Hypofractionated Stereotactic Ablative Radiotherapy for Recurrent or Oligometastatic Tumours in Children and Young Adults.

AIMS: Cancer remains a leading cause of death in children and adolescents in the developed world. Despite advances in oncological management, rates of primary treatment failure remain significant. Radiation of recurrent or metastatic disease improves survival in adults but there is little data to support clinical decision making in the paediatric/teenage and young adult population. MATERIALS AND METHODS: We present a retrospective case series of 14 patients treated with stereotactic ablative body radiotherapy or stereotactic radiosurgery at The Royal Marsden Hospital from September 2011 to December 2015. Eligible patients were aged <25 years, with Lansky/Karnofsky performance status ≥60 with confirmed relapsed or metastatic tumour in fewer than three sites. Follow-up was in accordance with standard clinical care and included regular outpatient review and radiological surveillance. Local control, progression-free survival and overall survival are presented. RESULTS: Data for 14 patients with 18 treated lesions were included. The median patient age was 15 years (range 5-20 years). Nine patients were treated for local recurrence and five for metastatic lesions. All patients had already undergone multiple previous treatments. Eleven patients had undergone previous radiotherapy. The median interval between the completion of initial radiotherapy and reirradiation was 29.0 months (range 0.2-49.5 months). The median follow-up was 3.4 years (range 0.28-6.4 years). The 1-year local control rate was 78.6% and the 2-year local control rate was 57.1%. Overall median survival was 58.4 months (95% confidence interval 33.8-82.9 months). Cumulative biologically effective doses (BED) over 200 Gy were associated with late toxicity (P = 0.04). CONCLUSION: Radical doses of short-course hypofractionated radiotherapy can achieve excellent local control and may contribute to the prolongation of overall survival. There is a need for prospective trials exploring the use of ablative radiotherapy in metastatic disease in paediatric/teenage and young adult patients in order to establish safe and effective treatment schedules.

Cervical dilation at time of caesarean delivery in nulliparous women: a population-based cohort study.

OBJECTIVES: Our objective was to describe contemporary practice patterns in the timing of caesarean delivery in relation to cervical dilation, overall and by indication for caesarean. Our secondary objective was to examine how commonly caesarean delivery was performed for labour dystocia at dilations below 4 cm or without the use of oxytocin, overall and between hospitals. DESIGN: Retrospective, population-based cohort study. SETTING: Ontario, Alberta, and British Columbia, Canada, 2008-2012. POPULATION: Nulliparous women in labour who delivered term singletons in cephalic position. METHODS: Histograms were used to examine the distribution of cervical dilation at time of caesarean delivery, overall and by indication for caesarean. Funnel plots were used to illustrate variation in hospital-level rates of caesarean deliveries for labour dystocia that were performed early (<4 cm dilation) or without the use of oxytocin. MAIN OUTCOME MEASURES: Cervical dilation (in centimetres) at time of caesarean delivery. RESULTS: The population-based cohort comprised 392 025 women, of whom 18.8% had a caesarean delivery. Of first-stage caesareans for labour dystocia in women who entered labour spontaneously, 13.6% (95% CI 12.9, 14.2) had dilations <4 cm [hospital-level inter-quartile range (IQR): 6.2% to 20.0%] and 29.5% (95% CI 28.6, 30.4) did not receive oxytocin to treat their dystocia (hospital-level IQR: 22.1-54.6%). CONCLUSIONS: The proportion of caesareans done before 4 cm dilation or without oxytocin varies substantially across hospitals and suggests the need for institutions to review their practices and ensure that management of labour practice guidelines are followed. TWEETABLE ABSTRACT: Many caesareans for labour dystocia are performed early during labour (<4 cm dilation) or without oxytocin.

Evaluation of safety monitoring guidelines based on MRI lesion activity in multiple sclerosis.

