• Automated breast tissue measurement of women at increased risk of breast cancer

      Patel, H G; Astley, Susan; Hufton, Alan P; Harvie, Michelle N; Hagan, K; Marchant, Thomas E; Hillier, Valerie F; Howell, Anthony; Warren, R; Boggis, C; et al. (2006)
    • Automated delineation of radiotherapy volumes: are we going in the right direction?

      Whitfield, Gillian A; Price, P; Price, Gareth J; Moore, Christopher J; The Christie Hospital NHS Foundation Trust, Manchester (2013-01)
      Rapid and accurate delineation of target volumes and multiple organs at risk, within the enduring International Commission on Radiation Units and Measurement framework, is now hugely important in radiotherapy, owing to the rapid proliferation of intensity-modulated radiotherapy and the advent of four-dimensional image-guided adaption. Nevertheless, delineation is still generally clinically performed with little if any machine assistance, even though it is both time-consuming and prone to interobserver variation. Currently available segmentation tools include those based on image greyscale interrogation, statistical shape modelling and body atlas-based methods. However, all too often these are not able to match the accuracy of the expert clinician, which remains the universally acknowledged gold standard. In this article we suggest that current methods are fundamentally limited by their lack of ability to incorporate essential human clinical decision-making into the underlying models. Hybrid techniques that utilise prior knowledge, make sophisticated use of greyscale information and allow clinical expertise to be integrated are needed. This may require a change in focus from automated segmentation to machine-assisted delineation. Similarly, new metrics of image quality reflecting fitness for purpose would be extremely valuable. We conclude that methods need to be developed to take account of the clinician's expertise and honed visual processing capabilities as much as the underlying, clinically meaningful information content of the image data being interrogated. We illustrate our observations and suggestions through our own experiences with two software tools developed as part of research council-funded projects.
    • Automated gross tumour volume contour generation for large-scale analysis of early stage lung cancer patients planned with 4D-CT

      Davey, Angela; van Herk, Marcel; Faivre-Finn, Corinne; Brown, Sean; McWilliam, Alan; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom. (2020)
      Purpose: Early stage lung cancer patients undergoing stereotactic ablative radiotherapy receive four-dimensional computed tomography (4D-CT) for treatment planning. Often, an internal gross target volume (iGTV), which approximates the motion envelope of a tumour over the breathing cycle, is delineated without defining a gross tumour volume (GTV). However, the GTV volume and shape are important parameters for prognostic and dose modelling, and there is interest in radiomic features extracted from the GTV and surrounding tissue. We demonstrate and validate a method to generate the GTV from an iGTV contour to aid retrospective analysis on routine data. Method: It is possible to reconstruct the geometry of a tumour with knowledge of tumour motion and the motion envelope formed during respiration. To demonstrate this, tumour motion path was estimated with local rigid registration, and the iGTV positioned incrementally at stations along the reverse path. It is shown that tumour volume is the largest set common to the intersection of the iGTV at the different positions, so hence can be derived. This was implemented for 521 lung lesions on 4D-CT. Eleven patients with a GTV delineation performed by a radiation oncologist on a reference phase (50%) were used for validation. The generated GTV was compared to that delineated by expert using distance-to-agreement, volume, and distance between centres of mass. An overall success rate was determined by detecting registration inaccuracy and performing a quality check on the routine iGTV. For successfully generated contours, GTV volume was compared to iGTV volume in a prognostic model for overall survival. Results: For the validation dataset, distance-to-agreement mean (0.79-1.55mm) and standard deviation (0.68-1.51mm) was comparable to expected observer variation. Difference in volume was less than 5cm3 , and average difference in position was 1.21mm. Deviations in shape and position were mainly caused by delineation interpretation differences between iGTV and GTV as opposed to algorithm performance. For the complete dataset, an acceptable contour was generated for 94% of patients using statistical and visual assessment to detect failures. Generated GTV volumes improved prognostic model performance over iGTV volumes. Conclusion: A method to generate a GTV from an iGTV and 4D-CT dataset was developed. This method facilitates data analysis of early stage lung cancer patients treated in the routine setting i.e. data mining, prognostic modelling, and radiomics. Generation failure detection removes the need for visual assessment of all contours, reducing a time-consuming aspect of big-data analysis. Favourable prognostic performance of generated GTV volumes over iGTV ones demonstrates opportunities to use this methodology for future study.
    • An automated knowledge based treatment planning solution for prostate VMAT

