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Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.
No full textBACKGROUND
Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design.
METHODS
The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial done at 110 National Health Service hospitals in the UK. There were three potential randomisations in the study: induction treatment, intensification treatment, and maintenance treatment. Here, we report the results of the randomisation to intensification treatment. Eligible patients were aged 18 years or older and had symptomatic or non-secretory, newly diagnosed multiple myeloma, had completed their assigned induction therapy as per protocol (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) and achieved a partial or minimal response. For the intensification treatment, patients were randomly assigned (1:1) to cyclophosphamide (500 mg daily orally on days 1, 8, and 15), bortezomib (1·3 mg/m subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment.
FINDINGS
Between Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0-43·5), median progression-free survival was 30 months (95% CI 25-36) with CVD and 20 months (15-28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48-0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0-83·5) in the CVD group and 78·5% (72·3-84·6) in the no CVD group (HR 0·98, 95% CI 0·67-1·43, p=0·93). The most common grade 3 or 4 adverse events for patients taking CVD were haematological, including neutropenia (18 [7%] patients), thrombocytopenia (19 [7%] patients), and anaemia (8 [3%] patients). No deaths in the CVD group were deemed treatment related.
INTERPRETATION
Intensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK.
FUNDING
Cancer Research UK, Celgene, Amgen, Merck, Myeloma UK
The intra-operative use of biological products: A multi-centre regional patient perspective of a potential consenting conundrum.
No full textHIT communication paper: strategies and tips to increase your chances of winning an EACVI grant.
No full textUrine steroid metabolomics as a novel tool for detection of recurrent adrenocortical carcinoma.
No full textCONTEXT
Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC).
OBJECTIVE, DESIGN, SETTING
This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for post-operative recurrence detection after microscopically complete (R0) resection of ACC.
PATIENTS AND METHODS
135 patients from 14 clinical centers provided post-operative urine samples, which were analyzed by gas chromatography-mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians, or when analyzed by Random Forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard.
RESULTS
Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine "steroid fingerprint" at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by three blinded experts detected recurrence by the time of radiological diagnosis in 50-72% of cases, improving to 69-92%, if a pre-operative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22-39% of patients. Specificities varied considerably, ranging from 61 to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity=specificity=81%).
CONCLUSION
Urine steroid metabolomics is a promising tool for post-operative recurrence detection in ACC; availability of a pre-operative urine considerably improves the ability to detect ACC recurrence
The Pathophysiology, Presentation and Management of Ischaemic Colitis: A Systematic Review.
No full textThere are currently no guidelines on the long-term management of patients after an episode of acute ischaemic colitis. Our aim was to review the literature on the pattern of presentation and the pathophysiology of this condition and to understand the current status of the acute and long-term management of ischaemic colitis. Furthermore, we aim to provide recommendations for the clinicians in regard to the acute and long-term management of ischaemic colitis. A review of the English literature over the last 15 years was performed using Embase and Medline. Search terms were ischaemic OR ischemic, colitis OR colon. Two reviewers screened the papers against pre-determined eligibility criteria. A senior consultant surgeon performed a final overview. Three hundred sixty-eight papers were identified on the initial search; 318 were irrelevant and 17 were conference abstracts; both were excluded. Thirty-three full articles were assessed for suitability; nine were further excluded. Twenty-four articles were included in the final analysis and cross-referenced against those listed in the systematic reviews. There is a large clinical heterogeneity in inclusion criteria (histological, radiological, endoscopic, surgical specimen). Twelve out of 24 articles included patients only based on histological diagnosis. The definition of right and left (or nonright) ischaemic colitis was variable based on whether hepatic or splenic flexure was used as the cut-off point. Five retrospective case series highlighted that patients with isolated right-sided ischaemic colitis had a worse prognosis than those with left-sided colitis (higher mortality, need for surgery, length of hospital stay). The overall recurrence was 9%. There is a need for a higher-level evidence to guide clinicians on the long-term management of patients following an episode of acute colonic ischaemia. Further evidence is required to determine whether right colonic ischaemia should be managed differently from left
EAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees†.
