Cross-sectional Survey of Medical student perceptions of And desires for Research and Training pathways (SMART): an analysis of prospective cohort study of UK medical students

Objective: Clinician-scientists are critical to medical innovation and research. However, the number of clinician scientists in the UK has been declining steadily over the last decade. One of the cited reasons is poor student recruitment to academic training pathways. The SMART study aims to assess current student perceptions on research and identify key factors influencing whether a student is interested in research. Design: We conducted a cross-sectional survey study between January and May 2022. Setting: This was a multi-centre national study with data collected across 40 universities offering medical courses in the UK. Participants: Participants were UK medical students enrolled in medicine for 21/22 academic year. Main outcome and measure: The main outcomes were related to participant perceptions on research and whether they were interested in engaging with research in their future career. These measures were correlated with demographic and non-demographic details using regression analyses. Results: One thousand seven hundred seventy-four individuals participated in the SMART survey from 40 medical schools. Nearly half the participants felt there were barriers preventing them from doing research (46.67%) and almost three-quarters felt it was at least somewhat difficult to combine research with medical school (73.49%). Of the options available, most commonly students did not want to pursue an academic career (43.11%) or training pathway (42.49%). However, most participants felt it was useful to do research at medical school (59.54%) and were also interested in doing more research in the future (69.16%). Regression analysis identified many factors influencing student’s perceptions of research including year of study, gender, socioeconomic status, family background, research exposure at medical school, ethnicity, and country of pre-university education. Conclusions: The SMART study is the first of its kind in the UK, shedding light on medical student perceptions. While some express strong interest in academic careers, a larger proportion show a broader interest in research. Demographic factors like gender, parental occupation, and socioeconomic status play a role. Further exploration is needed for specific groups to address barriers, promote research, and boost academic pathway recruitment

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries

BACKGROUND: The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe. METHODS: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries. RESULTS: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease. CONCLUSIONS: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Additional file 2 of Extracellular matrix profiles determine risk and prognosis of the squamous cell carcinoma subtype of non-small cell lung carcinoma

Additional file 2: Table S1. Differentially Expressed Hallmark Pathways in ECM-High vs ECM-Low Tumors. Table S2. Differentially Expressed MSigDb C2 Pathways in ECM-High vs ECM-Low Tumors. Table S3. Ligand-Receptor Interactions in ECM-High vs ECM-Low Tumors

Additional file 1 of Extracellular matrix profiles determine risk and prognosis of the squamous cell carcinoma subtype of non-small cell lung carcinoma

Additional file 1: Supplementary Materials and Methods. Figure S1. The extracellular matrix is significantly dysregulated in tumor compared with non-tumor tissue in SqCC. Figure S2. ECM changes associated with increased lung cancer risk and premalignant progression. Figure S3. A) tSNE plot visualization of the expression scores for matrix risk signature genes with positive (B) and negative (C) odds ratios for different cell types (A) in SqCC scRNAseq data presented in Fig. 2D. D) ROC analysis of the minimum matrix risk signature distinguishing progressive from regressive premalignant lesions. E) Matrix risk score at age at diagnosis in the TCGA cohort. Blue line shows linear regression with standard error indicated by grey shading. p=0.00073, r=-0.23, Spearman’s correlation. Figure S4. The ECM-High matreotype is associated with poor prognosis. A-B) Relative Cluster Stability Index (A) and p-values (B) for different cluster numbers confirm the presence of three major matreotypes in SqCC. C) The correlation plot for samples corresponding to the heatmap in Fig. 3A). D) Heatmap of marker genes for the ECM-High and ECM-Low matreotypes in the TCGA cohort. E-F) Matreotype association with survival in early stage (E, Stage I and II) patients (Ci) and late stage patients (F, Stage III and IV) patients in the TCGA LUSC cohort. G) Recurrence-free survival for ECM-High and ECM-Low matreotypes in the UHN cohort of early-stage tumors (log-rank p=0.19). H) Representative H&E and picrosirius red-stained tissue microarray cores corresponding to high (upper panel) and low (lower panel) picrosirius-red-stained tumors. Scale bar = 500 μm. I-J) Overall survival of patients according to picosirius red staining for tumors across all stages (I, univariate cox-proportional hazards model HR = 1.76 [1.04-2.98], p=0.035; multivariate coxproportional hazards model HR = 1.87 [1.09-3.2], p=0.023) and stages I and IIA only (J, univariate cox-proportional hazards model HR = 2.4 [1.3-4.4], p=0.0051; multivariate cox-proportional hazards model HR = 2.4 [1.3-4.4], p=0.0051)). Multivariate cox-proportional hazards models include stage as a clinical covariate. Figure S5. A) Mutational frequency plot showing no enrichment of driver mutations or FGFR amplification in each matreotype. B) Mutational frequency plot showing the top mutated genes differentially enriched in the ECM-High vs ECMLow matreotype tumors. C) Disease-specific survival of adenocarcinoma samples assigned to SqCC matreotypes shows no significant association of SqCC matreotypes with prognosis in the adenocarcinoma subtype (log-rank p=0.74). D-E) The hazard ratios for Disease-specific survival (D) and Progression-Free Survival (E) of ECM-High pan-cancer tumors compared with ECM-Low matreotypes in multiple cancer types. Red dots indicate tumor types with significant hazard ratios for the ECM-High matreotype compared with the ECM-Low matreotype. Hazard ratios and confidence intervals are in Additional File 1: Table S8. Figure S6. SqCC Matreotypes have distinct immunological ecosystems. Figure S7. Extracellular Matrix components contribute to signaling pathways associated with prognosis. Figure S8. ECM-driven integrin signaling is associated with EMT and fibroblast activation in the ECM-High matreotype. Figure S9. The poor prognosis matreotype overlaps with ECM remodeling in Idiopathic Pulmonary Fibrosis. Table S1. Matrix Risk Score. Table S2. Pan-Cancer Risk Score Results. Table S3. Optimized Minimum Matrisomal Linear Model for Premalignant Progression. Table S4. Clinicodemographic Features of the TCGA Matreotypes. Table S5. Clinicodemographic Features of the NCI-MD cohort. Table S6. Clinicodemographic Features of the Tissue Microarray Cohort. Table S7. Cox Proportional Hazards Model Analysis of Picrosirius Red stained TMAs. Table S8. Pan-Cancer Prognostic Matreotype Results