      Wood, Joe; Aznar, Marianne Camille; Whitehurst, Philip; The Christie NHS Foundation Trust, Christie Medical Physics & Engineering, Manchester, (2020)
      Purpose or Objective This work aimed to develop a novel approach to knowledge based (KB) prostate VMAT treatment planning. Material and Methods Converting well defined PTV dose criteria into optimisation objectives is relatively straightforward. OARs, however, present a greater challenge because they sit in steep dose gradients and their size, shape and position relative to PTVs vary between patients. Precisely predicting optimal OAR DVH parameters is therefore difficult and uncertainties in the predictions ultimately become manifest in the degree to which treatment plans are dosimetrically optimal. The optimal PTV-OAR dose gradient (i.e. dose fall-off per unit distance) is characterised primarily by delivery machine parameters and not patient anatomy. On this basis, a model of the ideal prostate treatment plan was developed – see Figure 1, where the colour gradients represent achievable PTV-OAR dose gradients. Results For 114 of the 142 test cases, at least one of the new plans (average or 25th percentile) met all of the dose criteria for prostate radiotherapy at The Christie. Furthermore, for 105 of the test cases, at least one of the new plans was superior to the original clinical plan. In Figure 2, PTVRectum dose gradient is plotted against PTV-Bladder dose gradient for the KB training data (transparent red), clinical test data (solid red), average new treatment plans (yellow) and 25th percentile new treatment plans (blue). Figure 2: Treatment plans generated using KB dose gradient optimisation (blue and yellow) show more consistent and steeper PTV-OAR dose gradients than corresponding clinical treatment plans (red). Visual review of the new treatment plans for 10 patients from the test cohort showed that all were considered clinically acceptable. Conclusion A novel approach to KB treatment planning for prostate VMAT has been proposed, trained and tested. Initial results show that treatment plans generated automatically from the predictions of the model are clinically acceptable in more than 80 % of cases and show superior and more consistent OAR sparing than their corresponding clinical treatment plans. Although there is scope for refinement of the predictions, this method shows promise for realising significant efficiencies within treatment planning departments and with the transfer of knowledge between centres.
    • Automated microbeam observation environment for biological analysis—Custom portable environmental control applied to a vertical microbeam system

      England, M; Bigelow, A; Merchant, Michael J; Velliou, E; Welch, D; Brenner, D; Kirkby, Karen J; Ion Beam Centre, University of Surrey, Guildford, Surrey GU2 7XH (2017-02)
    • Automated Monte-Carlo re-calculation of proton therapy plans using Geant4/Gate: implementation and comparison to plan-specific quality assurance measurements

