Post-Operative Radiotherapy for Soft Tissue Sarcoma of the Anterior Compartment of the Thigh: Should the Sartorius Muscle be Included?

Purpose: The clinical target volume (CTV) of post-operative radiotherapy for soft tissue sarcoma of the limbs conventionally includes the whole of the transverse cross-section of the affected anatomical compartment. In the anterior thigh sartorius appears to lie within its own fascial compartment and can be safely excluded. We investigated the potential impact of omitting sartorius from the anterior muscle compartment on patients with soft tissue sarcoma of the thigh

Post-Operative Radiotherapy for Soft Tissue Sarcoma of the Anterior Compartment of the Thigh: Should the Sartorius Muscle be Included?

PURPOSE: The clinical target volume (CTV) of post-operative radiotherapy for soft tissue sarcoma of the limbs conventionally includes the whole of the transverse cross-section of the affected anatomical compartment. In the anterior thigh sartorius appears to lie within its own fascial compartment and can be safely excluded. We investigated the potential impact of omitting sartorius from the anterior muscle compartment on patients with soft tissue sarcoma of the thigh. PATIENTS AND METHODS: We used the planning CT data from six patients who had previously received post-operative radiotherapy for soft tissue sarcoma of the thigh. The anterior compartments were outlined twice, initially including and then excluding the sartorius muscle. The volumes of the anterior compartment (i.e., the CTVs), both with and without sartorius, and the corresponding planning target volumes (PTVs) were calculated. Treatment plans were prepared for each PTV. For both volumes the unirradiated normal tissue corridor was outlined on each CT slice. The volume and circumference of the unirradiated corridor were then calculated. RESULTS: For all six patients there was an important improvement in normal tissue sparing by excluding sartorius. The mean reduction in volume of the anterior compartment when sartorius was excluded was 10% (95% Confidence Interval 8-12%), whilst the mean decrease in PTV was 11% (95% CI 7-14%). There was a substantial increase in the volume of the unirradiated normal tissue corridor, with a mean value of 77% (95% CI 41-114%) when sartorius was excluded. In addition, the percentage increase in the size of the unirradiated normal tissue corridor, expressed as a percentage of the whole leg circumference, was 10% (95% CI 8-13%). When sartorius was included in the anterior compartment, the circumference of the unirradiated corridor was less than one-third of the whole leg circumference in four of the six patients. When sartorius was excluded, the circumference of the unirradiated corridor was greater than one-third of the leg circumference over the entire length of the target volume in all patients. DISCUSSION: It is essential to know the anatomy of the sartorius muscle to be able to exclude it from the anterior compartment. The increase in the size of the normal tissue corridor when sartorius is excluded should deliver clinical advantage by decreasing the normal tissue adverse effects.Peer Reviewe

Experiences of learning through collaborative evaluation from a masters programme in professional education

This paper presents findings from a collaborative evaluation project within a masters programme in professional education. The project aimed to increase knowledge of research methodologies and methods through authentic learning where participants worked in partnership with the tutor to evaluate the module which they were studying. The project processes, areas of the course evaluated and the data collection methods are outlined. The findings focus on key themes from evaluating the effectiveness of using a collaborative evaluation approach, including: enhanced student engagement; creativity of the collaborative evaluation approach; equality between the tutor and students; and enhanced research skills. Discussion focuses on the outcomes and effectiveness of the project and tutor reflections on adopting a collaborative approach. This paper highlights lessons from the project relevant to those interested in staff-student partnership approaches and those facilitating postgraduate learning and teaching programmes and educational research courses

STROGAR – STrengthening the Reporting Of Genetic Association studies in Radiogenomics

AbstractDespite publication of numerous radiogenomics studies to date, positive single nucleotide polymorphism (SNP) associations have rarely been reproduced in independent validation studies. A major reason for these inconsistencies is a high number of false positive findings because no adjustments were made for multiple comparisons. It is also possible that some validation studies were false negatives due to methodological shortcomings or a failure to reproduce relevant details of the original study. Transparent reporting is needed to ensure these flaws do not hamper progress in radiogenomics. In response to the need for improving the quality of research in the area, the Radiogenomics Consortium produced an 18-item checklist for reporting radiogenomics studies. It is recognised that not all studies will have recorded all of the information included in the checklist. However, authors should report on all checklist items and acknowledge any missing information. Use of STROGAR guidelines will advance the field of radiogenomics by increasing the transparency and completeness of reporting

