Does the Consumption of Green Tea Reduce the Risk of Lung Cancer Among Smokers ? Experimental and epidemiological studies were reviewed to assess whether the consumption of green tea could reduce the risk of lung cancer in smokers . Articles published since 1990 were located by searching electronic databases PubMed , Ovid and Science Direct , using keywords ` lung cancer ' , ` tea ' and ` smoking ' without any restriction on language . After relevant articles had been located , further papers were obtained from their reference lists . Evidence from experimental studies -LRB- in vitro animal and human trials -RRB- suggested that regular intake of green tea may be protective against tobacco carcinogens . However , the mechanism behind the protective effect is only partly understood . In most of the epidemiological studies reviewed , the green tea exposure was within 5 years of the interview or follow-up , which would coincide with the induction period and latent period of lung cancer . Longer term studies are thus needed to further quantify the cancer risk . There is some evidence suggesting regular intake of green tea at high level -LRB- > 3 cups per day -RRB- may reduce the risk of smokers developing lung cancer . Improvement in measuring green tea intake is required in order to confirm the evidence from epidemiological studies . Introduction Lung cancer has become one of the leading causes of death in both developed and developing countries -LRB- 1,2 -RRB- . Most of the deaths from lung cancer are due to smoking tobacco products . Worldwide in 2000 , tobacco smoking contributed 77 % of the lung cancer deaths in males aged 30 -- 69 years , and 82 % in males over 70 years -LRB- 1,2 -RRB- . In 2003 , for example , the prevalence of smoking in China was estimated to be 58.9 % among adult males , while Chinese smokers are four times more likely to die from lung cancer than non-smokers -LRB- 3 -RRB- . Although elimination of tobacco smoke exposure is the obvious strategy to control lung cancer , no country has been completely successful in implementing an effective intervention . The efficacy of smoking cessation programs may be enhanced if they are conducted in conjunction with other complementary therapies . Epidemiological and experimental studies have suggested that green tea may be protective against cancer in different sites -LRB- 4 -- 21 -RRB- . In particular , recent evidence from in vitro , animal and human trial studies indicated the possibility that the consumption of green tea may reduce the risk of lung cancer among smokers -LRB- 2,22 -- 35 -RRB- , yet findings from epidemiological studies remained inconsistent . The aim of this review is to assess evidence from experimental and epidemiological studies whether green tea is a risk modifier for those exposed to tobacco smoke . The focus is on the measurement of green tea exposure undertaken in these studies . Methods Articles published since 1990 were located by searching electronic databases PubMed , Ovid and Science Direct , using keywords ` lung cancer ' , ` tea ' and ` smoking ' without any restriction on language . After relevant articles had been located , further papers were obtained from their reference lists . A total of 78 relevant articles were eventually found . Results and Discussion In vitro and Animal Studies Both in vitro and animal studies have demonstrated that green tea or tea polyphenols have a chemopreventive effect against carcinogens from tobacco and is dependent on both the period and dose of the exposure . Period of exposure The period of exposure to green tea or tea polyphenols and the period of exposure to carcinogens must overlap . In one in vitro study , green tea polyphenols were introduced once into the living cell environment 2 h before exposing the cells to a smoke solution for 30 min . Result showed that green tea polyphenols can reduce DNA strand breakage induced by cigarette smoke in cultured human bronchial cells A549 -LRB- 32 -RRB- . In another in vitro study , human lymphoid cells were exposed to one single dose of green tea extracting solution 2 h before adding benzo -LRB- a -RRB- pyrene-diol-epoxide -LRB- BPDE -RRB- -- a metabolic production of benzo -LRB- a -RRB- pyrene -LRB- B -LRB- a -RRB- P -RRB- , which is a major component of tobacco . The results demonstrated that green tea can significantly reduce DNA damage caused by BPDE -LRB- 22 -RRB- . Similarly in four other animal studies -LRB- 23,29,33,34 -RRB- , mice were given green tea prior to or within 48 h of exposure to tobacco carcinogens , and the green tea was continuously administered for 16 weeks or 9 months . Other experimental conditions such as diet , humidity , temperature and dark/light cycle were controlled . Three out of the four studies found a reduction in the incidence and the size of lung cancer tumors due to drinking green tea -LRB- 23,33,34 -RRB- . Dose of exposure The preventive effect of green tea is likely to be related to the concentration of green tea as well as the dose of carcinogens . In experimental studies both cells and animals were often treated with relatively high doses of carcinogens and green tea . For example , in a study which showed a protective effect of green tea , the concentration of tobacco carcinogens used was equivalent to the amount contained in the sidestream smoke from one cigarette dissolved in 24 ml of water , while the concentration of green tea polyphenol was set at 250 μg ml − 1 , corresponding to 116.5 μg ml − 1 of epigallocatechin-3-gallate -LRB- EGCG -RRB- -LRB- 32 -RRB- . Moreover , the bioavailability of different green tea polyphenols has been a concern in animal and human studies . Green tea polyphenols are not usually stable , specifically , in water , EGCG can oxidize more than 50 % within 12 h , yet green tea used in experimental studies was typically prepared every 48 h -LRB- 33,34 -RRB- to every 7 days -LRB- 29 -RRB- . In some studies where mice were exposed to both NNK -LSB- 4 - -LRB- methylnitrosamino -RRB- -1 - -LRB- 3-pyridyl -RRB- -1-butanone -RSB- and green tea , the NNK dosage administered was usually equal to that experienced by a smoker in a lifetime -LRB- 36 -RRB- . In one experiment mice were randomized into different groups and given green tea solution at concentrations of 0.2 % , 0.4 % and 0.6 % as drinking fluid 24 h after treating with NNK . Comparing with the control group that drank only water , the protective effect of green tea was only evident at the 0.6 % concentration level -LRB- 33 -RRB- . In another study -LRB- 29 -RRB- , mice were exposed to high levels of environmental tobacco smoke for 5 months , while being given 1.25 % green tea -LRB- 2.5 g tea leave mixed with 200 ml boiling water -RRB- . The results indicated green tea had little effect on reducing tumor incidence or multiplicity