Medical Research Council Trial Research Articles

Comparing one dose of HPV vaccine in girls aged 9–14 years in Tanzania (DoRIS) with one dose in young women aged 15–20 years in Kenya (KEN SHE): an immunobridging analysis of randomised controlled trials

The first randomised controlled trial of single-dose human papillomavirus (HPV) vaccine efficacy, the Kenya single-dose HPV-vaccine efficacy (KEN SHE) trial, showed greater than 97% efficacy against persistent HPV16 and HPV18 infection at 36 months among women in Kenya. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), the first randomised trial of the single- dose regimen in girls aged 9-14 years, the target age range for vaccination, with those after one dose of the same vaccine in KEN SHE. In the DoRIS trial, 930 girls aged 9-14 years in Tanzania were randomly assigned to one, two, or three doses of the 2-valent vaccine (Cervarix) or the 9-valent vaccine (Gardasil-9). The proportion seroconverting and geometric mean concentrations (GMCs) at month 24 after one dose were compared with those in women aged 15-20 years who were randomly assigned to one dose of the same vaccines at the same timepoint in KEN SHE. Batched samples were tested together by virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial:KEN SHE) was predefined as a lower bound of the 95% CI less than 0·50. Month 24 HPV16 and HPV18 antibody GMCs in DoRIS were similar or higher than those in KEN SHE. 2-valent GMC ratios were 0·90 (95% CI 0·72-1·14) for HPV16 and 1·02 (0·78-1·33) for HPV18. 9-valent GMC ratios were 1·44 (95% CI 1·14-1·82) and 1·47 (1·13-1·90), respectively. Non-inferiority of antibody GMCs and seropositivity was met for HPV16 and HPV18 for both vaccines. HPV16 and HPV18 immune responses in young girls 24 months after a single dose of 2-valent or 9-valent HPV vaccine were comparable to those in young women who were randomly assigned to a single dose of the same vaccines and in whom efficacy had been shown. A single dose of HPV vaccine, when given to girls in the target age range for vaccination, induces immune responses that could be effective against persistent HPV16 and HPV18 infection at least two years after vaccination. The UK Department of Health and Social Care, the Foreign, Commonwealth, & Development Office, the Global Challenges Research Fund, the UK Medical Research Council and Wellcome Trust Joint Global Health Trials scheme, the Bill and Melinda Gates Foundation, the US National Cancer Institute; the US National Institutes of Health, and the Francis and Dorothea Reed Endowed Chair in Infectious Diseases. For the KiSwahili translation of the abstract see Supplementary Materials section.

Long-term oxygen therapy in COPD: what is the evidence?

Thomas L Petty was the founder of modern long-term oxygen therapy (LTOT).1 In 1967, Petty's group published the seminal study of six patients with severe chronic airway obstruction, in whom LTOT improved clinical status, exercise capacity, secondary erythrocythemia, and pulmonary hypertension.2 Notably, all patients had severe hypoxaemia (partial pressure of oxygen [PaO2] 41·5–46·5 mm Hg) and four patients were severely hypercapnic (partial pressure of carbon dioxide [PaCO2] 55·0–61·5 mm Hg). Thereafter, two randomised controlled trials that were initiated in the 1970s established a clear survival benefit related to LTOT in patients with chronic obstructive pulmonary disease (COPD) with severe resting hypoxaemia: the Nocturnal Oxygen Therapy Trial (NOTT)3 and the British Medical Research Council (BMRC) trial.

