Delivering a Research-Enabled Multistakeholder Partnership for Enhanced Patient Care at a Population Level: The Northern Ireland Comprehensive Cancer Program

The last 20 years have seen significant advances in cancer care in Northern Ireland, leading to measureable improvements in patient outcomes. Crucial to this transformation has been an ethos that recognizes the primacy role of research in effecting heath care change. The authors' model of a cross-sectoral partnership that unites patients, scientists, health care professionals, hospital trusts, bioindustry, and government agencies can be truly transformative, empowering tripartite clinical-academic-industry efforts that have already yielded significant benefit and will continue to inform strategy and its implementation going forward.

A quality control program for mutation detection in KIT and PDGFRA in gastrointestinal stromal tumours.

BACKGROUND: Although most gastrointestinal stromal tumours (GIST) carry oncogenic mutations in KIT exons 9, 11, 13 and 17, or in platelet-derived growth factor receptor alpha (PDGFRA) exons 12, 14 and 18, around 10% of GIST are free of these mutations. Genotyping and accurate detection of KIT/PDGFRA mutations in GIST are becoming increasingly useful for clinicians in the management of the disease. METHOD: To evaluate and improve laboratory practice in GIST mutation detection, we developed a mutational screening quality control program. Eleven laboratories were enrolled in this program and 50 DNA samples were analysed, each of them by four different laboratories, giving 200 mutational reports. RESULTS: In total, eight mutations were not detected by at least one laboratory. One false positive result was reported in one sample. Thus, the mean global rate of error with clinical implication based on 200 reports was 4.5%. Concerning specific polymorphisms detection, the rate varied from 0 to 100%, depending on the laboratory. The way mutations were reported was very heterogeneous, and some errors were detected. CONCLUSION: This study demonstrated that such a program was necessary for laboratories to improve the quality of the analysis, because an error rate of 4.5% may have clinical consequences for the patient.

Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

BACKGROUND: Patient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial.

METHODS: The CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b-T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923.

FINDINGS: 2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50·0 months (IQR 38·4-64·2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59). We saw no differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months.

INTERPRETATION: The incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer.

FUNDING: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

Availability of stage at diagnosis, cancer treatment delay and compliance with cancer guidelines as cancer registry indicators for cancer care in Europe:Results of EUROCHIP-3 survey

EUROCHIP (European Cancer Health Indicators Project) focuses on understanding inequalities in the cancer burden, care and survival by the indicators "stage at diagnosis," "cancer treatment delay" and "compliance with cancer guidelines" as the most important indicators. Our study aims at providing insight in whether cancer registries collect well-defined variables to determine these indicators in a comparative way. Eighty-six general European population-based cancer registries (PBCR) from 32 countries responded to the questionnaire, which was developed by EUROCHIP in collaboration with ENCR (European Network of Cancer Registries) and EUROCOURSE. Only 15% of all the PBCR in EU had all three indicators available. The indicator "stage at diagnosis" was gathered for at least one cancer site by 81% (using TNM in 39%). Variables for the indicator "cancer treatment delay" were collected by 37%. Availability of type of treatment (30%), surgery date (36%), starting date of radiotherapy (26%) and starting date of chemotherapy (23%) resulted in 15% of the PBCRs to be able to gather the indicator "compliance to guidelines". Lack of data source access and qualified staff were the major reasons for not collecting all the variables. In conclusion, based on self-reporting, a few of the participating PBCRs had data available which could be used for clinical audits, evaluation of cancer care projects, survival and for monitoring national cancer control strategies. Extra efforts should be made to improve this very efficient tool to compare cancer burden and the effects of the national cancer plans over Europe and to learn from each other. © 2012 UICC.

An outpatient respiratory rehabilitation program:Findings from a community hospital

Objectives: To determine patient satisfaction with a community hospital's respiratory rehabilitation program and to assess changes in patient physical and emotional function and quality of life. Design: Pre- and post-program measures were made on a variety of physiological and psychosocial factors. A modified version of the Chronic Respiratory Disease Questionnaire was administered before and after the 8-week multidisciplinary and comprehensive respiratory rehabilitation program. The post-program questionnaire also included a number of service delivery and patient satisfaction and quality-of-life questions. Setting: Respiratory Rehabilitation Program at St. Joseph's Hospital, a community hospital in Brantford, Ont., in active partnership with the Brant County Lung Association. Brant County is located in Central West Ontario, and has both urban and rural areas and a population of approximately 125 000 people. Participants: Twenty-nine patients, with a diagnosis of moderate to severe chronic obstructive pulmonary disease (COPD) who were referred to the Fall 1997 and Spring 1998 programs, were enrolled in the study. Outcome measures: Changes in physical and emotional function, health knowledge, skills mastery, quality of life and satisfaction with the program. Results: Twenty-one of 29 patients completed the program. Statistically significant and clinically important improvements were found between all pre- and post-program evaluation scores (distance walked, fatigue, dyspnea, emotional function, skills mastery and health knowledge). Participants were very satisfied with the program and felt it improved their quality of life. Conclusion: The positive outcomes reported rom randomized controlled trials of respiratory rehabilitation programs can be achieved in a community hospital setting.

