The Christie School of Oncology: Christie Research Publications Repository
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An update on access to novel treatment for metastatic melanoma in Europe - A 2024 survey of the European melanoma registry and the European association of dermato-oncology
No full textAdvances in cancer treatments have significantly improved their effectiveness, yet access to first-line therapies remains limited. A 2017 survey revealed that over 25 % of metastatic melanoma patients in Europe lacked access to recommended therapies. To address this, the European Association of Dermato-Oncology and the European Melanoma Registry conducted a follow-up study on the registration and reimbursement of first-line treatments.A web-based survey using LimeSurvey was distributed to melanoma experts across 27 European countries from February to April 2022 and updated from February to April 2024. The questionnaire covered the percentage of patients receiving recommended treatments, as well as treatment authorization and reimbursement dates for systemic and adjuvant therapies.There has been significant improvement in the registration and reimbursement of BRAFi/MEKi, anti-PD1, and anti-PD1/anti-CTLA4 therapies, increasing from 48 %, 63 %, and 37 % in 2017 to 96 %, 96 %, and 78 % in 2024, respectively. Despite these gains, restrictions persist. Anti-PD1/anti-CTLA4 combination immunotherapy is still not available without restrictions in 48 % of the surveyed countries. The nivolumab/relatlimab combination is licensed only for PDL-1-negative melanoma and reimbursed in seven countries of Europe. Tebentafusp is reimbursed in 15 countries and talimogene laherpervec in 5. In 2024, adjuvant treatments for stage III melanoma are reimbursed in 22 countries for dabrafenib/trametinib and 24 of 27 for anti-PD1 antibodies. Pembrolizumab and nivolumab are reimbursed in 15 and 8 countries, respectively, for stage IIB/IIC disease.While there have been improvements in the reimbursement of metastatic melanoma treatments in Europe, challenges and discrepancies remain. Further efforts at European and global levels are needed to harmonize and enhance access to cancer medicines
Whole-body integral dose and post-radiotherapy lymphocytopaenia in solid tumours
No full textOBJECTIVE: Since modern radiotherapy techniques such as intensity-modulated radiotherapy (IMRT) pivot on a strategy of dose redistribution, it may increase integral dose and consequently worsening of lymphocytopaenia. In this study, our objective was twofold: first to validate the correlation between integral body dose and post-treatment lymphocytopaenia in a cohort of patients treated with curative-intent radiotherapy and second to validate its prognostic impact. METHODS AND ANALYSIS: Patients treated with curative intent radiotherapy with complete blood counts were included in the study. Data on the following variables were collected: treatment site, prescribed dose, use of concurrent chemotherapy, mean body dose, mean body volume, treatment technique and disease-free survival. RESULTS: A total of 116 patients were included for analysis. There was a significant decline in lymphocyte counts after radiotherapy (2.2×10(9)/L vs 0.8×10(9)/L; p<0.001). Multivariate linear regression analysis of post-treatment lymphocytopaenia revealed a significant correlation with pretreatment lymphocyte counts, integral body dose, use of IMRT and use of concurrent radiosensitising chemotherapy. Univariate survival analysis was performed in 37 patients with squamous cell carcinoma of the head and neck. In the Cox proportional hazards model, post-treatment lymphocyte count was statistically significant as a continuous variable (Hazard Ratio=0.998, p=0.01) and as a dichotomous variable. CONCLUSION: The negative correlation between integral body dose and post-treatment lymphocytopaenia was validated, and post-treatment lymphocytopaenia is an adverse prognostic factor in patients with head and neck cancer treated with curative-intent radiotherapy
Cell Surface Proteomics Reveals Hypoxia-Regulated Pathways in Cervical and Bladder Cancer
No full textBackground Plasma membrane proteins (PMPs) play key roles in cell signalling, adhesion, and trafficking, and are attractive therapeutic targets in cancer due to their surface accessibility. However, their typically low abundance limits detection by conventional proteomic approaches. METHODS: To improve PMP detection, we employed a surface proteomics workflow combining cell surface biotinylation and affinity purification prior to LC-MS/MS analysis in cervical (SiHa) and bladder (UMUC3) cancer cell lines cultured under normoxic (21% O(2)) or hypoxic (0.1% O(2)) conditions. RESULTS: In SiHa cells, 43 hypoxia-upregulated proteins were identified exclusively in the biotin-enriched fraction, including ITGB2, ITGA7, AXL, MET, JAG2, and CAV1/CAV2. In UMUC3 cells, 32 unique upregulated PMPs were detected, including CD55, ADGRB1, SLC9A1, NECTIN3, and ACTG1. These proteins were not observed in corresponding whole-cell lysates and are associated with extracellular matrix remodelling, immune modulation, and ion transport. Biotinylation enhanced the detection of membrane-associated pathways such as ECM organisation, integrin signalling, and PI3K-Akt activation. Protein-protein interaction analysis revealed links between membrane receptors and intracellular stress regulators, including mitochondrial proteins. CONCLUSIONS: These findings demonstrate that surface biotinylation improves the sensitivity and selectivity of plasma membrane proteomics under hypoxia, revealing hypoxia-responsive proteins and pathways not captured by standard whole-cell analysis
