Now showing items 1-20 of 11955

    • Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial

      Powles, T.; Plimack, E. R.; Soulieres, D.; Waddell, Thomas K; Stus, V.; Gafanov, R.; Nosov, D.; Pouliot, F.; Melichar, B.; Vynnychenko, I.; et al. (2020)
      Background: The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. Methods: In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with, NCT02853331. Findings: Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. Interpretation: With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma.
    • Renal myopericytoma: A case report and literature review

      Riley, T.; Shenjere, Patrick; Jain, A.; Sunder, S.; North Manchester General Hospital, Pennine Acute NHS Hospitals Trust, Delaunay's Road, Manchester, M8 5RB (2021)
      Renal myopericytoma is an extremely rare entity with just 11 cases reported in the literature. We report the case of a 57 year old Caucasian man who was found to have a renal myopericytoma following nephrectomy for suspected renal cell carcinoma. Renal myopericytoma has a distinct morphological overlap with other pericytic tumours and significant histological variation has been noted between cases reported to date. Further characterising this novel tumour is vital to identify subtypes within this spectrum, understand its behaviour and to identify imaging trends which may lead to pre-operative diagnosis in order to potentially avoid radical treatment.
    • Correction to: the impact of COVID-19 on interventional radiology services in the UK

      Zhong, J.; Datta, Anubhav; Gordon, T.; Adams, S.; Guo, T.; Abdelaziz, M.; Barbour, F.; Palkhi, E.; Adusumilli, P.; Oomerjee, M.; et al. (2021)
    • Practical recommendations for the management of patients with gastroenteropancreatic and thoracic (carcinoid) neuroendocrine neoplasms in the COVID-19 era

      Rodriguez-Freixinos, V.; Capdevila, J.; Pavel, M.; Thawer, A.; Baudin, E.; O'Toole, D.; Herrmann, K.; Welin, S.; Grozinsky-Glasberg, S.; de Herder, W. W.; et al. (2020)
      Neuroendocrine neoplasms (NENs) are a heterogeneous family of uncommon tumours with challenging diagnosis, clinical management and unique needs that almost always requires a multidisciplinary approach. In the absence of guidance from the scientific literature, along with the rapidly changing data available on the effect of COVID-19, we report how 12 high-volume NEN centres of expertise in 10 countries at different stages of the evolving COVID-19 global pandemic along with members of international neuroendocrine cancer patient societies have suggested to preserve high standards of care for patients with NENs. We review the multidisciplinary management of neuroendocrine neoplasms during the COVID-19 pandemic, and we suggest potential strategies to reduce risk and aid multidisciplinary treatment decision-making. By sharing our joint experiences, we aim to generate recommendations for proceeding to other institutions facing the same challenges.
    • Tribute to David Thwaites

      Georg, D.; van der Heide, U. A.; Aznar, Marianne Camille; Baumann, M.; Division Medical Radiation Physics, Department of Radiation Oncology, Medical University of Vienna/AKH Wien, Austria. (2020)
    • Radiation oncology in the new virtual and digital era

      Aznar, Marianne Camille; Bacchus, C.; Coppes, R. P.; Deutsch, E.; Georg, D.; Haustermans, K.; Hoskin, P.; Krause, M.; Lartigau, E. F.; Löck, S.; et al. (2020)
    • Education to improve cancer care for LGBTQ+ patients in the UK

      Berner, A. M.; Webster, R.; Hughes, D. J.; Tharmalingam, H.; Saunders, Daniel; Barts Cancer Institute, Queen Mary University of London, London, UK; Gender Identity Clinic, The Tavistock and Portman NHS Foundation Trust, London, UK. (2020)
    • Correction to: Infantile fibrosarcoma with TPN3-NTRK3 fusion in a boy with Bloom Syndrome

      Huson, S. M.; Staab, T.; Pereira, M.; Ward, H.; Paredes, R.; Evans, D. G.; Baumhoer, D.; O'Sullivan, J.; Cheesman, E.; Schindler, D.; et al. (2021)
    • A practical guide to cancer subclonal reconstruction from DNA sequencing