The PROMoting the USE of SWATs (PROMETHEUS) programme: Lessons learnt and future developments for SWATs

Introduction The PROMETHEUS programme (PROMoting THE USE of SWATs) was funded by the UK Medical Research Council (MRC) and Clinical Trials Unit (CTU) infrastructure funding from the National Institute for Health Research (NIHR). The purpose was to develop strategies to increase the recruitment and retention evidence base. This paper aims to present observations from this work. Observations The PROMETHUS programme funded 42 SWATs, the average cost of each SWAT was £4007. A central coordination point enabled a concentrated effort in SWAT research activity leading to a rapid increase in the evidence base. The methodological feasibility of undertaking a coordinated SWAT design was established. The international Trial Forge SWAT Network was developed in 2021 to connect research groups in response for the need to connect teams undertaking methodological research. A SWAT reporting template and a database of researchers willing to peer review SWATs are also needed to improve the reporting of SWATs. Discussion There is a need to develop a strategy to aid teams to identify a suitable SWAT for their host trial populations and a mechanism to communicate SWAT research priorities. Work is needed to increase the awareness of the methodological importance of SWAT research with research teams and develop engagement strategies to increase SWAT activity. Continued collaboration with the HRA is necessary to refine the SWAT approvals process. Conclusion The coordination PROMETHEUS provided is crucial to increasing the recruitment retention evidence base. The Trial Forge Network will be key to provide ongoing networking and dissemination opportunities.

Changes in orthopaedic operating theatre practice, monitored using settle plates.

The importance of ultraclean air in reducing deep infection was studied by Charnley who showed that the rate decreased as the airborne bacterial load was reduced. The effectiveness was shown in a large Medical Research Council (MRC) trial, but registry data have not shown a consistent benefit. Because we treat patients with rheumatoid arthritis, we decided to look at our theatre air quality. In phase 1 we monitored air quality using settle plates, exposed for one hour after the incision, on the instrument trolleys in a joint replacement theatre. In phase 1 the scrub person did not wear a body exhaust system. In phase 2 all three staff used a body exhaust system, and we played close attention to the orientation and position of the surgical lights and trolleys. In phase 1 we grew 0.24 colonies/plate/hour in the ultraclean zone, which is comparable to the Charnley trial findings. In the second phase we grew 0.03 colonies/plate/hour (p<0.001). When plates were placed on the trolleys in controlled positions there was a tendency for the colonies to appear on the corners of the trolleys at the edge of the clean zone (NS). The study showed that in phase 1 colony counts comparable to the original Charnley studies were achieved. Colony counts of 0.03 colonies/plate/hour can be achieved in contemporary practice, with all team members using body exhausts.

Hypertension in elderly Egyptians

Global census studies reveal that the elderly are the most rapidly growing population group in both industrialized and less industrialized nations. During 1991 and 1992, three major interventional trials dealt with hypertension in older subjects and the value of antihypertensive treatment in the elderly. These were the American Systolic Hypertension in the Elderly Program [SHEP], the Swedish Trial in Old Patients with Hypertension [STOP-Hypertension], and the British Medical Research Council Trial on treatment of hypertension in older adults. All three trials showed that therapy for hypertension in the elderly reduces the risk of stroke and cardiovascular events. In 1993 evidence from the Egyptian Hypertension Project highlighted hypertension as a national public health problem that must be addressed. Guidelines for primary prevention among all sectors of the community are discussed

Amiloride: A review.

Amiloride is a potassium retaining diuretic and natriuretic which acts by reversibly blocking luminal epithelial sodium channels (ENaCs) in the late distal tubule and collecting duct. Amiloride is indicated in oedematous states, and for potassium conservation adjunctive to thiazide or loop diuretics for hypertension, congestive heart failure and hepatic cirrhosis with ascites. Historical studies on its use in hypertension were poorly controlled and there is insufficient data on dose-response. It is clearly highly effective in combination with thiazide diuretics where it counteracts the adverse metabolic effects of the thiazides and its use in the Medical Research Council Trial of Older Hypertensive Patients, demonstrated convincing outcome benefits on stroke and coronary events. Recently it has been shown to be as effective as spironolactone in resistant hypertension but there is a real need to establish its potential role in the much larger number of patients with mild to moderate hypertension in whom there is a paucity of information with amiloride particularly across an extended dose range.

Impact of retrospective data verification to prepare the ICON6 trial for use in a marketing authorization application.