OBJECTIVE: We evaluate variants of a commonly used data safety monitoring guideline in clinical trials in multiple sclerosis (MS) that flags patients who, at a follow-up visit, have 5 or more contrast-enhancing lesions (CELs) above their baseline count. METHODS: We apply the guideline to a relapsing cohort and a secondary progressive cohort. We assess the number of patients that meet the guideline and describe the characteristics of these patients; we also examine the value of the guideline in predicting relapse occurrence in the 28 days following that MRI. These analyses were repeated for thresholds varying from 1 to 10 CELs above baseline. RESULTS: Between 4% and 6% of patients met the threshold of 5 in both cohorts; patients with higher baseline counts and higher T2 lesion burden were more apt to meet the threshold. After adjustment for other covariates, the odds ratio (OR) of relapse associated with meeting the threshold is significant (p < 0.05) or near significant (0.05 ≤ p < 0.10) for thresholds between 5 and 8 for the relapsing cohort, but not for the secondary progressive cohort. Across thresholds, the adjusted OR is consistently greater than 1, and there is an increasing trend as the threshold increases from 1 to 7. CONCLUSIONS: A guideline based on crossing a threshold CEL count above baseline may be valuable in monitoring patient safety. Further study should be conducted using different datasets to assess the generalizability of these results.

Accessing fertility treatment in New Zealand: a comparison of the clinical priority access criteria with a prediction model for couples with unexplained subfertility.

BACKGROUND: In New Zealand, public funding for assisted reproductive technology (ART) is restricted to subfertile women who are unlikely to conceive spontaneously, based on clinical and social criteria known as the clinical priority access criteria (CPAC) score. The objective of this study was to compare this CPAC score with a prediction model for predicting spontaneous conception, developed in the Netherlands (the Hunault model). METHODS: We performed a cohort study and included couples with unexplained subfertility and assessed the measure of agreement and the performance of the CPAC score and the Hunault prediction score. RESULTS: Of 663 couples referred, 249 (38%) couples had unexplained subfertility. Of 246 women with full follow-up data, there were 143 women (58%) who had a live birth during the follow-up period, 65 (26%) after fertility treatment and 78 (32%) after natural conception. There were 100 couples (41%) who had a Hunault prediction score of <30%, which is the Dutch treatment threshold, and 36 couples (15%) who had a CPAC score of >65, which is the New Zealand threshold for publically funded treatment. There were 69 couples (28%) who meet the threshold for treatment in the Netherlands but did not meet the New Zealand threshold for public funding. The kappa coefficient as a measure of agreement of the two scores and their treatment thresholds was 0.30, suggesting a fair agreement. The area under the curve for the CPAC and Hunault scores were both 0.63, but the Hunault model performed better in calibration. CONCLUSIONS: The CPAC score correlates fairly with the Hunault prediction score, although using the Hunault prediction model 26% more couples would be recommended for ART. The discriminative capacities of both scores were comparable, but the Hunault prediction score performed better in calibration. Funding models in New Zealand should consider treating those women with unexplained subfertility who are least likely to conceive spontaneously.

Pathways to immunity: temporal dynamics of the bumblebee (Bombus terrestris) immune response against a trypanosomal gut parasite.

Immune response dynamics in insects from natural host-parasite associations are poorly understood, despite accumulating evidence of ecological immune phenomena in these systems. Using a gene discovery approach, we have identified genes relating to signalling, enzymatic processes and respiration that were up-regulated in the bumblebee, Bombus terrestris, during infection with the trypanosomatid parasite, Crithidia bombi. In addition, we have mapped dynamic changes in the temporal expression of these genes and three candidate antimicrobial peptide (AMP) immune genes, Abaecin, Defensin and Hymenoptaecin, from 1 to 24 h after C. bombi infection. We show that dynamic changes in expression occur for individual genes at distinct phases of the immune response to C. bombi that correspond to early, intermediate and late stages of infection.

Novel mutations in the sacsin gene in ataxia patients from Maritime Canada.

We ascertained two families in Eastern Canada segregating a form of ataxia consistent with a recessive mode of inheritance. We performed a whole genome scan using dense SNP genotyping, and despite an absence of shared homozygosity in the families we defined linkage to a small region on chromosome 13. Direct DNA resequencing was employed to screen biologically relevant candidate genes in the interval, and two presumptive pathogenic mutations were found in the gene encoding sacsin. One variant is an obligate truncating mutation, the second is a missense variant in a highly conserved residue. Unexpectedly, one family was homozygous for the missense mutation, the other compound heterozygous for the two mutations. Our results expand the genotype phenotype correlation of mutations in the sacsin gene, and highlight the challenge of diagnosing genetically heterogeneous disorders on primarily clinical grounds. We demonstrate that whole genome genotyping on a modest scale can be productive in research, and potentially in a clinical context.

