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  • Survival in patients with multiple primary melanomas: Systematic review and meta-analysis

    Peek, G.; Olsen, C. M.; Baade, P.; Youlden, D. R.; Aitken, J. F.; Green, Adèle C; Khosrotehrani, K.; Queensland Skin and Cancer Foundation, Queensland Institute of Dermatology, South-Brisbane, Queensland, Australia. (2020)
    Background: The literature surrounding survival of patients with multiple primary melanomas (MPM) yields variable and opposing findings, constrained by statistical challenges. Objectives: To critically examine the available literature regarding survival of patients with MPM compared with a single primary melanoma and detail statistical methods used. Methods: Electronic searches were performed of PubMed, Embase, Web of Science, and Scopus, with cross-checking of references, for the period January 1956 to June 2019. Studies published in English examining survival in patients with multiple melanomas were included. Case studies and small case series were excluded. Results: There were 14 studies eligible for inclusion. Conclusions on survival varied markedly depending on the statistical method used. Four studies that accounted for survival bias by partitioning the survival time were included in the quantitative review, with 3 of these reporting a survival disadvantage for MPM, whereas the fourth showed no difference in survival. The pooled hazard ratio was 1.39 (95% confidence interval, 1.07-1.81) but with significant heterogeneity (I2 = 96.8%, Phet < .001). Limitations: Studies showed significant heterogeneity in methodology. Conclusion: When data were analyzed with robust statistical methods, patients with MPM had a survival disadvantage compared with patients with a single primary melanoma.
  • Sample pooling strategies for SARS-CoV-2 detection

    Lagopati, N.; Tsioli, P.; Mourkioti, I.; Polyzou, A.; Papaspyropoulos, A.; Zafiropoulos, A.; Evangelou, K.; Sourvinos, G.; Gorgoulis, Vassilis G; Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Greece. (2020)
    The worldwide COVID-19 pandemic outburst has caused a serious public health issue with increasing needs of accurate and rapid diagnostic and screening testing. This situation requires an optimized management of the chemical reagents, the consumables, and the human resources, in order to respond accurately and effectively, controlling the spread of the disease. Testing on pooled samples maximizes the number of tested samples, by minimizing the time and the lab supplies needed. The general conceptualization of the pooling method is based on mixing samples together in a batch. Individual testing is needed only if a specific pool exhibits a positive result. The development of alternative hybrid methods, based on "in house" protocols, utilizing commercially available consumables, in combination with a reliable pooling method would provide a solution, focusing on the better exploitation of the personnel and the lab supplies, allowing for rapid screening of a population in a reasonably short time.
  • Impact of lineage plasticity to and from a neuroendocrine phenotype on progression and response in prostate and lung cancers

    Rubin, M. A.; Bristow, Robert G; Thienger, P. D.; Dive, Caroline; Imielinski, M.; Department for BioMedical Research, University of Bern and Inselspital, 3010 Bern, Switzerland; Bern Center for Precision Medicine, University of Bern and Inselspital, 3010 Bern, Switzerland. (2020)
    Intratumoral heterogeneity can occur via phenotype transitions, often after chronic exposure to targeted anticancer agents. This process, termed lineage plasticity, is associated with acquired independence to an initial oncogenic driver, resulting in treatment failure. In non-small cell lung cancer (NSCLC) and prostate cancers, lineage plasticity manifests when the adenocarcinoma phenotype transforms into neuroendocrine (NE) disease. The exact molecular mechanisms involved in this NE transdifferentiation remain elusive. In small cell lung cancer (SCLC), plasticity from NE to nonNE phenotypes is driven by NOTCH signaling. Herein we review current understanding of NE lineage plasticity dynamics, exemplified by prostate cancer, NSCLC, and SCLC.
  • Making connections: p53 and the cathepsin proteases as co-regulators of cancer and apoptosis