Background:The ICON6 trial (ISRCTN68510403) is a phase III academic-led, international, randomized, three-arm, double-blind, placebo-controlled trial of the addition of cediranib to chemotherapy in recurrent ovarian cancer. It investigated the use of placebo during chemotherapy and maintenance (arm A), cediranib alongside chemotherapy followed by placebo maintenance (arm B) and cediranib throughout both periods (arm C). Results of the primary comparison showed a meaningful gain in progression-free survival (time to progression or death from any cause) when comparing arm A (placebo) with arm C (cediranib). As a consequence of the positive results, AstraZeneca was engaged with the Medical Research Council trials unit to discuss regulatory submission using ICON6 as the single pivotal trial.Methods:A relatively limited level of on-site monitoring, single data entry and investigator’s local evaluation of progression were used on trial. In order to submit a license application, it was decided that (a) extensive retrospective source data verification of medical records against case report forms should be performed, (b) further quality control checks for accuracy of data entry should be performed and (c) blinded independent central review of images used to define progression should be undertaken. To assess the value of these extra activities, we summarize the impact on both efficacy and safety outcomes.Results:Data point changes were minimal; those key to the primary results had a 0.47% error rate (36/7686), and supporting data points had a 0.18% error rate (109/59,261). The impact of the source data verification and quality control processes were analyzed jointly. The conclusion drawn for the primary outcome measure of progression-free survival between arm A and arm C was unchanged. The log-rank test p-value changed only at the sixth decimal place, the hazard ratio does not change from 0.57 with the exception of a marginal change in its upper bound (0.74–0.73) and the median progression-free survival benefit from arm C remained at 2.4 months. Separately, the blinded independent central review of progression scans was performed as a sensitivity analysis. Estimates and p values varied slightly but overall demonstrated a difference in arms, which is consistent with the initial result. Some increases in toxicity were observed, though these were generally minor, with the exception of hypertension. However, none of these increases were systematically biased toward one arm.Conclusion:The conduct of this pragmatic, academic-sponsored trial was sufficient given the robustness of the results, shown by the results remaining largely unchanged following retrospective verification despite not being designed for use in a marketing authorization. The burden of such comprehensive retrospective effort required to ensure the results of ICON6 were acceptable to regulators is difficult to justify.

The effectiveness of ultra-clean air operating theatres in the prevention of deep infection in joint arthroplasty surgery.

Deep infection was identified as a serious complication in the earliest days of total hip arthroplasty. It was identified that airborne contamination in conventional operating theatres was the major contributing factor. As progress was made in improving the engineering of operating theatres, airborne contamination was reduced. Detailed studies were carried out relating airborne contamination to deep infection rates. In a trial conducted by the United Kingdom Medical Research Council (MRC), it was found that the use of ultra-clean air (UCA) operating theatres was associated with a significant reduction in deep infection rates. Deep infection rates were further reduced by the use of a body exhaust system. The MRC trial also included a detailed microbiology study, which confirmed the relationship between airborne contamination and deep infection rates. Recent observational evidence from joint registries has shown that in contemporary practice, infection rates remain a problem, and may be getting worse. Registry observations have also called into question the value of "laminar flow" operating theatres. Observational evidence from joint registries provides very limited evidence on the efficacy of UCA operating theatres. Although there have been some changes in surgical practice in recent years, the conclusions of the MRC trial remain valid, and the use of UCA is essential in preventing deep infection. There is evidence that if UCA operating theatres are not used correctly, they may have poor microbiological performance. Current UCA operating theatres have limitations, and further research is required to update them and improve their microbiological performance in contemporary practice. Cite this article: Bone Joint J 2018;100-B:1264-9.