of the tumors . However , none of the animals in the green tea treatment group experienced early death while > 10 % of the mice in the control group experienced early deaths , probably due to an overdose of carcinogens exposure -LRB- 29 -RRB- . Findings from these experiments suggest that green tea may not be effective to inhibit the formation or growth of lung tumor under high level of carcinogens exposure and over a long duration . Human Trials Short-term effect Because a single dose of green tea intake only produces a short-term antioxidant effect , regular consumption seems necessary . In a human study -LRB- 37 -RRB- , 21 non-smokers consumed 300 ml of green tea solution or about three cups . Ferric reducing ability of plasma -LRB- FRAP-assay -RRB- was used to determine the antioxidant activity in plasma . The results of this study showed that green tea consumption produced a significant increase in antioxidant activity within 30 -- 120 min of exposure , but after 120 min the antioxidant activity appeared to decrease . Another human trial with 10 healthy subjects similarly found a short-term increase of plasma antioxidant induced by drinking two to three cups of green tea at one time -LRB- 38 -RRB- . Such a short-term increase seemed to correspond with the relatively short half-life of tea polyphenols -LRB- 30 -RRB- . In one pharmacokinetic study -LRB- 39 -RRB- , 30 healthy participants ingested 200 mg of EGCG equivalent to two cups of green tea . Blood samples were collected at 0.5 , 1 , 2 , 4 , 6 , 8 and 24 h after the EGCG administration . This experiment found that the mean half-life of EGCG in plasma was only 118 min . Protective effect from regular consumption Regular green tea consumption could be protective over an extended period . In one pilot study -LRB- 35 -RRB- , three non-smokers and three smokers -LRB- consumed more than 10 cigarettes per day -RRB- drank two cups of green tea in the morning , two cups in the afternoon and one cup at night daily for 4 weeks . Each cup of green tea contained 400 -- 500 mg of green tea extract . Oral keratinocytes were harvested from each subject for analysis . Outcomes included a reduction in smoking-induced DNA damage , increased apoptosis and a further decrease in the number of cells carrying damaged DNA -LRB- 35 -RRB- . In a randomized control trial -LRB- 27 -RRB- , 133 smokers who smoked at least 10 cigarettes per day during the past year were randomized into three groups consuming at least four cups daily of either -LRB- i -RRB- decaffeinated green tea , -LRB- ii -RRB- decaffeinated black tea , or -LRB- iii -RRB- water . After 4 months of intervention , smokers who drank decaffeinated green tea had a significant decrease in their urinary 8-hydroxydeoxyguanosine -LRB- 8-OHdG -RRB- level , but no significant changes were observed in both water and black tea groups . Similar reduction in urinary 8-OHdG level was observed among HbsAg positive volunteers who took daily capsules containing green tea polyphenols equivalent to two to four cups of tea for 3 months -LRB- 40 -RRB- . In an intensive observational study -LRB- 25 -RRB- , the frequencies of sister-chromatid exchange -LRB- SCE -RRB- in peripheral lymphocytes were measured as markers of smoking-induced DNA damage . The frequencies of SCE were significantly higher among smokers who were non-tea drinkers , than those of non-smokers and smokers who consumed green tea at least two to three cups per day during the past 6 months . The differences between the latter two groups , however , were not significant . It is possible that consuming high levels of green tea over a long period may reduce the DNA damage caused by tobacco smoking . Lung tumor treatment Only one clinical trial used green tea for treatment of lung cancer -LRB- 41 -RRB- . In this Phase I study , 17 advanced lung cancer patients were given green tea extract at a single dose of 3 g m − 2 per day for 4 weeks . The dosage equates to 20 cups of green tea , which has been found to be the maximum tolerated dose . Unfortunately , no effect of the treatment was observed . Therefore , green tea is unlikely to be an effective cytotoxic agent against existing tumor . Limitation of human trials Except two studies -LRB- 27,40 -RRB- , most human intervention studies involved small sample sizes generally less than 50 subjects . In addition to ethical concerns , there were neither direct measurement on the concentration of green tea polyphenols in lung tissue nor on the change of lung tissue after green tea exposure . Instead , the effects of green tea were measured by the change in DNA damage and apoptosis of oral cells -LRB- 35 -RRB- , changes in biomarkers of DNA damage such as 8-OHdG and SCE -LRB- 25,27,40 -RRB- , and changes in plasma antioxidant capacity -LRB- 30,37,38 -RRB- . Trials with sufficient sample size and longer period of follow-up are needed to confirm the protective effect of green tea . Mechanisms Based on Experimental Studies As shown in Fig. 1 , carcinogens contained in cigarette smoke are activated by Phase I enzymes in the body , leading to the formation of DNA adducts -LRB- 36 -RRB- . If DNA adducts escape cellular repair mechanisms , it may result in miscoding and eventually a stable mutation . Blocking any step in the pathway would reduce the incidence of lung cancer among smokers -LRB- 36 -RRB- . Table 1 provides the possible mechanisms of chemoprevention effect of green tea . The evidence suggested that catechins in green tea , especially EGCG , may prevent the formation of a mutated cell . Figure 1 . Mechanism of tobacco carcinogens inducing lung cancer . Table 1 . Possible mechanism of actionPossible mechanism of chemoprevention effect of green teaReferencesActing as antioxidant to prevent DNA damage and reduce the formation of DNA adducts -LRB- 11,22,25,27,35,40 -RRB- Increasing apoptosis and preventing the persistence of miscoding DNA -LRB- possibly by inducing gene regulation -RRB- -LRB- 11,26,31,33,35,40,43,44 -RRB- Activating Phase II detoxifying enzymes , and increasing the excretion of carcinogens -LRB- possibly by inducing gene regulation -RRB- -LRB- 2,8,28,31 -RRB- In both animal and in vitro studies , green tea was found to increase the activities of Phase II enzymes -LRB- 2,8,28,31 -RRB- . Phase II enzymes transform carcinogens into non-toxic molecules for subsequent excretion -LRB- 42 -RRB- . The amount of carcinogens that may be further activated , as well as DNA adducts , are thus reduced . The antioxidant properties of green tea have also been demonstrated in trials involving smokers . It reduced the urine concentration of 8-OHdG , a strong biomarker of DNA damage -LRB- 27 -RRB- . Moreover , green tea extract could inhibit the formation of human DNA adducts -LRB- 11,22,35 -RRB- . Once carcinogen DNA adducts have formed , persistent mutation is likely unless cells with DNA adducts are removed by apoptosis -LRB- 36 -RRB- . Human -LRB- 35 -RRB- , animal -LRB- 11,33 -RRB- and in vitro studies -LRB- 26,43,44 -RRB- have shown that green tea can induce apoptosis among injured cells exposed to carcinogens from tobacco smoke . However , smoking may be regarded as a chronic exposure , since long duration of tobacco smoking has greater impact on lung caner risk than the amount smoked per day -LRB- 45 -RRB- . Therefore , a long exposure to green tea is needed in order to reduce the damage caused by tobacco carcinogens . Epidemiological Studies Induction time and latent period of lung carcinoma Latent period refers to the time between disease occurrence and detection , while tumor induction time commences when the effect of the exposure occurs until all of the component causes involved in one sufficient cause are satisfied -- the time of disease occurrence -LRB- 46 -RRB- . Exposure within the induction and latent periods is irrelevant to the formation of a tumor -LRB- 47 -RRB- . Moreover , the incidence of lung cancer does not appear to be lower among ex-smokers who quit smoking within 5 years than current smokers -LRB- 48,49 -RRB- . This indicates that the sum of induction period and latent period of lung cancer caused by tobacco smoking may be longer than 5 years . Logically , no reduction in incidence of lung carcinoma is expected among current smokers who drink green tea for 5 years prior to the calculation of incidence , regardless of their consumption level . Measurement of green tea exposure and other limitations Table 2 summarizes epidemiological studies on tea and lung cancer . Three case -- control studies -LRB- 50 -- 52 -RRB- found a significantly lower risk of lung cancer among non-smokers with a high consumption of green or black tea , but no protective effect was evident among smokers -LRB- 50,51 -RRB- . However , the period of tea consumption referred to 5 years or less before the diagnosis or interview . Although the subjects might have been drinking tea for a long time , the duration and quantity of tea consumption was not assessed , so the effect of green tea could not be fully justified . Cohort studies , on the other hand , were based on information of tea consumption at the beginning of the study -LRB- 53 -- 55 -RRB- and suggested that tea consumption increased with age -LRB- 54,55 -RRB- . In particular , the Japanese study -LRB- 53 -RRB- with a long follow-up period of 14 years showed that people consuming green tea two to four times per day had a relative risk of 0.78 -LRB- 95 % CI = 0.6 -- 1.0 -RRB- , when compared with those drinking once or less per day and after adjustment for potential confounders . But for subjects drinking green tea more than five times per day , the relative risk was only 0.79 -LRB- 95 % CI = 0.59 -- 1.1 -RRB- , the non-significance result probably due to insufficient sample size at this high level of consumption -LRB- 53 -RRB- . Table 2 . Epidemiology studies on tea and lung cancerCountryStudy designSample sizeTea type and highest consumption levelReference period of intakeSmoking status of subjectsResultsChina -LRB- 50 -RRB- Population-based case -- control studyCases : 649 Controls : 675Green tea : > 1500 g tea leaves per year5 years before interviewSmokers and non-smokersOR = 0.65 ; 95 % CI = 0.45 -- 0.93 for non-smokers OR = 0.94 ; 95 % CI = 0.40 -- 2.22 for smokersCanada -LRB- 52 -RRB- Population-based case -- control studyCases : 582 Controls : 582Type unspecified : > 7 cups per day2 years before studyNon-smokersOR = 0.4 ; 95 % CI = 02 -- 0.7 USA -LRB- 51 -RRB- Population based case -- control studyCases : 161 Controls 483Green tea : > 1 cup per day1 year before diagnosis or interviewSmokers and non-smokersOR = 0.9 ; 95 % CI = 0.5 -- 1.6 Japan -LRB- 53 -RRB- Cohort study -LRB- 1980 -- 94 -RRB- Subjects : 38 540 Person-years at risk : unspecified Cases : 436Green tea : > 5 times per dayUnspecified ; survey taken at start of studySmokers and non-smokersRR = 0.78 ; 95 % CI = 0.6 -- 1.0 for people drinking tea 2 -- 4 times per dayJapan -LRB- 54 -RRB- Cohort study -LRB- 1986 -- 95 -RRB- Subjects : 8552 Person-years at risk : 71 248.5 Cases : 384Green tea : > 10 cups per dayUnspecified ; survey taken at start of studySmokers and non-smokersCancer in all sites RR = 0.68 for males ; 95 % CI = 0.39 -- 1.21 RR = 0.57 for females ; 95 % CI = 0.33 -- 0.98 OR , odds ratio ; RR , relative risk ; CI , confidence interval . In summary , there is only limited evidence from epidemiological studies that green tea is protective against lung cancer among smokers . Moreover , green tea exposure was generally taken to be within 5 years of interview or follow-up , which would have little impact on the incidence of lung cancer . Conclusion Our review suggests that regular intake of green tea at high levels -LRB- > 3 cups per day -RRB- may offer protection against tobacco carcinogens for smokers , provided that the duration of green tea consumption is sufficiently long to cover the smoking period . For epidemiology studies , improvement in measuring green tea intake is required in order to confirm the chemopreventive effect of green tea observed in in vitro animal and human trials .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O


The efficacy of anakinra in an adolescent with colchicine-resistant familial Mediterranean fever Colchicine is the treatment of choice in familial Mediterranean fever -LRB- FMF -RRB- for the prevention of both attacks and secondary amyloidosis . The overall nonresponder rate is about 5 -- 10 % . Anakinra is known to have good effectiveness in a severe autoinflammatory syndrome -LSB- chronic infantile neurological cutaneous and articular -LRB- CINCA -RRB- syndrome -RSB- and other recurrent hereditary periodic fevers . Pyrin -- the protein involved in FMF -- has a role in activating the proinflammatory cytokine interleukin -LRB- IL -RRB- -1 β . We report the effectiveness of the addition of an IL-1-receptor inhibitor -LRB- anakinra -RRB- to colchicine in controlling the febrile attacks and acute phase response in an adolescent with FMF resistant to colchicine . Case report A 15-year-old girl with familial Mediterranean fever -LRB- FMF -RRB- was admitted to our hospital because of the persistence of recurrent fever attacks -LRB- twice a month -RRB- , accompanied by chest and abdominal pain with headache , despite taking colchicine at a high dose -LRB- 2 mg/kg per day -RRB- . She suffered severe discomfort and complained of several school absences . Acute phase reactants -LSB- erythrocyte sedimentation rate -LRB- ESR -RRB- 110 , C-reactive protein -LRB- CRP -RRB- 43 mg % -RSB- and serum interferon-γ -LRB- 125.4 pg/ml -RRB- were high during the crises . There was no proteinuria , but given the severity