Newborns with C8-acylcarnitine level over the 90th centile have an increased frequency of the common MCAD 985A>G mutation.

Medium chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most commonly inherited defect of fatty acid oxidation. This autosomal recessive disorder is characterized by the tendency to become profoundly hypoglycaemic under fasting stress conditions, leading to lethargy, coma, brain injury and/or death. The most common mutation resulting in MCAD deficiency ascertained through individuals of northern European descent presenting with clinical symptoms is a single base-pair change (985A>G) that accounts for up to 90% of these abnormal alleles. In the general Nova Scotia population, which comprises largely individuals of northern European descent, this mutation is present at a frequency of 1 in 68. A recently implemented newborn screening programme for MCAD deficiency uses tandem mass spectrometry (MS/MS) to analyse blood spots from newborns for C8-acylcarnitine. After reviewing initial data from this newborn screening programme, we hypothesized that there was an unexpectedly high frequency of individuals with an MCAD 985A>G mutation and C8-acylcarnitine levels at the upper end of the normal range. A sample representing the upper 90th centile was screened for the presence of the 985A>Gmutation and 61 heterozygotes were identified, establishing a high frequency (1/10) of this 985A>G mutation in this selected population. We have demonstrated a relationship between heterozygosity for 985A>G and C8-acylcarnitine levels. These results contribute to the interpretation of C8-acylcarnitine levels and the establishment of a more clinically relevant screening cut-off point.

Predictive, pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000.

Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.

Treatment of gustatory hyperlacrimation (crocodile tears) with injection of botulinum toxin into the lacrimal gland.

PURPOSE: To establish the efficacy and safety of botulinum toxin in the treatment of Crocodile Tear Syndrome and record any possible complications. METHODS: Four patients with unilateral aberrant VII cranial nerve regeneration following an episode of facial paralysis consented to be included in this study after a comprehensive explanation of the procedure and possible complications was given. On average, an injection of 20 units of botulinum toxin type A (Dysport) was given to the affected lacrimal gland. The effect was assessed with a Schirmer's test during taste stimulation. Careful recording of the duration of the effect and the presence of any local or systemic complications was made. RESULTS: All patients reported a partial or complete disappearance of the reflex hyperlacrimation following treatment. Schirmer's tests during taste stimulation documented a significant decrease in tear secretion. The onset of effect of the botulinum toxin was typically 24-48 h after the initial injection and lasted 4-5 months. One patient had a mild increase in his preexisting upper lid ptosis, but no other local or systemic side effects were experienced. CONCLUSIONS: The injection of botulinum toxin type A into the affected lacrimal glands of patients with gusto-lacrimal reflex is a simple, effective and safe treatment.

Feeding broiler chickens wheat and barley diets containing whole, ground and pelleted grain.

The effect of grain form (whole, mash, or pelleted) on the live performance of broiler chickens was determined. In the first trial, six regimens compared the feeding of whole wheat: 1) 0% of diet for the whole trial (0 to 48 d); 2) 5% at 6 d, 20% at 13 d, 35% at 27 d; 3) 5% at 6 d, 35% at 13 d, 50% at 27 d; 4) 5% at 0 d, 20% at 6 d, 35% at 13 d, 50% at 27 d; 5) 5% at 6 d, 50% at 13 d, 65% at 27 d; and 6) 5% at 0 d, 20% at 6 d, 50% at 13 d, 65% at 27d. Each feeding regimen was replicated with steam-pelleted and mash supplements. None of the feed was diluted. The second trial was similar, except that whole barley was fed instead of whole wheat. Feeding mash supplements slowed growth at all ages and lowered mortality caused by sudden death syndrome and ascites plus right heart failure. Cumulative feed:gain was increased by feeding mash supplements in Trial 1. Total weight gain was unaffected by feeding whole wheat but was decreased by most levels of whole barley. Whole-grain diets increased cumulative feed:gain. Feeding whole wheat decreased skeletal problems. Whole-grain diets increased gizzard size but did not alter carcass yield. Feeding whole-grain and mash supplements caused at least a temporary loss in growth rate and feed efficiency but in some cases improved bird health.