Pembrolizumab plus chemotherapy versus chemotherapy for advanced esophageal cancer: 5-year extended follow-up for the randomized phase III KEYNOTE-590 study
No full textBackground: The global KEYNOTE-590 trial was the first to show a significant improvement in survival with immunotherapy plus chemotherapy in the first-line treatment of esophageal cancer (EC) and supported the approval of pembrolizumab plus chemotherapy in this setting. After a median follow-up of 22.6 months, pembrolizumab plus chemotherapy compared with placebo plus chemotherapy had a manageable safety profile and significantly improved survival of participants with previously untreated advanced EC. Results of a median follow-up of 58.8 months (range 49.2-70.6 months) are reported. Patients and methods: Adults with previously untreated advanced EC or Siewert type 1 gastroesophageal junction cancer were randomly assigned 1 : 1 to receive chemotherapy with or without pembrolizumab. Study outcomes were efficacy and safety. Results: Overall, 749 participants received pembrolizumab plus chemotherapy (n = 373) or placebo plus chemotherapy (n = 376). Median overall survival was 12.3 months versus 9.8 months [hazard ratio (HR) 0.72, 95% confidence interval (CI) 0.62-0.84] with pembrolizumab plus chemotherapy versus placebo plus chemotherapy; 5-year survival rates were 10.6% and 3.0%. Median progression-free survival (PFS) was 6.3 months versus 5.8 months (HR 0.64, 95% CI 0.54-0.75); 5-year PFS rates were 5.5% and not reached. Grade >= 3 treatment-related adverse events occurred in 71.9% and 67.6% of participants in the pembrolizumab plus chemotherapy and placebo plus chemotherapy groups, respectively. Conclusion: Data from KEYNOTE-590 continue to show durable efficacy after 5 years, and pembrolizumab plus chemotherapy more than tripled the 5-year overall survival rate compared with placebo plus chemotherapy, with no new safety signals. These results support first-line therapy with pembrolizumab plus chemotherapy as standard for previously untreated patients with advanced EC with programmed death-ligand 1 combined positive score >= 1
NAC regulates metabolism and cell fate in intestinal stem cells
No full textIntestinal stem cells (ISCs) face the challenge of integrating metabolic demands with unique regenerative functions. Studies have shown an intricate interplay between metabolism and stem cell capacity; however, it is still not understood how this process is regulated. Combining ribosome profiling and CRISPR screening in intestinal organoids, we identify the nascent polypeptide-associated complex (NAC) as a key mediator of this process. Our findings suggest that NAC is responsible for relocalizing ribosomes to the mitochondria and regulating ISC metabolism. Upon NAC inhibition, intestinal cells show decreased import of mitochondrial proteins, which are needed for oxidative phosphorylation, and, consequently, enable the cell to maintain a stem cell identity. Furthermore, we show that overexpression of NACα is sufficient to drive mitochondrial respiration and promote ISC identity. Ultimately, our results reveal the pivotal role of NAC in regulating ribosome localization, mitochondrial metabolism, and ISC function, providing insights into the potential mechanism behind it
Study protocol: multi-centre, randomised controlled clinical trial exploring stromal targeting in locally advanced pancreatic cancer; STARPAC2
No full textBACKGROUND: Pancreatic cancer (PDAC: pancreatic ductal adenocarcinoma, the commonest form), a lethal disease, is best treated with surgical excision but is feasible in less than a fifth of patients. Around a third of patients presentlocally advanced, inoperable, non-metastatic (laPDAC), whose stadrd of care is palliative chemotherapy; a small minority are down-sized sufficiently to enable surgical excision. We propose a phase II clinical trial to test whether a combination of standard chemotherapy (gemcitabine & nab-Paclitaxel: GEM-NABP) and repurposing All Trans Retinoic Acid (ATRA) to target the stroma may extend progression-free survival and enable successful surgical resection for patients with laPDAC, since data from phase IB clinical trial demonstrate safety of GEM-NABP-ATRA combination to patients with advanced PDAC with potential therapeutic benefit. METHODS: Patients with laPDAC will receive at least six cycles of GEM-NABP with 1:1 randomisation to receive this with or without ATRA to assess response, until progression or intolerance. Those with stable/responding disease may undergo surgical resection. Primary endpoint is progression free survival (PFS) defined as the time from the date of randomisation to the date of first documented tumour progression (response evaluation criteria in solid tumours [RECIST] v1.1) or death from any cause, whichever occurs first. Secondary endpoints include objective response rate (ORR), overall survival (OS), safety and tolerability, surgical resection rate, R0 surgical resection rate and patient reported outcome measures (PROMS) as measured by questionnaire EQ-5D-5L. Exploratory endpoints include a decrease or increase in CA19-9 and serum Vitamin A over time correlated with ORR, PFS, and OS. DISCUSSION: STARPAC2 aims to assess the role of stromal targeting in laPDAC. TRIAL REGISTRATION: EudraCT: 2019-004231-23; NCT04241276; ISRCTN11503604
Analysis of outcomes of patients with oligodendroglioma with focus on volumetric reduction