PC02.01 Surgery - PRO

Surgery in the treatment of small cell lung cancer (SCLC) was commonplace up until the mid-1970’s when the results of the medical research council (MRC) trial compared surgery to radiation and found no improvement with the addition of surgery. A later trial compared chemoradiation with adjuvant surgery to chemoradiation alone also failed to show an improvement with surgery. These two results have been used to justify nihilism amongst thoracic oncologists with respect to the use of surgery. However, modern screening, staging, minimally-invasive surgery and adjuvant therapy have changed the situation for the treatment of early SCLC. Modern evidence, albeit retrospective, supports a greater utility for surgery in the treatment of early SCLC than what may have been suggested by older randomized trials that are no longer applicable in the modern era. Surgery has much to offer in the treatment of early SCLC and this lecture will outline the potential utility of surgery - in particular anatomic resection and systematic lymph node dissection - as part of a multimodality treatment regimen. small cell lung cancer, Thoracic Surgery

Protocol for the mixed-methods process and context evaluation of the TB & Tobacco randomised controlled trial in Bangladesh and Pakistan: a hybrid effectiveness–implementation study

IntroductionTuberculosis (TB) remains a significant public health problem in South Asia. Tobacco use increases the risks of TB infection and TB progression. The TB& Tobacco placebo-controlled randomised trial aims to...

John Guyett Scadding's scepticism and pragmatism in addressing treatment uncertainties in clinical practice.

Open in a separate window John Guyett Scadding (1907–1999), my father, features quite prominently in the James Lind Library (JLL). The JLL includes reports of his controlled trials using alternate allocation and blinding to assess the effects of sulphonamides on gastrointestinal infections during 1944 and 1945;1–3 an article written by him for the JLL in 2002 reflecting on these studies4 and his comments in conversation with Iain Chalmers and Mike Clarke5 on the move from alternate allocation to concealed random allocation for the iconic Medical Research Council trial of streptomycin for pulmonary tuberculosis.6 Because clinical research done by my father covered a key moment in the history of controlled clinical trials, I was invited by the editors of the James Lind Library to provide some biographical information about him. My immediate reaction was that my father’s life and achievements had already been covered by some excellent obituaries (see Appendix 1), for example, Citron’s citation in Munk’s Roll written for the Royal College of Physicians of London. Accordingly, this article focuses on information and personal characteristics which I believe are of relevance to his clinical research in the 1940s. In addition to my own and my family’s and colleagues’ recollections of my father, I have drawn on published obituaries and a document entitled ‘The Institute of Diseases of the Chest, 1946–1972: a personal history’,7 from which I quote quite extensively.

Pharmacotherapy for hypertension in adults aged 18 to 59 years.

Hypertension is an important risk factor for adverse cardiovascular events including stroke, myocardial infarction, heart failure and renal failure. The main goal of treatment is to reduce these events. Systematic reviews have shown proven benefit of antihypertensive drug therapy in reducing cardiovascular morbidity and mortality but most of the evidence is in people 60 years of age and older. We wanted to know what the effects of therapy are in people 18 to 59 years of age. To quantify antihypertensive drug effects on all-cause mortality in adults aged 18 to 59 years with mild to moderate primary hypertension. To quantify effects on cardiovascular mortality plus morbidity (including cerebrovascular and coronary heart disease mortality plus morbidity), withdrawal due adverse events and estimate magnitude of systolic blood pressure (SBP) and diastolic blood pressure (DBP) lowering at one year. The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to January 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work. Randomized trials of at least one year' duration comparing antihypertensive pharmacotherapy with a placebo or no treatment in adults aged 18 to 59 years with mild to moderate primary hypertension defined as SBP 140 mmHg or greater or DBP 90 mmHg or greater at baseline, or both. The outcomes assessed were all-cause mortality, total cardiovascular (CVS) mortality plus morbidity, withdrawals due to adverse events, and decrease in SBP and DBP. For dichotomous outcomes, we used risk ratio (RR) with 95% confidence interval (CI) and a fixed-effect model to combine outcomes across trials. For continuous outcomes, we used mean difference (MD) with 95% CI and a random-effects model as there was significant heterogeneity. The population in the seven included studies (17,327 participants) were predominantly healthy adults with mild to moderate primary hypertension. The Medical Research Council Trial of Mild Hypertension contributed 14,541 (84%) of total randomized participants, with mean age of 50 years and mean baseline blood pressure of 160/98 mmHg and a mean duration of follow-up of five years. Treatments used in this study were bendrofluazide 10 mg daily or propranolol 80 mg to 240 mg daily with addition of methyldopa if required. The risk of bias in the studies was high or unclear for a number of domains and led us to downgrade the quality of evidence for all outcomes.Based on five studies, antihypertensive drug therapy as compared to placebo or untreated control may have little or no effect on all-cause mortality (2.4% with control vs 2.3% with treatment; low quality evidence; RR 0.94, 95% CI 0.77 to 1.13). Based on 4 studies, the effects on coronary heart disease were uncertain due to low quality evidence (RR 0.99, 95% CI 0.82 to 1.19). Low quality evidence from six studies showed that drug therapy may reduce total cardiovascular mortality and morbidity from 4.1% to 3.2% over five years (RR 0.78, 95% CI 0.67 to 0.91) due to reduction in cerebrovascular mortality and morbidity (1.3% with control vs 0.6% with treatment; RR 0.46, 95% CI 0.34 to 0.64). Very low quality evidence from three studies showed that withdrawals due to adverse events were higher with drug therapy from 0.7% to 3.0% (RR 4.82, 95% CI 1.67 to 13.92). The effects on blood pressure varied between the studies and we are uncertain as to how much of a difference treatment makes on average. Antihypertensive drugs used to treat predominantly healthy adults aged 18 to 59 years with mild to moderate primary hypertension have a small absolute effect to reduce cardiovascular mortality and morbidity primarily due to reduction in cerebrovascular mortality and morbidity. All-cause mortality and coronary heart disease were not reduced. There is lack of good evidence on withdrawal due to adverse events. Future trials in this age group should be at least 10 years in duration and should compare different first-line drug classes and strategies.