    Soond, S. M.; Savvateeva, L. V.; Makarov, V. A.; Gorokhovets, N. V.; Townsend, Paul A; Zamyatnin, A. A., Jr.; Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya Str. 8-2, 119991 Moscow, Russia. (2020)
    While viewed as the "guardian of the genome", the importance of the tumor suppressor p53 protein has increasingly gained ever more recognition in modulating additional modes of action related to cell death. Slowly but surely, its importance has evolved from a mutated genetic locus heavily implicated in a wide array of cancer types to modulating lysosomal-mediated cell death either directly or indirectly through the transcriptional regulation of the key signal transduction pathway intermediates involved in this. As an important step in determining the fate of cells in response to cytotoxicity or during stress response, lysosomal-mediated cell death has also become strongly interwoven with the key components that give the lysosome functionality in the form of the cathepsin proteases. While a number of articles have been published highlighting the independent input of p53 or cathepsins to cellular homeostasis and disease progression, one key area that warrants further focus is the regulatory relationship that p53 and its isoforms share with such proteases in regulating lysosomal-mediated cell death. Herein, we review recent developments that have shaped this relationship and highlight key areas that need further exploration to aid novel therapeutic design and intervention strategies.
  • Integrative p53, micro-RNA and cathepsin protease co-regulatory expression networks in cancer

    Soond, S. M.; Kozhevnikova, M. V.; Townsend, Paul A; Zamyatnin, A. A., Jr.; Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya str. 8-2, 119991 Moscow, Russia. (2020)
    As the direct regulatory role of p53 and some of its isoform proteins are becoming established in modulating gene expression in cancer research, another aspect of this mode of gene regulation that has captured significant interest over the years is the mechanistic interplay between p53 and micro-RNA transcriptional regulation. The input of this into modulating gene expression for some of the cathepsin family members has been viewed as carrying noticeable importance based on their biological effects during normal cellular homeostasis and cancer progression. While this area is still in its infancy in relation to general cathepsin gene regulation, we review the current p53-regulated micro-RNAs that are generating significant interest through their regulation of cathepsin proteases, thereby strengthening the link between activated p53 forms and cathepsin gene regulation. Additionally, we extend our understanding of this developing relationship to how such micro-RNAs are being utilized as diagnostic or prognostic tools and highlight their future uses in conjunction with cathepsin gene expression as potential biomarkers within a clinical setting.
  • Development impact analysis of gemtuzumab ozogamicin for the treatment of CD33-positive acute myeloid leukemia

    Reynolds, K. A.; Schlessinger, D. I.; Yanes, A. F.; Godinez-Puig, V.; Chen, B. R.; Kurta, A. O.; Cotseones, J. K.; Chiren, S. G.; Iyengar, S.; Ibrahim, S. A.; et al. (2020)
    Background: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. Objective: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. Methods: One hundred nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, respectively, in two rounds of Delphi exercises. Outcomes scored 'critically important' (scored 7,8, or 9) by 70% of patients and 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. Results: A core set of seven outcomes was finalized at the consensus meeting: serious or persistent adverse events, patient-reported quality of life, complete response, partial response, recurrence-free survival, progression-free survival, and disease-specific survival. Conclusions: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes
  • NADPH oxidases are required for full platelet activation in vitro and thrombosis in vivo but dispensable for plasma coagulation and hemostasisand apoptosis

    Vara, D.; Mailer, R. K.; Tarafdar, Anuradha; Wolska, N.; Heestermans, M.; Konrath, S.; Spaeth, M.; Renné, T.; Schröder, K.; Pula, G.; et al. (2020)
    Objective: Using 3KO (triple NOX [NADPH oxidase] knockout) mice (ie, NOX1-/-/NOX2-/-/NOX4-/-), we aimed to clarify the role of this family of enzymes in the regulation of platelets in vitro and hemostasis in vivo. Approach and Results: 3KO mice displayed significantly reduced platelet superoxide radical generation, which was associated with impaired platelet aggregation, adhesion, and thrombus formation in response to the key agonists collagen and thrombin. A comparison with single-gene knockouts suggested that the phenotype of 3KO platelets is the combination of the effects of the genetic deletion of NOX1 and NOX2, while NOX4 does not show any significant function in platelet regulation. 3KO platelets displayed significantly higher levels of cGMP-a negative platelet regulator that activates PKG (protein kinase G). The inhibition of PKG substantially but only partially rescued the defective phenotype of 3KO platelets, which are responsive to both collagen and thrombin in the presence of the PKG inhibitors KT5823 or Rp-8-pCPT-cGMPs, but not in the presence of the NOS (NO synthase) inhibitor L-NG-monomethyl arginine. In vivo, triple NOX deficiency protected against ferric chloride-driven carotid artery thrombosis and experimental pulmonary embolism, while hemostasis tested in a tail-tip transection assay was not affected. Procoagulatory activity of platelets (ie, phosphatidylserine surface exposure) and the coagulation cascade in platelet-free plasma were normal. Conclusions: This study indicates that inhibiting NOXs has strong antithrombotic effects partially caused by increased intracellular cGMP but spares hemostasis. NOXs are, therefore, pharmacotherapeutic targets to develop new antithrombotic drugs without bleeding side effects.
  • First-in-human phase i study of MP0250, a first-in-class DARPin drug candidate targeting VEGF and HGF, in patients with advanced solid tumors

