Dosimetric factors associated with weight loss during (chemo)radiotherapy treatment for lung cancer.

BACKGROUND/OBJECTIVES: Thoracic radiotherapy (RT) is associated with acute toxicities, including oesophagitis, which can have an impact on nutritional intake and subsequently lead to malnutrition. This study aimed to identify RT dosimetric factors associated with ⩾5% weight loss in patients receiving treatment for non-small-cell lung cancer (NSCLC). METHODS: Radiation dose data to the oesophagus (including mean, maximum dose and oesophageal length) were retrospectively analysed for a cohort of 54 NSCLC patients treated with concurrent chemoradiotherapy between 2004 and 2006. Weight change was calculated using the lowest weight during the 90 days from RT commencement compared with the start of RT. RESULTS: Four patients for whom weight was not available at the start or end of treatment were excluded, leaving 50 patients for analysis. The prevalence of significant weight loss during the 90 days from RT commencement was 22% (median weight loss=9.1%, range=5.9-22.1). Dosimetric factors significantly associated with ⩾5% weight loss were maximum dose to the oesophagus (P=0.046), absolute oesophageal length receiving 40 Gy (odds ratio (OR)=1.18, P=0.04), 50 Gy (OR=1.20, P=0.02) and 60 Gy (OR=1.32, P=0.005) to the partial circumference, relative oesophageal length receiving 50 Gy (OR=1.03, P=0.03) and 60 Gy (OR=1.07, P=0.005) to the partial circumference. CONCLUSIONS: Multiple dosimetric factors were associated with significant weight loss. Of these factors, absolute and relative length of the oesophagus receiving 60 Gy to the partial circumference were more strongly related. Understanding the dosimetric factors associated with weight loss may aid early identification and intervention in patients at nutritional risk.

The structure of the small animal consultation.

OBJECTIVES: To analyse the structure of small animal consultations in order to increase understanding of the consultation processes, locate decision-making in the wider practice context and stimulate further research. METHODS: Analysis of 48 video-recorded consultations from first opinion small animal practices. These consultations were time and thematically coded in order to enable analysis. RESULTS: The mean length of the recorded consultations was 11 minutes and 45 seconds with a range of 4-28 minutes. Analysis indicates that both the clinical tasks and communication taking place in the consultation are often performed in an iterative and interactive fashion in contrast to the sequential methods frequently being taught. CLINICAL SIGNIFICANCE: This study shows that the consultation is a complex process that is often performed in an iterative and interactive fashion and that may be difficult to complete within the 10 minutes frequently allocated. This warrants further research.

Ethical and evidential considerations on the use of novel therapies in veterinary practice.

Novel therapies may be necessary both in the interests of the individual animal and in the advancement of veterinary science. However, special consideration is necessary to safeguard the welfare of the animals, ensure fully informed consent from the owner, determine the procedure's value in other cases and appropriately disseminate results. This article reviews ethical and evidential considerations raised when novel therapies are undertaken in veterinary practice, based on a series of committee meetings and intervening discussions held between members of the British Small Animal Veterinary Association Scientific Committee and Officers (2010-2011). The aim of this article is to encourage the advancement of novel veterinary therapies while safeguarding the welfare of animals.

Four BSE cases with an L-BSE molecular profile in cattle from Great Britain.

Bovine spongiform encephalopathy (BSE) is a prion disease of cattle which was first observed in Great Britain (GB) in 1986. Throughout the subsequent BSE epidemic, cases identified by passive surveillance have shown consistent histopathological, immunohistochemical, biochemical and biological properties. However, since the start of active surveillance in 2001, across Europe and elsewhere, approximately 67 cases with different biochemical characteristics have been identified by Western blotting (WB). These cases fall into two categories; 'H-type' (H-BSE) or 'L-type' (L-BSE), based on the relatively heavy (H-BSE) or light (L-BSE) mass of the unglycosylated band of the prion protein, as compared with WB against that obtained from classical BSE (C-BSE) cases. Here we report the detection and confirmation of the first four L-BSE cases by active surveillance in GB, two of which were born after the reinforced feed ban of 1996 (BARB cases). These four L-BSE cases were found in relatively old cattle (age range; 11-21 years old) and the carcases did not enter the human food chain or animal feed chains.