In memoriam: Dr. Andrew Czeizel.

In memoriam: Dr. Andrew Czeizel.

No-touch pancreatectomy for invasive ductal carcinoma of the pancreas

The UK Medical Research Council trial MRC UKALLX was designed to investigate the benefit of one or two courses of additional intensification therapy in children with acute lymphoblastic leukaemia receiving standard treatment. From 1985 to 1990 1612 children, comprising more than 90% of eligible cases in the UK, were treated with intensive induction therapy, central nervous system directed therapy with cranial irradiation and intrathecal methotrexate, and continuing treatment for 2 years. 1171 children were randomised to receive additional intensification therapy at 5 weeks, 20 weeks, both, or neither. At follow-up of at least 3 years disease-free survival for all children at 5 years was 62% (95% confidence interval [Cl] 60·0-64·4), a significant improvement over the 56% (53·0-59·6) found in the preceding MRC UKALL trial. The 5-year disease-free survival was 71% (65·5-76·1) for children randomised to two blocks of intensification therapy, this being significantly better than the 62% (56·6-68·0), 61% (55·7-67·1), and 57% (50·9-62·7) rates for the groups randomised to one intensification block at 5 weeks, one at 20 weeks, and no intensification, respectively. The benefits of intensification therapy were seen irrespective of clinical factors known to influence outcome such as age, sex, and initial leucocyte count. We conclude that the addition of two courses of intensification therapy has produced a 14% improvement in disease-free survival and an 11% improvement in overall survival for the randomised patients. This additional treatment is of benefit to all children with acute lymphoblastic leukaemia, even those traditionally deemed at lower risk of relapse.

