The Christie School of Oncology: Christie Research Publications Repository
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Patterns of systemic treatment for melanoma: an insight on trends and costs between 2019-2023 from the English systemic anti-cancer therapy national database
No full textINTRODUCTION: Checkpoint inhibitors (CPI) and targeted therapy (TT) have revolutionised the outcomes for melanoma. Other than the approval of pembrolizumab for resected stage IIB/IIC in February 2023, there were no changes in the Systemic Anti-Cancer Therapy (SACT) treatments available for melanoma in England between 2019 and 2023. The national SACT dataset provides an insight on systemic treatment use during this timeframe. The purpose of this study was to evaluate the patterns of use and costs of SACT for melanoma between 2019 and 2023. MATERIALS AND METHODS: Data on prescriptions of SACT for adjuvant and metastatic disease between April 2019 to March 2023 were obtained from the SACT dataset and joinpoint regression analyses were used to look for any trends and change in trends. The list prices reported on the British National Formulary (BNF) were used to model drug acquisition costs. RESULTS: Data were available from a total of 71 Hospital Trusts. There was a non significant increasing trend in the adjuvant prescriptions (semestral percentage change = 3.25, 95% confidence interval [CI] -2.15-8.96, p = 0.22) and a non significant negative trend in the metastatic prescriptions (semestral percentage change = -0.59, 95% CI -3.02-1.92, p = 0.64) from April 2019 to March 2023. The estimated costs for SACT in the same timeframe were approximately £ 1.2 billion. Despite an increase in the spending on adjuvant therapy, the total costs in the financial year 2022-2023 decreased compared to 2019-2020 due to a slight reduction in the spending on metastatic treatment. CONCLUSIONS: The opposite trends seen for adjuvant and metastatic prescriptions are a potential indicator of the impact of adjuvant treatment on development of distant metastases
Efficacy and safety of low-dose tolvaptan (7.5 mg) in the treatment of inpatient hyponatremia: a retrospective study
No full textOBJECTIVES: The recommended dose of tolvaptan for hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone is 15 mg. We evaluated the efficacy of an initial 7.5 mg dose and determined the frequency where sodium (Na+) correction exceeded safe limits, defined as an increment of ≥10 mmol/L, within the initial 8 or 24 hours of administration. METHODS: A retrospective review of patients with syndrome of inappropriate antidiuretic hormone treated in a single academic hospital in London. The initial dose was 7.5 mg and the second dose was 7.5 or 15 mg. RESULTS: One hundred eighty-one patients were included. With the initial dose, the mean Na + increase was 4.54 ± 3.70 mmol/L (P < .0001) after 4-12 hours, with 8.7% demonstrating an increase exceeding 10 mmol/L. Between 18-30 hours, the mean Na + increase was 6.15 ± 3.51 mmol/L (P < .0001), with 19.4% over-correcting. Over-correction was more likely in patients with a pre-dose Na + concentration of ≤127 mmol/L (OR 13.64, 95% CI 1.80-102.95). No cases of osmotic demyelination syndrome were observed. For patients needing a second dose, the increment in Na + concentration showed no significant difference between 7.5 and 15 mg (P = .532). CONCLUSION: In our view, tolvaptan can be initiated with a 7.5 mg dose, accompanied by Na + monitoring at 12 and 24 hours. If a second dose is necessary, 7.5 mg is comparably effective to a 15 mg dose, depending on the initial response. Further monitoring should include Na + concentration at around 24 hours after the second dose
New rectum dose surface mapping methodology to identify rectal subregions associated with toxicities following prostate cancer radiotherapy
No full textBACKGROUND AND PURPOSE: Growing evidence suggests that spatial dose variations across the rectal surface influence toxicity risk after radiotherapy. Existing methodologies employ a fixed, arbitrary physical extent for rectal dose mapping, limiting their analysis. We developed a method to standardise rectum contours, unfold them into 2D cylindrical surface maps, and identify subregions where higher doses increase rectal toxicities. MATERIALS AND METHODS: Data of 1,048 patients with prostate cancer from the REQUITE study were used. Deep learning based automatic segmentations were generated to ensure consistency. Rectum length was standardised using linear transformations superior and inferior to the prostate. The automatic contours were validated against the manual contours through contour variation assessment with cylindrical mapping. Voxel-based analysis of the dose surface maps for the manual and automatic contours against individual rectal toxicities was performed using Student's t permutation test and Cox Proportional Hazards Model (CPHM). Significance was defined by permutation testing. RESULTS: Our method enabled the analysis of 1,048 patients using automatic segmentation. Student's t-test showed significance (p < 0.05) in the lower posterior for clinical-reported proctitis and patient-reported bowel urgency. Univariable CPHM identified a 3 % increased risk per Gy for clinician-reported proctitis and a 2 % increased risk per Gy for patient-reported bowel urgency in the lower posterior. No other endpoints were significant. CONCLUSION: We developed a methodology that unfolds the rectum to a 2D surface map. The lower posterior was significant for clinician-reported proctitis and patient-reported bowel urgency, suggesting that reducing the dose in the region could decrease toxicity risk
