Exercise and manual physiotherapy arthritis research trial (EMPART): a multicentre randomised controlled trial

BACKGROUND: Osteoarthritis (OA) of the hip is a major cause of functional disability and reduced quality of life. Management options aim to reduce pain and improve or maintain physical functioning. Current evidence indicates that therapeutic exercise has a beneficial but short-term effect on pain and disability, with poor long-term benefit. The optimal content, duration and type of exercise are yet to be ascertained. There has been little scientific investigation into the effectiveness of manual therapy in hip OA. Only one randomized controlled trial (RCT) found greater improvements in patient-perceived improvement and physical function with manual therapy, compared to exercise therapy. METHODS AND DESIGN: An assessor-blind multicentre RCT will be undertaken to compare the effect of a combination of manual therapy and exercise therapy, exercise therapy only, and a waiting-list control on physical function in hip OA. One hundred and fifty people with a diagnosis of hip OA will be recruited and randomly allocated to one of 3 groups: exercise therapy, exercise therapy with manual therapy and a waiting-list control. Subjects in the intervention groups will attend physiotherapy for 6-8 sessions over 8 weeks. Those in the control group will remain on the waiting list until after this time and will then be re-randomised to one of the two intervention groups. Outcome measures will include physical function (WOMAC), pain severity (numerical rating scale), patient perceived change (7-point Likert scale), quality of life (SF-36), mood (hospital anxiety and depression scale), patient satisfaction, physical activity (IPAQ) and physical measures of range of motion, 50-foot walk and repeated sit-to stand tests. DISCUSSION: This RCT will compare the effectiveness of the addition of manual therapy to exercise therapy to exercise therapy only and a waiting-list control in hip OA. A high quality methodology will be used in keeping with CONSORT guidelines. The results will contribute to the evidence base regarding the clinical efficacy for physiotherapy interventions in hip OA

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era

Cardiac toxicity following thoracic radiation.

While the data regarding radiotherapy (RT)-induced cardiovascular disease in lung cancer patients is limited, the cardiotoxic effects of RT have been thoroughly documented in long-term survivors of breast cancer and Hodgkin\u27s disease. Herein we review data illustrating the cardiotoxic effects of thoracic RT in lung and breast cancer patients. Older RT techniques for treating the breast/chest wall and draining lymph nodes resulted in a relatively high dose being delivered to a substantial volume of heart, and convincing evidence exists of excess cardiovascular morbidity and mortality in patients treated with these techniques. While modern RT techniques have reduced radiation exposure to the heart, they have not eliminated it. In patients treated with modern techniques, there are conflicting data regarding the impact of radiation on late cardiovascular morbidity and mortality. Thus, it is prudent to reduce cardiac exposure as much as possible. Techniques to reduce further cardiac exposure (eg, respiratory gating, intensity modulated radiation therapy) are currently under investigation. Further work is needed to quantify the frequency and severity of cardiac injury and develop preventative methods

Late effects of breast radiotherapy in young women.

Radiotherapy (RT) to the breast or chest wall of young women is associated with long-term cardiotoxicity and an increased risk of secondary breast cancers. As many patients with early stage breast cancer and Hodgkin\u27s disease are cured of their disease, there is significant concern regarding the long term risks of therapy. Older RT techniques for treating the breast/chest wall and draining lymph nodes for breast cancer resulted in a relatively high dose being delivered to a substantial volume of heart, and convincing evidence exists of excess cardiovascular morbidity and mortality in patients treated with these techniques. While modern RT techniques have reduced radiation exposure to the heart, they have not eliminated it. Many large studies of Hodgkin\u27s disease survivors have demonstrated a clear risk of secondary breast cancer development after mantle RT for Hodgkin\u27s disease. The risk of developing breast cancer after mantle RT appears to be related to age at time of irradiation, dose delivered to the breast tissue, and whether or not chemotherapy is incorporated into the overall treatment plan. In this article we review late cardiac complications associated with tangential breast RT and the risk of developing a secondary breast cancer after mantle RT for Hodgkin\u27s disease

Definition of postlumpectomy tumor bed for radiotherapy boost field planning: CT versus surgical clips.

