Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer.

PURPOSE: This Nordic multicenter phase II study evaluated the efficacy and safety of oxaliplatin combined with the Nordic bolus schedule of fluorouracil (FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer. PATIENTS AND METHODS: Eighty-five patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1, followed by a 3-minute bolus injection with FU 500 mg/m(2) and, 30 minutes later, by a bolus injection with FA 60 mg/m(2) every second week. The same doses of FU and FA were also given on day 2. RESULTS: Fifty-one of 82 assessable patients achieved a complete (n = 4) or partial (n = 47) response, leading to a response rate of 62% (95% CI, 52% to 72%). Nineteen patients showed stable disease, and 12 patients had progressive disease. Thirty-eight of the 51 responses were radiologically confirmed 8 weeks later (confirmed response rate, 46%; 95% CI, 36% to 58%). The estimated median time to progression was 7.0 months (95% CI, 6.3 to 7.7 months), and the median overall survival was 16.1 months (95% CI, 12.7 to 19.6 months) in the intent-to-treat population. Neutropenia was the main adverse event, with grade 3 to 4 toxicity in 58% of patients. Febrile neutropenia developed in seven patients. Nonhematologic toxicity consisted mainly of neuropathy (grade 3 in 11 patients and grade 2 in another 27 patients). CONCLUSION: Oxaliplatin combined with the bolus Nordic schedule of FU+FA (Nordic FLOX) is a well-tolerated, effective, and feasible bolus schedule as first-line treatment of metastatic colorectal cancer that yields comparable results compared with more complex schedules.     

Gastric mucosa lesions induced by duodenogastric reflux increase penetration of N-[3H]-methyl-N-nitro-N-nitrosoguanidine into corpus mucosa of rats

The mucosal changes by which duodenogastric reflux may predispose to gastric cancer have not been fully clarified. In this study in rats, duodenal fluid was directed into the stomach through a gastroenterostomy (jejunal reflux, N = 29) or through the pylorus (pyloric reflux, N = 30) and compared with 30 controls. Twenty-four weeks later the stomach was exposed to N-[³H]methyl-N-nitro-N-nitrosoguanidine ([³H]MNNG). The corpus mucosa was examined for proliferating cells (bromodeoxyuridine labeled) and cells at risk of methyl-N-nitro-N-nitrosoguanidine-induced carcinogenesis (cells labeled with bromodeoxyuridine and [³H]MNNG). The number of double-labeled cells increased from 0.8 ± 0.1/mm mucosa in the control group to 5.2 ± 0.9 in the jejunal reflux group (P < 0.05) and 2.7 ± 0.5 in the pyloric reflux group (P < 0.05). An erosion or ulcer appeared at the gastroenterostomy in 52% of animals with jejunal reflux and 17% of those with pyloric reflux (P < 0.006). Within erosions the mean number of double-labeled cells was 9.6 ± 2.2 in the jejunal reflux group and 7.7 ± 4.8 in the pyloric reflux group, and significantly higher than in the nonlesion area of the mucosa (0.6 ± 0.2 and 0.8 ± 0.3). In erosions the distance between the gastric lumen and the proliferating cells was significantly shorter and the cell proliferation significantly higher than in the nonlesion area of the mucosa. We conclude that duodenogastric reflux increases the penetration of [³H]MNNG into the corpus mucosa of rats and also induces mucosa lesions, which further increase the penetration of [³H]MNNG into the corpus mucosa.     

