Intra- and interfraction breathing variations during curative radiotherapy for lung cancer.

BACKGROUND AND PURPOSE: This study aimed at quantifying the breathing variations among lung cancer patients over full courses of fractionated radiotherapy. The intention was to relate these variations to the margins assigned to lung tumours, to account for respiratory motion, in fractionated radiotherapy. MATERIALS AND METHODS: Eleven lung cancer patients were included in the study. The patients' chest wall motions were monitored as a surrogate measure for breathing motion during each fraction of radiotherapy by use of an external optical marker. The exhale level variations were evaluated with respect to exhale points and fraction-baseline, defined for intra- and interfraction variations respectively. The breathing amplitude was evaluated as breathing cycle amplitudes and fraction-max-amplitudes defined for intra- and interfraction breathing, respectively. RESULTS: The breathing variations over a full treatment course, including both intra- and interfraction variations, were 15.2mm (median over the patient population), range 5.5-26.7mm, with the variations in exhale level as the major contributing factor. The median interfraction span in exhale level was 14.8mm, whereas the median fraction-max-amplitude was 6.1mm (median of patient individual SD 1.4). The median intrafraction span in exhale level was 1.6mm, and the median breathing cycle amplitude was 4.0mm (median of patient individual SD 1.4). CONCLUSIONS: The variations in externally measured exhale levels are larger than variations in breathing amplitude. The interfraction variations in exhale level are in general are up to 10 times larger than intrafraction variations. Margins to account for respiratory motion cannot safely be based on one planning session, especially not if relying on measuring external marker motion. Margins for lung tumours should include interfraction variations in breathing.     

Comparative in vivo evaluation of technetium and iodine labels on an anti-HER2 affibody for single-photon imaging of HER2 expression in tumors.

In vivo diagnosis with cancer-specific targeting agents that have optimal characteristics for imaging is an important development in treatment planning for cancer patients. Overexpression of the HER2 antigen is high in several types of carcinomas and has predictive and prognostic value, especially for breast cancer. A new type of targeting agent, the Affibody molecule, was described recently. An Affibody dimer, His6-(ZHER2:4)2 (15.4 kDa), binds to HER2 with an affinity of 3 nmol/L and might be used for the imaging of HER2 expression. The use of 99mTc might improve the availability of the labeled conjugate, and Tc(I)-carbonyl chemistry enables the site-specific labeling of the histidine tag on the Affibody molecule. The goals of the present study were to prepare 99mTc-labeled His6-(ZHER2:4)2 and to evaluate its targeting properties compared with the targeting properties of 125I-4-iodobenzoate-His6-(ZHER2:4)2 [125I-His6-(ZHER2:4)2]. METHODS: The labeling of His6-(ZHER2:4)2 with 99mTc was performed with an IsoLink kit. The specificity of 99mTc-His6-(ZHER2:4)2 binding to HER2 was evaluated in vitro with SK-OV-3 ovarian carcinoma cells. The comparative biodistributions of 99mTc-His6-(ZHER2:4)2 and 125I-His6-(ZHER2:4)2 in tumor-bearing BALB/c nu/nu mice were determined. RESULTS: The labeling yield for 99mTc-His6-(ZHER2:4)2 was approximately 60% (50 degrees C), and the radiochemical purity was greater than 97%. The conjugate was stable during storage and under histidine and cysteine challenges and demonstrated receptor-specific binding. The biodistribution study demonstrated tumor-specific uptake levels (percentage injected activity per gram of tissue [%IA/g]) of 2.6 %IA/g for 99mTc-His6-(ZHER2:4)2 and 2.3 %IA/g for 125I-His6-(ZHER2:4)2 at 4 h after injection. Both conjugates provided clear imaging of SK-OV-3 xenografts at 6 h after injection. The tumor-to-nontumor ratios were much more favorable for the radioiodinated Affibody. CONCLUSION: The use of Tc(I)-carbonyl chemistry enabled us to prepare a stable, site-specifically labeled 99mTc-His6-(ZHER2:4)2 conjugate that was able to bind to HER2-expressing cells in vitro and in vivo. The indirectly radioiodinated conjugate provided better tumor-to-liver ratios. The labeling of Affibody molecules with 99mTc should be investigated further.     

