Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas

The COVID-19 pandemic has resulted in unprecedented changes to the lives of patients with cancer. To evaluate the impact of the COVID-19 pandemic on the mental health and well-being of patients with colorectal cancer, we conducted a prospective longitudinal questionnaire study at a UK tertiary cancer centre. In total, 216 participants were included: mean age 65 years, 57% (n = 122) male, 92% (n = 198) of white ethnicity. Amongst participants who completed the screening psychometric questionnaire, 24% (n = 48/203) reported anxiety (GAD-7 ≥ 5), 15% (n = 31/204) depressive symptoms (PHQ-9 ≥ 10), 3% (n = 5/190) probable post-traumatic stress disorder (PC-PTSD-5 ≥ 4), and 31% (n = 66/213) poor well-being (WHO-5 < 50). In the subgroup (n = 95/216, 44%) who consented to and completed a follow-up survey 6 months later, there was a significant increase in the number of participants at risk of depression (4% vs. 13%, p = 0.021). Self-reported concern about the COVID-19 pandemic impacting one’s mental health is associated with increased likelihood of anxiety, depression, and poor well-being, in respective multivariate analyses. In conclusion, screening for the mental health impact of the COVID-19 pandemic is essential to ensure timely action from all key stakeholders and to avoid potentially longer-term detrimental consequences.

PICO-SM was a prospective longitudinal study investigating the psychological impact of the COVID-19 pandemic on patients with colorectal cancer treated in a large UK tertiary cancer centre. Here, we present the impact of the third wave of the pandemic (December 2021 to February 2022), when the Omicron variant became prevalent in the UK, and the complete longitudinal comparison across the entire duration of this study. Patients were invited to complete a questionnaire, including screening psychometric tools. In total, n = 312 patients were included in the final analysis. Specifically, in this Omicron-predominant wave, n = 96 patients were studied in detail: the mean age was 64 years, 64% were male, 33% reported poor well-being, 27% anxiety, 11% depressive symptoms, and 3% trauma-related symptoms. The participants who had investigations cancelled (OR 9.22, 95% CI 1.09–77.85; p = 0.041) or felt that the pandemic would affect their mental health (OR 3.82, 95% CI 1.96–7.44; p < 0.001) had an increased risk of anxiety according to a multivariate analysis. Similarly, independent predictors of poor well-being included concern that the pandemic would affect their cancer treatment (OR 4.59, 95% CI 1.03–20.56; p = 0.046) or mental health (OR 3.90, 95% CI 1.38–11.03; p = 0.010). The psychological distress experienced by patients, particularly anxiety, remained high during the third wave of the COVID-19 pandemic. These results align with our previously reported findings, emphasising the importance of continuing cancer treatment amidst an ongoing humanitarian emergency.

The purpose of this study was to determine the importance of the HIF-1 and PI3K pathways in the development of a) a metastatic phenotype and b) desensitization to radiotherapy, in thyroid carcinomas. In vitro scratch wound migration assays and cell spreading assays were performed under various oxygen tensions in the presence or absence of two PI3K inhibitors PI-103 and GDC-0941 (GDC-0941 is currently in clinical trials). The role of HIF-1α and PI3K on these processes was also assessed via genetic inhibition of HIF-1α and PI3K by use of a dominant negative variant (dnHIF) and by over expressing WT PTEN in PTEN-null FTC133 cells. For in vivo studies, follicular (FTC133) and anaplastic (8505c) thyroid carcinoma cells were manufactured to stably express eGFP and implanted sub-cutaneously. Mice were treated with PI-103 and GDC-0941 by intra-peritoneal injection and oral gavage. Spontaneous metastatic colonization to the lungs was confirmed by viewing eGFP postive colonies cultured from digested lung tissue and further by immuno-blotting for eGFP. For irradiation studies, cells were exposed to 0,2,4,6 GY external beam radiation. Both PI3K and hypoxia increased cell migration, cell adhesion and cell spreading on extra-cellular matrix molecules. These processes are key in the development of a metastatic phenotype. Genetic and pharmacological inhibition of both PI3K and HIF-1α reduced the migratory, adhesive and cell spreading potential of thyroid carcinoma cells under varying oxygen tensions. Additionally, pharmacological and genetic inhibition of PI3K and HIF-1α reduced both PI3K and HIF-1 activity resulting in reduced activation of PI3K target proteins (pAKT, pGSK-3β) and reduced expression of HIF-1 target genes (CA-9, VEGF, LDH-A, GLUT-1). In vivo, PI-103 and GDC-0941 reduced PI3K and HIF-1α activity as well as PI3K and HIF-1 target genes in primary follicular and anaplastic tumors. Importantly, mice bearing dnHIF-FTC133 tumors and those treated with GDC-0941 had reduced number of metastatic colonies in the lungs of follicular thyroid tumor bearing mice. Radiation induced HIF-1α activity and expression. GDC-0941 combined with radiation blocked HIF-1 induction, prolonged DNA double-strand breaks and reduced clonogenic survival suggesting a radio-sensitising effect. These data link PI3K, HIF-1 activation and aggressive disease in thyroid carcinoma and suggest PI3K may be an important therapeutic target. One attractive approach would be combination therapy with external beam radiation. The latter is the first line treatment in patients suffering from anaplastic thyroid carcinoma but is seldom successful. With the known desensitizing effects of HIF-1 and PI3K activity on radiation treatment, a combined approach involving both radiation and a PI3K inhibitor may improve both the therapeutic response within the local tumor and reduce metastatic potential. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1483. doi:10.1158/1538-7445.AM2011-1483