Experimental bovine spongiform encephalopathy: detection of PrP(Sc) in the small intestine relative to exposure dose and age.

European regulations for the control of bovine spongiform encephalopathy (BSE) decree destruction of the intestines from slaughtered cattle, therefore producers have been obliged to import beef casings from countries with a negligible BSE risk. This study applies immunohistochemical and biochemical approaches to investigate the occurrence and distribution of disease-associated prion protein (PrP(Sc)) in the duodenum, jejunum and ileum of cattle orally exposed to a 1 g or 100 g dose of a titrated BSE brainstem homogenate. Samples were derived from animals at various times post exposure. Lymphoid follicles were counted and the frequency of affected follicles recorded. No PrP(Sc) was detected in the duodenum or jejunum of animals exposed to a 1 g dose or in the duodenum of animals receiving a 100 g dose. PrP(Sc) was detected in the lymphoid tissue of the ileum of 1/98 (1.0%) animals receiving the 1 g dose and in the jejunum and ileum of 8/58 (13.8%) and 45/99 (45.5%), respectively, of animals receiving the 100 g dose. The frequency of PrP(Sc)- positive follicles was less than 1.5% per case and biochemical tests appeared less sensitive than immunohistochemistry. The probability of detecting lymphoid follicles in the ileum declined with age and for the 100 g exposure the proportion of positive follicles increased, while the proportion of positive animals decreased with age. Detection of PrP(Sc) in intestinal neural tissue was rare. The results suggest that the jejunum and duodenum of BSE-infected cattle contain considerably less BSE infectivity than the ileum, irrespective of exposure dose. In animals receiving the low exposure dose, as in most natural cases of BSE, the rarity of PrP(Sc) detection compared with high-dose exposure, suggests a very low BSE risk from food products containing the jejunum and duodenum of cattle slaughtered for human consumption.

Two unusual bovine spongiform encephalopathy cases detected in Great Britain.

Bovine spongiform encephalopathy (BSE) was first identified in Great Britain (GB) in 1986 and was subsequently detected in many other countries, worldwide. A decade after the start of the bovine epidemic, the first cases of new variant Creutzfeldt-Jakob disease (vCJD) in humans were linked to probable ingestion of BSE infected tissue, highlighting a new zoonotic disease. An abnormal protease-resistant protein (PrP(res)) in a diseased subject, derived from a post-translational change of a normal host cellular membrane protein (PrP(c)), is a reliable disease marker for the whole group of neurodegenerative transmissible spongiform encephalopathies (TSEs). Immunology-based techniques, such as Western immunoblotting, have previously indicated that BSE cases all give a uniform molecular profile for PrP(res). Periodic lesion profiling of the spongiform change throughout different brain regions of infected mice and cattle has also indicated a single agent for BSE. However, in 2001 rapid testing for PrP(res) was introduced for the active surveillance of ruminants within Europe, and approximately 40 BSE cases have now been recognized that differ in their molecular profiles from those typically found. These unusual BSE cases have been detected in several European countries, and in Japan and the USA. At present, the cases appear as two distinct types based on the molecular mass (Mm) of the unglycosylated PrP(res) protein band relative to that of classical BSE. One type is of a higher Mm (H-type) and the other shows a lower Mm (L-type). Transmission studies in mice have shown that both H-type and L-type BSE have biological characteristics that are different from those of the classical BSE agent. This study describes the prion protein (PRNP) genotype and molecular profiles of the first two cases of H-type BSE detected in GB in comparison with those obtained for classical BSE, scrapie in sheep from GB and a control H-type BSE case from France.

Interplanner variability in carrying out three-dimensional conformal radiation therapy for non-small-cell lung cancer.

