The Christie School of Oncology: Christie Research Publications Repository
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Single cell RNA sequencing analysis of prostate zones and their role in tumour progression
No full textControversies in NEN: An ENETS position statement on the treatment of patients with Grade 3 well-differentiated neuroendocrine tumours of the gastro-enteropancreatic tract
No full textGrade 3 neuroendocrine tumours (NET G3) represent approximately 20% of high-grade neuroendocrine neoplasms, and the recent identification of this entity has given rise to many unanswered questions relating to clinical management. The prognosis for these patients is worse than for those with Grade 1-2 well-differentiated NET, but better than for those with Grade 3 poorly differentiated neuroendocrine carcinoma. This consensus statement aims to address some uncertainties and explore unmet needs in the management of patients with NET G3. Firstly, the role of surgery in localised disease will be discussed as well as the dilemma in relation to the use of neo-adjuvant and/or adjuvant treatment in this setting. Treatment of oligometastatic digestive NET G3 will also be examined, including the positioning of surgery and ablative therapy. In the advanced setting, traditionally, chemotherapy in the form of temozolomide/capecitabine or 5-fluorouracil-based therapies, rather than platinum/etoposide, is considered a first-line treatment option, with second-line therapy dependent on what was used first-line. More recently, following the results of the NETTER-2 trial, Peptide Receptor Radionuclide Therapy with (177)Lu-DOTATATE may be an option for selected patients with somatostatin receptor positive NET G3. There is limited data on the use of immunotherapy and targeted therapy in this disease group to date, and some available evidence will be presented. The role for re-biopsy to guide treatment decision-making in patients with digestive NET G3 and whether NET G3 outside of the digestive tract should be treated similarly will also be scrutinised. Prospective studies with translational end-points are required to enable a better understanding of this diagnosis and to facilitate more optimal treatment discoveries
Chronic skin toxicities in breast cancer survivors: a systematic review and meta-analysis of radiotherapy techniques
No full textPURPOSE: This study assessed the impact of radiotherapy (RT) techniques on chronic skin reactions and health-related quality of life (HRQoL) in breast cancer patients, comparing conventional RT with modern techniques such as intensity-modulated RT (IMRT). METHODS: A comprehensive search was conducted in Embase, MEDLINE, and Cochrane CENTRAL from inception to April 26, 2024. Conventional RT, which uses 2D or 3D imaging to shape radiation beams without dynamic intensity modulation, was compared with alternate RT techniques for adjuvant breast cancer treatment. Primary outcomes included chronic grade ≥ 2 skin toxicities (hyperpigmentation, breast fibrosis, telangiectasia, edema, and atrophy/retraction) and HRQoL, assessed mainly with EORTC QLQ-C30 and QLQ-BR23 modules. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random-effects model. RESULTS: From 1305 screened studies, nine articles representing seven studies (2418 patients), including three randomized controlled trials, met inclusion criteria. Most studies used conventional fractionation (45-50 Gray in 25 fractions). IMRT was associated with a lower incidence of chronic grade ≥ 2 hyperpigmentation (RR: 0.39, 95%CI: 0.17-0.89, I(2) = 0%) compared to conventional RT. No significant differences were found for grade ≥ 2 breast fibrosis, telangiectasia, edema, and atrophy/retraction. Cosmetic outcomes from IMRT were favorable in the short term, with no long-term differences. Three studies reported no significant HRQoL differences between IMRT and conventional RT. CONCLUSION: IMRT may reduce certain chronic skin toxicities compared to conventional RT. However, consistent long-term differences in cosmetic outcomes or HRQoL were not observed. These findings are limited by the small number of studies and variability in reporting standards
Implementing routine electronic patient-reported outcome measures (ePROMS) for patients with primary tumours of the central nervous system
No full textIn vitro measurement of proton RBE: A multi-centric comparison using a harmonized setup
No full textBACKGROUND AND PURPOSE: This study presents a multi-center comparison of in vitro cell survival measurements and RBE calculations following proton irradiations conducted under harmonized experimental conditions across six European institutions participating in the INSPIRE framework. MATERIALS AND METHODS: V79-4 cells were irradiated using spread-out Bragg peak (SOBP) proton fields of two configurations delivering 6 and 8 Gy with widths of 6 and 4 cm, respectively. Each center adhered to a standardized protocol, utilizing the same phantom design to minimize uncertainties related to sample positioning. X-ray reference irradiations were also performed to assess cell radiosensitivity across the participating centers. RESULTS: Despite the consistent protocol, significant inter-institutional variability was observed in the survival measurements. For both treatment plans, the largest variation was detected in the most distal points of the SOBP (coefficients of variation of 43 % and 60 % for the 6 Gy and 8 Gy plans, respectively). Kruskal-Wallis statistical test confirmed the significant differences between the centers for each of the measured position in the proton field for both SOBP configurations. Discrepancies were observed in calculated RBE data as well, albeit preserving the expected trend for the values to slightly increase towards the distal edge of the SOBP (up to 1.5 and 1.3 for the 6 Gy and 8 Gy plans, respectively). CONCLUSION: The results of the study highlight the minimal biological variation one could expect performing proton RBE measurements in well-aligned experimental conditions and challenges in conducting large-scale, multi-center radiobiological experiments and inter-comparisons between literature data sets