Aim: Paediatric prescriptions are almost 50% more likely to contain an error than adult orders. The risk of prescription error is further increased when prescribing for malignant disease.¹ In 2017 the Trust introduced ChemoCare, an electronic prescribing system for paediatric chemotherapy. The primary aim of this study was to investigate whether implementing ChemoCare has affected the incidence and type of errors made in paediatric chemotherapy prescriptions, compared with written prescriptions. A secondary aim was to explore possible reasons why these prescribing errors may occur. Since 2014 it has been mandatory for all NHS England specialist trusts to send monthly submissions to the Systemic Anti-Cancer Therapy (SACT) Database, regarding the treatment of malignant disease in secondary care.² Therefore, the study also analysed Trust compliance with communicating treatment data to SACT.Methods: Data collection took place over a four-week period in Spring 2018. Prescriptions were reviewed by pharmacists and categorised as written or electronic. Prescriptions were then checked for 7 different error types; calculation error, drug prescribed on wrong day, incorrect drug prescribed for cycle, incorrect dose of concomitant medications, incorrect surface area used, not adjusted dose for previous age or weight related toxicities, no drug prescribed. The Fisher’s Exact test was employed to detect significance between chemotherapy prescription type and error incidence. A written questionnaire was designed to obtain the views of consultants, pharmacists and specialist trainees, and explore possible reasons why prescription errors occur. ChemoCare treatment data was retrospectively reviewed in order to determine how many prescribed cycles had been marked as ‘completed’.Results: 143 prescriptions were analysed. 34.4%(n=21) of written prescriptions contained errors, compared with 11.4% (n=5) of electronic orders. Two of the error types measured ‘wrong calculation’ and ‘wrong drug prescribed for cycle’ occurred significantly more frequently in written than electronic prescriptions. The Fisher’s Exact test produced p values of 0.017 and 0.008 respectively. Of the 409 treatment cycles prescribed and administered on the electronic system, 56.5% (n=231) had not been marked as ‘completed’, so would not be returned to SACT as administered chemotherapy. Failure to communicate accurate chemotherapy data to SACT not only limits research opportunities to progress safety aspects of delivering chemotherapy, but also has significant cost implications for the Trust, as chemotherapy treatment costs are not recovered.Conclusion: This study supports the use of an electronic prescribing system for ordering paediatric chemotherapy, given the significant reduction in errors compared with written prescriptions. The introduction of a chemotherapy-specific safe prescribing poster is suggested in order to improve compliance with ChemoCare. Further studies analysing national compliance with data return to SACT, are required to identify cost implications for the NHS and subsequent areas for quality improvement.References: Avery AJ, Ghaleb M, Barber N, et al. Investigating the prevalence and causes of prescribing errors in general practice: The practice study. Pharmacoepidemiol Drug Saf 2012;21:4. NCRAS. Systemic Anti-Cancer Therapy Dataset [Internet]. [cited 2018 June 26]. Available from: http://www.ncin.org.uk/collecting_and_using_data/data_collection/chemotherapy