No full textBACKGROUND
Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.
OBJECTIVE
To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.
DESIGN
A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference.
SETTING
Online Delphi survey and consensus conference.
PARTICIPANTS
The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).
RESULTS AND LIMITATIONS
Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease.
CONCLUSIONS
These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach
Facial injury management undertaken at US and UK medical treatment facilities during the Iraq and Afghanistan conflicts: a retrospective cohort study.
No full textOBJECTIVES
To perform the first direct comparison of the facial injuries sustained and treatment performed at USA and UK deployed medical treatment facilities (MTFs) in support of the military campaigns in Iraq and Afghanistan.
SETTING
The US and UK Joint Theatre Trauma Registries were scrutinised for all patients with facial injuries presenting alive to a UK or US deployed MTF between 1 March 2003 and 31 October 2011.
PARTICIPANTS
US and UK military personnel, local police, local military and civilians.
PRIMARY AND SECONDARY OUTCOME MEASURES
An adjusted multiple logistic regression model was performed using tracheostomy as the primary dependent outcome variable and treatment in a US MTF, US or UK military, mandible fracture and treatment of mandible fracture as independent secondary variables.
RESULTS
Facial injuries were identified in 16 944 casualties, with the most common being those to skin/muscle (64%), bone fractures (36%), inner/middle ear (28%) and intraoral damage (11%). Facial injuries were equally likely to undergo surgery in US MTF as UK MTF (OR: 1.06, 95% CI 0.4603 to 1.142, p=0.6656); however, variations were seen in injury type treated. In US MTF, 692/1452 (48%) of mandible fractures were treated by either open or closed reduction compared with 0/167 (0%) in UK MTF (χ: 113.6; p≤0.0001). US military casualties who had treatment of their mandible fracture (open reduction and internal fixation or mandibulo-maxillary fixation) were less likely to have had a tracheostomy than those who did not undergo stabilisation of the fractured mandible (OR: 0.61, 95% CI 0.44 to 0.86; p=0.0066).
CONCLUSIONS
The capability to surgically treat mandible fractures by open or closed reduction should be considered as an integral component of deployed coalition surgical care in the future
Developing an intervention around referral and admissions to intensive care: a mixed-methods study
No full textElevated lactate levels in the cerebrospinal fluid associated with bacterial meningitis.
No full textCardiomyocyte functional screening: interrogating comparative electrophysiology of high-throughput model cell systems.
No full textCardiac arrhythmias of both atrial and ventricular origin are an important feature of cardiovascular disease. Novel antiarrhythmic therapies are required to overcome current drug limitations related to effectiveness and pro-arrhythmia risk in some contexts. Cardiomyocyte culture models provide a high-throughput platform for screening antiarrhythmic compounds, but comparative information about electrophysiological properties of commonly used types of cardiomyocyte preparations is lacking. Standardization of cultured cardiomyocyte microelectrode array (MEA) experimentation is required for its application as a high-throughput platform for antiarrhythmic drug development. The aim of this study was to directly compare the electrophysiological properties and responses to isoproterenol of three commonly used cardiac cultures. Neonatal rat ventricular myocytes (NRVMs), immortalized atrial HL-1 cells, and custom-generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured on microelectrode arrays for 48-120 h. Extracellular field potentials were recorded, and conduction velocity was mapped in the presence/absence of the β-adrenoceptor agonist isoproterenol (1 µM). Field potential amplitude and conduction velocity were greatest in NRVMs and did not differ in cardiomyocytes isolated from male/female hearts. Both NRVMs and hiPSC-CMs exhibited longer field potential durations with rate dependence and were responsive to isoproterenol. In contrast, HL-1 cells exhibited slower conduction and shorter field potential durations and did not respond to 1 µM isoproterenol. This is the first study to compare the intrinsic electrophysiologic properties of cultured cardiomyocyte preparations commonly used for in vitro electrophysiology assessment. These findings offer important comparative data to inform methodological approaches in the use of MEA and other techniques relating to cardiomyocyte functional screening investigations of particular relevance to arrhythmogenesis