Deaths certified as asthma and use of medical services: A national case-control study

This is an open access publication. The official published version can be accessed from the link below.Background: Studies have linked asthma death to either increased or decreased use of medical services. Methods: A population based case-control study of asthma deaths in 1994–8 was performed in 22 English, six Scottish, and five Welsh health authorities/boards. All 681 subjects who died were under the age of 65 years with asthma in Part I on the death certificates. After exclusions, 532 hospital controls were matched to 532 cases for age, district, and date of asthma admission/death. Data were extracted blind from primary care records. Results: The median age of the subjects who died was 53 years; 60% of cases and 64% of controls were female. There was little difference in outpatient attendance (55% and 55%), hospital admission for asthma (51% and 54%), and median inpatient days (20 days and 15 days) in the previous 5 years. After mutual adjustment and adjustment for sex, using conditional logistic regression, three variables were independently associated with asthma death: fewer general practice contacts (odds ratio 0.82 (95% confidence interval (CI) 0.74 to 0.91) per 5 contacts) in the previous year, more home visits (1.14 (95% CI 1.08 to 1.21) per visit) in the previous year, and fewer peak expiratory flow recordings (0.83 (95% CI 0.74 to 0.92) per occasion) in the previous 3 months. These associations were similar after adjustment for markers of severity, psychosocial factors, systemic steroids, short acting bronchodilators and antibiotics, although the association with peak flow was weakened and just lost significance. Conclusion: Asthma death is associated with less use of primary care services. Both practice and patient factors may be involved and a better understanding of these may offer possibilities for reducing asthma death.This study was funded jointly between the National Research and Development Asthma Management Programme (contract number AM1/ 05/002) and the National Asthma Campaign through a grant from Glaxo Wellcome (now GlaxoSmithKline)

Good Statistical Practice—development of tailored Good Clinical Practice training for statisticians

\ua9 The Author(s) 2024.Background: Statisticians are fundamental in ensuring clinical research, including clinical trials, are conducted with quality, transparency, reproducibility and integrity. Good Clinical Practice (GCP) is an international quality standard for the conduct of clinical trials research. Statisticians are required to undertake training on GCP but existing training is generic and, crucially, does not cover statistical activities. This results in statisticians undertaking training mostly unrelated to their role and variation in awareness and implementation of relevant regulatory requirements with regards to statistical conduct. The need for role-relevant training is recognised by the UK NHS Health Research Authority and the Medicines and Healthcare products Regulatory Agency (MHRA). Methods: The Good Statistical Practice (GCP for Statisticians) project was instigated by the UK Clinical Research Collaboration (UKCRC) Registered Clinical Trials Unit (CTU) Statisticians Operational Group and funded by the National Institute for Health and Care Research (NIHR), to develop materials to enable role-specific GCP training tailored to statisticians. Review of current GCP training was undertaken by survey. Development of training materials were based on MHRA GCP. Critical review and piloting was conducted with UKCRC CTU and NIHR researchers with comment from MHRA. Final review was conducted through the UKCRC CTU Statistics group. Results: The survey confirmed the need and desire for the development of dedicated GCP training for statisticians. An accessible, comprehensive, piloted training package was developed tailored to statisticians working in clinical research, particularly the clinical trials arena. The training materials cover legislation and guidance for best practice across all clinical trial processes with statistical involvement, including exercises and real-life scenarios to bridge the gap between theory and practice. Comprehensive feedback was incorporated. The training materials are freely available for national and international adoption. Conclusion: All research staff should have training in GCP yet the training undertaken by most academic statisticians does not cover activities related to their role. The Good Statistical Practice (GCP for Statisticians) project has developed and extensively piloted new, role-specific, comprehensive, accessible GCP training tailored to statisticians working in clinical research, particularly the clinical trials arena. This role-specific training will encourage best practice, leading to transparent and reproducible statistical activity, as required by regulatory authorities and funders

Effect of pathologic tumor response and nodal status on survival in the medical research council adjuvant gastric infusional chemotherapy trial