The nocturnal jejunal migrating motor complex: defining normal ranges by study of 51 healthy adult volunteers and meta-analysis

Interdigestive human small bowel motility is characterized by the migrating motor complex (MMC). The aims of this study were to: (i) establish the normal range of variables of the nocturnal jejunal MMC and (ii) incorporate these data in a subsequent meta-analysis. Eighty-one recordings were performed by prolonged (24 h) ambulatory manometry in 51 subjects in two centres. Quantitative analysis was undertaken of 419 Phase III and 332 Phase II episodes. Adjusted mean values of seven variables were calculated using a mixed-effects model. Meta-analysis of pooled published data to generate a reliable 95% reference range was also performed. Adjusted mean values and confidence intervals are presented for all seven variables. Intrasubject variances were large in comparison with intersubject. Meta-analysis of 19 studies (356 pooled patients) meeting inclusion criteria produced wide reference ranges. At least five such ranges are useful for the detection of abnormality in the individual. This is the largest study of normal volunteers presented to date, with ranges for many variables produced using appropriate statistical methodology. A model for definition of abnormality has been proposed. We recommend that these data may be used by investigators in this field as a complement to other existing indicators of small bowel dysmotility.     

Activation of peripheral 5-HT4 receptors attenuates colonic sensitivity to intraluminal distension

Tegaserod is a 5-HT(4) receptor partial agonist approved for the treatment of irritable bowel syndrome in women with constipation and in both men and women with chronic constipation. The efficacy of tegaserod is based on the importance of 5-HT(4) receptors regulating intestinal peristalsis and secretion, and possibly visceral sensory pathways. Our aim was to investigate the effect of tegaserod on colorectal sensitivity using models of normal and exaggerated responsiveness to colorectal distension (CRD). The visceromotor responses (VMR) to CRD at graded pressures (0-60 mmHg) were measured by the number of reflex abdominal contractions. Acute colorectal hypersensitivity was induced by intracolonic infusion of dilute acetic acid. Chronic hypersensitivity was observed in rats following spontaneous resolution of trinitrobenzenesulfonic acid-induced colitis. Rats with normosensitive colons served as controls. Tegaserod (0.1-10 mg kg(-1)) caused dose-dependent reduction of the VMR to CRD in control rats and in those with colonic hypersensitivity. 5-HT(4) antagonists reversed the effects of tegaserod in rats with normosensitive colons, and partially inhibited effects in rats with colonic hypersensitivity. Central administration of tegaserod had no inhibitory effect. These results support the assumption that colonic hypersensitivity could be normalized by tegaserod acting, at least in part, through peripheral 5-HT(4) receptors.     

Effect of female sex hormone supplementation and withdrawal on gastrointestinal and colonic transit in postmenopausal women

Females are disproportionately affected by constipation, which is often aggravated during pregnancy. Bowel function also changes during the luteal phase of the menstrual cycle. The aim was to compare the effects of acute administration of female sex steroids on gastric emptying, small bowel transit and colonic transit in healthy postmenopausal subjects. A second aim was to determine whether withdrawal of the hormones was associated with a change in transit. Forty-nine postmenopausal females were randomized to receive for 7 days 400 mg day(-1) micronized progesterone, 0.2 mg day(-1) oestradiol, combination of the two, or placebo. Treatment groups were balanced on age. Participants underwent whole gut transit measurement by scintigraphy using a 99m-labeled technetium-egg meal and 111-labeled indium-charcoal via a delayed-release capsule. Transit measurement was repeated after withdrawal of the study medications. The primary endpoints were ascending colon (AC) emptying half-life time (t1/2) and colonic geometric centre (GC) at 24 h. Secondary analysis variables were GC at 4 and 48 h, gastric emptying t1/2 and colonic filling at 6 h. There was a significant overall effect of progesterone on colonic transit with shorter AC emptying t1/2 and significantly greater colonic GC at 48 h. No transit endpoints were altered by oestradiol or combined hormonal treatment relative to placebo. Oestradiol and progesterone resulted in looser stool consistency. Withdrawal of the hormone supplement was not associated with significant alteration in transit. Micronized progesterone does not retard colonic transit in postmenopausal females.     

Antibodies against 5-hydroxymethyl-2'-deoxyuridine are associated with lifestyle factors and GSTM1 genotype: a report from the Malm? Diet and Cancer cohort.

Plasma autoantibodies (aAbs) against the oxidized DNA base derivative 5-hydroxymethyl-2'-deoxyuridine (5-HMdU) are potential biomarkers of cancer risk and oxidative stress. We examined their association with a number of cancer risk factors: smoking, alcohol habits, body fatness, and absence of the glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) in a sample from the population-based Malm? Diet and Cancer cohort (Sweden). This was a cross-sectional study of 264 men and 280 women, 46-67 years of age. Anti-5-HMdU aAb concentration was determined by an ELISA. Data on tobacco exposure were collected through a questionnaire. Alcohol consumption was estimated by a modified diet history method. Body fatness was assessed by a bioimpedance method. The absence or presence of genes coding for GSTM1 and GSTT1 was determined in granulocyte DNA by a multiplex PCR technique. aAb titers were significantly greater in those with high alcohol consumption. Current smokers lacking GSTM1, particularly men, had greater aAb titers compared with nonsmokers or persons expressing GSTM1. Body fatness was inversely associated with antibody titers in men. GSTT1 genotype was not associated with aAb titers. Overall, women had higher aAb titers than men. Adjustment for potential confounders (history of chronic diseases, anti-inflammatory medication, and season of blood sampling) did not change the results. Our study shows that a high alcohol consumption, smoking in combination with lack of GSTM1, and low body fatness (in men) is associated with high titers of anti-5-HMdU aAbs in this population.     