Abstract PR11: Genomic approaches for risk assessment in acute myeloid leukemia

Abstract Acute myeloid leukemia is heterogeneous with respect to clinical outcome and molecular pathogenesis. Approximately 20% of AML cases are refractory to induction chemotherapy, and about 50% of patients ultimately relapse within a time interval that ranges from months to years. At the molecular level, diverse chromosomal abnormalities and genetic mutations have been observed across patients1. Although several clinical factors (age, white blood cell count), cytogenetic aberrations (t[15;17] translocation, loss of chromosome 5) 2-4, and genetic mutations (DNMT3A, FLT3) have been associated with differences in survival 5,6, these factors are of limited prognostic utility. Moreover, few studies have integrated sequence data with clinical and cytogentic factors to build predictive models of patient outcome. Here, we sought to identify genomic predictors of refractory disease or early relapse. We used whole genome and exome sequencing to analyze the genomes of 71 adult de novo AML patients treated with anthracycline and cytarabine-based induction chemotherapy. Of these, 34 had refractory disease or relapsed within 6 months, 12 relapsed in 6-12 months, and 25 had a long first remission (&amp;gt;12 months). We also developed an enhanced exome sequencing (EES) approach to identify and follow leukemia-associated variants over time. In 12 additional patients that achieved morphologic remission after induction chemotherapy, we used EES to identify and track variants at time of diagnosis, time of morphologic remission (roughly 30 days later), and a final time point corresponding to eventual relapse (n=8) or extended remission (n=4). No novel coding or non-coding variants present at the time of diagnosis were found to be predictive of refractory disease or early relapse. Using EES, however, we were able to detect leukemia-associated variants in the initial remission bone marrow in all eight patients who eventually relapsed. One persistent leukemia-associated variant was also detected in one patient still in remission, but all other variants in that patient were eliminated. We also detected 64 somatic variants that became enriched following chemotherapy, but were not detected in the original leukemic cells. These may represent relapse-specific variants or oligoclonal hematopoiesis after bone marrow recovery. Overall, our data suggest that the persistence of leukemia-associated variants after bone marrow recovery from cytotoxic therapy is strongly correlated with relapse, and may be used to complement more traditional, morphologic measures of leukemic cell clearance. 1. Cancer Genome Atlas Research N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. The New England Journal of Medicine 2013;368:2059-74. 2. Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100:4325-36. 3. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010;116:354-65. 4. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. The New England Journal of Medicine 2008;358:1909-18. 5. Kihara R, Nagata Y, Kiyoi H, et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia 2014;28:1586-95. 6. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. The New England Journal of Medicine 2010;363:2424-33. Citation Format: Jeffery M. Klco, Christopher A. Miller, Malachi Griffith, Allegra Petti, David H. Spencer, Shamika Ketkar-Kulkarni, Lukas D. Wartman, Matthew Christopher, Tamara L. Lamprecht, Jacqueline E. Payton, Jack Baty, Sharon E. Heath, Obi L. Griffith, Dong Shen, Jasreet Hundal, Gue Su Chang, Robert S. Fulton, Michelle O'laughlin, Catrina Fronick, Vincent Magrini, Ryan Demeter, David E. Larson, Shashikant Kulkarni, Bradley A. Ozenberger, John S. Welch, Matthew J. Walker, Timothy A. Graubert, Peter Westervelt, Jerald P. Radich, Daniel C. Link, Elaine R. Mardis, John F. DiPersio, Richard K. Wilson. Genomic approaches for risk assessment in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR11.