This study evaluated the variability among six radiation therapy planners in planning radiation treatment for four patients with lung cancer using two treatment protocols. The interplanner variability for target conformity and homogeneity was smaller than the variability among the patients and planning approaches. The same was found for the dose volume indices achieved for most critical structures, indicating that interplanner variability is not likely to be an important source of variation in radiotherapy studies if concise treatment protocols are followed.

Dose escalation of radical radiation therapy in non-small-cell lung cancer using positron emission tomography/computed tomography-defined target volumes: are class solutions obsolete?

This study investigated the maximum theoretical radiation dose that could safely be delivered to 20 patients diagnosed with non-small-cell lung cancer. Two three-dimensional conformal radiation therapy (RT) class-solution techniques (A and B) and an individualized three-dimensional conformal RT technique (C) were compared at the standard dose of 60 Gy (part I). Dose escalation was then attempted for each technique successfully at 60 Gy, constrained by predetermined limits for lung and spinal canal (part II). Part I and part II data were reanalysed to include oesophageal dose constraints (part III). In part I, 60 Gy was successfully planned using techniques A, B and C in 19 (95%), 18 (90%) and 20 (100%) patients, respectively. The mean escalated dose attainable for part II using techniques A, B and C were 76.4, 74 and 97.8 Gy, respectively (P < 0.0005). One (5%) patient was successfully planned for 120 Gy using techniques A and B, whereas four (20%) were successfully planned using technique C. Following the inclusion of additional constraints applied to the oesophagus in part III, the amount of escalated dose remained the same for all patients who were successfully planned at 60 Gy apart from two patients when technique C was applied. In conclusion, individualized three-dimensional conformal RT facilitated greater dose conformation and higher escalation of dose in most patients. With modern planning tools, simple class solutions are obsolete for conventional dose radical RT in non-small-cell lung cancer. Highly individualized conformal planning is essential for dose escalation.

Comparison of CT and positron emission tomography/CT coregistered images in planning radical radiotherapy in patients with non-small-cell lung cancer.

Imaging with F-18 fluorodeoxyglucose positron emission tomography (PET) significantly improves lung cancer staging, especially when PET and CT information are combined. We describe a method for obtaining CT and PET images at separate acquisitions, which allows coregistration and incorporation of PET information into the radiotherapy (RT) planning process for non-small-cell lung cancer. The influence of PET information on RT planning was analysed for 10 consecutive patients. Computed tomography and PET images were acquired with the patient in an immobilization device, in the treatment position. Using specially written software, PET and CT data were coregistered using fiducial markers and imported into our RT planning system (Cadplan version 6). Treatment plans were prepared with and without access to PET/CT coregistered images and then compared. PET influenced the treatment plan in all cases. In three cases, geographic misses (gross tumour outside planning target volume) would have occurred had PET not been used. In a further three cases, better planning target volume marginal coverage was achieved with PET. In four patients, three with atelectasis, there were significant reductions in V20 (percentage of the total lung volume receiving 20 Gy or more). Use of coregistered PET/CT images significantly altered treatment plans in a majority of cases. This method could be used in routine practice at centres without access to a combined PET/CT scanner .

Increased risk of myocardial infarction as first manifestation of ischaemic heart disease and nonselective nonsteroidal anti-inflammatory drugs.