      Tarabichi, M.; Salcedo, A.; Deshwar, A. G.; Ni Leathlobhair, M.; Wintersinger, J.; Wedge, David C; Van Loo, P.; Morris, Q. D.; Boutros, P. C.; The Francis Crick Institute, London, UK. (2021)
      Subclonal reconstruction from bulk tumor DNA sequencing has become a pillar of cancer evolution studies, providing insight into the clonality and relative ordering of mutations and mutational processes. We provide an outline of the complex computational approaches used for subclonal reconstruction from single and multiple tumor samples. We identify the underlying assumptions and uncertainties in each step and suggest best practices for analysis and quality assessment. This guide provides a pragmatic resource for the growing user community of subclonal reconstruction methods.
    • Circulating tumour DNA as a biomarker in resectable and irresectable stage IV colorectal cancer; a systematic review and meta-analysis

      Jones, R. P.; Pugh, S. A.; Graham, J.; Primrose, J. N.; Barriuso, Jorge; School of Cancer Studies, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Department of Hepatobiliary Surgery, Liverpool University Teaching Hospitals NHS Foundation Trust, Liverpool, UK. (2021)
      Background: For patients with metastatic colorectal cancer, stratification for treatment (surgery or chemotherapy) is often based on crude clinicopathological characteristics like tumour size and number of lesions. Circulating tumour DNA (ctDNA) acts as a potential biomarker of disease trajectory and biology, allowing better stratification. This study aims to systematically review ctDNA in stage IV colorectal cancer to assess its potential role as a prospective biomarker to guide management decisions. Methods: A literature search was performed to identify studies where the measurement of ctDNA in stage IV colorectal cancer was correlated with a clinical outcome (radiological response, secondary resection rate, PFS, DFS or OS). Results: Twenty-eight studies were included, reporting on 2823 patients. Circulating tumour DNA was detectable in between 80% and 90% of patients prior to treatment. Meta-analysis identified a strong correlation between detectable ctDNA after treatment (surgery or chemotherapy) and overall survival (HR 2.2, 95% CI 1.79-2.69, p < 0.00001), as well as progression-free survival (HR 3.15, 95% CI 2.10-4.73, p < 0.00001). ctDNA consistently offered an early marker of long-term prognosis in irresectable disease, with changes after one cycle of systemic therapy demonstrating prognostic value. In resectable disease treated with curative intent, detection of ctDNA offered a lead time over radiological recurrence of 10 months. Conclusion: Circulating tumour DNA is detectable in the majority of resectable and irresectable patients. The presence of ctDNA is clearly associated with shorter overall survival, with changes in ctDNA an early biomarker of adverse disease behaviour. Prospective trials are essential to test its clinical efficacy.
    • Nanomedicine: photo-activated nanostructured titanium dioxide, as a promising anticancer agent

      Lagopati, N.; Evangelou, K.; Falaras, P.; Tsilibary, E. C.; Vasileiou, P. V. S.; Havaki, S.; Angelopoulou, A.; Pavlatou, E. A.; Gorgoulis, Vassilis G; Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Faculty of Medicine, School of Health Science, National and Kapodistrian University of Athens, 75, Mikras Asias Str., Goudi, GR 11527 Athens, Greece; (2020)
      The multivariate condition of cancer disease has been approached in various ways, by the scientific community. Recent studies focus on individualized treatments, minimizing the undesirable consequences of the conventional methods, but the development of an alternative effective therapeutic scheme remains to be held. Nanomedicine could provide a solution, filling this gap, exploiting the unique properties of innovative nanostructured materials. Nanostructured titanium dioxide (TiO2) has a variety of applications of daily routine and of advanced technology. Due to its biocompatibility, it has also a great number of biomedical applications. It is now clear that photo-excited TiO2 nanoparticles, induce generation of pairs of electrons and holes which react with water and oxygen to yield reactive oxygen species (ROS) that have been proven to damage cancer cells, triggering controlled cellular processes. The aim of this review is to provide insights into the field of nanomedicine and particularly into the wide context of TiO2-NP-mediated anticancer effect, shedding light on the achievements of nanotechnology and proposing this nanostructured material as a promising anticancer photosensitizer.
    • Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

      Conti, D. V.; Darst, B. F.; Moss, L. C.; Saunders, E. J.; Sheng, X.; Chou, A.; Schumacher, F. R.; Olama, A. A. A.; Benlloch, S.; Dadaev, T.; et al. (2021)
      Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
    • Cellular senescence and failure of myelin repair in multiple sclerosis