Purpose: The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial established perioperative epirubicin, cisplatin, and fluorouracil chemotherapy as a standard of care for patients with resectable esophagogastric cancer. However, identification of patients at risk for relapse remains challenging. We evaluated whether pathologic response and lymph node status after neoadjuvant chemotherapy are prognostic in patients treated in the MAGIC trial. Materials and Methods: Pathologic regression was assessed in resection specimens by two independent pathologists using the Mandard tumor regression grading system (TRG). Differences in overall survival (OS) according to TRG were assessed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses using the Cox proportional hazards method established the relationships among TRG, clinical-pathologic variables, and OS. Results: Three hundred thirty resection specimens were analyzed. In chemotherapy-treated patients with a TRG of 1 or 2, median OS was not reached, whereas for patients with a TRG of 3, 4, or 5, median OS was 20.47 months. On univariate analysis, high TRG and lymph node metastases were negatively related to survival (Mandard TRG 3, 4, or 5: hazard ratio [HR], 1.94; 95% CI, 1.11 to 3.39; P = .0209; lymph node metastases: HR, 3.63; 95% CI, 1.88 to 7.0; P < .001). On multivariate analysis, only lymph node status was independently predictive of OS (HR, 3.36; 95% CI, 1.70 to 6.63; P < .001). Conclusion: Lymph node metastases and not pathologic response to chemotherapy was the only independent predictor of survival after chemotherapy plus resection in the MAGIC trial. Prospective evaluation of whether omitting postoperative chemotherapy and/or switching to a noncross-resistant regimen in patients with lymph node-positive disease whose tumor did not respond to preoperative epirubicin, cisplatin, and fluorouracil may be appropriate

Mismatch Repair Deficiency, Microsatellite Instability, and Survival: An Exploratory Analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial

Importance: Mismatch repair (MMR) deficiency (MMRD) and microsatellite instability (MSI) are prognostic for survival in many cancers and for resistance to fluoropyrimidines in early colon cancer. However, the effect of MMRD and MSI in curatively resected gastric cancer treated with perioperative chemotherapy is unknown. Objective: To examine the association among MMRD, MSI, and survival in patients with resectable gastroesophageal cancer randomized to surgery alone or perioperative epirubicin, cisplatin, and fluorouracil chemotherapy in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. Design, Setting, and Participants: This secondary post hoc analysis of the MAGIC trial included participants who were treated with surgery alone or perioperative chemotherapy plus surgery for operable gastroesophageal cancer from July 1, 1994, through April 30, 2002. Tumor sections were assessed for expression of the MMR proteins mutL homologue 1, mutS homologue 2, mutS homologue 6, and PMS1 homologue 2. The association among MSI, MMRD, and survival was assessed. Main Outcomes and Measures: Interaction between MMRD and MSI status and overall survival (OS). Results: Of the 503 study participants, MSI results were available for 303 patients (283 with microsatellite stability or low MSI [median age, 62 years; 219 males (77.4%)] and 20 with high MSI [median age, 66 years; 14 males (70.0%)]). A total of 254 patients had MSI and MMR results available. Patients treated with surgery alone who had high MSI or MMRD had a median OS that was not reached (95% CI, 11.5 months to not reached) compared with a median OS among those who had neither high MSI nor MMRD of 20.5 months (95% CI, 16.7-27.8 months; hazard ratio, 0.42; 95% CI, 0.15-1.15; P\u2009=\u2009.09). In contrast, patients treated with chemotherapy plus surgery who had either high MSI or MMRD had a median OS of 9.6 months (95% CI, 0.1-22.5 months) compared with a median OS among those who were neither high MSI nor MMRD of 19.5 months (95% CI, 15.4-35.2 months; hazard ratio, 2.18; 95% CI, 1.08-4.42; P\u2009=\u2009.03). Conclusions and Relevance: In the MAGIC trial, MMRD and high MSI were associated with a positive prognostic effect in patients treated with surgery alone and a differentially negative prognostic effect in patients treated with chemotherapy. If independently validated, MSI or MMRD determined by preoperative biopsies could be used to select patients for perioperative chemotherapy

Outcomes for transformed follicular lymphoma in the rituximab era: the Royal Marsden experience 2003-2013.

