Now showing items 1-20 of 12847

    • BH3-mimetics: recent developments in cancer therapy

      Townsend, Paul A; Kozhevnikova, M. V.; Cexus, O. N. F.; Zamyatnin, A. A., Jr.; Soond, S. M.; University of Surrey, Guildford, UK. (2021)
      The hopeful outcomes from 30 years of research in BH3-mimetics have indeed served a number of solid paradigms for targeting intermediates from the apoptosis pathway in a variety of diseased states. Not only have such rational approaches in drug design yielded several key therapeutics, such outputs have also offered insights into the integrated mechanistic aspects of basic and clinical research at the genetics level for the future. In no other area of medical research have the effects of such work been felt, than in cancer research, through targeting the BAX-Bcl-2 protein-protein interactions. With these promising outputs in mind, several mimetics, and their potential therapeutic applications, have also been developed for several other pathological conditions, such as cardiovascular disease and tissue fibrosis, thus highlighting the universal importance of the intrinsic arm of the apoptosis pathway and its input to general tissue homeostasis. Considering such recent developments, and in a field that has generated so much scientific interest, we take stock of how the broadening area of BH3-mimetics has developed and diversified, with a focus on their uses in single and combined cancer treatment regimens and recently explored therapeutic delivery methods that may aid the development of future therapeutics of this nature.
    • On Target 2: updated guidance for image-guided radiotherapy

      McNair, H. A.; Franks, K. N.; van Herk, Marcel; Royal Marsden NHS Foundation Trust, Sutton, UK; Institute of Cancer Research, London, UK (2021)
    • Manchester Intermittent versus Daily Diet App Study (MIDDAS): A pilot randomized controlled trial in patients with type 2 diabetes

      McDiarmid, S.; Harvie, Michelle N; Johnson, R.; Vyas, A.; Aglan, A.; Moran, J.; Ruane, H.; Hulme, A.; Sellers, K.; Issa, B. G.; et al. (2021)
      Aims: To test the feasibility and potential efficacy of remotely supported intermittent low energy diets (ILEDs) and continuous low energy diets (CLEDs) in people with type 2 diabetes (T2D) and the feasibility of a Randomized Controlled Trial (RCT) comparing the two approaches. Materials and methods: Seventy-nine adults with overweight/obesity and T2D (≤8 years duration) were randomized 1:1 to CLED (eight weeks/56 days of daily Optifast 820kcal (3430kJ) diet) or isoenergetic ILED (two days of Optifast and five days of a Mediterranean diet/week for 28 weeks). Weight maintenance/continued weight loss was undertaken for the remainder of the 52 weeks. Both groups received frequent telephone and/or the Oviva app support. Feasibility outcomes included study uptake, retention, app usage, dietary adherence, weight loss, and change in HbA1c at 52 weeks. Results: We enrolled 39 ILED and 40 CLED participants and 27 (69%) ILED and 30 CLED (75%) attended 52-week follow-up. Eighty-nine percent (70/79) started using the app and 86% (44/51) still used the app at 52 weeks. Intention-to-treat analysis at 52 weeks showed percentage weight loss was mean (CI) -5.4% (-7.6, -3.1%) for ILED and -6.0% (-7.9, -4.0%) for CLED. HbA1c<48mmol/mol was achieved in 42% of both groups. Mean (CI) changes in the T2D medication effect score (MES) were 0.0008 (-0.3, 0.3) for ILED and -0.5 (-0.8, -0.3) for CLED. Conclusion: The study demonstrates the feasibility and potential efficacy of remotely delivered ILED and CLED programs for weight loss and HbA1c reduction, and the feasibility of an RCT comparing the two approaches.
    • A phase I/II study to assess the safety and efficacy of pazopanib and pembrolizumab combination therapy in patients with advanced renal cell carcinoma

      Chowdhury, S.; Infante, J. R.; Hawkins, Robert E; Voss, M. H.; Perini, R.; Arkenau, T.; Voskoboynik, M.; Aimone, P.; Naeije, I.; Reising, A.; et al. (2021)
      Background: This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma. Patients and methods: This was an open-label, two-part, multicenter study involving treatment-naïve patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted. Results: Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group. Conclusions: Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach.
    • Proton therapy in supradiaphragmatic lymphoma: predicting treatment-related mortality to help optimize patient selection