Characterization of Mechanical Effects and β-Adrenoceptor Binding of Prenalterol in Rat Myocardium

Abstract: The partial β-agonist prenalterol has been found to differ from the full agonist isoprenaline in some aspects of its cardiac action. We therefore studied in rat myocardium whether prenalterol elicited the same qualitative changes of the contraction-relaxation cycle as was previously found for isoprenaline. We also measured binding of prenalterol to β-adrenoceptors. Prenalterol augmented relaxation more than contraction and thus evoked the same qualitative changes of the contraction-relaxation cycle as did isoprenaline. However, the response developed slowlier than that to isoprenaline, and the effect on relaxation followed a more protracted time course than the effect on contraction. Prenalterol bound non-selectively to β₁- and β₂-adrenoceptors in both heart and lung broken cell preparations. pK_d for binding to β-adrenoceptors and pD₂ values for functional effects in heart were similar, i.e. prenalterol had to occupy half the amount of β-adrenoceptors in order to evoke half-maximal functional effects. The non-selective α-blocker phentolamine potentiated the effects of prenalterol on contraction, but did not change the equilibrium binding of prenalterol to cardiac β-adrenoceptors. Phentolamine did not change the potency and efficacy of isoprenaline. Thus, although prenalterol qualitatively evoked the same response as isoprenaline, it also exhibited some properties which differed.     

Profiles and time course of acute radiation toxicity symptoms during conformal radiotherapy for cancer of the prostate

Symptoms of gastrointestinal toxicity are dose-limiting for pelvic radiotherapy (RT). Existing toxicity registrations (RTOG/EORTC) are helpful in defining maximal tolerated doses, but tend to underestimate the total toxicity burden by excluding several minor complaints. We have applied a more detailed and quantitative recording of symptoms and related these scores to RT-induced endoscopic and histopathologic changes. Prevalence and severity of specific toxicity symptoms were recorded before, during (weeks 2 and 6) and 2 and 8 weeks after RT in 96 patients undergoing external beam RT for localized prostate cancer. RTOG/EORTC acute toxicity and ad hoc total toxicity scores (TTS) were recorded. TTS scores were calculated by adding scores based on visual analog scale (VAS) grading of individual symptoms. Fifty of the patients also underwent sequential proctoscopy with mucosal biopsy. Individual symptoms increased, but differed in prevalence and intensity during and after RT. TTS increased during the entire treatment course in spite of normalizing histopathologic and endoscopic changes from week 2 onwards. Twenty-seven patients had no RTOG/EORTC toxicity, four had grade 3 and none had grade 4 toxicity. All patients with grade 0 had increased TTS. Thus, TTS appeared more sensitive than RTOG/EORTC scoring. The study demonstrates that multiple toxicity symptoms contribute to total toxicity in response to pelvic RT. TTS is a feasible and sensitive method for detecting and quantifying acute toxicity and unveils morbidity which remains hidden with the RTOG/EORTC score system. The development and timing of symptoms may give clues to pathogenesis, treatment, and prophylaxis.     

Nordic 5-fluorouracil/leucovorin bolus schedule combined with oxaliplatin (Nordic FLOX) as first-line treatment of metastatic colorectal cancer

This study combined oxaliplatin with the Nordic bolus schedule of 5-fluorouracil (5-FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer. Twenty-seven patients were treated every second week with oxaliplatin 85 mg/m² as a 2-h infusion on day 1, followed by a 3-min bolus injection with 5-FU 500 mg/m² and 30 min later a bolus injection with FA 60 mg/m² given on days 1 and 2. Seventeen patients achieved a complete (n=2) or partial (n=15) response, leading to a confirmed response rate of 63% (95% CI 45-81%). The estimated median times to progression and survival were 8.9 and 18.7 months, respectively. Neutropenia grade 3-4 toxicity was seen in 63% of patients, neuropathy grade 3 in one patient and grade 2 in 12 patients. Oxaliplatin combined with the bolus Nordic schedule of 5-FU/FA (Nordic FLOX) appears to be well tolerated, effective and feasible as first-line treatment of metastatic colorectal cancer yielding results comparable with those obtained by more complex schedules.     

Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats

Rationale Recently, we provided evidence for a cannabinoid mechanism in relapse to cocaine seeking in rats. There is also increasing evidence for functional cross-talk between cannabinoid and opioid systems in several physiological processes. Objectives This study was designed to evaluate whether the cannabinoid system plays a role in mediating the reinforcing and motivational effects of heroin and heroin-paired stimuli. Methods Male Wistar rats were trained to self-administer heroin (50 μg/kg per infusion) on fixed (FR5) or progressive ratio schedules of reinforcement in the presence of a discriminative and discrete heroin-associated cue. The selective cannabinoid CB1 antagonist SR141716A was given 30 min before the session to determine its effect on responding for heroin. Separate groups of rats were subjected to extinction training during which heroin-associated cues were absent and no heroin was delivered. During subsequent reinstatement tests, the effects of the cannabinoid agonist HU210 and the antagonist SR141716A on reinstatement of heroin seeking were evaluated. Results The cannabinoid antagonist dose-dependently reduced responding for heroin on the FR5 schedule and to a greater extent on the progressive ratio schedule. HU210 (20 μg/kg) reinstated heroin seeking behaviour following a 2-week extinction period, whereas SR141716A dose-dependently attenuated heroin seeking that was provoked by a priming injection of heroin (0.25 mg/kg) and heroin seeking that was triggered by re-exposure to heroin paired stimuli. Conclusions The results show that the reinforcing and motivational effects of heroin and heroin-paired stimuli are mediated, at least in part, by activation of cannabinoid CB1 receptors. Therefore, the present study provides a rationale for the use of cannabinoid antagonists in the treatment of opiate addiction.     

升主动脉心外膜超声成像在冠状动脉旁路移植术中的价值

目的探讨心外膜超声技术在冠状动脉旁路移植术中检查升主动脉的临床意义.方法应用心外膜超声探头在45例非体外循环旁路移植术中对升主动脉进行检查,判定是否形成粥样斑块及其程度,同时与术者触诊所得出的结果进行比较.术者根据斑块部位及程度改变手术方法及方式.结果45例中正常20例,动脉粥样斑块形成25例,其中轻度9例、中度10例、重度6例.心外膜超声技术对升主动脉粥样斑块的检出率明显高于触诊检查.所有病例未发生围手术期中风.结论应用心外膜超声技术可以较触诊更敏感地发现升主动脉粥样斑块形成,可以降低围手术期中风的发生率,具有重要的临床价值.     

Visual assessment of intra ventricular flow from colour M-mode Doppler images

Left intra ventricular filling was studied by colour M-mode Doppler ultrasound to determine whether the flow pattern can be assessed visually, and explore its relation to left ventricular (LV) function. Patients with coronary artery disease (CAD) or dilated cardiomyopathy (DCM) were divided into three groups according to angiographically evaluated LV function. The groups were compared with a control group of 54 healthy volunteers. The mitral to apical delay of early diastolic flow was qualitatively assessed from printed colour M-mode images, twice by four independent observers blinded to the subject's status. The repeatability of the assessments as determined by the kappa statistic was good intra observer (k=0.75) and moderate inter observer (k=0.53). The CAD-group with angiographically normal LV function (n=25) had flow patterns resembling those observed in the control group. The group with ejection fraction (EF) <50% (n=19) had flow patterns clearly different from the control group. Patients with regional wall motion abnormality (RWMA) but EF >50% (n=16) exhibited flow patterns intermediate between the control and the low EF group. Among the 50 CAD patients there was a negative correlation between EF and the presence of delay of apical peak velocity (Spearman's r _s =–0.62, p < 0.0001). A visible delay of apical peak velocity had a sensitivity towards DCM of 83% and specificity of 75%. The sensitivity towards CAD with either RWMA or low EF was 55% and the specificity 75%. In conclusion, visual assessment of intra ventricular flow patterns was feasible and allowed discrimination between normal and diseased ventricles.Abbreviations CAD coronary artery disease - DCM dilated cardiomyopathy - EF ejection fraction - LV left ventricle/left ventricular - LVEDP left ventricular end diastolic pressure - RWMA regional wall motion abnormality Marie Stugaard and Torkel Steen were recipients of fellowships from the Norwegian Council on Cardiovascular Diseases during the study.     