Immune cell senescence drives responsiveness to immunotherapy in melanoma
No full textBackgroundImmunotherapy has significantly improved cancer treatment. However, it is not effective in all cancer patients, rendering the need to further delineate the differences among responders and non-responders at the molecular and cellular level. Unresponsiveness to immunotherapy has been attributed to dysfunctional immune cell states such as T-cell exhaustion and anergy, whereas the contribution of cellular senescence remains elusive. Herein, we have investigated the role of immune cell senescence in the response to checkpoint inhibitors in melanomas where these immunotherapies are applied as a first line treatment.MethodsTwo senescence detecting complementary approaches were utilized in a case control study we conducted. First, we implemented a senescence molecular signature we developed, termed"SeneVick", retrospectively in a single cell RNA-seq dataset from melanoma patients who received immunotherapy. Prior to this analysis, the signature was extensively validated in a variety of cell/tissue contexts, senescence types and species. Second, cellular senescence was assessed via an established experimental algorithmic approach in circulating immune cells of an analogous melanoma clinical cohort.ResultsMelanoma patients who did not respond to immunotherapy exhibited increased cellular senescence in the CD8 + T-cell, CD4 + T-cell, B-cell (CD19 + /CD20 +) and NK cell compartments compared to responders. This phenomenon was independent of patients' clinical features (age, sex, melanoma type, stage) and not an outcome of immunotherapy, in contrast to conventional anti-cancer treatments. Interestingly, alterations of cell-to-cell interactions among the immune sub-populations in non-responders compared to responders were identified, supporting, along with cytotoxicity assays, that senescent immune cells display immunosuppressive properties driving defective immune responses and treatment failure.ConclusionOverall, our findings provide evidence that cellular senescence within the immune cell compartment of the tumor micro-environment is a potent determinant of the response to immunotherapy and pave the way for strategies targeting it as promising approaches to improve the outcome of such interventions
Bleeding Complications in JAK2-Variant Essential Thrombocythemia: A Revisit in 2025
No full textEssential thrombocythemia (ET) is a myeloproliferative neoplasm characterised by sustained thrombocytosis. Paradoxically, bleeding complications remain an under-recognised clinical challenge. Compared with CALR-mutated patients, those harbouring the JAK2-V617F variant appear more prone to haemorrhage. This may be secondary to acquired von Willebrand syndrome (AvWS) and intrinsic platelet dysfunction. AvWS in ET arises from extreme platelet counts driving the adsorption and proteolysis of high-molecular-weight von Willebrand factor (VWF) multimers, producing a qualitative VWF defect akin to type 2A von Willebrand disease. However, the platelet count threshold for AvWS is variable, and patients with platelet counts below 1000 × 10(9)/L may still exhibit clinically significant VWF anomalies. Diagnosis relies on tests such as VWF activity and antigen levels. Perioperative management of patients with AvWS focuses on correcting the VWF defect and/or lowering platelet counts. Ultimately, clinicians must balance between preventing thrombosis and bleeding by tailoring management to each patient. Clinical Trail RegistrationThe authors have confirmed clinical trial registration is not needed for this submission
A Guide to Breast Cancer Research: An Introduction