      Ntentas, G.; Dedeckova, K.; Andrlik, M.; Aznar, Marianne Camille; Shakir, R.; Ramroth, J.; Begum, R.; Kubeš, J.; Darby, S. C.; Mikhaeel, N. G.; et al. (2021)
      Purpose: In some Hodgkin lymphoma (HL) patients, proton beam therapy (PBT) may reduce the risk of radiation-related cardiovascular disease (CVD) and second cancers (SC) compared with photon radiotherapy (photon-RT). Our aim was to identify those who benefit most from PBT in terms of predicted 30-year absolute mortality risks (AMR30) from CVD and SC, taking into account individual background, chemotherapy, radiation and smoking-related risks. Methods and materials: Eighty patients with supradiaphragmatic HL treated with PBT during 2015-2019 were re-planned using optimal photon-RT. To identify patients predicted to derive the greatest benefit from PBT compared to Photon-RT, doses and AMR30 from CVD and SC of the lung, breast and esophagus were compared for all patients and across patient subgroups. Results: For patients with mediastinal disease below the origin of the left main coronary artery (n=66, 82%), PBT reduced mean dose to heart, left ventricle and heart valves by 1.0, 2.7 and 3.6 Gray (Gy) respectively. Based on US mortality rates, PBT reduced CVD AMR30 by 0.2%, from 5.9% to 5.7%. The benefit was larger if the mediastinal disease overlapped longitudinally with the heart by ≥40% (n=23, 29%), where PBT reduced mean dose to heart, left ventricle and heart valves by 3.2, 5.6, and 5.1Gy respectively, and reduced CVD AMR30 by 0.8%, from 7.0% to 6.2%. For patients with axillary disease (n=25, 31%), PBT reduced mean lung dose by 2.8Gy and lung cancer AMR30 by 0.6%, from 2.7% to 2.1%. Breast and esophageal doses were also lower with PBT but effects on AMR30 were negligible. The effect of smoking on CVD and lung cancer AMR30 was much larger than radiation and chemotherapy and the differences between radiation modalities. Conclusions: The predicted benefit of PBT is not universal and is limited to certain categories of lymphoma patients with lower mediastinal or axillary disease. Smoking cessation should be strongly encouraged in smokers requiring thoracic radiotherapy.
    • The role of circular RNAs in DNA damage response and repair

      Papaspyropoulos, A.; Hazapis, O.; Lagopati, N.; Polyzou, A.; Papanastasiou, A. D.; Liontos, M.; Gorgoulis, Vassilis G; Kotsinas, A.; Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National Kapodistrian University of Athens (NKUA), 75 Mikras Asias Str., Goudi, GR-11527 Athens, Greece (2021)
      Circular RNAs (circRNA) comprise a distinct class of non-coding RNAs that are abundantly expressed in the cell. CircRNAs have the capacity to regulate gene expression by interacting with regulatory proteins and/or other classes of RNAs. While a vast number of circRNAs have been discovered, the majority still remains poorly characterized. Particularly, there is no detailed information on the identity and functional role of circRNAs that are transcribed from genes encoding components of the DNA damage response and repair (DDRR) network. In this article, we not only review the available published information on DDRR-related circRNAs, but also conduct a bioinformatic analysis on data obtained from public repositories to uncover deposited, yet uncharacterized circRNAs derived from components of the DDRR network. Finally, we interrogate for potential targets that are regulated by this class of molecules and look into potential functional implications.
    • A prostate cancer proteomics database for SWATH-MS based protein quantification

      Muazzam, Ammara; Chiasserini, D.; Kelsall, J.; Geifman, N.; Whetton, Anthony D; Townsend, Paul A; Manchester Cancer Research Centre, Division of Cancer Sciences, Faculty of Biology, School of Medical Sciences, Medicine and Health, University of Manchester, Wilmslow Road, Manchester M20 4GJ, UK (2021)
      Prostate cancer is the most frequent form of cancer in men, accounting for more than one-third of all cases. Current screening techniques, such as PSA testing used in conjunction with routine procedures, lead to unnecessary biopsies and the discovery of low-risk tumours, resulting in overdiagnosis. SWATH-MS is a well-established data-independent (DI) method requiring prior knowledge of targeted peptides to obtain valuable information from SWATH maps. In response to the growing need to identify and characterise protein biomarkers for prostate cancer, this study explored a spectrum source for targeted proteome analysis of blood samples. We created a comprehensive prostate cancer serum spectral library by combining data-dependent acquisition (DDA) MS raw files from 504 patients with low, intermediate, or high-grade prostate cancer and healthy controls, as well as 304 prostate cancer-related protein in silico assays. The spectral library contains 114,684 transitions, which equates to 18,479 peptides translated into 1227 proteins. The robustness and accuracy of the spectral library were assessed to boost confidence in the identification and quantification of prostate cancer-related proteins across an independent cohort, resulting in the identification of 404 proteins. This unique database can facilitate researchers to investigate prostate cancer protein biomarkers in blood samples. In the real-world use of the spectrum library for biomarker detection, using a signature of 17 proteins, a clear distinction between the validation cohort's pre- and post-treatment groups was observed. Data are available via ProteomeXchange with identifier PXD028651.
    • Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