of the clinical picture , we performed a rectal biopsy to definitely exclude the presence of amyloidosis and it was negative . Anakinra was started at 50 mg/day -LRB- 1 mg/kg per day -RRB- subcutaneously , without stopping colchicine . Approval was obtained from an Ethics Committee -LRB- Burlo Garofolo Health Authority -RRB- . In the following 3 months the patient developed only three mild episodes of abdominal pain without fever , which resolved in a few hours . During these episodes acute phase reactants were negative . Moreover , serum interferon-γ was low -LRB- 23 pg/ml -RRB- . After 3 months , anakinra was discontinued to confirm its real efficacy , without stopping colchicine . Following this interruption , the girl complained of eight fever attacks in 3 months accompanied by abdominal pain , vomiting , chest pain , and headache . Anakinra was reintroduced . Since then -LRB- 15 months of follow-up -RRB- , the patient has been in good health , without any fever attacks or abdominal or chest pain . There have been no adverse effects due to anakinra , apart from minor local stinging and erythema at the injection sites , which gradually diminished . Discussion Colchicine is the recommended treatment of FMF since it can prevent the febrile attacks and the development of amyloidosis , even though a few patients develop amyloidosis also when on colchicine treatment -LSB- 3 , 5 -RSB- . However , approximately one third of the patients have a partial remission and about 5 -- 10 % are nonresponders -LSB- 3 -RSB- ; another 2 -- 5 % do not tolerate the drug well -LSB- 3 -RSB- . In single case reports several drugs -LRB- interferon-α , infliximab , thalidomide , etanercept -RRB- have been suggested as a possible alternative treatment for these cases -LSB- 3 , 6 -RSB- . Anakinra is a recombinant form of the human interleukin -LRB- IL -RRB- -1-receptor antagonist that targets type I IL-1-receptor which is expressed in many tissues . There are some studies and case reports that show a good efficacy of anakinra in a severe autoinflammatory syndrome -LRB- CINCA , chronic infantile neurological cutaneous and articular syndrome -RRB- -LSB- 2 -RSB- and other recurrent hereditary periodic fevers -LSB- 4 -RSB- . Despite the elevated costs -LRB- approximately 50 $ per 100 mg -RRB- its use appears justified in some inflammatory diseases that lack alternative treatments . Since pyrin -- the protein involved in FMF -- activates the precursor form of IL-1β into its biologically active fragments there is a rationale for testing anakinra in FMF -LSB- 1 , 5 -RSB- . Moreover , anakinra did appear to be effective in suppressing acute phase reactants in a patient with FMF -LRB- a nonresponder to the treatment with colchicine -RRB- and amyloidosis -LSB- 1 -RSB- . In our case , the addition of anakinra to colchicine had a dramatic therapeutic benefit without relevant side effects . As the febrile attacks recurred after discontinuing anakinra and disappeared again after reintroduction , we believe in the real therapeutic efficacy of this drug . In light of the present evidence -LSB- 3 , 5 -RSB- , colchicine should be continued in order to prevent further developments of amyloidosis .

O O O B O O O O O B I I O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O


Feasibility study of computed tomography colonography using limited bowel preparation at normal and low-dose levels study The purpose was to evaluate low-dose CT colonography without cathartic cleansing in terms of image quality , polyp visualization and patient acceptance . Sixty-one patients scheduled for colonoscopy started a low-fiber diet , lactulose and amidotrizoic-acid for fecal tagging 2 days prior to the CT scan -LRB- standard dose , 5.8 -- 8.2 mSv -RRB- . The original raw data of 51 patients were modified and reconstructed at simulated 2.3 and 0.7 mSv levels . Two observers evaluated the standard dose scan regarding image quality and polyps . A third evaluated the presence of polyps at all three mSv levels in a blinded prospective way . All observers were blinded to the reference standard : colonoscopy . At three times patients were given questionnaires relating to their experiences and preference . Image quality was sufficient in all patients , but significantly lower in the cecum , sigmoid and rectum . The two observers correctly identified respectively 10/15 -LRB- 67 % -RRB- and 9/15 -LRB- 60 % -RRB- polyps ≥ 10 mm , with 5 and 8 false-positive lesions -LRB- standard dose scan -RRB- . Dose reduction down to 0.7 mSv was not associated with significant changes in diagnostic value -LRB- polyps ≥ 10 mm -RRB- . Eighty percent of patients preferred CT colonography and 13 % preferred colonoscopy -LRB- P < 0.001 -RRB- . CT colonography without cleansing is preferred to colonoscopy and shows sufficient image quality and moderate sensitivity , without impaired diagnostic value at dose-levels as low as 0.7 mSv . Introduction Since computed tomography colonography -LRB- CTC -RRB- has shown good results in detecting clinically relevant polyps -LSB- 1 -- 6 -RSB- , studies have been performed focusing on increasing patient acceptance by reducing the bowel preparation . This can be done by adding an oral contrast agent to meals -LRB- fecal tagging -RRB- -LSB- 7 -- 12 -RSB- in combination with a low-fiber diet , and sometimes lactulose for stool softening , thereby obviating extensive cleansing . Different studies have been performed using barium , iodine or a combination of both as tagging material . However , only a limited number of these studies on CTC have used limited bowel preparation . Few have evaluated the diagnostic value and patient acceptance of CTC . In parallel with the development of limited bowel preparation strategies , -LRB- ultra -RRB- low-dose protocols have been evaluated -LSB- 13 -- 15 -RSB- . To our knowledge , to date no studies have evaluated the effect of dose reduction on sensitivity and specificity in patients with a limited bowel preparation . Only one study -LSB- 7 -RSB- has evaluated limited bowel preparation at a relatively low dose level -LRB- 140 kVp , 10 mAs -RRB- . This study has shown very good results ; however , these data have not been reproduced yet . Moreover , as only one dose-level was studied , the effect of dose reduction remains unknown . The purpose of this study was to evaluate limited bowel-preparation CTC using an oral contrast agent -LRB- amidotrizoic acid -RRB- in terms of image quality , patient acceptance and polyp visualization using conventional colonoscopy -LRB- CC -RRB- as a reference standard . A second objective was to determine the effect of substantially reducing the radiation dose levels on the diagnostic accuracy of limited bowel preparation CTC , again using CC as the reference standard . Materials and methods Study population