AIMS: Selective cyclooxygenase (COX)-2 inhibitors have recently been implicated as enhancing risk of myocardial infarction (MI). Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are also effective COX-2 inhibitors, so we investigated the hypothesis that they too increase risk of MI. METHODS: We conducted a case-control study with direct structured interview of cases and controls. Cases were all subjects (N = 205) with a first nonfatal MI who had no previously recognized cardiovascular disease. Community controls (N = 258) were randomly selected from the same practice as the index case. Hospital controls (N = 205) were those admitted at the same time as index cases for nonmyocardial conditions not influenced by NSAID use. The effects of aspirin, NSAIDs and previously recognized influences on MI were investigated by unconditional logistic regression analysis. RESULTS: NSAID use was associated with an increase risk of MI with an odds ratio of 1.77 (1.03, 3.03) vs. community controls and 2.61 (1.38, 4.95) vs. hospital controls. These values were 5.00 (1.18, 21.28) and 7.66 (0.87, 67.48), respectively, in aspirin users. Results were similar when naproxen was grouped with aspirin. Odds ratios for smoking and for use of antidiabetic medication were 3.91 (2.52, 6.04) and 3.92 (1.25, 12,33), respectively, vs. community controls. CONCLUSIONS: Like selective COX-2 inhibitors, non-selective NSAIDs [corrected] are associated with an increased risk of MI. The extent to which this reflects interference with aspirin warrants further investigation.

Novel synthetic routes to several new, differentially substituted ruthenium tris(4,4 disubstituted-2,2-bipyridine) complexes.

The stepwise synthesis of several novel Ru(tris(pp)) complexes (pp = 4,4'-disubstituted-2,2'-bipyridine; substituent = H, Me, chiral ester, or chiral amide) is described, where the pp ligands may be the same, or different, in each complex. All of the complexes detailed have been resolved into their pure delta- and lambda-enantiomers or diastereomers. The complexes, which are prepared starting from RuCl3, contain novel ligand architectures, with a range of chiral esters and amides attached to the 4,4'-positions of the bpy ligands. It was postulated that these chiral groups would be capable of inducing chirality at the metal center, but our investigations have shown this not to be the case, and in all reactions completely racemic products were formed. Resolution by chiral HPLC, and the subsequent characterization of the products through NMR, UV-vis, and circular dichroism (CD) spectroscopy, has been carried out; the characteristics of the CD spectra have been discussed with respect to the electron-donating/ withdrawing ability of the groups at the 4,4'-positions. The X-ray crystal structure of the optically pure complex lambda-[Ru(dmbpy)2(4,4'-bis((R)-(+)-alpha-phenylethylamido)-2,2'-bipyridine)] x 2PF6 x 2CHCl3 was obtained and solved using direct methods. This result, in conjunction with the CD spectra, enabled the complete and unambiguous assignment of the stereocenters of all of the novel Ru(tris(bpy)) complexes prepared in this investigation.

Diastereoselective preparation and characterization of ruthenium bis(bipyridine) sulfoxide complexes.

A new concept in the synthesis of optically active octahedral ruthenium complexes was realized for the first time when cis- or trans-Ru(bpy)2Cl, (cis- or trans-1) was reacted with either (R)-(+)- or (S)-(-)-methyl p-tolyl sulfoxide (2 or 3); this novel asymmetric synthesis leads to the diastereoselective formation of the ruthenium bis(bipyridine) complex cis-delta-[Ru(bpy)2(2)Cl]Cl (4) (49.6% de) or cis-lambda-[Ru(bpy)2(3)Cl]Cl (5) (48.4% de), respectively. cis- or trans-Ru(dmbpy)2Cl2 (cis- or trans-6) (dmbpy = 4,4'-dimethyl-2,2'-bipyridine) also reacts with 2 or 3, leading to the diastereoselective formation of cis-delta-[Ru(dmbpy)2(2)Cl]Cl (7) (59.5% de) or cis-lambda-[Ru(dmbpy)2(3)Cl]Cl (8) (57.2% de), respectively. The diastereoselectivity of these reactions is governed solely by the chirality of the sulfoxide nucleophile. This represents the first process by which a sigma-bonded ligand occupying only a single coordination site has had such an important influence on the stereochemical outcome of a ruthenium bis(bipyridine) complex formation. These novel complexes were fully characterized by elemental analysis and IR, UV/vis, and 1H, 13C, and 2D NMR spectroscopy. An investigation into the chiroptical properties of these novel ruthenium bis(bipyridine) sulfoxide complexes has been carried out, and circular dichroism spectra are used to assign absolute stereochemistry.