      Fraser, M.; Livingstone, J.; Wrana, J. L.; Finelli, A.; He, H. H.; van der Kwast, T.; Zlotta, A. R.; Bristow, Robert G; Boutros, P. C.; Department of Surgery, Division of Urology, University of Toronto, Toronto, ON, Canada. (2021)
      Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent. Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability. ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices. These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer.
    • Experimental challenges to modeling prostate cancer heterogeneity

      Flores-Téllez, Teresita; Baena, Esther; Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Alderley Edge, Macclesfield, SK10 4TG (2022)
      Tumor heterogeneity plays a key role in prostate cancer prognosis, therapy selection, relapse, and acquisition of treatment resistance. Prostate cancer presents a heterogeneous diversity at inter- and intra-tumor and inter-patient levels which are influenced by multiple intrinsic and/or extrinsic factors. Recent studies have started to characterize the complexity of prostate tumors and these different tiers of heterogeneity. In this review, we discuss the most common factors that contribute to tumoral diversity. Moreover, we focus on the description of the in vitro and in vivo approaches, as well as high-throughput technologies, that help to model intra-tumoral diversity. Further understanding tumor heterogeneities and the challenges they present will guide enhanced patient risk stratification, aid the design of more precise therapies, and ultimately help beat this chameleon-like disease.
    • Mutational characterization of cutaneous melanoma supports divergent pathways model for melanoma development

      Millán-Esteban, D.; Peña-Chilet, M.; García-Casado, Z.; Manrique-Silva, E.; Requena, C.; Bañuls, J.; López-Guerrero, J. A.; Rodríguez-Hernández, A.; Traves, V.; Dopazo, J.; et al. (2021)
      According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being BRAF. The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included NF1, ROS1, GNA11, and RAC1. We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.
    • VinCaP: a phase II trial of vinflunine in locally advanced and metastatic squamous carcinoma of the penis

      Nicholson, S.; Tovey, H.; Elliott, Tony; Burnett, S. M.; Cruickshank, C.; Bahl, A.; Kirkbride, P.; Mitra, A. V.; Thomson, A. H.; Vasudev, N.; et al. (2021)
      Background: We investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit. Methods: Twenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming-A'Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m2, given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of <15%, with a true CBR of >40% being probable. Results: Twenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression. Conclusions: Pre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease.
    • Positive attributes of anti-TERT CD4 T-Helper Type 1 immune responses in melanoma

      Nagore, E.; Virós, Amaya; Kumar, R.; Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain (2021)
      Nardin et al's (2021) study on melanoma reports anti-TERT CD4 T helper type (Th) 1 responses in more than half of patients. Besides indicating a trend for improved survival, increased anti-TERT CD4 Th1 responses predicted better outcomes for patients treated with immune checkpoint inhibitors. Thus, harnessing systemic anti-TERT CD4 Th1 responses together with tumor-specific elevation of telomerase can potentially open new avenues for biomarkers and treatment in melanoma.
    • Blast cells surviving acute myeloid leukemia induction therapy are in cycle with a signature of FOXM1 activity