Patients of the Onze Lieve Vrouwe Gasthuis at increased risk for colorectal cancer -LRB- personal or family history of colorectal polyps or cancer -RRB- -LSB- 16 -RSB- who were scheduled to undergo CC between April 2002 and August 2003 were invited to participate in the study . Exclusion criteria were : impossibility to understand the information/informed consent , age below 18 years , pregnancy and inflammatory bowel disease . The study was approved by the institutional review board of the Onze Lieve Vrouwe Gasthuis and Academic Medical Center . All patients gave written informed consent . CTC bowel preparation and scanning protocol Four weeks prior to the CC patients were asked to ingest amidotrizoic acid -LRB- 20 mg/ml , made by the hospital pharmacy , 11.7 mg I/ml ; corresponding to approximately 30 times diluted Gastrografin370 ® -RRB- three times a day -LRB- 100 ml at breakfast and lunch , 300 ml at dinner -RRB- with a low-fiber diet -LRB- well cooked vegetables and meat , no fibrous fruit , no whole-wheat products , no nuts -RRB- starting 2 days prior to CTC . Lactulose -LRB- 12 g , lactulose CF powder 6 g/sachet , Centrafarm , Etten-Leur , The Netherlands -RRB- was taken in the morning for 3 days prior to CTC for stool softening . Twenty mg of butylscopolaminebromide -LRB- Buscopan ; Boehringer-Ingelheim , Ingelheim , Germany -RRB- , when contraindicated , 1 mg of glucagon hydrochloride -LRB- Glucagen ; Novo-Nordisk , Bagsvaerd , Denmark -RRB- was administered intravenously . The colon was insufflated with a CO2-air mixture -LRB- 13.2 % vol . -RRB- using a flexible catheter until patients experienced discomfort -LRB- ± 2 -- 3 l -RRB- . Patients were scanned in prone and supine position with a four-slice MX8000 -LRB- Philips Medical Systems , Best , The Netherlands -RRB- CT scanner -LRB- 120 kV , rotation time 0.75 s , pitch 1.25 , collimation 4 * 2.5 mm , section thickness 3.2 mm , and reconstruction interval 1.6 mm , 50 or 70 milliampere-second -LRB- mAs -RRB- ; 70 mAs if the abdominal circumference was > 102.5 cm , scan time 20 -- 25 s -RRB- . Colonoscopy Prior to CC , each patient was instructed to ingest 4 l of a macrogol solution -LRB- Colofort macrogol 4000 sachets , Ipsen , Hoofddorp , The Netherlands -RRB- , starting on the evening prior to the CC . CC was performed by one of three experienced gastroenterologists of the Onze Lieve Vrouwe Gasthuis -LRB- experience as gastroenterologist : 23 , 12 and 4 years -RRB- and recorded on videotape . Patients received sedatives -LSB- 5 mg midazolam -LRB- Dormicum ; Roche , Basel , Switzerland -RRB- -RSB- and analgesics -LSB- 0.05 mg fentanyl -LRB- Janssen Pharmaceuticals , Beerse , Belgium -RRB- -RSB- at the request of the patient . If polyps were present , the location was determined and size was estimated , based on comparison with an open biopsy forceps prior to removal . A polyp was considered flat if its height was less than one-half of the diameter of the lesion -LSB- 17 -RSB- . Only segments visualized at CC were used for analysis . Simulation of low-dose CT colonography To study polyp detection at lower dose , CTC examinations were simulated with a lower dose/mAs-value using an established simulation technique -LSB- 18 , 19 -RSB- that has been applied in two earlier CTC studies -LSB- 13 , 14 -RSB- . This simulation method consists of the controlled increase of noise in the raw CT transmission data prior to reconstruction of the images . In this way , scans were simulated at 20 mAs -LRB- in the order of 2.3 mSv for two scans : supine and prone -RRB- and 6 mAs -LRB- ± 0.7 mSv -RRB- . A previous simulation study has demonstrated that the radiation dose of CTC after extensive bowel cleansing can be reduced down to 0.2 mSv -LSB- 13 -RSB- . Since the contrast between tissue and tagged fecal material in limited bowel preparation colons is lower than that between air and tissue , we chose 0.7 mSv as the lowest simulated dose-level next to 2.3 mSv . CTC evaluation An unblinded research fellow -LRB- J.F. , experience : evaluated 300 CTC -RRB- matched findings at CC -LRB- polyps ≥ 6 mm and colorectal cancer -RRB- with the CTC data to provide a frame of reference for true positive findings at CTC . Only exact matches in shape , size and location were scored as a positive match . All images were then independently evaluated using a primary 2D display mode by three blinded observers . The first observer -LRB- research fellow , R.v.G. , experience : compared > 300 CTCs with CC videos -RRB- evaluated the original CTC scan for image quality and for polyps . Scores were assigned -LRB- per patient/segment , Table 1 -RRB- for overall image quality , luminal distension , homogeneity and presence of stool . The second observer evaluated the original CTC for polyps and marked those examinations that were not diagnostic . If both observers rated a CTC as not diagnostic , this patient was excluded from analysis . The third observer first evaluated the simulated 0.7 mSv scans for presence of polyps at least 4 weeks after the simulated 2.3 mSv scans , and again at least 4 weeks later the original CTC scans . All lesions were measured and screenshots were taken . The second observer -LRB- V.v.d.H. , experience : 8 years of clinical CT experience as abdominal radiologist -RRB- and the third observer -LRB- A.v.R. , a research fellow in radiology with no prior experience with CTC -RRB- had had a learning curve in evaluating 50 CTCs with CC feedback . Table 1Scales used by observer 1 to rate image quality -LRB- upper part -RRB- and scales used by the patients to rate experience and preferenceObserver 1 : ScaleImage quality -LRB- patient , segment -RRB- * 1 : poor , not diagnostic ; 2 : moderate , diagnostic with limitations ; 3 : good , diagnostic with minor limitations ; 4 : excellent , no limitationsDistension -LRB- segment -RRB- 1 : collapsed ; 2 : poorly distended ; 3 : only moderately distended but segment is distended over its full length ; 4 : good ; 5 : very goodHomogeneity -LRB- segment -RRB- 1 : poor ; 2 : moderate ; 3 : good ; 4 : very goodPresence of stool -LRB- segmemt -RRB- 1 : large amount of stool , segment fully filled ; 2 : moderate amount of stool , ~ 50 % of lumen filled ; 3 : small amount of stool ; 4 : only contrast layer on the wall ; 5 : no stool at allPatients : Most burdensome aspectCTC preparation : diet , lactulose , contrast agentCTC : iv puncture , catheter placing , insufflation , breathholds , prone positionCC : iv puncture , moving of scope , air insufflation , monitoring after CCHow burdensome/painfulNot , mild , moderate , severe , extremePreferenceDefinitely CTC , probably CTC , possibly CTC , indifferent , possibly CC , probably CC , definitely CCMost reluctant factorCC , bowel preparation prior to the CC , CTC , the limited bowel preparation prior to