Improving response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Introduction: Response to neoadjuvant chemoradiotherapy (NCRT) for locally advanced rectal cancer (LARC) varies considerably. There is a need to unravel the elusive biological mechanisms behind treatment resistance in LARC and discover radiosensitising treatments using the latest experiment models. Methods: Next generation sequencing (NGS) was performed on archival specimens from 23 LARC patients (retrospective cohort) to identify differentially expressed genes associated with NCRT response. Six patient derived organoid (PDO) models were derived (prospective cohort) from colorectal cancer (CRC) patients; genetically and immunohistochemically characterised. In vitro viability assays were conducted to determine PDO response to radiotherapy. NGS was performed on PDOs pre- and post-irradiation. Chemoradiotherapy viability assays using targeted pathway inhibitors were performed using HCT116 CRC cell line and PDOs. AKT phosphorylation following chemoradiotherapy was assessed using western blots. Results: The first 6 out of 16 CRC PDO lines successfully derived in the laboratory were characterised through genomics and immunohistochemistry. Several genes and biological pathways of interest in radiotherapy response (sensitivity or resistance) were identified on differential expression analyses and Gene Set Enrichment Analysis of the retrospective FFPE sample and prospective organoid sample transcriptomes. The PI3K/AKT/mTOR pathway upregulation was associated with radiotherapy resistance in retrospective and prospective cohort sample transcriptomic analyses. Radiotherapy was associated with significantly increased AKT phosphorylation in HCT116. The use of PI3K and mTOR dual inhibitors apitolisib and dactolisib radiosensitised HCT116 and PDOs in vitro and led to inhibition of radiation induced AKT phosphorylation. These drugs radiosensitised radioresistant PDO lines and HCT116 with maximal inhibitory concentration levels within previously published ranges for humans. Dual inhibitors may also possess chemotherapy sensitising properties in the absence of radiotherapy. Conclusion: The PI3K/AKT/mTOR pathway upregulation is associated with NCRT resistance. The role of dual PI3K and mTOR inhibitors as radiosensitisers in LARC patients warrants further preclinical and clinical research

Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism

Global changes in transcriptional regulation and RNA metabolism are crucial features of cancer development. However, little is known about the role of the core promoter in defining transcript identity and post-transcriptional fates, a potentially crucial layer of transcriptional regulation in cancer. In this study, we use CAGE-seq analysis to uncover widespread use of dual-initiation promoters in which non-canonical, first-base-cytosine (C) transcription initiation occurs alongside first-base-purine initiation across 59 human cancers and healthy tissues. C-initiation is often followed by a 5' terminal oligopyrimidine (5'TOP) sequence, dramatically increasing the range of genes potentially subjected to 5'TOP-associated post-transcriptional regulation. We show selective, dynamic switching between purine and C-initiation site usage, indicating transcription initiation-level regulation in cancers. We additionally detail global metabolic changes in C-initiation transcripts that mark differentiation status, proliferative capacity, radiosensitivity, and response to irradiation and to PI3K-Akt-mTOR and DNA damage pathway-targeted radiosensitization therapies in colorectal cancer organoids and cancer cell lines and tissues.</p

The perceived impact of the Covid-19 pandemic on medical student education and training – an international survey

Abstract: Background: The Covid-19 pandemic led to significant changes and disruptions to medical education worldwide. We evaluated medical student perceived views on training, their experiences and changes to teaching methods during the pandemic. Methods: An online survey of medical students was conducted in the Autumn of 2020. An international network of collaborators facilitated participant recruitment. Students were surveyed on their perceived overall impact of Covid-19 on their training and several exposure variables. Univariate analyses and adjusted multivariable analysis were performed to determine strengths in associations. Results: A total of 1604 eligible participants from 45 countries took part in this survey and 56.3% (n = 860) of these were female. The median age was 21 (Inter Quartile Range:21–23). Nearly half (49.6%, n = 796) of medical students were in their clinical years. The majority (n = 1356, 84.5%) were residents of a low or middle income country. A total of 1305 (81.4%) participants reported that the Covid-19 pandemic had an overall negative impact on their training. On adjusted analysis, being 21 or younger, females, those reporting a decline in conventional lectures and ward based teaching were more likely to report an overall negative impact on their training (p ≤ 0.001). However, an increase in clinical responsibilities was associated with lower odds of participants reporting a negative impact on training (p < 0.001). The participant’s resident nation economy and stage of training were associated with some of the participant training experiences surveyed (p < 0.05). Conclusion: An international cohort of medical students reported an overall significant negative impact of the Covid-19 pandemic on their undergraduate training. The efficacy of novel virtual methods of teaching to supplement traditional teaching methods warrants further research

Malnutrition is associated with adverse postoperative outcome in patients undergoing elective colorectal cancer resections.