Angiogenesis in gastric ulcers: impaired in patients taking non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drug (NSAID) therapy is associated with delayed gastroduodenal ulcer healing. In rats the degree of angiogenesis (new vessel formation) within the ulcer bed correlates strongly with the extent and speed of ulcer healing and may be inhibited by NSAIDs. This study therefore assessed the vascularity of 38 antral gastric ulcers immunohistochemically, using CD31 a vascular endothelial cell marker, in 17 patients taking NSAIDs and 19 control patients. In the superficial granulation tissue NSAID therapy was associated with a significant reduction in the median number of capillaries (13.5 (IQR: 9.5-18) v 23.5 (14-31) (p < 0.005)), number of vessel buds (6 (4-12.5) v 17 (12-23) (p < 0.05)), and maximum vessel diameter (29 (20.75-30.75) v 33.75 (24-45) (p < 0.05)) when compared with controls. In deep granulation tissue NSAID therapy was similarly associated with a significant reduction in the number of capillaries (9 (6.5-12) v 14 (9-19.25) (p < 0.04)), number of vessel buds (5 (3.5-8.5) v 13 (7-16.5) (p < 0.01)), and maximum vessel diameter (23 (18-20.5) v 33 (21.5-45) (p < 0.02)). There were no differences in vascularity in the adjacent glandular mucosa. Impairment of angiogenesis may be an important mechanism of NSAID related delayed ulcer healing.

Interobserver variation in assessment of gastroduodenal lesions associated with non-steroidal anti-inflammatory drugs.

Video endoscopic images were used to investigate whether gastroenterologists could agree on the definition of lesions within the stomach seen at endoscopy, with particular reference to those seen in patients taking non-steroidal anti-inflammatory drugs. Seven experienced endoscopists, unaware of the patients' clinical history or drug consumption, recorded their classification for 93 randomised video images of gastric lesions. There was complete agreement in the diagnosis of ulceration for nine images from patients who were not taking non-steroidal anti-inflammatory drugs; eight of nine were classified as deep ulcers, with 86% agreement for this subclassification. By contrast, the overall agreement for lesions in patients taking non-steroidal anti-inflammatory drugs was only 55%. Only nine of 44 ulcers were subclassified as deep, and there was considerable cross classification of non-haemorrhagic erosions and ulcers. In conclusion, ulcers that occur in patients taking non-steroidal anti-inflammatory drugs differ from those in patients who are not taking these drugs in that they are often more superficial and difficult to distinguish from erosions. The prognostic importance of these lesions is, therefore, uncertain.

Enhanced gastric mucosal leukotriene B4 synthesis in patients taking non-steroidal anti-inflammatory drugs.

The effects of longstanding non-steroidal anti-inflammatory drug (NSAID) treatment on gastric mucosal synthesis of leukotriene B4 (LTB4), leukotriene C4 (LTC4), and prostaglandin E2 (PGE2) was studied. Gastric antral biopsies in 65 patients with arthritis taking NSAIDs and 23 control patients were taken and eicosanoid concentrations, stimulated by vortex mixing or calcium ionophore, were measured by radioimmunoassay. Median gastric mucosal synthesis of LTB4 was increased in patients taking NSAIDs compared with non-users: (0.9(0.2-2.5) pg/mg v 0 (0-0.6) pg/mg (p < 0.001)). These differences persisted when subgroups of patients were analysed according to Helicobacter pylori colonisation or degree of mucosal injury. Synthesis of LTB4 was strongly associated with the presence of type C (chemical) gastritis. Increased synthesis of LTC4 was associated with Helicobacter pylori colonisation but not NSAID use. Synthesis of PGE2 was decreased in patients taking NSAIDs compared with control patients (p < 0.001). Enhanced gastric mucosal synthesis of LTB4 in patients taking NSAIDs may represent a primary effect of these drugs and could be implicated in the pathogenesis of gastritis and ulceration associated with NSAIDs.