Deweyan tools for inquiry and the epistemological context of critical pedagogy

This article develops the notion of resistance as articulated in the literature of critical pedagogy as being both culturally sponsored and cognitively manifested. To do so, the authors draw upon John Dewey\u27s conception of tools for inquiry. Dewey provides a way to conceptualize student resistance not as a form of willful disputation, but instead as a function of socialization into cultural models of thought that actively truncate inquiry. In other words, resistance can be construed as the cognitive and emotive dimensions of the ongoing failure of institutions to provide ideas that help individuals both recognize social problems and imagine possible solutions. Focusing on Dewey\u27s epistemological framework, specifically tools for inquiry, provides a way to grasp this problem. It also affords some innovative solutions; for instance, it helps conceive of possible links between the regular curriculum and the study of specific social justice issues, a relationship that is often under-examined. The aims of critical pedagogy depend upon students developing dexterity with the conceptual tools they use to make meaning of the evidence they confront; these are background skills that the regular curriculum can be made to serve even outside social justice-focused curricula. Furthermore, the article concludes that because such inquiry involves the exploration and potential revision of students\u27 world-ordering beliefs, developing flexibility in how one thinks may be better achieved within academic subjects and topics that are not so intimately connected to students\u27 current social lives, especially where students may be directly implicated

Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.

Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08-4.69, p-value 4.16×10(-8)) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90-3.86, p-value=3.21×10(-8)). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.This work was supported by Cancer Research UK (C1094/A11728 to CMLW and NGB for the RAPPER study, C26900/A8740 to GCB, and C8197/A10865 to AMD), the Royal College of Radiologists (C26900/ A8740 to GCB), the National Institute for Health Research (GCB; no grant number), Addenbrooke's Charitable Trust (GCB; no grant number), Institute of Cancer Research (National Institute for Health Research) Biomedical Research Centre (C46/A2131 to DPD and SG), the National Institute for Health Research Cambridge Biomedical Research Centre (NGB; no grant number), UK Medical Research Council (RG70550 to LD), the Joseph Mitchell Trust (AMD; no grant number), the Experimental Cancer Medicine Centre (CMLW; no grant number), Cancer Research UK Program grant Section of Radiotherapy (C33589/ A19727 to SLG), the United States National Institutes of Health (1R01CA134444 to BSR and HO, 2P30CA014520-34 to SB, and 1K07CA187546-01A1 to SLK), the American Cancer Society (RSGT-05- 200-01-CCE to BSR), the U.S. Department of Defense (PC074201 to BSR and HO), Mount Sinai Tisch Cancer Institute Developmental Fund Award (BSR; no grant number), the Instituto de Salud Carlos III (FIS PI10/00164 and PI13/02030 to AV and PI13/01136 to AC), Fondo Europeo de Desarrollo Regional (FEDER 2007–2013 to AV and AC; no grant number), Instituto de Salud Carlos III (FIS PI10/00164 and PI13/ 02030 to AV and PI13/01136 to AC), Xunta de Galicia and the European Social Fund (POS-A/2013/034 to LF), and the Alberta Cancer Board Research Initiative Program (103.0393.71760001404 to MP). AMD receives support from the REQUITE study, which is funded by the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 601826. Laboratory infrastructure for the RAPPER study was funded by Cancer Research UK [C8197/A10123] and the Manchester Experimental Cancer Medicine Centre. The RAPPER cohort comprises individuals and data recruited into the RT01 and CHHiP UK radiotherapy trials. The RT01 trial was supported by the UK Medical Research Council. The CHHiP trial (CRUK/06/016) was supported by the Department of Health and Cancer Research UK (C8262/A7253); trial recruitment was facilitated within centers by the National Institute for Health Research Cancer Research Network. DPD and SLG acknowledge NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and Institute of Cancer Research.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ebiom.2016.07.02

Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus

Meta-GWAS identifies the heritability of acute radiation-induced toxicities in head and neck cancer