      Williams, Mark S; Basma, Naseer J; Amaral, Fabio M R; Wiseman, Daniel H; Somervaille, Tim C P; Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, Oglesby Cancer Research Building, The University of Manchester, 555 Wilmslow Road, Manchester, M20 4GJ, UK (2021)
      Background: Disease relapse remains common following treatment of acute myeloid leukemia (AML) and is due to chemoresistance of leukemia cells with disease repopulating potential. To date, attempts to define the characteristics of in vivo resistant blasts have focused on comparisons between leukemic cells at presentation and relapse. However, further treatment responses are often seen following relapse, suggesting that most blasts remain chemosensitive. We sought to characterise in vivo chemoresistant blasts by studying the transcriptional and genetic features of blasts from before and shortly after induction chemotherapy using paired samples from six patients with primary refractory AML. Methods: Leukemic blasts were isolated by fluorescence-activated cell sorting. Fluorescence in situ hybridization (FISH), targeted genetic sequencing and detailed immunophenotypic analysis were used to confirm that sorted cells were leukemic. Sorted blasts were subjected to RNA sequencing. Lentiviral vectors expressing short hairpin RNAs were used to assess the effect of FOXM1 knockdown on colony forming capacity, proliferative capacity and apoptosis in cell lines, primary AML cells and CD34+ cells from healthy donors. Results: Molecular genetic analysis revealed early clonal selection occurring after induction chemotherapy. Immunophenotypic characterisation found leukemia-associated immunophenotypes in all cases that persisted following treatment. Despite the genetic heterogeneity of the leukemias studied, transcriptional analysis found concerted changes in gene expression in resistant blasts. Remarkably, the gene expression signature suggested that post-chemotherapy blasts were more proliferative than those at presentation. Resistant blasts also appeared less differentiated and expressed leukemia stem cell (LSC) maintenance genes. However, the proportion of immunophenotypically defined LSCs appeared to decrease following treatment, with implications for the targeting of these cells on the basis of cell surface antigen expression. The refractory gene signature was highly enriched with targets of the transcription factor FOXM1. shRNA knockdown experiments demonstrated that the viability of primary AML cells, but not normal CD34+ cells, depended on FOXM1 expression. Conclusions: We found that chemorefractory blasts from leukemias with varied genetic backgrounds expressed a common transcriptional program. In contrast to the notion that LSC quiescence confers resistance to chemotherapy we find that refractory blasts are both actively proliferating and enriched with LSC maintenance genes. Using primary patient material from a relevant clinical context we also provide further support for the role of FOXM1 in chemotherapy resistance, proliferation and stem cell function in AML.
    • Towards harmonizing clinical linear energy transfer (LET) reporting in proton radiotherapy: a European multi-centric study

      Hahn, C.; Ödén, J.; Dasu, A.; Vestergaard, A.; Fuglsang Jensen, M.; Sokol, O.; Pardi, C.; Bourhaleb, F.; Leite, A.; de Marzi, L.; et al. (2021)
      Background: Clinical data suggest that the relative biological effectiveness (RBE) in proton therapy (PT) varies with linear energy transfer (LET). However, LET calculations are neither standardized nor available in clinical routine. Here, the status of LET calculations among European PT institutions and their comparability are assessed. Materials and methods: Eight European PT institutions used suitable treatment planning systems with their center-specific beam model to create treatment plans in a water phantom covering different field arrangements and fulfilling commonly agreed dose objectives. They employed their locally established LET simulation environments and procedures to determine the corresponding LET distributions. Dose distributions D1.1 and DRBE assuming constant and variable RBE, respectively, and LET were compared among the institutions. Inter-center variability was assessed based on dose- and LET-volume-histogram parameters. Results: Treatment plans from six institutions fulfilled all clinical goals and were eligible for common analysis. D1.1 distributions in the target volume were comparable among PT institutions. However, corresponding LET values varied substantially between institutions for all field arrangements, primarily due to differences in LET averaging technique and considered secondary particle spectra. Consequently, DRBE using non-harmonized LET calculations increased inter-center dose variations substantially compared to D1.1 and significantly in mean dose to the target volume of perpendicular and opposing field arrangements (p < 0.05). Harmonizing LET reporting (dose-averaging, all protons, LET to water or to unit density tissue) reduced the inter-center variability in LET to the order of 10-15% within and outside the target volume for all beam arrangements. Consequentially, inter-institutional variability in DRBE decreased to that observed for D1.1. Conclusion: Harmonizing the reported LET among PT centers is feasible and allows for consistent multi-centric analysis and reporting of tumor control and toxicity in view of a variable RBE. It may serve as basis for harmonized variable RBE dose prescription in PT.
    • Sociodemographic and geographical variation in access to systemic anti-cancer therapies for women with advanced breast cancer: a systematic review