      Aitkenhead, Adam H; Sitch, Peter; Richardson, Jenny C; Winterhalter, Carla; Patel, Imran; Mackay, Ranald I; Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Manchester, UK. (2020)
      Objectives: Software re-calculation of proton pencil beam scanning plans provides a method of verifying treatment planning system (TPS) dose calculations prior to patient treatment. This study describes the implementation of AutoMC, a Geant4 v10.3.3/Gate v8.1 (Gate-RTion v1.0)-based Monte-Carlo (MC) system for automated plan re-calculation, and presents verification results for 153 patients (730 fields) planned within year one of the proton service at The Christie NHS Foundation Trust. Methods: A MC beam model for a Varian ProBeam delivery system with four range-shifter options (none, 2 cm, 3 cm, 5 cm) was derived from beam commissioning data and implemented in AutoMC. MC and TPS (Varian Eclipse v13.7) calculations of 730 fields in solid-water were compared to physical plan-specific quality assurance (PSQA) measurements acquired using a PTW Octavius 1500XDR array and PTW 31021 Semiflex 3D ion chamber. Results: TPS and MC showed good agreement with array measurements, evaluated using ? analyses at 3%, 3 mm with a 10% lower dose threshold:>94% of fields calculated by the TPS and >99% of fields calculated by MC had ? ? 1 for>95% of measurement points within the plane. TPS and MC also showed good agreement with chamber measurements of absolute dose, with systematic differences of <1.5% for all range-shifter options. Conclusions: Reliable independent verification of the TPS dose calculation is a valuable complement to physical PSQA and may facilitate reduction of the physical PSQA workload alongside a thorough delivery system quality assurance programme. Advances in knowledge: A Gate/Geant4-based MC system is thoroughly validated against an extensive physical PSQA dataset for 730 clinical fields, showing that clinical implementation of MC for PSQA is feasible.
    • Automated prognostic pattern detection shows favourable diffuse pattern of FOXP3(+) Tregs in follicular lymphoma.

      Nelson, L; Mansfield, J; Lloyd, R; Oguejiofor, K; Salih, Zena; Menasce, Lia P; Linton, Kim M; Rose, C; Byers, R; Medical School, The University of Manchester, Oxford Road, Manchester M13 9PT (2015-10-20)
      Histopathological prognostication relies on morphological pattern recognition, but as numbers of biomarkers increase, human prognostic pattern-recognition ability decreases. Follicular lymphoma (FL) has a variable outcome, partly determined by FOXP3 Tregs. We have developed an automated method, hypothesised interaction distribution (HID) analysis, to analyse spatial patterns of multiple biomarkers which we have applied to tumour-infiltrating lymphocytes in FL.
    • Automated sarcopenia assessment and its predictive power in lung cancer radiotherapy patients

      Green, A; Cipriano, Claudia; Vasquez Osorio, Eliana; Weaver, Jamie M; van Herk, Marcel; McWilliam, Alan; The University of Manchester Department 58-Radiotherapy Related Research, Manchester (2019)
    • An automated workflow for patient-specific quality control of contour propagation.

      Beasley, William J; McWilliam, Alan; Slevin, Nicholas J; Mackay, Ranald I; van Herk, Marcel; Division of Molecular and Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. (2016-12-21)
      Contour propagation is an essential component of adaptive radiotherapy, but current contour propagation algorithms are not yet sufficiently accurate to be used without manual supervision. Manual review of propagated contours is time-consuming, making routine implementation of real-time adaptive radiotherapy unrealistic. Automated methods of monitoring the performance of contour propagation algorithms are therefore required. We have developed an automated workflow for patient-specific quality control of contour propagation and validated it on a cohort of head and neck patients, on which parotids were outlined by two observers. Two types of error were simulated-mislabelling of contours and introducing noise in the scans before propagation. The ability of the workflow to correctly predict the occurrence of errors was tested, taking both sets of observer contours as ground truth, using receiver operator characteristic analysis. The area under the curve was 0.90 and 0.85 for the observers, indicating good ability to predict the occurrence of errors. This tool could potentially be used to identify propagated contours that are likely to be incorrect, acting as a flag for manual review of these contours. This would make contour propagation more efficient, facilitating the routine implementation of adaptive radiotherapy.
    • Automatic mining of symptom severity from psychiatric evaluation notes.

      Karystianis, G; Nevado, A; Kim, C; Dehghan, Azad; Keane, J; Nenadic, G; Centre for Health Informatics, Australian Institute of Health Innovation, Macquarie University, Sydney, Australia (2017-12-22)
      As electronic mental health records become more widely available, several approaches have been suggested to automatically extract information from free-text narrative aiming to support epidemiological research and clinical decision-making. In this paper, we explore extraction of explicit mentions of symptom severity from initial psychiatric evaluation records. We use the data provided by the 2016 CEGS N-GRID NLP shared task Track 2, which contains 541 records manually annotated for symptom severity according to the Research Domain Criteria.
    • Automatic tracking of implanted fiducial markers in cone beam CT projection images.

