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  Prostate cancer evolution from multilineage primary to single lineage metastases with implications for liquid biopsy

  Woodcock, D. J.; Riabchenko, E.; Taavitsainen, S.; Kankainen, M.; Gundem, G.; Brewer, D. S.; Ellonen, P.; Lepistö, M.; Golubeva, Y. A.; Warner, A. C.; et al. (2020)

  The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. We infer detailed reconstructions of tumor phylogenies in ten prostate cancer patients with fatal disease, and investigate them in conjunction with histopathology and tumor DNA extracted from blood and cerebrospinal fluid. Substantial evolution occurs within the prostate, resulting in branching into multiple spatially intermixed lineages. One dominant lineage emerges that initiates and drives systemic metastasis, where polyclonal seeding between sites is common. Routes to metastasis differ between patients, and likely genetic drivers of metastasis distinguish the metastatic lineage from the lineage that remains confined to the prostate within each patient. Body fluids capture features of the dominant lineage, and subclonal expansions that occur in the metastatic phase are non-uniformly represented. Cerebrospinal fluid analysis reveals lineages not detected in blood-borne DNA, suggesting possible clinical utility.
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  CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth

  Zhuang, X.; Maione, F.; Robinson, J.; Bentley, M.; Kaul, B.; Whitworth, K.; Jumbu, N.; Jinks, E.; Bystrom, J.; Gabriele, P.; et al. (2020)

  Engineering T cells to express chimeric antigen receptors (CARs) specific for antigens on hematological cancers has yielded remarkable clinical responses, but with solid tumors, benefit has been more limited. This may reflect lack of suitable target antigens, immune evasion mechanisms in malignant cells, and/or lack of T cell infiltration into tumors. An alternative approach, to circumvent these problems, is targeting the tumor vasculature rather than the malignant cells directly. CLEC14A is a glycoprotein selectively overexpressed on the vasculature of many solid human cancers and is, therefore, of considerable interest as a target antigen. Here, we generated CARs from 2 CLEC14A-specific antibodies and expressed them in T cells. In vitro studies demonstrated that, when exposed to their target antigen, these engineered T cells proliferate, release IFN-?, and mediate cytotoxicity. Infusing CAR engineered T cells into healthy mice showed no signs of toxicity, yet these T cells targeted tumor tissue and significantly inhibited tumor growth in 3 mouse models of cancer (Rip-Tag2, mPDAC, and Lewis lung carcinoma). Reduced tumor burden also correlated with significant loss of CLEC14A expression and reduced vascular density within malignant tissues. These data suggest the tumor vasculature can be safely and effectively targeted with CLEC14A-specific CAR T cells, offering a potent and widely applicable therapy for cancer.
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  Evaluation of GATE-RTion (GATE/Geant4) Monte Carlo simulation settings for proton pencil beam scanning quality assurance

  Winterhalter, Carla; Taylor, Michael J; Boersma, D.; Elia, A.; Guatelli, S.; Mackay, Ranald I; Kirkby, Karen J; Maigne, L.; Ivanchenko, V.; Resch, A. F.; et al. (2020)

  Purpose: Geant4 is a multi-purpose Monte Carlo simulation tool for modeling particle transport in matter. It provides a wide range of settings, which the user may optimize for their specific application. This study investigates GATE/Geant4 parameter settings for proton pencil beam scanning therapy. Methods: GATE8.1/Geant4.10.3.p03 (matching the versions used in GATE-RTion1.0) simulations were performed with a set of prebuilt Geant4 physics lists (QGSP_BIC, QGSP_BIC_EMY, QGSP_BIC_EMZ, QGSP_BIC_HP_EMZ), using 0.1mm-10mm as production cuts on secondary particles (electrons, photons, positrons) and varying the maximum step size of protons (0.1mm, 1mm, none). The results of the simulations were compared to measurement data taken during clinical patient specific quality assurance at The Christie NHS Foundation Trust pencil beam scanning proton therapy facility. Additionally, the influence of simulation settings was quantified in a realistic patient anatomy based on computer tomography (CT) scans. Results: When comparing the different physics lists, only the results (ranges in water) obtained with QGSP_BIC (G4EMStandardPhysics_Option0) depend on the maximum step size. There is clinically negligible difference in the target region when using High Precision neutron models (HP) for dose calculations. The EMZ electromagnetic constructor provides a closer agreement (within 0.35 mm) to measured beam sizes in air, but yields up to 20% longer execution times compared to the EMY electromagnetic constructor (maximum beam size difference 0.79 mm). The impact of this on patient-specific quality assurance simulations is clinically negligible, with a 97% average 2%/2 mm gamma pass rate for both physics lists. However, when considering the CT-based patient model, dose deviations up to 2.4% are observed. Production cuts do not substantially influence dosimetric results in solid water, but lead to dose differences of up to 4.1% in the patient CT. Small (compared to voxel size) production cuts increase execution times by factors of 5 (solid water) and 2 (patient CT). Conclusions: Taking both efficiency and dose accuracy into account and considering voxel sizes with 2 mm linear size, the authors recommend the following Geant4 settings to simulate patient specific quality assurance measurements: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (in the phantom and range-shifter) and 10 mm (world); best agreement to measurement data was found for QGSP_BIC_EMZ reference physics list at the cost of 20% increased execution times compared to QGSP_BIC_EMY. For simulations considering the patient CT model, the following settings are recommended: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (phantom/range-shifter) and 10 mm (world) if the goal is to achieve sufficient dosimetric accuracy to ensure that a plan is clinically safe; or 0.1 mm (phantom/range-shifter) and 1 mm (world) if higher dosimetric accuracy is needed (increasing execution times by a factor of 2); most accurate results expected for QGSP_BIC_EMZ reference physics list, at the cost of 10-20% increased execution times compared to QGSP_BIC_EMY.
• ACUFOCIN: Randomized clinical trial of ACUpuncture plus standard care versus standard care alone FOr Chemotherapy Induced peripheral Neuropathy (CIPN)