PURPOSE: To compare the location and extent of the tumor bed as defined by surgical clips and computed tomography (CT) scans, after lumpectomy, for electron boost planning as part of breast radiotherapy. METHODS AND MATERIALS: Planning CT images of 31 operated breasts in 30 patients who underwent lumpectomy were reviewed. One or more clips were placed in the lumpectomy cavity. Serial CT images were used to measure the depth and transverse and longitudinal dimensions. The area and geometric center of the tumor bed were defined by the clips and CT. RESULTS: The CT and clip measurements were identical for the maximal tumor depth in 27 of 30 patients. The CT bed extended beyond the clips by 0-7 mm medially in the transverse/longitudinal extent (multiclip patients). The median distance between the geometric centers in the coronal plane for the tumor bed center was larger for patients with single clips than for those with multiple clips (p \u3c 0.025). Tumor bed areas in the coronal plane defined by both methods correlated strongly. However, the CT-defined area was larger by 13.9 mm2. The CT bed was more readily visible in patients with a shorter interval between surgery and radiotherapy. CONCLUSION: The maximal depth of the tumor bed was similar using the two methods. The extent and centers of the clip-and CT-determined beds differed significantly. This may indicate an underestimation of the tumor bed as defined by clips only and justifies integration of CT information in boost field planning

An Evaluation of Health Numeracy among Radiation Therapists and Dosimetrists

Purpose: Medical errors in radiation oncology sometimes involve tasks reliant on practitioners’ grasp of numeracy. Numeracy has been shown to be suboptimal across various health care professionals. Herein, we assess health numeracy among American Society of Radiologic Technologists (ASRT) members. Methods and materials: The Numeracy Understanding for Medicine instrument (NUMi), an instrument to measure numeracy in the general population, was adapted to oncology for this study and distributed to ASRT members (n = 14,228) in 2017. Per NUMi scoring, health numeracy scores were categorized as low (0-7), low average (8-12), high average (13-17), or high (18-20). The impact of cGy versus Gy on numeracy performance was investigated. Spearman’s rho and a Wilcox-Mann-Whitney test were used for comparisons between the different groups. Results: A total of 662 eligible participants completed the instrument and identified as radiation oncology professionals. In the cGy and Gy NUMi scores, approximately 2% of respondents scored low-average, approximately 40% scored high-average, and approximately 58% scored high, with a median score of 18.0. Although the optimum NUMi score for ASRT members is unknown, one might expect our cohort to have numeracy skills at least as high as college freshmen. Roughly one-sixth of our study group scored at or below the average score of college freshmen (NUMi = 15). In the subset analysis of NUMi questions pertaining to radiation dose unit (cGy vs Gy), respondents performed better with cGy (mean score: 2.94; range, 2-3) versus Gy (mean: 2.91; range, 0-3; P = .011). Conclusions: In this study of limited sample size, overall numeracy is quite good compared with the general population. However, the range of scores is wide, and some respondents have lower scores that may be concerning, suggesting that numeracy may be an issue that requires improvement for a subset of the studied cohort. Performance was superior with the unit cGy; thus, the adoption of cGy as the standard unit is reasonable

Assessment of the residual error in soft tissue setup in patients undergoing partial breast irradiation: results of a prospective study using cone-beam computed tomography.

PURPOSE: On-board cone-beam computed tomography (CBCT) provides soft tissue information that may improve setup accuracy in patients undergoing accelerated partial breast irradiation (APBI). We used CBCT to assess the residual error in soft tissue after two-dimensional kV/MV alignment based on bony anatomy. We also assessed the dosimetric impact of this error. METHODS AND MATERIALS: Ten patients undergoing APBI were studied as part of an institutional review board-approved prospective trial. Patients were aligned based on skin/cradle marks plus orthogonal kV/MV images registered based on bony landmarks to digitally reconstructed radiographs from the planning CT. A subsequent CBCT was registered to the planning CT using soft tissue information. This residual error and its dosimetric impact was measured. RESULTS: The root-mean-square of the residual error was 3, 4, and 4 mm, in the right-left, anterior-posterior, and superior-inferior directions, respectively. The average vector sum was 6+/-2 mm. Average reductions in mean dose to the lumpectomy cavity, clinical target volume (CTV), and planning target volume were 0.1%, 0.4%, and 1%, respectively. The mean difference in the clinical target and planning target volumes that received 95% of the prescribed dose (V95) were 1% and 4%. CONCLUSIONS: In this initial study with a modest number of patients, the residual error in soft tissue was typically \u3c5 \u3emm, and with the field margins used, the resultant dosimetric consequences were modest. In patients immobilized in a customized cradle, setup using orthogonal kV images thus appears accurate and reproducible. The CBCT technique may have particular utility in patients with larger breast volumes or breast deformations. Further studies involving larger numbers of patients are needed to further assess the utility of CBCT