      Marchant, Thomas E; Skalski, A; Matuszewski, B; Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Manchester, UK. tom.marchant@physics.cr.man.ac.uk (2012-03)
      This paper describes a novel method for simultaneous intrafraction tracking of multiple fiducial markers. Although the proposed method is generic and can be adopted for a number of applications including fluoroscopy based patient position monitoring and gated radiotherapy, the tracking results presented in this paper are specific to tracking fiducial markers in a sequence of cone beam CT projection images.
    • Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production.

      Capparelli, C; Guido, C; Whitaker-Menezes, D; Bonuccelli, G; Balliet, R; Pestell, T; Goldberg, A; Pestell, R; Howell, Anthony; Sneddon, Sharon; et al. (2012-06-15)
      Senescent fibroblasts are known to promote tumor growth. However, the exact mechanism remains largely unknown. An important clue comes from recent studies linking autophagy with the onset of senescence. Thus, autophagy and senescence may be part of the same physiological process, known as the autophagy-senescence transition (AST). To test this hypothesis, human fibroblasts immortalized with telomerase (hTERT-BJ1) were stably transfected with autophagy genes (BNIP3, CTSB or ATG16L1). Their overexpression was sufficient to induce a constitutive autophagic phenotype, with features of mitophagy, mitochondrial dysfunction and a shift toward aerobic glycolysis, resulting in L-lactate and ketone body production. Autophagic fibroblasts also showed features of senescence, with increased p21(WAF1/CIP1), a CDK inhibitor, cellular hypertrophy and increased β-galactosidase activity. Thus, we genetically validated the existence of the autophagy-senescence transition. Importantly, autophagic-senescent fibroblasts promoted tumor growth and metastasis, when co-injected with human breast cancer cells, independently of angiogenesis. Autophagic-senescent fibroblasts stimulated mitochondrial metabolism in adjacent cancer cells, when the two cell types were co-cultured, as visualized by MitoTracker staining. In particular, autophagic ATG16L1 fibroblasts, which produced large amounts of ketone bodies (3-hydroxy-butyrate), had the strongest effects and promoted metastasis by up to 11-fold. Conversely, expression of ATG16L1 in epithelial cancer cells inhibited tumor growth, indicating that the effects of autophagy are compartment-specific. Thus, autophagic-senescent fibroblasts metabolically promote tumor growth and metastasis, by paracrine production of high-energy mitochondrial fuels. Our current studies provide genetic support for the importance of "two-compartment tumor metabolism" in driving tumor growth and metastasis via a simple energy transfer mechanism. Finally, β-galactosidase, a known lysosomal enzyme and biomarker of senescence, was localized to the tumor stroma in human breast cancer tissues, providing in vivo support for our hypothesis. Bioinformatic analysis of genome-wide transcriptional profiles from tumor stroma, isolated from human breast cancers, also validated the onset of an autophagy-senescence transition. Taken together, these studies establish a new functional link between host aging, autophagy, the tumor microenvironment and cancer metabolism.
    • Autotransplantation of ovarian tissue and the risk of disease transmission.

      Radford, John A; Cancer Research UK Department of Medical Oncology, Christie Hospital, Manchester M20 4BX, UK. john.radford@man.ac.uk (2004-04-05)
      Temporary ovarian function has been reported following reimplantation of frozen/thawed cortical tissue and it is hoped that in time this technique will allow women sterilised by treatment for cancer to regain their fertility. There is however a concern, supported by animal data, that ovarian tissue may be contaminated by disease capable of causing a relapse after transplantation. One experiment, in which ovarian tissue from women with lymphoma was xenografted into immunodeficient mice, showed no evidence of transmission but these results require confirmation and no data exists for other malignancies. For the time being, therefore, it is recommended that harvesting and reimplantation of ovarian tissue should only take place within the confines of carefully designed clinical trials.
    • Availability of EGFR mutation status at first oncology consultation for advanced non-squamous non-small cell lung cancer patients. A pilot experience from the Christie.