the CTC * The items were scored per patient and per segment . Polyp detection and image quality A polyp detected at CTC was labeled as true positive if three criteria were met : segmental location and location within the segment corresponded with CC -LRB- when situated near the borders of the segment , localization in the adjacent segment was also accepted -RRB- , the polyp size as estimated by the endoscopist -LRB- open forceps -RRB- corresponded with size as measured on CTC -LRB- 50 % margin based on the CC size was allowed -RRB- , and appearance -LRB- morphology -RRB- closely resembled that of the corresponding polyp at videotaped CC . The unblinded research fellow determined the nature of false-positive findings ≥ 10 mm by reviewing the videotaped CC and CTC . If the polyp was possibly missed at CC , a repeat CC was called for . Patient questionnaires Patient experience and preference were evaluated by six questionnaires -LRB- scales are shown in Table 1 -RRB- : 2 weeks prior to the CTC , directly after the CTC bowel preparation , after the CTC , after the CC preparation , after the CC and 5 weeks later . The first and the last questionnaires were sent by mail . After the CTC bowel preparation , patients were asked how burdensome they rated the CTC bowel preparation , and the most burdensome aspect . After CTC they rated how much pain they had experienced and how burdensome the CTC had been . Prior to CC patients were asked how burdensome the extensive bowel preparation had been . After the CC they were asked how much pain they had experienced and how burdensome the CC had been . After the CC and 5 weeks later , patients were asked for their preference for either CTC or CC assuming that both techniques were equally accurate , while in 20 % of CTC examinations clinically relevant lesions would be shown , necessitating a therapeutic CC . Two weeks prior to the CTC , directly after the CC and 5 weeks later , patients were asked what they were most reluctant to undergo . Statistical analysis Differences in quality between CTC images of different segments were assessed using ordinal regression analysis . For this analysis we first determined the best segment and used this segment as reference segment . The regression coefficient of each segment estimates the change in the log transformed diagnostic odds ratio -LRB- DOR -RRB- compared to the reference segment . It can be interpreted , after antilogarithm transformation as relative diagnostic odds ratio -LRB- RDOR -RRB- . A lower RDOR implies inferior image quality of the respective segment compared to the reference segment . Differences in polyp detection rates between CC and lower dose CTC were assessed with the McNemar test for paired proportions . The Wilcoxon signed rank test statistic was used to evaluate differences in patient experience between CTC and CC and to evaluate differences in preference between the questionnaire filled out directly after the procedures and 5 weeks later . The data were first dichotomized as preference for CTC versus preference for CC . These differences were tested using the chi-square test statistic . All P-values < 0.05 were considered to indicate statistical significance . Results Sixty-three eligible patients -LRB- 53 % -RRB- gave written informed consent . Two patients were excluded . One patient was excluded since he did not undergo CC for unknown reasons . In another patient with a 20-mm carcinoma opposite the ileocecal valve at CC , the CTC was rated as of no diagnostic value by both observers -LRB- parts of the large bowel not in the field of view , stool not tagged sufficiently , and breathing movement artifacts -RRB- . Therefore , 61 patients were analyzed -LRB- Table 2 -RRB- ; 51 of these 61 patients could be reviewed regarding dose reduction . Table 2Baseline characteristics of the study populationIncluded61Male/female40/21Age in years : mean ± sd † -LRB- range -RRB- 61 ± 12 -LRB- 27 -- 81 -RRB- Indication : H/O † colorectal polyps38H/O colorectal carcinoma9F/H † of colorectal polyps or cancer14Coexistent complains : Abdominal pain/hematochezia/altered bowel habits12/4/3Colonoscopy : number of polyps/patients with polyps : Any size94/38 ≥ 6 mm28/20 ≥ 10 mm15/12 ≥ 10 mm initial colonoscopy13/11Morphology of polyps ≥ 6 mm -LRB- sessile/stalked/flat / CRC -RRB- 12/7/7 / 2Morphology of polyps ≥ 10 mm -LRB- sessile/stalked/flat / CRC -RRB- 3/6/4 / 2Colonoscopy : no . of patients receiving Sed + analg/sed/analg / none29/7/3 / 22Stool consistency prior to CTC -LRB- diarrhea/soft/normal -RRB- 15/13/33Abdominal pain prior to CTC -LRB- major/minor -RRB- 1/7Flatulence prior to CTC -LRB- major/minor -RRB- 3/27Spasmolitycs during CTC -LRB- Buscopan/Glucagon/neither -RRB- 47/12/2 † sd : standard deviation ; H/O : history of ; F/H : family history , sed : sedatives . Analg : analgesics In five patients it was not possible to fully inspect the colon endoscopically . In one patient a 14-mm polyp was seen at CTC in a segment not inspected at CC and confirmed at surgery -LRB- not included in the analysis -RRB- . In two patients , repeat CC showed a 30-mm polyp and a 30-mm carcinoma -LRB- included in the analyses -RRB- , both missed at the initial CC . Image quality Overall image quality was rated as excellent in 2 patients , good in 41 and moderate in 18 . One patient who received a score of poor/not diagnostic was excluded . Image quality was significantly lower -LRB- Fig. 1 -RRB- in the cecum -LRB- both positions -RRB- , sigmoid -LRB- prone position -RRB- and rectum -LRB- supine position -RRB- . This was mainly due to inferior homogeneity in the cecum and rectum and inferior distension in the sigmoid and rectum . Fig. 1Figure showing RDOR with confidence intervals of all six segments of the colorectum in both prone and supine position regarding overall image quality , distension , presence of stool and homogeneity . All segments are compared to the best segment -LRB- DOR by definition 1 -RRB- . Confidence intervals not reaching 1 indicate significantly inferior results Diagnostic value Including the findings at repeat CC , 12 patients had 15 polyps ≥ 10 mm -LRB- including 2 carcinomas of 35 mm and 30 mm -RRB- while 20 patients had in total 28 polyps ≥ 6 mm -LRB- Fig. 2 -RRB- . Twenty-three of 61 patients did not have any polyps at colonoscopy . The initial CC detected 13 of the 15 large polyps -LRB- sensitivity 87 % -RRB- . The per-patient sensitivity for the initial CC was 92 % -LRB- 11/12 -RRB- . The unblinded research fellow was able to match 13/15 -LRB- 87 % -RRB- large polyps -LRB- in 10/12 patients : 83 % -RRB- , while 2 large flat lesions were not visible in retrospect . For polyps ≥ 6 mm he matched 23/28 -LRB- 87 % -RRB- polyps -LRB- 3 additional flat lesions not visible in a patient with already a large flat lesion -RRB- in 18/20 -LRB- 