No full text'A Guide to Breast Cancer Research: From Cells and Molecular Mechanisms to Therapy' is designed as a comprehensive reference for early career investigators and postgraduate students. This book aims to provide a broad overview of contemporary breast cancer research. It covers key areas including development and cancer, metastasis and immunology, subtypes, signalling, therapy, and resistance. This book is organised into seven sections addressing mammary gland development, model systems, cellular origins and heterogeneity, cellular and molecular bases, signalling pathways, metastasis and immunity, and treatment and resistance mechanisms. A few topics such as specific signalling pathways, some emerging therapies, imaging technologies, and AI applications are only briefly mentioned or omitted, reflecting the ever-evolving nature of breast cancer research. This book emphasises the importance of collaboration in advancing cancer research. Initiatives like the Cancer Moonshot and Cancer Grand Challenges advocate for 'radical collaboration' of researchers with shared visions and resources. We also note the significance of global efforts in breast cancer research, the need for addressing disparities in care across different regions and for equity in healthcare. Overall, this book showcases milestones and advances in breast cancer research over the past three decades, reflecting significant progress in understanding and treating the disease, which has led to improved patient outcomes
Conservatively managed non-functioning pituitary macroadenomas-cohort study from the UK Non-functioning Pituitary Adenoma Consortium
No full textOBJECTIVE: Surveillance is often adopted for asymptomatic non-functioning pituitary macroadenomas (macroNFPAs). Due to low-quality evidence, uncertainty remains on optimal frequency of imaging/biochemical monitoring and indications for surgery. We assessed the natural history and outcomes of patients with macroNFPA who had monitoring as initial management choice from the UK NFPA Consortium. DESIGN: This was a multicentre, retrospective, cohort study involving 21 UK endocrine departments. METHODS: Clinical, imaging, and hormonal data of 949 patients followed up between January, 1, 2005 and March, 1, 2022 were analysed. RESULTS: Incidence rate for tumour enlargement was 9.8 per 100 patient-years (95% CI, 8.8-10.8), with cumulative probabilities 1.6%, 8.1%, 18.4%, 29.2%, and 43.6% at 6-month, 1-year, 2-year, 3-year, and 5-year follow-up, respectively; rates were higher in tumours abutting/displacing optic chiasm than those not in contact with it. Amongst macroNFPAs not in contact with optic chiasm showing enlargement within 6 months, none impacted visual fields. In tumours with enlargement and continued monitoring (median 2.6 years), further growth occurred in 60.5% (33.8% probability at 2 years), stability in 35.5%, and shrinkage in 4.0%. Rates of new pituitary hormone deficits were 4.0%-4.9%, mainly driven by tumour enlargement. After transsphenoidal surgery, rates of hypopituitarism reversal were 12%-17% and those of additional anterior pituitary hormone deficits were 12%-15% (permanent vasopressin deficiency 3.5%). CONCLUSIONS: Our data provide evidence for monitoring protocols. MacroNFPAs not in contact with optic chiasm require less frequent imaging, and first follow-up scan can be delayed to 1 year. After first enlargement, variable tumour behaviour can occur. New hypopituitarism in stable tumours is rare, challenging necessity of regular pituitary function assessment
The utilisation of sentimag magtrace for dynamic sentinel node biopsy in cN0 penile cancer
No full textTranslation of dynamic contrast-enhanced imaging onto a magnetic resonance-guided linear accelerator in patients with head and neck cancer
No full textBACKGROUND AND PURPOSE: Magnetic resonance imaging - linear accelerator (MRI-linac) systems permit imaging of tumours to guide treatment. Dynamic contrast enhanced (DCE)-MRI allows investigation of tumour perfusion. We assessed the feasibility of performing DCE-MRI on a 1.5 T MRI-linac in patients with head and neck cancer (HNC) and measured biomarker repeatability and sensitivity to radiotherapy effects. MATERIALS AND METHODS: Patients were imaged on a 1.5 T MRI-linac or a 1.5 T diagnostic MR system twice before treatment. DCE-MRI parameters including K(trans) were calculated, with the optimum pharmacokinetic model identified using corrected Akaike information criterion. Repeatability was assessed by within-subject coefficient of variation (wCV). Treatment effects were assessed as change measured at week 2 of radiotherapy. RESULTS: 14 patients were recruited (6 scanned on diagnostic MR and 8 on MRI-linac), with a total of 24 lesions. Baseline K(trans) estimates were comparable on both MR systems; 0.13 [95 %CI: 0.10 to 0.16] min(-1) (diagnostic MR) and 0.15 [0.12 to 0.18] min(-1) (MRI-linac). wCV values were 22.6 % [95 % CI: 16.2 to 37.3 %] (diagnostic MR) and 11.7 % [8.4 to 19.3 %] (MRI-linac). Combined cohort increase in K(trans) was significant (p < 0.01). Similar results were seen for other DCE-MRI parameters. CONCLUSIONS: DCE-MRI is feasible on a 1.5 T MRI-linac system in patients with HNC. Parameter estimates, repeatability, and sensitivity to treatment were similar to those measured on a conventional diagnostic MR system. These data support performing DCE-MRI in studies on the MRI-linac to assess treatment response and adaptive guidance based on tumour perfusion