      Evans, M; Summers, Yvonne J; Taylor, Paul; Harris, Maggie A; Bayman, Neil A; Faivre-Finn, Corinne; Sheikh, Hamid Y; Burt, Paul A; Blackhall, Fiona H; Califano, Raffaele; et al. (2013-12)
    • Avelumab expanded access program in metastatic Merkel cell carcinoma: efficacy and safety findings from patients in Europe and the Middle East

      Ascierto, P. A.; Orlova, K.; Grignani, G.; Dudzisz-Śledź, M.; Fenig, E.; Chiarion Sileni, V.; Fazio, N.; Samimi, M.; Mortier, L.; Gebhardt, C.; et al. (2021)
      Incidence rates of Merkel cell carcinoma (MCC), an uncommon skin cancer with an aggressive disease course, have increased in recent decades. Limited treatment options are available for patients with metastatic MCC (mMCC). Avelumab, an anti-programmed cell death-ligand 1 monoclonal antibody, became the first approved treatment for mMCC after the results of the phase 2 JAVELIN Merkel 200 study. Prior to its regulatory approval, an expanded access program (EAP) enabled compassionate use of avelumab in patients with mMCC. Here we report findings from patients enrolled in the EAP in Europe and the Middle East. Efficacy and safety data were provided at the discretion of treating physicians. Between March 2, 2016, and December 22, 2018, 403 requests for avelumab were received from 21 countries, and avelumab was supplied to 335 patients. Most patients (96.7%) received avelumab as second-line or later treatment. In 150 patients for whom response data were available, the objective response rate was 48.0%, and in responding patients, median duration of treatment was 7.4 months (range, 1.0-41.7 months). The most common treatment-related adverse events were infusion-related reaction (2.4%) and pyrexia (2.1%), and no new safety signals were observed. Overall, results from European and Middle Eastern patients enrolled in this EAP confirm the efficacy and safety of avelumab treatment observed in previous studies in patients with mMCC.
    • Avelumab in combination regimens for relapsed/refractory DLBCL: results from the Phase Ib JAVELIN DLBCL study

      Hawkes, E. A.; Phillips, T.; Budde, L. E.; Santoro, A.; Saba, N. S.; Roncolato, F.; Gregory, G. P.; Verhoef, G.; Offner, F.; Quero, C.; et al. (2021)
      Background: Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis despite the availability of multiple treatment options. Preliminary evidence suggests that DLBCL may be responsive to programmed death ligand 1 (PD-L1)/programmed death 1 inhibitors. Objective: The JAVELIN DLBCL study was conducted to assess whether a combination of agents could augment and sustain the antitumor immunity of avelumab, an anti-PD-L1 antibody, in R/R DLBCL. Methods: This was a multicenter, randomized, open-label, parallel-arm study with a phase Ib and a phase III component. Reported here are the results from the phase Ib study, wherein 29 adult patients with DLBCL were randomized 1:1:1 to receive avelumab in combination with utomilumab (an immunoglobulin G2 4-1BB agonist) and rituximab (arm A), avelumab in combination with utomilumab and azacitidine (arm B), or avelumab in combination with bendamustine and rituximab (arm C). The primary endpoints were dose-limiting toxicities and objective response as assessed by the investigator per Lugano Response Classification criteria. Results: Of the seven patients in arm A, one (14.3%) experienced two grade 3 dose-limiting toxicities (herpes zoster and ophthalmic herpes zoster); no dose-limiting toxicities were reported in arms B or C. No new safety concerns emerged for avelumab. One partial response was reported in arm A, three complete responses in arm C, and no responses in arm B. Given the insufficient antitumor activity in arms A and B and the infeasibility of expanding arm C, the study was discontinued before initiation of the phase III component. Conclusions: The low level of clinical activity suggests that PD-L1 inhibitor activity may be limited in R/R DLBCL. CLINICALTRIALS.
    • Avenzoar's (1091-1162) clinical description of cancer.