PURPOSE Malnutrition results in a significant increase in postoperative morbidity and mortality after abdominal surgery. Apart from the anthropometric assessments, malnutrition can be also assessed using laboratory scores, with the most widely used being Onodera's Prognostic Nutritional Index (PNI). The purpose of our study was to assess if the presence of malnutrition as calculated by the Onodera's PNI was associated with higher postoperative morbidity after elective colorectal cancer resection. METHODS We performed a retrospective analysis of our institutional database including the patients who underwent elective colorectal cancer resection over a 24-month period. PNI scores were calculated and correlated amongst other parameters, such as cancer stage, severity of postoperative complications, unplanned transfusion of blood products, need for unplanned level 2/3 care after surgery and overall length of hospitalization. RESULTS A total of 213 patients were included in this analysis, with 22.5% being classified as malnourished based on the preoperative PNI. Of note, PNI values were inversely associated with advanced-stage disease, severity of postoperative complications and unplanned intensive care unit (ICU) admission postoperatively. Also, malnourished patients had a statistically significant prolonged length of in-hospital stay. No difference in PNI scores was identified between groups requiring unplanned blood products' transfusions. CONCLUSIONS Preoperative malnutrition status as defined by PNI is associated with greater postoperative morbidity after elective surgery for colorectal cancer. Routine nutritional assessment and ad hoc nutritional support prior to surgery could contribute to an improvement of postoperative outcome after colorectal cancer resections

Malnutrition is associated with adverse postoperative outcome in patients undergoing elective colorectal cancer resections.

PURPOSE Malnutrition results in a significant increase in postoperative morbidity and mortality after abdominal surgery. Apart from the anthropometric assessments, malnutrition can be also assessed using laboratory scores, with the most widely used being Onodera's Prognostic Nutritional Index (PNI). The purpose of our study was to assess if the presence of malnutrition as calculated by the Onodera's PNI was associated with higher postoperative morbidity after elective colorectal cancer resection. METHODS We performed a retrospective analysis of our institutional database including the patients who underwent elective colorectal cancer resection over a 24-month period. PNI scores were calculated and correlated amongst other parameters, such as cancer stage, severity of postoperative complications, unplanned transfusion of blood products, need for unplanned level 2/3 care after surgery and overall length of hospitalization. RESULTS A total of 213 patients were included in this analysis, with 22.5% being classified as malnourished based on the preoperative PNI. Of note, PNI values were inversely associated with advanced-stage disease, severity of postoperative complications and unplanned intensive care unit (ICU) admission postoperatively. Also, malnourished patients had a statistically significant prolonged length of in-hospital stay. No difference in PNI scores was identified between groups requiring unplanned blood products' transfusions. CONCLUSIONS Preoperative malnutrition status as defined by PNI is associated with greater postoperative morbidity after elective surgery for colorectal cancer. Routine nutritional assessment and ad hoc nutritional support prior to surgery could contribute to an improvement of postoperative outcome after colorectal cancer resections

The Effectiveness of a Foundation Year 1 Doctor Preparation Course for Final Year Medical Students.

Background Starting work as a junior doctor can be daunting for any medical student. There are numerous aspects of the hidden curriculum which many students fail to acquire during their training. Objectives To evaluate the effectiveness of a novel foundation year one (FY1) doctor preparation course focusing on certain core topics, practical tips and components of the hidden curriculum. The primary objective was to improve the confidence level and knowledge of final year medical students transitioning to FY1 doctors. Method A 2-day, practical course titled 'Preparation 2 Practice' delivering hands-on, small-group and lecture-based teaching, covering core medical student undergraduate curriculum topics in medicine and surgery. The course content spanned therapeutics, documentation skills and managing acute clinical tasks encountered by FY1 doctors during an on-call shift. A pre- and post-course survey and knowledge assessment were carried out to assess the effectiveness of the course. The assessment was MCQ-based, derived from topics covered within our course. The 20-question test and a short survey were administered electronically. Results Twenty students from a single UK medical school attended the course. 100% participation was observed in the pre- and post-course test and survey. The median post-course test result was 22 (IQR 20.25-23.75) which was higher than the median pre-course test score of 18.75 (IQR 17-21.75). A Wilcoxon sign rank test revealed a statistically significant difference between the pre- and post-course test results ( = .0003). The self-reported confidence score of delegates on starting work as a junior doctor was also significantly higher following the course ( = .004). Conclusion The results show a significant improvement in perceived confidence and knowledge on core curriculum topics amongst final year medical students having attended our FY1 doctor preparation course. We conclude that there is scope for similar supplementary courses as an adjunct to the undergraduate medical curriculum