Abstract PR03: Genomic approaches for risk assessment in acute myeloid leukemia

Abstract Acute myeloid leukemia is heterogeneous with respect to clinical outcome and molecular pathogenesis. Approximately 20% of AML cases are refractory to induction chemotherapy, and about 50% of patients ultimately relapse within a time interval that ranges from months to years. At the molecular level, diverse chromosomal abnormalities and genetic mutations have been observed across patients1. Although several clinical factors (age, white blood cell count), cytogenetic aberrations (t[15;17] translocation, loss of chromosome 5) 2-4, and genetic mutations (DNMT3A, FLT3) have been associated with differences in survival 5,6, these factors are of limited prognostic utility. Moreover, few studies have integrated sequence data with clinical and cytogentic factors to build predictive models of patient outcome. Here, we sought to identify genomic predictors of refractory disease or early relapse. We used whole genome and exome sequencing to analyze the genomes of 71 adult de novo AML patients treated with anthracycline and cytarabine-based induction chemotherapy. Of these, 34 had refractory disease or relapsed within 6 months, 12 relapsed in 6-12 months, and 25 had a long first remission (&amp;gt;12 months). We also developed an enhanced exome sequencing (EES) approach to identify and follow leukemia-associated variants over time. In 12 additional patients that achieved morphologic remission after induction chemotherapy, we used EES to identify and track variants at time of diagnosis, time of morphologic remission (roughly 30 days later), and a final time point corresponding to eventual relapse (n=8) or extended remission (n=4). No novel coding or non-coding variants present at the time of diagnosis were found to be predictive of refractory disease or early relapse. Using EES, however, we were able to detect leukemia-associated variants in the initial remission bone marrow in all eight patients who eventually relapsed. One persistent leukemia-associated variant was also detected in one patient still in remission, but all other variants in that patient were eliminated. We also detected 64 somatic variants that became enriched following chemotherapy, but were not detected in the original leukemic cells. These may represent relapse-specific variants or oligoclonal hematopoiesis after bone marrow recovery. Overall, our data suggest that the persistence of leukemia-associated variants after bone marrow recovery from cytotoxic therapy is strongly correlated with relapse, and may be used to complement more traditional, morphologic measures of leukemic cell clearance. 1. Cancer Genome Atlas Research N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. The New England Journal of Medicine 2013;368:2059-74. 2. Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100:4325-36. 3. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010;116:354-65. 4. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. The New England Journal of Medicine 2008;358:1909-18. 5. Kihara R, Nagata Y, Kiyoi H, et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia 2014;28:1586-95. 6. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. The New England Journal of Medicine 2010;363:2424-33. This abstract is also presented as a poster at the Translation of the Cancer Genome conference. Citation Format: Jeffery M. Klco, Christopher A. Miller, Malachi Griffith, Allegra Petti, David H. Spencer, Shamika Ketkar-Kulkarni, Lukas D. Wartman, Matthew Christopher, Tamara L. Lamprecht, Jacqueline E. Payton, Jack Baty, Sharon E. Heath, Obi L. Griffith, Dong Shen, Jasreet Hundal, Gue Su Chang, Robert S. Fulton, Michelle O'laughlin, Catrina Fronick, Vincent Magrini, Ryan Demeter, David E. Larson, Shashikant Kulkarni, Bradley A. Ozenberger, John S. Welch, Matthew J. Walker, Timothy A. Graubert, Peter Westervelt, Jerald P. Radich, Daniel C. Link, Elaine R. Mardis, John F. DiPersio, Richard K. Wilson. Genomic approaches for risk assessment in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr PR03.

The Debate on Continuous Home Oxygen Therapy

Two studies published in the early 80s, namely the Nocturnal Oxygen Therapy Trial (NOTT) and the Medical Research Council Trial (MRC), laid the foundations for modern home oxygen therapy. Since then, little progress has been made in terms of therapeutic indications, and several prescription-associated problems have come to light. Advances in technology have gone hand in hand with growing disregard for the recommendations in clinical guidelines on oxygen therapy. The introduction of liquid oxygen brought with it a number of technical problems, clinical problems related to selecting candidate patients for portable delivery devices, and economic problems associated with the rising cost of the therapy. Continuous home oxygen therapy has been further complicated by the recent introduction of portable oxygen concentrators and the development in quick succession of a range of delivery devices with different levels of efficiency and performance. Modern oxygen therapy demands that clinicians evaluate the level of mobility of their patients and the mobility permitted by available oxygen sources, correctly match patients with the most appropriate oxygen source and adjust the therapy accordingly. The future of continuous home oxygen therapy lies in developing the ideal delivery device, improving the regulations systems and information channels, raise patient awareness and drive research.