Treatment of ulcerative colitis with fish oil supplementation: a prospective 12 month randomised controlled trial.

The effect of fish oil on the course of ulcerative colitis was investigated in a randomised blinded controlled study. Eighty seven patients received supplements of 20 ml HiEPA fish oil as triglyceride (4.5 g of eicosapentaenoic acid) or olive oil placebo daily for one year. The oils were given in addition to standard drug therapy and trial entry was stratified for disease activity. Fish oil significantly increased the eicosapentaenoic acid content of rectal mucosa to 3.2% of total fatty acids at six months, compared with 0.63% for patients on olive oil. This was associated with increased synthesis of leukotriene B5, and 53% suppression of leukotriene B4 synthesis by ionophore--stimulated neutrophils. Leukotriene B4 suppression persisted for at least two months after treatment was stopped. Treatment with fish oil resulted in measurable, but only limited clinical benefit. For patients entering the trial in relapse (n = 53), there was a significant reduction in corticosteroid requirement after one and two months treatment. There was a trend towards achieving remission (off corticosteroids) faster in the patients on fish oil, although differences were not significant. For patients in remission at trial entry or during the trial (n = 69), there was no significant difference in the rate of relapse by log rank analysis. We conclude that fish oil supplementation produces a modest corticosteroid sparing effect in active disease, but there is no benefit in maintenance therapy.

Antihypertensive effect of sialoadenectomy in one-kidney, one clip hypertension in the rat.

We have examined the effect of removal of the submandibular gland on one-kidney, one clip (1K1C) hypertension in the rat. Five weeks after application of a silver clip with a 0.20-mm gap, 15 hypertensive rats were sialoadenectomized. This was followed by a decrease in systolic blood pressure (SBP) within 1 day by 22 +/- 4 mmHg (+/- s.e.m.) and in nine rats pressure stabilized within 1 week at 133 +/- 5 (cf. 166 +/- 2 before sialoadenectomy). In the other six rats the initial hypotensive response was followed by a gradual return to hypertensive levels, reaching 178 +/- 4 mmHg 6 weeks later. Sham-sialoadenectomized rats remained hypertensive throughout. When a 0.15-mm gap clip was used in a similar experiment rats became hypertensive after 2 weeks, and sialoadenectomy lowered SBP to normal in half of them, after which pressure tended to return to hypertensive levels in most. No change in SBP was found in sham-operated hypertensive rats. Sialoadenectomy performed at the time of clipping with a 0.15-mm gap clip and unilateral nephrectomy delayed the development of hypertension. Systolic pressure then fell from 153 +/- 14 at 4 weeks to 105 +/- 8 at 12 weeks after operation in five rats, but continued to increase in eight rats from 148 +/- 10 at 4 weeks to 172 +/- 15 at 12 weeks. These experiments thus demonstrate that the submandibular gland may contribute to the onset and maintenance of one-kidney, one clip hypertension in the rat, particularly in less severe stenosis.

Effects of isolation and food restriction begun at 50 days on the development of age-associated renal disease in the male Wistar rat.

The development of proteinuria with increasing age was studied in three groups of male Wistar rats: ad libitum fed and isolated, ad libitum fed and group housed 6 to 8 rats per cage, and food restricted (one-third of the isolated ad libitum food intake) and isolated. Studies were begun at age 50 days and continued throughout life. Ad libitum fed rats when isolated ate more food, grew faster, had larger maximum body weights and developed proteinuria at a faster rate than those that were group housed. There was a small increase in the severity of glomerular pathology in old age. However, systolic blood pressure was not affected significantly by isolation, nor was life duration. Food restriction of isolated rats inhibited body growth, prevented the development of proteinuria, reduced the incidence of glomerular and tubular pathology in old age and prolonged life. Electron microscopic examination of the kidneys of old food-restricted rats revealed a much lower incidence of foot process retraction and spreading on the basement membrane of the glomerulus than in ad libitum fed rats. Cardiac enlargement was also prevented by long-term food restriction.