Predictions of survival up to 10 years after diagnosis for European women with breast cancer in 2000-2002

Few studies have addressed longer-term survival for breast cancer in European women. We have made predictions of 10-year survival for European women diagnosed with breast cancer in 2000-2002. Data for 114,312 adult women (15-99 years) diagnosed with a first primary malignant cancer of the breast during 2000-2002 were collected in the EUROCARE-4 study from 24 population-based cancer registries in 14 European countries. We estimated relative survival at 1, 5, and 10 years after diagnosis for women who were alive at some point during 2000-2002, using the period approach. We also estimated 10-year survival conditional on survival to 1 and 5 years after diagnosis. Ten-year survival exceeded 70% in most regions, but was only 54% in Eastern Europe, with the highest value in Northern Europe (about 75%). Ten-year survival conditional on survival for 1 year was 2-6% higher than 10-year survival in all European regions, and geographic differences were smaller. Ten-year survival for women who survived at least 5 years was 88% overall, with the lowest figure in Eastern Europe (79%) and the highest in the UK (91%). Women aged 50-69 years had higher overall survival than older and younger women (79%). Six cancer registries had adequate information on stage at diagnosis; in these jurisdictions, 10-year survival was 89% for local, 62% for regional and 10% for metastatic disease. Data on stage are not collected routinely or consistently, yet these data are essential for meaningful comparison of population-based survival, which provides vital information for improving breast cancer control. What's new? Policy-makers and health-care planners need accurate data on long-term survival to improve cancer control. This Europe-wide study of 10-year survival identified low survival in Eastern Europe for women with breast cancer in 2000-2002, and wide variation by age at diagnosis. Data on stage at diagnosis are crucial for meaningful comparison of population-based survival, and fundamental for improving breast cancer control, but our analyses confirmed that stage data are not collected routinely or consistently Copyright © 2012 UICC.

Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control.

METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights.

FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease.

INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems.

Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

BACKGROUND: Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.

METHODS: CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b-T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.

FINDINGS: Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9-77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0-90·2) in the 74 Gy group, 90·6% (88·5-92·3) in the 60 Gy group, and 85·9% (83·4-88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68-1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99-1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.

INTERPRETATION: Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.

FUNDING: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

Shooting for the Moon or Flying Too Near the Sun? Crossing the Value Rubicon in Precision Cancer Care

In his last two State of the Union addresses, President Barack Obama has focused on the need to deliver innovative solutions to improve human health, through the Precision Medicine Initiative in 2015 and the recently announced Cancer Moonshot in 2016. Precision cancer care has delivered clear patient benefit, but even for high-impact medicines such as imatinib mesylate (Glivec) in chronic myeloid leukaemia, the excitement at the success of this practice-changing clinical intervention has been somewhat tempered by the escalating price of this 'poster child' for precision cancer medicine (PCM). Recent studies on the costs of cancer drugs have revealed significant price differentials, which are a major causative factor behind disparities in the access to new generations of immunological and molecularly targeted agents. In this perspective, we will discuss the benefits of PCM to modern cancer control, but also emphasise how increasing costs are rendering the current approaches to integrating the paradigm of PCM unsustainable. Despite the ever increasing pressure on cancer and health care budgets, innovation will and must continue. Value-based frameworks offer one of the most rational approaches for policymakers committed to improving cancer outcomes through a public health approach.

Using hypnosis to facilitate direct observation of multiple tics and self-monitoring in a typically developing teenager

A hypnotic induction technique was used to facilitate direct observation of multiple tics in a typically developing teenager in a home setting. A comprehensive habit reversal program then was implemented, including awareness training, competing response training, relaxation training, self-monitoring, social support and contingency management. Duration of relaxation was then self-monitored using a changing criterion design. The procedure eliminated multiple tics and achieved long-term maintenance of treatment gains. Implications for assessing and treating tics are discussed.