Background and purpose: We aimed to the genetic components and susceptibility variants associated with acute radiation-induced toxicities (RITs) in patients with head and neck cancer (HNC). Materials and methods: We performed the largest meta-GWAS of seven European cohorts (n = 4,042). Patients were scored weekly during radiotherapy for acute RITs including dysphagia, mucositis, and xerostomia. We analyzed the effect of variants on the average burden (measured as area under curve, AUC) per each RIT, and standardized total average acute toxicity (STATacute) score using a multivariate linear regression. We tested suggestive variants (p < 1.0x10-5) in discovery set (three cohorts; n = 2,640) in a replication set (four cohorts; n = 1,402). We meta-analysed all cohorts to calculate RITs specific SNP-based heritability, and effect of polygenic risk scores (PRSs), and genetic correlations among RITS. Results: From 393 suggestive SNPs identified in discovery set; 37 were nominally significant (preplication < 0.05) in replication set, but none reached genome-wide significance (pcombined < 5 × 10-8). In-silico functional analyses identified “3′-5'-exoribonuclease activity” (FDR = 1.6e-10) for dysphagia, “inositol phosphate-mediated signalling” for mucositis (FDR = 2.20e-09), and “drug catabolic process” for STATacute (FDR = 3.57e-12) as the most enriched pathways by the RIT specific suggestive genes. The SNP-based heritability (±standard error) was 29 ± 0.08 % for dysphagia, 9 ± 0.12 % (mucositis) and 27 ± 0.09 % (STATacute). Positive genetic correlation was rg = 0.65 (p = 0.048) between dysphagia and STATacute. PRSs explained limited variation of dysphagia (3 %), mucositis (2.5 %), and STATacute (0.4 %). Conclusion: In HNC patients, acute RITs are modestly heritable, sharing 10 % genetic susceptibility, when PRS explains < 3 % of their variance. We identified numerus suggestive SNPs, which remain to be replicated in larger studies

Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus

The impact of multimorbidity on adult physical and mental health in low- and middle-income countries: what does the study on global ageing and adult health (SAGE) reveal?

BACKGROUND: Chronic diseases contribute a large share of disease burden in low- and middle-income countries (LMICs). Chronic diseases have a tendency to occur simultaneously and where there are two or more such conditions, this is termed as 'multimorbidity'. Multimorbidity is associated with adverse health outcomes, but limited research has been undertaken in LMICs. Therefore, this study examines the prevalence and correlates of multimorbidity as well as the associations between multimorbidity and self-rated health, activities of daily living (ADLs), quality of life, and depression across six LMICs. METHODS: Data was obtained from the WHO's Study on global AGEing and adult health (SAGE) Wave-1 (2007/10). This was a cross-sectional population based survey performed in LMICs, namely China, Ghana, India, Mexico, Russia, and South Africa, including 42,236 adults aged 18 years and older. Multimorbidity was measured as the simultaneous presence of two or more of eight chronic conditions including angina pectoris, arthritis, asthma, chronic lung disease, diabetes mellitus, hypertension, stroke, and vision impairment. Associations with four health outcomes were examined, namely ADL limitation, self-rated health, depression, and a quality of life index. Random-intercept multilevel regression models were used on pooled data from the six countries. RESULTS: The prevalence of morbidity and multimorbidity was 54.2 % and 21.9 %, respectively, in the pooled sample of six countries. Russia had the highest prevalence of multimorbidity (34.7 %) whereas China had the lowest (20.3 %). The likelihood of multimorbidity was higher in older age groups and was lower in those with higher socioeconomic status. In the pooled sample, the prevalence of 1+ ADL limitation was 14 %, depression 5.7 %, self-rated poor health 11.6 %, and mean quality of life score was 54.4. Substantial cross-country variations were seen in the four health outcome measures. The prevalence of 1+ ADL limitation, poor self-rated health, and depression increased whereas quality of life declined markedly with an increase in number of diseases. CONCLUSIONS: Findings highlight the challenge of multimorbidity in LMICs, particularly among the lower socioeconomic groups, and the pressing need for reorientation of health care resources considering the distribution of multimorbidity and its adverse effect on health outcomes