      Pearson, Sally Anne; Taylor, Sally; Marsden, A.; O'Reilly, J. D.; Howell, Sacha J; Yorke, Janelle; University of Manchester, England; (2021)
      Background: Equitable access to guideline concordant treatment with systemic anti-cancer therapies (SACT) is a key determinant in overall survival, progression free survival and improvement in quality of life for Advanced Breast Cancer (ABC). Variation in treatment receipt has been reported though remains poorly understood. A comprehensive understanding of factors which influence access and receipt of guideline concordant treatment is lacking. The review sought to address this through identifying and investigating factors associated with access to and receipt of guideline concordant SACT for women with ABC. Methods: Systematic searches of the literature were undertaken using EBSCO CINAHL Plus, Ovid MEDLINE, Ovid EMBASE, PsychINFO, Cochrane Library, JBI database and NHS Evidence. Methodological quality was assessed by two reviewers using the Joanna Briggs Institute critical appraisal tool (JBI, 2017) with the application of an overall GRADE quality rating. Studies were synthesised using a narrative synthesis approach. High levels of heterogeneity between studies precluded meta-analysis. Results: Thirteen international studies (n=13) published between 2009 and 2020 were included and reported 201,677 patients with ABC. Overall receipt of SACT ranged from 4% to 70%, factors associated with receipt were: • Age: younger patients had an increased likelihood of treatment receipt in a timelier manner • Race/ethnicity: patients of white origin were more likely to receive treatment in a timelier manner than patients of non-white origin. • Socioeconomic status: patients with higher socioeconomic status were more likely to receive treatment than their counterparts • Comorbidities: patients with fewer comorbidities were more likely to receive treatment • Place of care: patients treated at teaching, research and private institutions were more likely to receive timelier treatment • Geographical location: treatment receipt varied by geographical location Conclusion: A number of factors were associated with treatment receipt. Barriers included older age, non-white race, lower socioeconomic status, significant comorbidities, hospital setting and geographical location. However, due to limitations in overall methodological quality findings should be interpreted with caution. Implications for nursing, practice and research include the development and piloting of targeted interventions to address specific barriers in a socio-culturally sensitive manner and further research to understand the experience of women and clinicians is required.
    • The analysis of COVID-19 on ICU nurses with solutions to improve wellbeing

      Carter, Nicole; Christie Hospital, Manchester (2021)
      Introduction: To ease the psychological ramifications that COVID-19is having on ICU nurses, it is recommended that implementing aWellbeing Action Tool, would be beneficial in maintaining staffwellbeing and high quality patient care.Literature search: Robbins (2020) and Haskell et al. (2020) concludedthat leaders needed to find a solution to support staff to engage inself care. Glasper (2020) found that the wellbeing of nurses is crucialand support from colleagues is vital for both the nurse and patient; asthe care patients receive is only as good as the nurse deliveringit. Maben et al. (2020) and Yuanyuan-Mo (2020) conclude that earlyintervention from nurses is vital and supporting nurses practically andpsychologically must be made a priority.Findings: Synthesising the evidence, the themes emerged included;adopting an open culture, support of nurses and employing in selfcare.In December 2019, a public health emergency was declared (Purba,2020) with deaths passing 149.968, those being our friends, colleagues and family members and the support of nurses must bemade a priority. It is proposed that implementing an ICU WellbeingAction Tool, would prove beneficial for staff to adopt in selfcare andmaintain an open culture to access support.A survey carried out involving 3.500 ICU nurses found that 9 out of10 thought their mental health had declined.Discussion: It is acknowledged the pandemic isn't just a crisis in ourphysical health, but mental health too and finding a solution short andlong term is essential in maintaining staff health, as well as patientsafety, in order to maintain high-quality patient care on ICU. It sup-ports the evidence that staff must adopt an open culture in accessingsupport and employing self compassion to maintain their ownwellbeing and maintain patient safety.Implications for practice: This tool can be used by managers as a for-mal PDR approach or by yourself to develop one's own awareness ofstress triggers. It is recommended further research of this tool and theevaluation of it would be beneficial with the tool being transferable to other areas.
    • Tissue based biomarkers in non-clear cell RCC: Correlative analysis from the ASPEN clinical trial

      Halabi, S.; Yang, Q.; Carmack, A.; Zhang, S.; Foo, W. C.; Eisen, T.; Stadler, W. M.; Jones, R. J.; Garcia, J. A.; Vaishampayan, U. N.; et al. (2021)
      Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intention-to-treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1α, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.
    • Radial artery access for hepatic chemosaturation: the first description of technical feasibility