NuGO contributions to GenePattern

NuGO, the European Nutrigenomics Organization, utilizes 31 powerful computers for, e.g., data storage and analysis. These so-called black boxes (NBXses) are located at the sites of different partners. NuGO decided to use GenePattern as the preferred genomic analysis tool on each NBX. To handle the custom made Affymetrix NuGO arrays, new NuGO modules are added to GenePattern. These NuGO modules execute the latest Bioconductor version ensuring up-to-date annotations and access to the latest scientific developments. The following GenePattern modules are provided by NuGO: NuGOArrayQualityAnalysis for comprehensive quality control, NuGOExpressionFileCreator for import and normalization of data, LimmaAnalysis for identification of differentially expressed genes, TopGoAnalysis for calculation of GO enrichment, and GetResultForGo for retrieval of information on genes associated with specific GO terms. All together, these NuGO modules allow comprehensive, up-to-date, and user friendly analysis of Affymetrix data. A special feature of the NuGO modules is that for analysis they allow the use of either the standard Affymetrix or the MBNI custom CDF-files, which remap probes based on current knowledge. In both cases a .chip-file is created to enable GSEA analysis. The NuGO GenePattern installations are distributed as binary Ubuntu (.deb) packages via the NuGO repository.

School and Community Screening Shows Malawi, Africa, to Have a High Prevalence of Latent Rheumatic Heart Disease

Rheumatic heart disease (RHD) is the largest cardiac cause of morbidity and mortality in the world's youth. Early detection of RHD through echocardiographic screening in asymptomatic children may identify an early stage of disease, when secondary prophylaxis has the greatest chance of stopping disease progression. Latent RHD signifies echocardiographic evidence of RHD with no known history of acute rheumatic fever and no clinical symptoms.

OBJECTIVE: Determine the prevalence of latent RHD among children ages 5-16 in Lilongwe, Malawi.

DESIGN: This is a cross-sectional study in which children ages 5 through 16 were screened for RHD using echocardiography.

SETTING: Screening was conducted in 3 schools and surrounding communities in the Lilongwe district of Malawi between February and April 2014.

OUTCOME MEASURES: Children were diagnosed as having no, borderline, or definite RHD as defined by World Heart Federation criteria. The primary reader completed offline reads of all studies. A second reader reviewed all of the studies diagnosed as RHD, plus a selection of normal studies. A third reader served as tiebreaker for discordant diagnoses. The distribution of results was compared between gender, location, and age categories using Fisher's exact test.

RESULTS: The prevalence of latent RHD was 3.4% (95% CI = 2.45, 4.31), with 0.7% definite RHD and 2.7% borderline RHD. There was no significant differences in prevalence between gender (P = .44), site (P = .6), urban vs. peri-urban (P = .75), or age (P = .79). Of those with definite RHD, all were diagnosed because of pathologic mitral regurgitation (MR) and 2 morphologic features of the mitral valve. Of those with borderline RHD, most met the criteria by having pathological MR (92.3%).

CONCLUSION: Malawi has a high rate of latent RHD, which is consistent with other results from sub-Saharan Africa. This study strongly supports the need for a RHD prevention and control program in Malawi.

High prevalence of Schistosoma japonicum and Fasciola gigantica in bovines from Northern Samar, the Philippines

The cause of zoonotic schistosomiasis in the Philippines is Schistosoma japonicum, which infects up to 46 mammalian hosts, including humans and bovines. In China, water buffaloes have been identified as major reservoir hosts for schistosomiasis japonica, contributing up to 75% of human transmission. In the Philippines, water buffaloes (carabao; Bubalus bubalis carabanesis) have, historically, been considered unimportant reservoirs. We therefore revisited the possible role of bovines in schistosome transmission in the Philippines, using the recently described formalin-ethyl acetate sedimentation (FEA-SD) technique and a qPCR assay to examine fecal samples from 153 bovines (both carabao and cattle) from six barangays in Northern Samar. A high prevalence of S. japonicum was found using qPCR and FEA-SD in both cattle (87.50% and 77.08%, respectively) and carabao (80.00% and 55.24%, respectively). The average daily egg output for each bovine was calculated at 195,000. High prevalence and infection intensity of F. gigantica was also found in the bovines by qPCR and FEA-SD (95.33% and 96.00%, respectively). The identification of bovines as major reservoir hosts for S. japonicum transmission suggests that bovine treatment and/or vaccination, as one becomes available, should be included in any future control program that aims to reduce the disease burden due to schistosomiasis in the Philippines.