  Wardley, Andrew M; Ryder, W David J; Misra, Vivek; Hall, P. S.; Mackereth, Peter A; Stringer, Jacqui; The Christie NHS Foundation Trust, Manchester Academic Health Science Centre & Division of Cancer Sciences (2020)

  Background: CIPN is a dose limiting toxicity, and a major clinical challenge. This study aims to explore the use of acupuncture with standard care (Acu +SC) against SC alone, to reduce symptoms of CIPN. Methods: A phase II, randomised, parallel group design was used to investigate the effectiveness of a 10 week course of acupuncture to manage CIPN. Patients experiencing CIPN ? Grade II (CTCAE v4.03), recording a ‘Most Troublesome’ CIPN symptom score of ? 3 using the "Measure Yourself Medical Outcome Profile" (MYMOP 2), were randomised (1:1) to either Acu+SC or SC alone. The primary end-point was a ? 2 point improvement in MYMOP2 score at week 10 (logistic regression adjusted for stratification factors and baseline MYMOP2 score). The necessary sample size was 100 patients;120 were randomised to allow for attrition (90% power; 10% one-sided alpha), for a hypothesised improvement in success proportions from 30% to 55%. Results: 120 patients were randomised to ACUFOCIN; diagnosis: breast 61 (51%), multiple myeloma 9 (8%), GI 48 (40%), gynaecological 2 (2%). MYMOP2 score for most troubling CIPN symptom at baseline: 3-4 33 (28%), 5-6 87 (73%). CTCAE CIPN at baseline; grade II 103 (86%), grade III 17 (14%). Baseline characteristics were balanced between arms. Primary outcome data were available for 108 participants with 36/54 (67%) successes in the Acu+SC arm compared to 18/55 (33%) in the SC arm. Adjusted success odds ratio was 4.3 (95% CI 1.9-9.6; p < 0.001; Acu+SC vs SC). Additionally, 27/53 (51%) participants achieved a CIPN success (grade ? I) in the Acu+SC arm compared to 4/56 (7%) in the SC arm with adjusted odds ratio 13.1 (95% CI 4.1-41.7; p < 0.001; Acu+SC vs SC). Significant reduction in week 10 pain score; mean difference (SC+Acu – SC alone) -1.45 with 95% CI (-2.25, -0.65) after adjustment for week 1 pain, breast cancer diagnosis and treatment complete status. (note pain on a 0-10 scale). Significant increase in the EORTC QLQ-C30 summary score; mean difference (SC+Acu – SC alone) 9.51 with 95% CI (5.01, 14.02) after adjustment for the baseline score, breast cancer diagnosis and treatment complete status. (note summary score on a 0-100 scale). Significant effects seen at week 10 are also present at week 6. The week 6 effect estimates are consistently less than the week 10 effects (but not usually statistically significantly so). Conclusions: In this patient cohort, a 10 week course of acupuncture significantly improved symptoms of CIPN. These results support further investigation within a phase III trial.
• Evaluation of patients' experiences transitioning to the breelib nebulizer for inhaled iloprost therapy for pulmonary arterial hypertension

  Yorke, Janelle; Punnett, Grant; Billings, C.; Armstrong, I.; School of Health Sciences, University of Manchester, Manchester (2020)

  Rationale: Inhaled Iloprost is an effective treatment for Pulmonary Arterial Hypertension (PAH) that requires patients to administer their own inhalations via a nebuliser. This can be a time consuming task for patients with multiple inhalations required each day. The new Breelib nebulizer has been shown to reduce inhalation time and we anticipated that this would lead to a better experience for patients. Methods: A prospective observational study was used to determine changes in reported outcomes of patients who had transitioned from an I-neb nebulizer to Breelib nebuliser for Iloprost administration. Outcomes were assessed prior to transition and one-week post transition to the Breelib nebulizer. Outcomes included disease specific Health Related Quality of Life (HRQL) with emPHasis-10, treatment satisfaction using the Treatment Satisfaction with Medicines Questionnaire (TSMED), fatigue using the Fatigue Severity Scale (FSS) and sleep quality with the Medical Outcomes Study sleep (MOS-sleep). Semi-structured interviews were also conducted to further explore patient’s experience of using the nebulised medication and analysed using thematic analysis. Results: Twenty-nine participants enrolled in the study (7 male; 22 female; idiopathic PAH 58%). There was a significant improvement in sleep adequacy (p=0.006). No other significant differences were found however scores for emPHasis-10 (mean: pre 31.7 and post 30.9), sleep disturbance and fatigue severity (mean: pre 48.9 and post 44.9) improved pre and post Breelib transition. Interviews with four participants identified Breelib as being easy to use compared to their previous experience, reduced inhalation time and being able to fit inhaler treatment around life. Conclusions: This small descriptive study suggests that transition to the Breelib nebulizer improves HRQL, fatigue and sleep adequacy; which may be related to decreased time spent self-administering inhaled therapy. Interviews described how inhaled PAH therapy limited everyday life and prevented patients from participating in many enjoyable activities. However, the benefits of transitioning to Breelib such as less preparation time were highly valued by patients and family members.

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