Histopathologic and bacteriologic evaluations of cellulitis detected in legs and caudal abdominal regions of turkeys.

The objective of this study was to identify the causative agent of cellulitis in turkeys. Eighteen flocks from nine producers were sampled at the local processing plant, and 37 birds with cellulitis on legs or caudal thoracic area were obtained. None of the 37 birds with cellulitis had lesions in other organs. On gross examination, lesions were categorized into two groups: cellulitis with unopened skin lesions (type a) and cellulitis with opened skin lesions (type b). Histopathologically, cellulitis with unopened skin lesions had dermal necrosis with underlying fibrin and inflammatory exudate but cellulitis with open skin lesions had chronic granulomatous/granulation tissue-type reaction associated with foreign material. A complete bacteriologic study was conducted on 25 of 37 birds. Bacteria were isolated from 12 of the 25 birds with cellulitis lesions. No aerobic, microaerophilic, or anaerobic bacteria were isolated from the remaining 13 birds with cellulitis lesions. Escherichia coli was isolated in low numbers in mixed cultures with Proteus mirabilis, Lactobacillus spp., Klebsiella spp., and Staphylococcus spp. in 9 of 12 lesions. The remaining few cases yielded P. mirabilis in pure culture or in mixed culture with Pseudomonas aeruginosa. Types a and b cellulitis lesions in turkeys could be associated with primary contact dermatitis and skin abrasions, respectively. Their occurrence is likely associated with different management practices.

Influence of whole barley and grit on live performance and health of turkey toms.

Live performance to 96 d was compared for 1,584 turkey toms reared on diets containing four levels of whole barley and two levels of insoluble grit (0 or 9 g/bird per wk). Nutrient specifications for all diets were similar. The six dietary treatments were 1) 0% whole barley plus grit, 2) Treatment 1 minus grit, 3) grit plus 5% whole barley at 0 d increasing to 35% by 19 d, 4) grit plus 5% whole barley at 0 d increasing to 50% by 19 d, 5) Treatment 4 minus grit, and 6) grit plus 5% whole barley at 19 d increasing to 50% by 40 d. The concentrate blended with the whole barley was fed as crumbles or pellets. Nutrients were not diluted. Compared to the control treatments, feeding 35% or more whole barley temporarily reduced weight gain and increased feed:gain prior to 68 d. Cumulative weight gain was reduced in Treatments 3 and 5 compared to treatments in which no barley was fed. Cumulative feed:gain was increased in Treatment 5 compared to Treatments 2 and 3. Total mortality and leg and skeletal problems were reduced in treatments where whole grain slowed early growth rate. Feeding grit had no effect on the live performance of birds fed similar levels of whole barley. In treatments in which whole barley was introduced at 0 d, gizzard pH was decreased at 18 d, and gizzard weight was increased at 32 d. Jejunal viscosity was unaffected by dietary treatment.

Noise reduction in oncology FDG PET images by iterative reconstruction: a quantitative assessment.

UNLABELLED: Tumor detection depends on the contrast between tumor activity and background activity and on the image noise in these 2 regions. The lower the image noise, the easier the tumor detection. Tumor activity contrast is determined by physiology. Noise, however, is affected by many factors, including the choice of reconstruction algorithm. Previous simulation and phantom measurements indicated that the ordered-subset expectation maximization (OSEM) algorithm may produce less noisy images than does the usual filtered backprojection (FBP) method, at equivalent resolution. To see if this prediction would hold in actual clinical situations, we quantified noise in clinical images reconstructed with both OSEM and FBP. METHODS: Three patients (2 with colon cancer, 1 with breast cancer) were imaged with FDG PET using a "gated replicate" technique that permitted accurate measurement of noise at each pixel. Each static image was acquired as a gated image sequence, using a pulse generator with a 1-s period, yielding 40 replicate images over the 10- to 15-min imaging time. The images were or were not precorrected for attenuation and were reconstructed with both FBP and OSEM at comparable resolution. From these data, images of pixel mean, SD, and signal-to-noise ratio (S/N) could be produced, reflecting only noise caused by the statistical fluctuations in the emission process. RESULTS: Noise did not vary greatly over each FBP image, even when image intensity varied greatly from one region to the next, causing S/N to be worse in low-activity regions than in high-activity regions. In contrast, OSEM had high noise in hot regions and low noise in cold regions. OSEM had a much better S/N than did FBP in cold regions of the image, such as the lungs (in the attenuation-corrected images), where improvements in S/N averaged 160%. Improvements with OSEM were less dramatic in hotter areas such as the liver (averaging 25% improvement in the attenuation-corrected images). In very hot tumors, FBP actually produced higher S/Ns than did OSEM. CONCLUSION: We conclude that OSEM reconstruction can significantly reduce image noise, especially in relatively low-count regions. OSEM reconstruction failed to improve S/N in very hot tumors, in which S/N may already be adequate for tumor detection.