A feasibility study of distress screening with psychometric evaluation and referral of cancer patients
No full textTo assess for associations of known psychometric scales GAD-7, PHQ-9, pc-PTSD-5 with demographics and clinical characteristics of cancer patients as well as identify their value in screening for distress and in guiding Psycho-Oncology evaluation. This prospective feasibility study employed three psychological testing questionnaires, specifically the GAD-7, PHQ-9, and PC-PTSD-5, for the purpose of distress screening. Patients with a diagnosis of colorectal cancer who scored highly on at least one psychometric scale (defined in previous studies of non-cancer populations as a GAD-7 score of 10 or above, a PHQ-9 score of 10 or above, or a PC-PTSD-5 score of 4 or above) were offered a referral for further assessment in the Psycho-Oncology service and triaged via a semi-structured interview. The relationship between patients' demographics and clinical characteristics and scores and outcomes was evaluated using the chi-square test. Fifty-four patients (30 females) of median age 60 years (range 36-81) were evaluated in the study. Thirty-four patients (63%) scored high on GAD-7, 40 (74%) on PHQ-9, and 8 (15%) on PC-PTSD-5 scales, respectively. Twenty-nine out of the 54 patients who underwent initial assessment with the psychometric scales (53.7%) accepted to be referred to the Psycho-Oncology service and were triaged via semi-structured interview while the rest 25/54 (46.3%) patients declined further assessment. Twenty-two of the patients who were interviewed (76%) required further specialist Psycho-Oncology intervention and the rest were signposted to community services. Patients younger than 65 years of age were more likely to score high according to the GAD-7 tool (p = 0.036). White Caucasian patients tended to score higher in the PHQ-9 questionnaire compared to non-white ones (p = 0.07). Prior history of mental disorder was significantly associated with higher scores in both GAD-7 (p = 0.041) and PC-PTSD-5 tools (p = 0.016). Patients who accepted a referral for psycho-oncology intervention demonstrated statistically elevated levels of anxiety on GAD-7 (p = 0.007) and diminished levels of depression on PHQ-9 (p = 0.042) compared to those who declined the referral. A clinical pathway involving a stepwise approach of psychometric scale evaluation and semi-structured interview can appropriately identify cancer patients with distress requiring further psychological support
Statistical framework for calling allelic imbalance in high-throughput sequencing data
No full textHigh-throughput sequencing facilitates large-scale studies of gene regulation and allows tracing the associations of individual genomic variants with changes in gene regulation and expression. Compared to classic association studies, the assessment of an allelic imbalance at heterozygous variants captures functional variant effects with smaller sample sizes, higher sensitivity, and better resolution. Yet, identification of allele-specific variants from allelic read counts remains challenging due to data-dependent biases and overdispersion arising from technical and biological variability. We present MIXALIME, a novel computational framework for calling allele-specific variants in diverse omics data with a repertoire of statistical models accounting for read mapping bias and copy number variation. We benchmark MIXALIME with DNase-Seq, ATAC-Seq, and CAGE-Seq data, and we demonstrate that the allelic imbalance highlights causal variants in GWAS results. Finally, as a showcase of the large-scale practical application of MIXALIME, we present an atlas of variants exhibiting allele-specific chromatin accessibility, built from thousands of available datasets obtained from diverse cell types
Spatial mapping of immune cell environments in NF2-related schwannomatosis vestibular schwannoma
No full textNF2-related Schwannomatosis (NF2 SWN) is a rare disease characterised by the growth of multiple nervous system neoplasms, including bilateral vestibular schwannoma (VS). VS tumours are characterised by extensive leucocyte infiltration. However, the immunological landscape in VS and the spatial determinants within the tumour microenvironment that shape the trajectory of disease are presently unknown. In this study, to elucidate the complex immunological networks across VS, we performed imaging mass cytometry (IMC) on clinically annotated VS samples from NF2 SWN patients. We reveal the heterogeneity in neoplastic cell, myeloid cell and T cell populations that co-exist within VS, and that distinct myeloid cell and Schwann cell populations reside within varied spatial contextures across characteristic Antoni A and B histomorphic niches. Interestingly, T-cell populations co-localise with tumour-associated macrophages (TAMs) in Antoni A regions, seemingly limiting their ability to interact with tumorigenic Schwann cells. This spatial landscape is altered in Antoni B regions, where T-cell populations appear to interact with PD-L1(+) Schwann cells. We also demonstrate that prior bevacizumab treatment (VEGF-A antagonist) preferentially reduces alternatively activated-like TAMs, whilst enhancing CD44 expression, in bevacizumab-treated tumours. Together, we describe niche-dependent modes of T-cell regulation in NF2 SWN VS, indicating the potential for microenvironment-altering therapies for VS