Controversias en oxigenoterapia continua domiciliaria

Two studies published in the early 80s, namely the Nocturnal Oxygen Therapy Trial (NOTT) and the Medical Research Council Trial (MRC), laid the foundations for modern home oxygen therapy. Since then, little progress has been made in terms of therapeutic indications, and several prescription-associated problems have come to light. Advances in technology have gone hand in hand with growing disregard for the recommendations in clinical guidelines on oxygen therapy. The introduction of liquid oxygen brought with it a number of technical problems, clinical problems related to selecting candidate patients for portable delivery devices, and economic problems associated with the rising cost of the therapy. Continuous home oxygen therapy has been further complicated by the recent introduction of portable oxygen concentrators and the development in quick succession of a range of delivery devices with different levels of efficiency and performance. Modern oxygen therapy demands that clinicians evaluate the level of mobility of their patients and the mobility permitted by available oxygen sources, correctly match patients with the most appropriate oxygen source and adjust the therapy accordingly. The future of continuous home oxygen therapy lies in developing the ideal delivery device, improving the regulations systems and information channels, raise patient awareness and drive research.

Outcomes in gastric and junctional cancer using neoadjuvant and adjuvant chemotherapy (epirubicin, oxaliplatin, and capecitabine) and radical surgery.

The MAGIC/UK Medical Research Council (MRC) trial set the standard of care for treatment of resectable gastric and junctional adenocarcinoma, demonstrating that perioperative chemotherapy with epirubicin, cisplatin and 5-fluorouracil (ECF) confers a survival benefit over surgery alone. The randomized ECF for advanced and locally advanced esophagogastric cancer (REAL-2) trial showed that, in the metastatic setting, the EOX regimen (epirubicin, oxaliplatin and capecitabine) is as effective as ECF, with a favourable toxicity profile. Consecutive patients with resectable gastric or junctional adenocarcinoma treated with perioperative EOX, between 2007 and 2012, were retrospectively analysed. Fifty-nine patients (12 female, 47 male), commenced EOX therapy; 47 underwent surgery. A good pathological response was seen in 34%, (16/47). Disease recurrence occurred in 19 patients (19/47, 40%). Median overall survival was 22 months, with 4-year survival of 47%. Chemotoxicities were consistent with those previously reported for this regimen. This study in a high-volume centre demonstrates that EOX in resectable gastric and junctional adenocarcinoma is associated with a reasonable safety profile, and efficacy consistent with that reported for ECF.

Chronic Domiciliary Oxygen Therapy–Year SEPAR

Oxygen was the “rst treatment shown to increase survival in patients with chronic obstructive pulmonary disease (COPD). Current recommendations for the prescription of continuous domiciliary oxygen therapy (CDO) are based on the results of 2 clinical trials published over 30 years ago: the Nocturnal Oxygen Therapy Trial (NOTT) and the Medical Research Council (MRC) study. 1,2 CDO is indicated in patients with COPD and resting PaO2 �55 mmHg or resting PaO2 between 56 and 59 mmHg with evidence of chronic pulmonary hypertension or polycythemia. Based on the hypothesis that the bene“cial effect of oxygen is a result of the correction of hypoxemia, irrespective of the cause, this indication has been extended by analogy to chronic respiratory failure caused by other respiratory (idiopathic pulmonary “brosis, cystic “brosis, etc.) and non-respiratory diseases (heart failure). However, the effectiveness of continuous oxygen therapy on survival in these other disease entities has not been demonstrated, and studies justifying indication in these cases are required. 3 In contrast with the results of the MRC or NOTT clinical trials, supplementary oxygen has not been shown to improve survival in patients with COPD and moderate hypoxemia. 4 However, these studies have been criticized for reporting a small number of patients, an inappropriately short study period and inadequate average daily administration of oxygen–approximately 13.5 h, clearly insuf“cient for showing effects on mortality. It is known, for example, that patients with COPD and chronic respiratory failure receiving CDO have a rebound effect, with pulmonary vascular resistance increasing when oxygen is suspended for periods as short as 3 h a day. Moreover, it is clear that the mortality rate in COPD patients with comorbidities is higher. Nevertheless, none of the studies analyzing the effects of CDO evaluate the in”uence of comorbidities in general or of cardiovascular disease in particular. It is currently unclear if continuous oxygen therapy reduces metabolic and/or cardiovascular death in hypoxemic COPD patients. Current guidelines do not provide any indications for “pure” patients (with no associated comorbidities), and the therapeutic effects of CDO are analyzed in groups that are poorly representative of COPD patients. 5