90 % -RRB- patients . Observers 1 and 2 correctly identified 10/15 -LRB- 67 % -RRB- and 9/15 -LRB- 60 % -RRB- polyps ≥ 10 mm , with respectively 5 and 8 false-positive lesions -LRB- Table 3 -RRB- . All but two were explained as stool . Fig. 2A 76-year-old woman with a 7-mm stalked polyp -LRB- arrow -RRB- submerged in a layer of tagged stool at CTC -LRB- original dose ; a : supine position , b prone position -RRB- and at colonoscopy -LRB- c -RRB- Table 3Performance characteristics per observer per size categoryVariablePolyps ≥ 10 mmPolyps ≥ 6 mmObserver : Observer : 1212Analysis according to polypSensitivity10/15 -LRB- 67 % -RRB- 9/15 -LRB- 60 % -RRB- 17/28 -LRB- 61 % -RRB- 15/28 -LRB- 54 % -RRB- FP582028PPV10/16 -LRB- 63 % -RRB- 9/17 -LRB- 53 % -RRB- 17/38 -LRB- 45 % -RRB- 15/43 -LRB- 35 % -RRB- Analysis according to patientSensitivity8/12 -LRB- 67 % -RRB- 8/12 -LRB- 67 % -RRB- 13/20 -LRB- 65 % -RRB- 13/20 -LRB- 65 % -RRB- Specificity45/49 -LRB- 92 % -RRB- 41/49 -LRB- 84 % -RRB- 30/41 -LRB- 73 % -RRB- 25/41 -LRB- 73 % -RRB- PPV8/12 -LRB- 67 % -RRB- 8/16 -LRB- 50 % -RRB- 13/24 -LRB- 54 % -RRB- 13/29 -LRB- 45 % -RRB- NPV45/49 -LRB- 92 % -RRB- 41/45 -LRB- 91 % -RRB- 30/37 -LRB- 81 % -RRB- 25/32 -LRB- 78 % -RRB- PPV : positive predictive value ; NPV : negative predictive value ; FP : false positives ; CI : confidence interval Polyp detection at lower dose-levels In 51 of 61 patients , we were able to simulate and reconstruct data at lower dose levels . In 10 of 61 patients this was not possible due to missing original raw data . Dose reduction down to 0.7 mSv was not associated with significant changes in diagnostic value for patients with lesions ≥ 10 mm -LRB- Table 4 , Figs. 3 and 4 -RRB- . Only focusing on the data of these 51 patients , reader 3 showed diagnostic values comparable to or even better than reviewer 1 and 2 : sensitivity for reviewer 1 and 2 both 5 out of 10 large polyps with respectively 5 and 8 false-positive lesions ≥ 10 mm and respectively 10 and 9 out of 20 polyps ≥ 6 mm with respectively 20 and 25 false-positives ≥ 6 mm . Specificity for patients without lesions ≥ 6 mm was significantly lower -LRB- P = 0.003 -RRB- at 6 mAs when compared to the original dose . Table 4Performance characteristics of observer 3 per dose levelVariablePolyps ≥ 10 mmPolyps ≥ 6 mmDose levelDose levelOriginal2 .3 mSv0 .7 mSvOriginal2 .3 mSv0 .7 mSvAnalysis according to polypSensitivity5/10 -LRB- 50 % -RRB- 7/10 -LRB- 70 % -RRB- 4 / 10 -LRB- 40 % -RRB- 11/20 -LRB- 55 % -RRB- 13/20 -LRB- 65 % -RRB- 10/20 -LRB- 50 % -RRB- FP22451120Analysis according to patientSensitivity5/9 -LRB- 56 % -RRB- 7/9 -LRB- 78 % -RRB- 4 / 9 -LRB- 44 % -RRB- 10/15 -LRB- 67 % -RRB- 12/15 -LRB- 60 % -RRB- 9/15 -LRB- 45 % -RRB- Specificity40/42 -LRB- 95 % -RRB- 40/42 -LRB- 95 % -RRB- 39/42 -LRB- 93 % -RRB- 33/36 -LRB- 92 % -RRB- 26/36 -LRB- 72 % -RRB- 23/36SS -LRB- 64 % -RRB- SS : statistically significant . FP : false positivesStatistical analysis -LRB- only performed on the per patient data -RRB- showed that only the specificity for patients without lesions ≥ 6 mm was significantly lower -LRB- P = 0.003 -RRB- at 0.7 mSv when compared to the original doseFig . 3Figure showing a large 12-mm false-positive lesion -LRB- arrow -RRB- in the transverse colon at three different dose levels in a 65-year-old male patient -LRB- a : 0.7 mSv , b : 2.3 mSv , c : original -RRB- . At lower dose levels it is more difficult to differentiate this lesion from a true-positive lesion -LRB- polyp -RRB- when fecal material is insufficiently tagged , this especially applied to smaller lesions . Well-tagged material is clearly differentiated from colon wall , even at 0.7 mSv -LRB- arrowhead -RRB- Fig. 4Figure showing a large 10-mm stalked polyp -LRB- arrowhead -RRB- in the sigmoid at three different dose levels in a 57-year-old male patient -LRB- a : 0.7 mSv , b : 2.3 mSv , c : original -RRB- Patient experience and preference The 6 questionnaires were filled out by respectively 58 -LRB- 95 % -RRB- , 61 -LRB- 100 % -RRB- , 61 -LRB- 100 % -RRB- , 56 -LRB- 92 % -RRB- , 57 -LRB- 93 % -RRB- and 57 -LRB- 93 % -RRB- patients . Two weeks prior to the CTC patients were most reluctant to undergo CC , then the CC bowel preparation , thirdly the limited CTC bowel preparation . The CTC was feared least . After both procedures -LRB- fifth questionnaire -RRB- , the order was the same . Five weeks later the bowel preparation prior to the CC was regarded to be the most burdensome , followed by the CC , then the CTC preparation and the CTC . None of the three aspects of the bowel preparation for CTC -LRB- the diet , lactulose and contrast agent -RRB- was rated significantly worse than the others -LRB- Fig. 5 -RRB- . Patients rated the limited bowel preparation -LRB- prior to CTC -RRB- less burdensome than the bowel preparation prior to CC -LRB- Fig. 6 , P < 0.001 -RRB- . Patients also experienced more pain during CC than during CTC -LRB- Fig. 6 , P < 0.001 -RRB- . The most burdening aspect of the CTC was insufflation of air -LRB- 58 % -RRB- . The most burdening aspect of CC was the movement of the scope -LRB- 59 % -RRB- . Directly after the CC -LRB- fifth questionnaire -RRB- 80 % -LRB- 43/54 -RRB- of the patients preferred CTC for their next examination , 13 % -LRB- 7 -RRB- preferred CC -LRB- P < 0.001 -RRB- and 7 % -LRB- 4 -RRB- were indifferent -LRB- Fig. 6 -RRB- . Five weeks after the procedures , 71 % -LRB- 39/55 -RRB- preferred CTC , 13 % -LRB- 7 -RRB- preferred CC -LRB- P < 0.001 -RRB- and 18 % -LRB- 10 -RRB- were indifferent . After 5 weeks there was no change -LRB- P = 0.12 -RRB- in preference of CTC as the next screening test . Fig. 5Graph showing how patients rated the three different components of CTC with limited bowel preparation . How burdensome were the diet , lactulose and the contrast agent?Fig . 