      Frost, Joshua | Najran, Pavan; Bell, Jon; Mullan, Damian; Radiology and Interventional Radiology, The Christie NHS Foundation Trust, Manchester (2021)
      Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System, Delcath Systems Inc, Wilmington, Delaware) is an interventional radiology procedure that delivers high doses of melphalan, a chemotherapeutic agent, directly to the liver in patients with unresectable primary and secondary liver tumours. Traditionally, CS-PHP is delivered by arterial access via the femoral artery. However, there can be many risks and adverse effects associated with femoral artery punctures, such as retroperitoneal haemorrhage and haematoma formation. The monitoring and bed rest required following the removal of a femoral arterial catheter may also cause significant distress to patients as they remain immobile, potentially prolonging their stay in hospital. The radial artery is an alternative access point, with fewer reported adverse events and increased patient tolerance when compared with femoral access. This case report details the first reported use of Hepatic CHEMOSAT® therapy being delivered via the radial artery. Two patients received hepatic chemosaturation with no reported complications. This report demonstrates that access via the radial artery is a feasible alternative for the delivery of chemotherapy, which may reduce morbidity and the risks usually associated with femoral access.
    • Pulmonary toxicities associated with the use of immune checkpointiInhibitors: an update from the immuno-oncology subgroup of the neutropenia, infection & myelosuppression study group of the Multinational Association for Supportive Care in Cancer

      Rapoport, B. L.; Shannon, V. R.; Cooksley, Timothy J; Johnson, D. B.; Anderson, L.; Blidner, A. G.; Tintinger, G. R.; Anderson, R.; Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa (2021)
      The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, with agents such as nivolumab, pembrolizumab, and cemiplimab targeting programmed cell death protein-1 (PD-1) and durvalumab, avelumab, and atezolizumab targeting PD-ligand 1 (PD-L1). Ipilimumab targets cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). These inhibitors have shown remarkable efficacy in melanoma, lung cancer, urothelial cancer, and a variety of solid tumors, either as single agents or in combination with other anticancer modalities. Additional indications are continuing to evolve. Checkpoint inhibitors are associated with less toxicity when compared to chemotherapy. These agents enhance the antitumor immune response and produce side- effects known as immune-related adverse events (irAEs). Although the incidence of immune checkpoint inhibitor pneumonitis (ICI-Pneumonitis) is relatively low, this complication is likely to cause the delay or cessation of immunotherapy and, in severe cases, may be associated with treatment-related mortality. The primary mechanism of ICI-Pneumonitis remains unclear, but it is believed to be associated with the immune dysregulation caused by ICIs. The development of irAEs may be related to increased T cell activity against cross-antigens expressed in tumor and normal tissues. Treatment with ICIs is associated with an increased number of activated alveolar T cells and reduced activity of the anti-inflammatory Treg phenotype, leading to dysregulation of T cell activity. This review discusses the pathogenesis of alveolar pneumonitis and the incidence, diagnosis, and clinical management of pulmonary toxicity, as well as the pulmonary complications of ICIs, either as monotherapy or in combination with other anticancer modalities, such as thoracic radiotherapy.
    • Prophylactic cranial irradiation (PCI), hippocampal avoidance (HA) whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) in small cell lung cancer (SCLC): Where do we stand?

      Crockett, Cathryn; Belderbos, J.; Levy, A.; McDonald, F.; Le Péchoux, C.; Faivre-Finn, Corinne; Radiotherapy Related Research, The Christie NHS Foundation Trust, Manchester, United Kingdom (2021)
      Small cell lung cancer (SCLC) is an aggressive form of lung cancer associated with an increased risk of develping brain metastases (BM), which are a significant cause of morbidity and mortality. Prophylactic cranial irradiation (PCI) was first introduced in the 1970s with the aim of reducing BM incidence and improving survival and quality of life (QoL). Prospective clinical trials and meta-analyses have demonstrated its effectiveness in reducing BM incidence and improving survival, across all stages of the disease following response to induction chemotherapy. Despite its long history, "unknowns" surrounding PCI use still exist and there are particular subgroups of patients for which its use remains controversial. PCI is known to cause neurocognitive toxicity which can have a significant impact on a patient's QoL. Strategies to minimise this, including the use of hippocampal avoidance radiotherapy techniques, neuroprotective drugs and stereotactic radiosurgery in place of whole brain radiotherapy for the treatment of BM, are under evaluation. This review offers a summary of the key PCI trials published to date and the current treatment recommendations based on available evidence. It also discusses the key questions being addressed in ongoing clinical trials and highlights others where there is currently a knowledge gap and therefore where further data are urgently required.