Low-dose lactulose produces a tonic contraction in the human colon

Lactulose (10-20 g day(-1)) is used to treat constipation. At this therapeutic dose, its effects on colonic motility remain unknown. Twenty-two healthy subjects swallowed a probe with an infusion catheter, six perfused catheters and a balloon connected to a barostat. Colonic phasic and tonic motor activity was recorded in fasting state. In group 1, four volunteers ingested 15 g lactulose and motility was recorded for 5 h after entry of lactulose into the caecum; in group 2, motility was recorded during (3 h) and 2 h after intracolonic infusion of isoosmotic and isovolumetric solutions containing sodium chloride alone (n = 9) or with 15 g lactulose (n = 9). In a last group of volunteers, isotopic colonic transit after ingestion of lactulose (10 g,n = 9) was assessed and compared with a control group (n = 17). Ingestion or intracolonic infusion of 15 g lactulose significantly decreased barostat bag volume (maximal decrease: 45 +/- 12% and 35 +/- 9% of basal value respectively). Phasic contractions remained unchanged. Tonic and phasic motility was unchanged by the isotonic and isovolumetric infusion of saline. Ingestion of lactulose significantly accelerated isotopic colonic transit time compared with the control group. We conclude that in healthy humans, 10-15 g ingestion or intracaecal infusion of lactulose produces a prolonged tonic contraction that may be involved in the laxative effect of lactulose.     

Mercury exposure of different origins among dentists and dental nurses

Mercury exposure was studied among dental personnel with the use of urinary mercury excretion rates and questionnaires. The study covered 314 dentists and dental nurses employed in public clinics and private practices in Stockholm. The obtained urinary mercury excretion rates were analyzed by stepwise regression for assigning them to different origins, such as environmental factors, number of amalgam surfaces, chewing of gum, kind of employment and profession, age, sex, amalgam handling time, and use of amalgam capsules. On the average the occupational contribution to the total urinary mercury excretion rate was small and of the same order as the contribution from their own amalgam fillings (approximately 2 micrograms of mercury/24 h). There were, however, individuals showing excretion rates close to the levels at which effects on the central nervous system and the kidneys have been reported.     

Effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on the dopaminergic and cholinergic receptors as evaluated by positron emission tomography in the Rhesus monkey

Summary The effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP) on the central cholinergic and dopaminergic systems in the Rhesus monkey brain were investigated by positron emission tomography (PET) with the muscarinic cholinergic receptor ligands (N-[¹¹C]methyl-benztropine) and dopaminergic receptor ligands selective for D₁ D₂, and D₃ subtypes ([¹¹C]SCH23390, N-[¹¹C]methyl-spiperone, and (+)[¹¹C]UH232, respectively). None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP used significantly affected the regional cerebral blood flow (rCBF as determined by Raichle's H₂ ¹⁵O method), and 10 mg/kg of R-THBP had little effect on the regional cerebral metabolic rate of glucose (rCMRglc) in the Rhesus monkey brain, as assessed by the graphical [¹⁸F]fluoro-deoxyglucose method. The effect of R-THBP on the muscarinic cholinergic system was dose dependent; while 3 mg/kg of R-THBP did not significantly alter the uptake ratio of N-[¹¹C]methyl-benztropine in several brain regions to that in the cerebellum, 10 and 30 mg/kg of R-THBP significantly reduced the uptake ratio in the thalamus, as well as in the frontal and temporal cortices. None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP tested affected [¹¹C]SCH23390 (dopamine D₁ receptor) binding. However, the k3 value for N-[¹¹C]methyl-spiperone (dopamine D₂ receptor) binding, which represents the association rate × B_max value, was significantly decreased in the striatum. The uptake ratio of (+)[¹¹C]UH232 (dopamine D₃ receptor) in the striatum to that in the cerebellum was also decreased by administration of R-THBP (3 and 30 mg/kg i.v.). These findings suggest that R-THBP acts on dopamine D₂ and D₃ receptors selectively without markedly affecting dopamine D₁ receptor binding. Furthermore, the changes in cholinergic and dopamine D₂ and D₃ receptors in vivo can not be attributed to a change in rCBF but may depend on the action of R-THBP.Abbreviations R-THBP 6R-L-erythro-5,6,7,8-tetrahydrobiopterin - PET positron emission tomography - rCBF regional cerebral blood flow - rCMRglc regional cerebral metabolic rate of glucose