      Karamanou, M; Tsoucalas, G; Saridaki, Z; Iavazzo, Christos; Androutsos, G; Department of History of Medicine, Medical School, University of Athens, Athens, Greece (2015)
      In the 11(th) and 12(th) century the Western caliphate flourished, making Cordoba the capital of physicians and philosophers. During that period lived and practised the famous physician Ibn Zuhr or Avenzoar. In his monumental treatise Al Taysir, Avenzoar provided the first clinical description of a polypoid colorectal tumour as well as the case of a uterine cancer and a basal cell carcinoma. His medical work remained popular through middle ages, influencing the development of western medicine.
    • Average cumulative relative dose of adjuvant chemotherapy is more important than average relative dose intensity for colorectal cancer survival, with implications for treating obese patients: The OCTOPUS consortium

      Slawinski, C.; Malcomson, Lee; Barriuso, Jorge; Guo, H.; Harkin, A.; Iveson, T.; Glynne-Jones, R.; Van de Velde, C; Renehan, Andrew G; University of Manchester, Manchester, United Kingdom (2021)
      Background:After curative surgery for colorectal cancer (CRC), some studies indicatepoorer survival in obese patients. Adjuvant chemotherapy (ACT) for CRC is commonlycapped at a body surface area (BSA) 2.2m2, potentially reducing chemotherapyaverage cumulative relative dose (ACRD) and average relative dose intensity (ARDI) inobese patients.Methods:Individual participant-level data from MOSAIC, SCOT, PROCTORSCRIPT, andCHRONICLE (CRC-ACT) randomised-trials, with derivable BMI, BSA, and chemotherapydoses, were included from the OCTOPUS consortium. ARDI and ACRD were calculatedas percentages of actual to expected (full BSA-based) dose intensity (cumulativedose/treatment duration in weeks) or cumulative dose, respectively, averaged acrossthe drugs in the regimen. Two-stage random-effects meta-analyses of linear or Coxproportional hazards regression models were performed to explore BMI-ARDI/-ACRDand ARDI-/ACRD-survival relationships, respectively. The primary outcome was dis-ease-free survival (DFS), and secondary outcomes were overall (OS) and cancer-specific (CSS) survival, in addition to ARDI and ACRD. All models where adjusted for age, sex, performance status, t-stage and n-stage (in addition to BMI in the survivalmodels).Results:7269 patients were eligible. BMI 5kg/m2 increments were associated with a2.04% reduction in cycle 1 dose (95% CI:-2.45,-1.64; p ACRD 5% increments wereassociated with improved DFS (HR 0.953 (0.926, 0.980); p¼0.001), OS (HR0.931(0.908, 0.955); p<0.001) and CSS (HR 0.941(0.924, 0.959); p<0.001) survival.However, no significant relationship was demonstrated for ARDI (DFS HR 1.015 (0.967,1.065); p¼0.552; OS HR 1.035 (0.990, 1.081); p 0.134; CSS HR 1.022 (0.982, 1.064); p¼0.282), nor for sex-interactions for both ACRD and ARDI.Conclusions:ACRD is more important than ARDI in determining survival. Elevated BMIis associated with a reduced cycle 1 dose and a modest ACRD reduction. These in-direct effects through under-treatment might explain poorer survival in obese pa-tients, rather than direct effects of obesity resulting from, for example, tumour biology.
    • Average duration of prior treatment lines predicts clinical benefit to eribulin chemotherapy in patients with metastatic breast cancer

      Coe, Faye; Misra, Vivek; McCabe, Yamini; Adderley, Helen; Woodhouse, Laura; Ayub, Zaheen; Wang, Xin; Howell, Sacha J; Ekholm, Maria; Department of Pharmacy, The Christie NHS Foundation Trust, Manchester, UK (2021)