Survival for transformed follicular lymphoma (tFL) has improved in the rituximab era and the need for upfront stem cell transplantation (SCT) is unclear. We evaluated the outcomes for all patients treated with first-line chemotherapy for histologically-proven tFL at our institution from 2003-2013 (n = 87). The majority of patients (89.7%) did not receive a SCT as part of first-line management. With a median follow-up of 7.8 years the 5-year overall survival (OS) for all patients was 61.7%. Patients treated with R-CHOP without upfront SCT (n = 55/87) had a 5-year OS of 64.3%. In a Cox regression analysis of the entire cohort (n = 87) International Prognostic Index (IPI) risk group and presence of B symptoms at transformation were independently associated with OS in multivariate analysis (MVA). Our analysis confirms the improved survival of tFL in the rituximab era even in the absence of upfront SCT consolidation

Visualising harms in publications of randomised controlled trials: consensus and recommendations

OBJECTIVE: To improve communication of harm in publications of randomised controlled trials via the development of recommendations for visually presenting harm outcomes. DESIGN: Consensus study. SETTING: 15 clinical trials units registered with the UK Clinical Research Collaboration, an academic population health department, Roche Products, and The BMJ. PARTICIPANTS: Experts in clinical trials: 20 academic statisticians, one industry statistician, one academic health economist, one data graphics designer, and two clinicians. MAIN OUTCOME: measures A methodological review of statistical methods identified visualisations along with those recommended by consensus group members. Consensus on visual recommendations was achieved (at least 60% of the available votes) over a series of three meetings with participants. The participants reviewed and critically appraised candidate visualisations against an agreed framework and voted on whether to endorse each visualisation. Scores marginally below this threshold (50-60%) were revisited for further discussions and votes retaken until consensus was reached. RESULTS: 28 visualisations were considered, of which 10 are recommended for researchers to consider in publications of main research findings. The choice of visualisations to present will depend on outcome type (eg, binary, count, time-to-event, or continuous), and the scenario (eg, summarising multiple emerging events or one event of interest). A decision tree is presented to assist trialists in deciding which visualisations to use. Examples are provided of each endorsed visualisation, along with an example interpretation, potential limitations, and signposting to code for implementation across a range of standard statistical software. Clinician feedback was incorporated into the explanatory information provided in the recommendations to aid understanding and interpretation. CONCLUSIONS: Visualisations provide a powerful tool to communicate harms in clinical trials, offering an alternative perspective to the traditional frequency tables. Increasing the use of visualisations for harm outcomes in clinical trial manuscripts and reports will provide clearer presentation of information and enable more informative interpretations. The limitations of each visualisation are discussed and examples of where their use would be inappropriate are given. Although the decision tree aids the choice of visualisation, the statistician and clinical trial team must ultimately decide the most appropriate visualisations for their data and objectives. Trialists should continue to examine crude numbers alongside visualisations to fully understand harm profiles

Rapid access clinic for unexplained lymphadenopathy and suspected malignancy: prospective analysis of 1000 patients.

Background:In patients presenting with peripheral lymphadenopathy, it is critical to effectively identify those with underlying cancer who require urgent specialist care. Methods:We analyzed a large dataset of 1000 consecutive patients with unexplained lymphadenopathy referred between 2001 and 2009 to the Royal Marsden Hospital (RMH) rapid access lymph node diagnostic clinic (LNDC). Results:Cancer was diagnosed in 14% of patients. Factors predictive for malignant disease were male sex, age, supraclavicular and multiple site involvement. Cancer-associated symptoms were present for a median of 8 weeks. The median time from referral to start of cancer therapy was 53 days. Fine needle aspiration (FNA) was performed in 83% of patients with malignancies. Sensitivity and specificity of FNA were limited (50 and 87%, respectively for any malignancy; 30 and 79%, respectively for lymphoma). The vast majority of cancer patients received diagnostic biopsies on the basis of suspicious clinical and ultrasound findings; the FNA result contributed to establishing the diagnosis in only 4 cases. Conclusions:In conclusion, we demonstrate that Oncologist-led rapid access clinics are successful concepts to assess patients with unexplained lymphadenopathy. Our data suggest that a routine use of FNA should be reconsidered in this setting

PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours.

PATRIOT is a phase I study of the ATR inhibitor, AZD6738, as monotherapy, and in combination with palliative radiotherapy. Here, we describe the protocol for this study, which opened in 2014 and is currently recruiting and comprises dose escalation of both drug and radiotherapy, and expansion cohorts