Noninvasive estimation of the aorta input function for measurement of tumor blood flow with.

Quantitative measurement of tumor blood flow with [15O]water can be used to evaluate the effects of tumor treatment over time. Since quantitative flow measurements require an input function, we developed the profile fitting method (PFM) to measure the input function from positron emission tomography images of the aorta. First, a [11C]CO scan was acquired and the aorta region was analyzed. The aorta diameter was determined by fitting the image data with a model that includes scanner resolution, the measured venous blood radioactivity concentration, and the spillover of counts from the background. The diameter was used in subsequent fitting of [15O]water dynamic images to estimate the aorta and background radioactivity concentrations. Phantom experiments were performed to test the model. Image quantification biases (up to 15%) were found for small objects, particularly for those in a large elliptical phantom. However, the bias in the PFM concentration estimates was much smaller (2%-6%). A simulation study showed that PFM had less bias and/or variability in flow parameter estimates than an ROI method. PFM was applied to human [11C]CO and [15O]water dynamic studies with left ventricle input functions used as the gold standard. PFM parameter estimates had higher variability than found in the simulation but with minimal bias. These studies suggest that PFM is a promising technique for the noninvasive measurement of the aorta [15O]water input function.

Phenotypic and genotypic characterization of virulence factors of Escherichia coli isolated from broiler chickens with simultaneous occurrence of cellulitis and other colibacillosis lesions.

The objective of this study was to characterize virulence factors of Escherichia coli isolates from broilers with simultaneous occurrence of cellulitis and other colibacillosis lesions. Thirty flocks were sampled and 237 birds with cellulitis were examined. Eighty-two (34.6%) of 237 birds condemned for cellulitis had gross lesions in the heart, air sacs, joints, or liver. In 58 chickens, E. coli was isolated from both the cellulitis and other lesions of colibacillosis, and 18.9% of the E. coli isolates from the 2 types of lesions belonged to the same O group. Escherichia coli of serogroups O78, O1, and O2 predominated. Isolates of the same serogroup that were derived from different lesions in the same birds had similar patterns of biotype, aerobactin production, serum sensitivity profile, antibiotic sensitivity, and K1 capsule production. Escherichia coli derived from cellulitis lesions produced virulence factors similar to those found in E. coli isolated from other colibacillosis lesions in poultry.

Self-sealing sclerotomies for sutureless pars plana vitrectomy.

OBJECTIVE: To determine the efficacy of self-sealing pars plana sclerotomies for vitrectomy and to identify complications associated with this new technique. METHOD: There were 150 self-sealing sclerotomies performed in 50 patients undergoing pars plana vitrectomy between October 1996 and March 1998. RESULTS: Of the 150 sclerotomies, 115 (76.6%) did not require suturing while 35 (23.3%) were closed with one radial 7.0 vicryl suture. The scleral tunnel incisions ensured minimal loss of intraocular fluids during instrument exchange and scleral plugs were not required to avoid ocular hypotony during scleral indentation. Distortion of scleral flap incisions requiring a suture were commonly seen in procedures using multiple instrumentations and extensive explants. CONCLUSIONS: Sutureless sclerotomies are simple to perform, save operative time, and reduce the risk of peroperative hypotony following removal of instruments or the infusion cannula. The technique reduces postoperative inflammation, suture-related problems including astigmatism, and allows more rapid rehabilitation.