Surgical versus non-surgical management of lateral compression type-1 pelvic fracture in adults 60 years and older: the L1FE RCT.

Background: Lateral compression type-1 pelvic fractures are a common fragility fracture in older adults. Patients who do not mobilise due to ongoing pain are at greater risk of immobility-related complications. Standard treatment in the United Kingdom is provision of pain relief and early mobilisation, unlike fragility hip fractures, which are usually treated surgically based on evidence that early surgery is associated with better outcomes. Currently there is no evidence on whether patients with lateral compression type-1 fragility fractures would have a better recovery with surgery than non-surgical management. Objectives: To assess the clinical and cost effectiveness of surgical fixation with internal fixation device compared to non-surgical management of lateral compression type-1 fragility fractures in older adults. Design: Pragmatic, randomised controlled superiority trial, with 12-month internal pilot; target sample size was 600 participants. Participants were randomised between surgical and non-surgical management (1 : 1 allocation ratio). An economic evaluation was planned. Setting: UK Major Trauma Centres. Participants: Patients aged 60 years or older with a lateral compression type-1 pelvic fracture, arising from a low-energy fall and unable to mobilise independently to a distance of 3 m and back due to pelvic pain 72 hours after injury. Interventions: Internal fixation device surgical fixation and non-surgical management. Participants, surgeons and outcome assessors were not blinded to treatment allocation. Main outcome measures: Primary outcome - average patient health-related quality of life, over 6 months, assessed by the EuroQol-5 Dimensions, five-level version utility score. Secondary outcomes (over the 6 months following injury) - self-rated health, physical function, mental health, pain, delirium, displacement of pelvis, mortality, complications and adverse events, and resource use data for the economic evaluation. Results: The trial closed early, at the end of the internal pilot, due to low recruitment. The internal pilot was undertaken in two separate phases because of a pause in recruitment due to the coronavirus disease 2019 pandemic. The planned statistical and health economic analyses were not conducted. Outcome data were summarised descriptively. Eleven sites opened for recruitment for a combined total of 92 months. Three-hundred and sixteen patients were assessed for eligibility, of whom 43 were eligible (13.6%). The main reason for ineligibility was that the patient was able to mobilise independently to 3 m and back (n = 161). Of the 43 eligible participants, 36 (83.7%) were approached for consent, of whom 11 (30.6%) provided consent. The most common reason for eligible patients not consenting to take part was that they were unwilling to be randomised to a treatment (n = 10). There were 11 participants, 5 randomised to surgical management with internal fixation device and 6 to non-surgical management. The average age of participants was 83.0 years (interquartile range 76.0, 89.0) and the EuroQol-5 Dimensions, five-level version utility score at 6 months post randomisation (n = 8) was 0.32 (standard deviation 0.37). A limitation of the trial was that study objectives were not addressed due to poor recruitment. Conclusions: It was not feasible to recruit to this trial in the current context. Further research to understand the treatment and recovery pathways of this group of patients, along with their outcomes, would be needed prior to undertaking a future trial. Future work: Exploration of equipoise across different healthcare professional groups. Investigate longer-term patient outcomes. Trial registration: This trial is registered as ISRCTN16478561. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/167/57) and is published in full in Health Technology Assessment; Vol. 28, No. 15. See the NIHR Funding and Awards website for further award information.

When older adults with weak bones fall onto their side, they can fracture the pelvis in a certain way known as a 'lateral compression type-1 fracture'; this summary will use 'pelvic fracture'. Pelvic fractures can heal without surgery; patients are offered pain relief and encouraged to move as much as they can after the injury. Pelvic fractures can be painful, and some people are not able to get up and walk for weeks. These fractures can cause health problems such as chest infections, urinary tract infections, pressure sores and blood clots. To avoid these problems, we are trying to find treatments to help people recover sooner. Pelvic surgeons think patients may benefit from surgery with an internal fixation device (a bar and screws) to stabilise the pelvis; however, there can be risks and complications with any surgery. This study aimed to find out which treatment is better for patients and better value for money for the National Health Service. This required 600 people aged over 60, in hospital with a pelvic fracture and having difficulty walking to take part. Three hundred would receive surgery and 300 would receive non-surgical treatment. Over 6 months, participants would complete questionnaires, a walking assessment and have X-rays to check healing. The trial had a 12-month run-in period to see if enough people would take part. The trial closed early as we were unable to recruit sufficient people into the study. Fewer older patients with pelvic fractures were identified than expected, 51% were able to walk after a few days and therefore were not eligible to be included in the study. Of the patients, 13.6% were eligible and 30.6% of those consented to take part. Restrictions on visitors during the coronavirus disease 2019 pandemic made it difficult to discuss the study with patients' families and fewer patients were admitted to hospital where the study was taking place. The research question could not be answered by this study at the present time.