Radiosensitising Cancer Using Phosphatidylinositol-3-Kinase (PI3K), Protein Kinase B (AKT) or Mammalian Target of Rapamycin (mTOR) Inhibitors.

Radiotherapy is routinely used as a neoadjuvant, adjuvant or palliative treatment in various cancers. There is significant variation in clinical response to radiotherapy with or without traditional chemotherapy. Patients with a good response to radiotherapy demonstrate better clinical outcomes universally across different cancers. The PI3K/AKT/mTOR pathway upregulation has been linked to radiotherapy resistance. We reviewed the current literature exploring the role of inhibiting targets along this pathway, in enhancing radiotherapy response. We identified several studies using in vitro cancer cell lines, in vivo tumour xenografts and a few Phase I/II clinical trials. Most of the current evidence in this area comes from glioblastoma multiforme, non-small cell lung cancer, head and neck cancer, colorectal cancer, and prostate cancer. The biological basis for radiosensitivity following pathway inhibition was through inhibited DNA double strand break repair, inhibited cell proliferation, enhanced apoptosis and autophagy as well as tumour microenvironment changes. Dual PI3K/mTOR inhibition consistently demonstrated radiosensitisation of all types of cancer cells. Single pathway component inhibitors and other inhibitor combinations yielded variable outcomes especially within early clinical trials. There is ample evidence from preclinical studies to suggest that direct pharmacological inhibition of the PI3K/AKT/mTOR pathway components can radiosensitise different types of cancer cells. We recommend that future in vitro and in vivo research in this field should focus on dual PI3K/mTOR inhibitors. Early clinical trials are needed to assess the feasibility and efficacy of these dual inhibitors in combination with radiotherapy in brain, lung, head and neck, breast, prostate and rectal cancer patients

Mental health symptoms in a cohort of hospital healthcare workers following the first peak of the COVID-19 pandemic in the UK.

BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic is likely to lead to a significant increase in mental health disorders among healthcare workers (HCW). AIMS We evaluated the rates of anxiety, depressive and post-traumatic stress disorder (PTSD) symptoms in a population of HCW in the UK. METHOD An electronic survey was conducted between the 5 June 2020 and 31 July 2020 of all hospital HCW in the West Midlands, UK using clinically validated questionnaires: the 4-item Patient Health Questionnaire(PHQ-4) and the Impact of Event Scale-Revised (IES-R). Univariate analyses and adjusted logistic regression analyses were performed to estimate the strengths in associations between 24 independent variables and anxiety, depressive or PTSD symptoms. RESULTS There were 2638 eligible participants who completed the survey (female: 79.5%, median age: 42 years, interquartile range: 32-51). The rates of clinically significant symptoms of anxiety, depression and PTSD were 34.3%, 31.2% and 24.5%, respectively. In adjusted analysis a history of mental health conditions was associated with clinically significant symptoms of anxiety (odds ratio (OR) = 2.3, 95% CI 1.9-2.7, P < 0.001), depression (OR = 2.5, 95% CI 2.1-3.0, P < 0.001) and PTSD (OR = 2.1, 95% CI 1.7-2.5, P < 0.001). The availability of adequate personal protective equipment (PPE), well-being support and lower exposure to moral dilemmas at work demonstrated significant negative associations with these symptoms (P ≤ 0.001). CONCLUSIONS We report higher rates of clinically significant mental health symptoms among hospital HCW following the initial COVID-19 pandemic peak in the UK. Those with a history of mental health conditions were most at risk. Adequate PPE availability, access to well-being support and reduced exposure to moral dilemmas may protect hospital HCW from mental health symptoms