6Graphs show patients ' experience of the bowel preparation -LRB- upper left -RRB- and the CTC examination -LRB- upper right -RRB- and patient preference for one of the two modalities -LRB- CTC with limited bowel preparation versus CTC with standard bowel preparation , lower -RRB- . How burdensome was the limited bowel preparation prior to CTC -LRB- grey -RRB- as compared to cleansing prior to CC -LRB- black -RRB- ? How burdensome were the CTC -LRB- grey -RRB- and CC -LRB- black -RRB- examinations -LRB- upper right graphs -RRB- ? What did participants prefer for their next examination -LRB- lower graph -RRB- directly after both examinations and in the questionnaire sent at home 5 weeks later ? Discussion This study demonstrates that CT colonography without cleansing is preferred to colonoscopy and shows moderate sensitivity -LRB- 60 -- 67 % -RRB- for polyps ≥ 10 mm without impaired diagnostic value at mSv levels as low as 0.7 mSv . Image quality was good on average . Nevertheless , the cecum , sigmoid and rectum showed overall reduced image quality . Although this can be caused by the pelvis causing more noise , reduced imaged quality must probably be attributed to inferior homogeneity in the cecum and rectum and inferior distension in the sigmoid and rectum in the prone position . In contrast to the known problems in CTC with distension , which are solved by dual positioning , inferior homogeneity in the cecum and rectum are typical for the limited bowel preparation protocol . Insufficient homogeneity in the cecum is probably caused by the fact that patients ate food after the last amount of contrast agent was taken , resulting in inadequately tagged stool . The inhomogeneous stool in the rectum probably was caused by the fact that in patients with a long transit time stool was already shaped before the fecal tagging was started . We assume that two adaptations are necessary to improve image quality . First , contrast must be taken as long as the patients are eating . Second , stool should be made softer , for example by replacing lactulose by a stronger osmotic laxative -LRB- e.g. , low-dose magnesium salts -RRB- , thereby also reducing the transit time and reducing the amount of non-tagged stool in the rectum . Although these adaptations increase the burden of the bowel preparation , they are slight and are required to improve image quality and thereby maybe the sensitivity and specificity . Our study showed an average sensitivity of 63 % for large polyps -LRB- with a limited number of large false-positive lesions -RRB- . This is lower than the 100 % average sensitivity described by Iannaccone et al. -LSB- 7 -RSB- using a more or less comparable bowel preparation ; no fiber-rich food and 200 ml of 370 mg/ml iodinated contrast agent in 48 h -LRB- which is 6.3 times the amount given in our study -RRB- , but no lactulose . In addition to the differences in bowel preparation , differences in experience of the readers or reader performance , difference in study groups -LRB- polyp prevalence and spectrum -RRB- might explain these discrepant results . A recent study -LSB- 20 -RSB- has shown inferior results regarding diagnostic value of CTC in populations at increased risk , as is used in the current study , possibly due to a relatively high number of hard-to-see polyps . When comparing our study with three large studies on CTC with extensive bowel preparation -LSB- 21 -- 23 -RSB- -LRB- showing per polyp sensitivities of respectively 52 % , 32 -- 73 % and 53 % for polyps ≥ 10 mm -RRB- , our results are comparable or slightly better . Since two of five -LRB- observer 1 -RRB- and two of six -LRB- observer 2 -RRB- missed polyps were not seen in retrospect by the unblinded observer , the problem of missing large polyps can be regarded as predominantly an interpretation problem rather than a visualization problem . Future developments , such as better homogeneity , better distension , better learning curve , intuitive display modes , electronic cleansing and computer-aided detection can help in reducing the number of missed polyps . Sensitivity and specificity were impaired at lower dose levels for patients with lesions ≥ 10 mm . This is especially of interest in screening protocols . Regarding lesions ≥ 6 mm , specificity was significantly lower at the simulated 0.7 mSv low-dose scans . Increased noise levels made it impossible to see the tiny air bubbles inside stool . These results may seem to be in contrast with those in an earlier report on low radiation dose CTC -LSB- 13 -RSB- showing fewer false-positive lesions . However , these studies in patients with extensively cleansed colons used a three-dimensional display mode and filters to smooth the bowel wall . By using these smoothing filters , small artifacts and small amounts of residual stool were masked when evaluating the colon three dimensionally . Making stool softer and scanning with thinner slices possibly allows for better visualization of the air bubbles , thereby reducing the number of false positives . Patient acceptance was found to be very good in the current study . Patient preference was convincingly in favor of CTC ; 71 % of patients preferred CTC with limited bowel preparation to CC for their next examination . Other studies have shown discrepant results on patient acceptance of CTC versus CC , some favoring CTC -LSB- 24 -- 27 -RSB- , others CC -LSB- 28 , 29 -RSB- . In a study where patients first underwent extensive cleansing and consecutively CTC and CC -LSB- 24 -RSB- fewer patients -LRB- 71 % directly after the CC -RRB- favored CTC when compared to our study -LRB- 80 % directly after CC -RRB- . This difference can not be attributed to the bowel preparation because of a different study setup . Several potential limitations must be considered . The number of patients included is relatively low , especially for determining the detection parameters at the 2.3 and 0.7 mSv levels . In the current study no segmental unblinding during CC was performed . Although repeat CC showed that two large false-positive lesions were missed at the initial CC , segmental unblinding has the advantage of evaluating all false positives . Since no electronic cleansing was used and many polyps were submerged , 3D evaluation of these lesions was not of additive value . However , 3D evaluation with electronic cleansing might have given better results , especially since most missed polyps were visible in retrospect . Although the two readers that had no previous experience in CTC underwent a learning curve of 50 patients , some studies have shown that this may not be sufficient for optimal polyp detection -LSB- 30 , 31 -RSB- . For CTC using limited bowel preparation , the learning curve is possibly even longer . When filling out the questionnaires , sensitivity for CC and CTC were assumed equal . If patients knew that the sensitivity of CTC was lower than for CC , this most likely would have influenced the preference for CTC negatively . In conclusion , these results show that CTC with the limited bowel preparation protocol used in this study is feasible , even when using doses as low as 0.7 mSv levels . Although sensitivity was not as high as previously reported , this is most likely not due to the limited bowel preparation , but to interpretation problems . Technical developments will probably increase the sensitivity , while minor adjustments in bowel preparation may reduce the number of false positives , especially when using low-dose protocols . Since patient acceptance was very good , this technique can be regarded as promising in screening patients of populations with a low prevalence of polyps .

O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B O O O O O O B I O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

ct colonography
fecal tagging
colonoscopy