracil, epirubicin, and cyclophosphamide for six cycles [83%] or doxorubicin and cyclophosphamide followed by paclitaxel) before undergoing one course of cyclophosphamide plus thiotepa plus carboplatin (STAMP V). Radiotherapy or hormone therapy was administered whenever indicated. Aliquots of apheresis-mononuclear blood cells were frozen from each patient. mRNA was isolated using an automatic nucleic acid extractor based on the magnetic beads technology; reverse transcription was performed using random hexamers. Cytokeratin 19, HER-2, P1B, PS2, and EGP2 transcripts were quantified to B-glucuronidase by real-time polymerase chain reaction (RT-PCR) using a linear DNA probe marked with a quencher and reporter fluorophores used in RT-PCR. Presence of PB micrometastases, estrogen receptor and progesterone receptor status, tumor size, age, tumor grade, number of nodes affected, and treatment with paclitaxel were included in the statistical analysis. RESULTS: Median follow-up was 68.3 months (range, 6 months to 103 months). Forty-seven relapses (56%) and 35 deaths (41.7%) were registered. Both tumor size and presence of micrometastases reached statistical significance according to the Cox multivariate model. Relapse hazard ratio (HR) for those patients with PB micrometastases was 269% (P = .006); death HR, 300% (P = .011). Time relapse was 53 months longer for patients without micrometastases: 31.3 v 84.2 months (P = .021). CONCLUSION: PB micrometastases presence after adjuvant chemotherapy predicts both relapse and death more powerful than classical factors in HRBC patients undergoing high-dose chemotherapy. Micrometastases search using a gene panel appears to be a more accurate procedure than classical approaches involving only one or two genes.

J Clin Oncol. 2006 Aug 1;24(22):3611-8

Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse.

PURPOSE: To demonstrate that it is possible to monitor the response to adjuvant therapy by repeated analysis of circulating epithelial tumor cells (CETCs) and to detect patients early who are at risk of relapse. PATIENTS AND METHODS: In 91 nonmetastatic primary breast cancer patients, CETCs were quantified using laser scanning cytometry of anti-epithelial cell adhesion molecule-stained epithelial cells from whole unseparated blood before and during adjuvant chemotherapy. RESULTS: Numbers of CETCs were analyzed before therapy, before each new cycle, and at the end of chemotherapy. The following three typical patterns of response were observed: (1) decrease in cell numbers (> 10-fold); (2) marginal changes in cell numbers (< 10-fold); and (3) an (sometimes saw-toothed) increase or an initial decrease with subsequent reincrease (> 10-fold) in numbers of CETCs. Twenty relapses (22%) were observed within the accrual time of 40 months, including one of 28 patients from response group 1, five of 30 patients from response group 2, and 14 of 33 patients from response group 3. The difference in relapse-free survival was highly significant for CETC (hazard ratio = 4.407; 95% CI, 1.739 to 9.418; P < .001) between patients with decreasing cell numbers and those with marginal changes and between patients with marginal changes and those with an increase of more than 10-fold (linear Cox regression model). CONCLUSION: These results show that peripherally circulating tumor cells are influenced by systemic chemotherapy and that an increase (even after initial response to therapy) of 10-fold or more at the end of therapy is a strong predictor of relapse and a surrogate marker for the aggressiveness of the tumor cells.

J Clin Oncol. 2008 Mar 10;26(8):1208-15

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