      Koutsoudaki, P. N.; Papadopoulos, D.; Passias, P. G.; Koutsoudaki, P.; Gorgoulis, Vassilis G; Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens (2020)
      Remyelination is a physiological response to demyelinating events aiming to restore saltatory conduction and preserve axonal integrity. Resident oligodendrocyte precursor cells (OPC) of the CNS tissue under appropriate conditions are mobilized to proliferate, migrate, and differentiate, in order to produce new myelin sheaths in the demyelinated lesion. In multiple sclerosis (MS), the most common immune-mediated demyelinating disease, remyelination efficiency declines with increasing age and disease duration. As myelin regeneration attempts in clinical trials so far are scarce, and have been met with limited success, the need to explore new remyelinating strategies is more compelling. Recently, ageing and cellular senescence have been implicated in the pathophysiology of a number of neurodegenerative diseases, including multiple sclerosis. Evidence on OPC senescence brings forward the possibility of exploiting cellular senescence as a possible target for promoting the endogenous remyelinating capacity of the CNS. Here we discuss the data indicating how cellular senescence affects remyelination, and the putative benefits to be drawn through the use of senolytic or senomorphic therapies targeting senescent cell populations in MS.
    • CRISPR-Cas9-mediated gene silencing in cultured human epithelia

      Gago, S.; Overton, Nicola L D; Bowyer, P.; Manchester Fungal Infection Group, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Core Technology Facility, The University of Manchester, Manchester, UK. (2021)
      CRISPR/Cas9 technology enables rapid and efficient genome editing in a variety of experimental systems. Genome editing using CRISPR/Cas9 has become an increasingly popular genetic engineering tool due to (1) an extensive array of commercial ready-to-use CRIPSR/Cas9 systems, (2) improved efficiency of cell delivery, and (3) the possibility to do multigene editing. Here, we describe a method to introduce single gene disruption in lung bronchial epithelial cells. This approach can be used to study host factors important for pathogen interaction or to identify and study genetic markers determining susceptibility to fungal disease.
    • Reference bias in the Illumina Isaac aligner

      Cornish, A. J.; Chubb, D.; Frangou, A.; Hoang, P. H.; Kaiser, M.; Wedge, David C; Houlston, R. S.; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG (2020)
    • Early detection of melanoma in specialised primary care practice in Australia

      Green, Adèle C; Pandeya, N.; Morton, S.; Simonidis, J.; Whiteman, D. C.; Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, 4006, Australia; CRUK Manchester and Faculty of Biology, Medicine and Health, University of Manchester, Manchester, (2020)
      Background: Primary care skin cancer clinics facilitate early treatment of melanoma in Australia. We investigated the clinical and histopathological features of melanomas diagnosed and treated in an established clinic in Brisbane. Methods: Retrospective audit of medical records of patients diagnosed with in situ or invasive primary cutaneous melanoma in a primary care clinic specializing in skin cancer, 2000-2017. Demographic and clinical data were standardly extracted by a medically-trained investigator. We used descriptive analyses to assess characteristics of patients and melanomas, and examine surgical management according to tumour thickness. Results: Of 380 patients (median age 57 years; 57 % male) newly diagnosed with 497 histologically-confirmed primary cutaneous melanomas, 369 were in situ and 128 invasive. Of the 369 in situ melanomas, 143 (39 %) were on the trunk and 87 (24 %) on the head and neck; 247 (67 %) were diagnosed by shave biopsy; and 141 (38 %) referred for wide local excision (WLE). Of the 128 invasive melanomas, only 21 (16 %) had thickness ≥ 0.8 mm and these occurred more often on head and neck than thin invasive melanomas (p = 0.02). The majority of invasive melanomas were diagnosed by excision biopsy, and WLE was carried out in a median of 3 days (melanomas ≥ 0.8 mm) and 2 days (<0.8 mm). The doctor detected the majority of in situ (83 %) and thin invasive (73 %) melanomas during surveillance, compared with 48 % of thicker invasive melanomas ≥ 0.8 mm (p < 0.001). Conclusion: In Australia, specialised primary care practice plays a major role in detection and treatment of early primary melanoma.
    • A RAC-GEF network critical for early intestinal tumourigenesis