The evolution of non-small cell lung cancer metastases in TRACERx.

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.

Lateral compression type 1 fracture fixation in the elderly (L1FE): study protocol for a randomised controlled trial (with internal pilot) comparing the effects of INFIX surgery and non-surgical management for treating patients with lateral compression type 1 (LC-1) fragility fractures.

BACKGROUND: Lateral compression type1 (LC-1) fragility fractures are a common, painful injury in older adults resulting in reduced mobility. The incidence of these fractures is increasing with the growing older adult population. The current standard of care is non-surgical management; however, patients with this injury are at risk of long-term immobility and related complications. INFIX is a pelvic fixation device used in younger patients with high-energy fractures. The device is fitted via a percutaneous technique with no external pin sites and has good purchase even in osteoporotic bone. It therefore has the potential to be well tolerated in patients with LC-1 fragility fractures. INFIX could improve patients' ability to mobilise and reduce the risk of immobility-related complications. However, there is a risk of complications related to surgery, and robust evidence is required on patient outcomes. This study will investigate the clinical and cost-effectiveness of surgical fixation with INFIX compared to non-surgical management of LC-1 fragility fractures in older adults. METHODS: A multi-centre randomised controlled trial of 600 patients allocated 1:1 to non-surgical management or INFIX surgery. The study will have a 12-month internal pilot to assess recruitment and trial feasibility. The primary outcome will be the patient quality of life over 6 months, measured by the patient-reported EQ-5D-5L. The secondary outcomes will include physical function, mental health, pain, delirium, imaging assessment, resource use, and complications. DISCUSSION: The L1FE study aims to compare the clinical and cost-effectiveness of surgical and non-surgical management of people aged 60 years and older with LC-1 fragility fractures. The trial is sufficiently powered and rigorously designed to inform future clinical and patient decision-making and allocation of NHS resources. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Registry ISRCTN16478561. Registered on 8 April 2019.

Arterial "inflammaging" drives vascular calcification in children on dialysis.

Children on dialysis have a cardiovascular mortality risk equivalent to older adults in the general population, and rapidly develop medial vascular calcification, an age-associated pathology. We hypothesized that premature vascular ageing contributes to calcification in children with advanced chronic kidney disease (CKD). Vessels from children with Stage 5 CKD with and without dialysis had evidence of increased oxidative DNA damage. The senescence markers p16 and p21 were also increased in vessels from children on dialysis. Treatment of vessel rings ex vivo with calcifying media increased oxidative DNA damage in vessels from children with Stage 5 CKD, but not in those from healthy controls. Vascular smooth muscle cells cultured from children on dialysis exhibited persistent DNA damage, impaired DNA damage repair, and accelerated senescence. Under calcifying conditions vascular smooth muscle cells from children on dialysis showed increased osteogenic differentiation and calcification. These changes correlated with activation of the senescence-associated secretory phenotype (SASP), an inflammatory phenotype characterized by the secretion of proinflammatory cytokines and growth factors. Blockade of ataxia-telangiectasia mutated (ATM)-mediated DNA damage signaling reduced both inflammation and calcification. Clinically, children on dialysis had elevated circulating levels of osteogenic SASP factors that correlated with increased vascular stiffness and coronary artery calcification. These data imply that dysregulated mineral metabolism drives vascular "inflammaging" by promoting oxidative DNA damage, premature senescence, and activation of a pro-inflammatory SASP. Drugs that target DNA damage signaling or eliminate senescent cells may have the potential to prevent vascular calcification in patients with advanced CKD.

Corrigendum: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

This corrects the article DOI: 10.1038/nature22364.

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.