The association between fluoride in drinking water and dental caries in Danish children. Linking data from health registers,environmental registers and administrative registers

Kirkeskov L, Kristiansen E, Bøggild H, von Platen‐Hallermund F, Sckerl H, Carlsen A, Larsen MJ, Poulsen S. The association between fluoride in drinking water and dental caries in Danish children. Linking data from health registers, environmental registers and administrative registers. Community Dent Oral Epidemiol 2010; 38: 206–212. © 2010 John Wiley & Sons A/S Abstract – Objectives: To study the association between fluoride concentration in drinking water and dental caries in Danish children. Methods: The study linked registry data on fluoride concentration in drinking water over a 10‐year period with data on dental caries from the Danish National Board of Health database on child dental health for 5‐year‐old children born in 1989 and 1999, and for 15‐year‐old children born in 1979 and 1989. The number of children included in the cohorts varied between 41.000 and 48.000. Logistic regression was used to assess the correlations, adjusting for gender and taxable family income as a proxy variable for socioeconomic status. Results: Fluoride concentration in drinking water varied considerably within the country from very low (<0.10 mg/l) to more than 1.5 mg/l. Only little variation was found over the 10‐year study period. Dental caries in both 5‐year‐olds and 15‐year‐olds decreased over the study period. An inverse relation between the risk of dental caries and fluoride concentration in drinking water was found in both primary and permanent teeth. The risk was reduced by approximately 20% already at the lowest level of fluoride exposure (0.125–0.25 mg/l). At the highest level of fluoride exposure (>1 mg/l), a reduction of approximately 50% was found. Similar findings were found if analysis was limited to children residing in the same place during the entire study period. Conclusions: The study confirmed previous findings of an inverse relation between fluoride concentration in the drinking water and dental caries in children. This correlation was found in spite of the extensive use of fluoridated toothpaste and caries‐preventive programs implemented by the municipal dental services in Denmark. Linking Danish health registers with environmental and administrative registers offers an opportunity for obtaining sample sizes large enough to identify health effect, which otherwise could not be identified.     

Both α1- and β-Adrenoceptor Stimulation Determine the Time Course of the Inotropic Effect of Noradrenaline in Rabbit Heart

It has been a matter of controversy whether α₁-adrenoceptor stimulation contributes to the final inotropic and lusitropic responses in mammalian myocardium to noradrenaline during concomitant and unopposed β-adrenoceptor stimulation. In the present paper we report studies that compare time courses of the inotropic and lusitropic responses to separate and combined α- and β-adrenoceptor stimulation, respectively, in electrically driven rabbit papillary muscles by a submaximal concentration of noradrenaline. Separate α₁- or β-adrenoceptor stimulation (presence of appropriate receptor blocker) showed the characteristic slow and fast development, respectively, of the inotropic responses. Qualitatively, the respective characteristic changes were also observed: α₁-adrenoceptor stimulation caused a negative lusitropic effect giving a prolongation of the time to peak tension (TPT), while β-adrenoceptor stimulation caused a pronounced positive lusitropic effect giving a shortening of TPT. The time course of the inotropic response to combined adrenoceptor stimulation had characteristics that deviated from the respective time courses to separate α₁- or β-adrenoceptor stimulation thus indicating a contribution from both adrenoceptor populations to the final inotropic response. Combined α₁- and β-adrenoceptor stimulation gave a pronounced positive lusitropic response as might be expected due to the obviously dominating role of the β-adrenergic component. However, the maximal lusitropic effect and the shortening of TPT were both slightly less during combined adrenoceptor stimulation compared to separate β-stimulation thus indicating an influence of the α₁ -adrenoceptor mediated negative lusitropic effect. Quantitatively, the separate α₁ - and the separate β-adrenoceptor mediated inotropic effects were not additive. In accordance with other recent studies, this indicated an inhibitory interaction between the two adrenergic receptor populations in myocardium.