      Pickering, K. A.; Gilroy, K.; Cassidy, J. W.; Fey, S. K.; Najumudeen, A. K.; Zeiger, L. B.; Vincent, D. F.; Gay, D. M.; Johansson, J.; Fordham, R. P.; et al. (2021)
      RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2-/- Vav3-/- Tiam1-/-), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.
    • Surrogate-free machine learning-based organ dose reconstruction for pediatric abdominal radiotherapy

      Virgolin, M.; Wang, Z.; Balgobind, B. V.; van Dijk, I.; Wiersma, J.; Kroon, P. S.; Janssens, G. O.; van Herk, Marcel; Hodgson, D. C.; Zaletel, L. Z.; et al. (2020)
      To study radiotherapy-related adverse effects, detailed dose information (3D distribution) is needed for accurate dose-effect modeling. For childhood cancer survivors who underwent radiotherapy in the pre-CT era, only 2D radiographs were acquired, thus 3D dose distributions must be reconstructed from limited information. State-of-the-art methods achieve this by using 3D surrogate anatomies. These can however lack personalization and lead to coarse reconstructions. We present and validate a surrogate-free dose reconstruction method based on Machine Learning (ML). Abdominal planning CTs (n=142) of recently-treated childhood cancer patients were gathered, their organs at risk were segmented, and 300 artificial Wilms' tumor plans were sampled automatically. Each artificial plan was automatically emulated on the 142 CTs, resulting in 42,600 3D dose distributions from which dose-volume metrics were derived. Anatomical features were extracted from digitally reconstructed radiographs simulated from the CTs to resemble historical radiographs. Further, patient and radiotherapy plan features typically available from historical treatment records were collected. An evolutionary ML algorithm was then used to link features to dose-volume metrics. Besides 5-fold cross validation, a further evaluation was done on an independent dataset of five CTs each associated with two clinical plans. Cross-validation resulted in mean absolute errors ≤0.6 Gy for organs completely inside or outside the field. For organs positioned at the edge of the field, mean absolute errors ≤1.7 Gy for Dmean, ≤2.9 Gy for D2cc, and ≤13% for V5Gyand V10Gy, were obtained, without systematic bias. Similar results were found for the independent dataset. To conclude, we proposed a novel organ dose reconstruction method that uses ML models to predict dose-volume metric values given patient and plan features. Our approach is not only accurate, but also efficient, as the setup of a surrogate is no longer needed.
    • A soft silicone foam dressing that aids healing and comfort in oncology care

      Pramod, Susy; Tissue Viability Nurse, The Christie NHS Foundation Trust, Manchester. (2021)
      Maintaining skin integrity plays a key role in the ongoing care and comfort of patients at the end of life. Unfortunately, patients receiving cancer treatments are at higher risk of altered skin integrity. Cancer treatments involve multiple modalities, all of which impair wound healing. Excess exudate can be distressing to patients, resulting in catastrophic damage to the wound bed and surrounding skin, reducing quality of life and increasing the need for specialist services. This article describes the use of the Kliniderm foam silicone range of dressings, in combination with best practice, in the treatment of wounds in the oncology setting. The case study evidence presented indicates that this range of dressings is useful in the management of radiotherapy and oncology wounds. It had a positive effect on the exudate level, wound-association pain and the peri-wound skin in these patients, aiding the management of the wound bed.
    • Preventing and managing device-related pressure ulcers in oncology

      Pramod, Susy; Tissue Viability Nurse, The Christie NHS Foundation Trust, Manchester, UK. (2021)
      There is growing evidence that medical device-related pressure ulcers (MDRPUs) are an increasing healthcare concern in all aspects of care. It is especially important to develop an individualised care plan for people at the end of life to prevent pressure ulceration and to treat this if it occurs. Tissue viability nurses have a responsibility to review and assess new prophylactic devices and dressings, to ensure a high standard of care is provided. This article describes the use of a soft silicone dressing, Kliniderm foam silicone lite, in combination with best practice, to prevent MDRPUs in the oncology setting. Three case studies show that the dressing helped avoid the occurrence of ulceration on the ears and nose in patients receiving oxygen through a nasal cannula.