No full textBackground This study aims to evaluate the surgical outcomes and prognostic factors influencing overall survival (OS) and progression-free survival (PFS) in patients with molecularly confirmed oligodendrogliomas focussing on the extent of resection (EOR) and volumetric analysis.Methods We conducted a retrospective analysis of 115 adult patients with oligodendroglioma at our institution from January 2010 to December 2020. Inclusion criteria encompassed histologically and molecularly confirmed grade 2 and 3 oligodendroglioma, age above 18 years, availability of pre- and postoperative imaging, and complete follow-up data. Surgical outcomes were categorized by EOR and volumetric assessments were performed using neuroimaging. Mean OS and PFS were calculated using the Kaplan-Meier method (As mortality was < 50%) and univariate/multivariate analyses were conducted to identify prognostic factors.Results The cohort had a median age of 42 years (range 18-77), with GTR achieved in 47% of primary operations. Median follow-up was 6.3 years. OS was significantly influenced by age (p < 0.0001) and EOR, with a mean OS of 134 months and a mean PFS of 117 months. Volumetric reduction of tumor volume greater than 80% correlated positively with both OS and PFS. The analysis also highlighted the importance of adjuvant therapy in improving PFS.Conclusion This study confirms that younger age, extensive volumetric reduction, and intraoperative adjuncts are associated with improved OS and PFS in patients with oligodendroglioma. While the EOR impacts OS significantly in grade 3 tumors, further research is necessary to determine optimal surgical strategies for grade 2 oligodendrogliomas
The current status of brachytherapy in Europe - a GEC-ESTRO Brachy-HERO survey
No full textA survey regarding utilisation of brachytherapy was distributed to European brachytherapy professionals. Eighty replies from 26 countries were received, two of which were outside Europe. The replies showed that brachytherapy is still widely used. The main indications for brachytherapy are gynaecological and prostate cancer, with >80 % of the responding countries performing brachytherapy for these indications. There is on average one brachytherapy centre per 0.8 million inhabitants, ranging from 0.4 per million to 2.3 per million inhabitants. The organisation of brachytherapy on national levels also varies from country to country, with less than half of the countries having a central brachytherapy registry. All in all, the survey shows that brachytherapy still plays a role on modern radiotherapy, but the field could benefit from a stronger collaboration both nationally and internationally
An open-source repository-based tool for quality control of imaging protocol compliance: demonstration in a multicentre MRI study
No full textOBJECTIVES: Clinical translation of advanced MRI techniques can be hindered by the challenges of performing standardized multicentre imaging trials. This work aims to develop and demonstrate an automated tool for monitoring imaging protocol deviations, enabling corrective action to be taken. METHODS: A Python-based tool, integrated into the imaging repository XNAT, was developed to compare DICOM series with an agreed imaging protocol, highlighting missing series and parameter deviations. This was demonstrated through retrospective analysis of a prospectively acquired dataset from a ten-site whole-body (WB) MRI study of patients with multiple myeloma. The acquired data were compared to the relevant radiological guidelines and to the site-specific imaging protocols agreed for the study. RESULTS: The rate of technical software failure was 0% across 174 examinations from 10 sites. The clinical guidelines were followed in 87.9% of examinations and compliance with the site-specific imaging protocol was greater than 75.0% for all parameters. Common deviations included number of averages for diffusion-weighted imaging (DWI) and repetition time for DWI and Dixon: 85.2%, 81.7%, and 75.1%, respectively. There was a statistically significant correlation between protocol compliance and overall exam radiological image quality. CONCLUSIONS: Repository-integrated software is presented for automated monitoring of imaging protocol compliance to support standardization in multicentre studies and clinical translation. ADVANCES IN KNOWLEDGE: This study presents a novel open-source repository-integrated software tool for automatically monitoring compliance with the expected imaging protocol. Standardized acquisition protocols are crucial in multicentre imaging studies and this tool has the potential to enhance research outcomes and support clinical translation
Cell-free and extrachromosomal DNA profiling of small cell lung cancer
No full textSmall cell lung cancer (SCLC) is highly aggressive with poor prognosis. Despite a relative prevalence of circulating tumour DNA (ctDNA) in SCLC, liquid biopsies are not currently implemented, unlike non-SCLC where cell-free DNA (cfDNA) mutation profiling in the blood has utility for guiding targeted therapies and assessing minimal residual disease. cfDNA methylation profiling is highly sensitive for SCLC detection and holds promise for disease monitoring and molecular subtyping; cfDNA fragmentation profiling has also demonstrated clinical potential. Extrachromosomal DNA (ecDNA), that is often observed in SCLC, promotes tumour heterogeneity and chemotherapy resistance and can be detected in blood. We discuss how these cfDNA profiling modalities can be harnessed to expand the clinical applications of liquid biopsy in SCLC