    Baird, R. D.; Linossi, C.; Middleton, M.; Lord, S.; Harris, A.; Rodón, J.; Zitt, C.; Fiedler, U.; Dawson, K. M.; Leupin, N.; et al. (2020)
    Purpose: A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment. Patients and methods: A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the dose-escalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n = 13, 8 mg/kg, once every 2 weeks and n = 8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts. Results: In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks. Conclusion: MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies.
  • Severity of COVID-19 in children with cancer: Report from the United Kingdom Paediatric Coronavirus Cancer Monitoring Project

    Millen, G. C.; Arnold, R.; Cazier, J. B.; Curley, H.; Feltbower, R. G.; Gamble, A.; Glaser, A. W.; Grundy, R. G.; Lee, L. Y. W.; McCabe, Martin G; et al. (2020)
    Background: Children with cancer are frequently immunocompromised. While children are generally thought to be at less risk of severe SARS-CoV-2 infection than adults, comprehensive population-based evidence for the risk in children with cancer is unavailable. We aimed to produce evidence of the incidence and outcomes from SARS-CoV-2 in children with cancer attending all hospitals treating this population across the UK. Methods: Retrospective and prospective observational study of all children in the UK under 16 diagnosed with cancer through data collection from all hospitals providing cancer care to this population. Eligible patients tested positive for SARS-CoV-2 on reverse transcription polymerase chain reaction (RT-PCR). The primary end-point was death, discharge or end of active care for COVID-19 for those remaining in hospital. Results: Between 12 March 2020 and 31 July 2020, 54 cases were identified: 15 (28%) were asymptomatic, 34 (63%) had mild infections and 5 (10%) moderate, severe or critical infections. No patients died and only three patients required intensive care support due to COVID-19. Estimated incidence of hospital identified SARS-CoV-2 infection in children with cancer under 16 was 3%. Conclusions: Children with cancer with SARS-CoV-2 infection do not appear at increased risk of severe infection compared to the general paediatric population. This is reassuring and supports the continued delivery of standard treatment.
  • COVID-19 and myeloma clinical research - experience from the CARDAMON clinical trial

    Camilleri, M.; Sive, J.; Wilson, W.; Pang, G.; Jenner, R.; Phillips, Elizabeth H; Popat, R.; Ramasamy, K.; Bygrave, C.; Dadaga, T.; et al. (2020)
  • More than meets the ISG15: emerging roles in the DNA damage response and beyond

    Sandy, Zac; da Costa, Isabelle Cristine; Schmidt, Christne K; Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M20 4GJ, UK. (2020)
    Maintenance of genome stability is a crucial priority for any organism. To meet this priority, robust signalling networks exist to facilitate error-free DNA replication and repair. These signalling cascades are subject to various regulatory post-translational modifications that range from simple additions of chemical moieties to the conjugation of ubiquitin-like proteins (UBLs). Interferon Stimulated Gene 15 (ISG15) is one such UBL. While classically thought of as a component of antiviral immunity, ISG15 has recently emerged as a regulator of genome stability, with key roles in the DNA damage response (DDR) to modulate p53 signalling and error-free DNA replication. Additional proteomic analyses and cancer-focused studies hint at wider-reaching, uncharacterised functions for ISG15 in genome stability. We review these recent discoveries and highlight future perspectives to increase our understanding of this multifaceted UBL in health and disease.
  • Modifying dietary patterns in cardiothoracic transplant patients to reduce cardiovascular risk: the AMEND-IT Trial

    Entwistle, T. R.; Miura, K.; Keevil, B. G.; Morris, J.; Yonan, N.; Pohl, M.; Green, Adèle C; Fildes, J. E.; The Ex-Vivo Lab, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. (2020)
    Cardiovascular disease (CVD) is common after cardiothoracic transplantation. In a pilot intervention we assessed feasibility and potential effectiveness of dietary interventions to reduce CVD risk. We recruited patients from a tertiary hospital and randomly allocated them to a Mediterranean or low-fat diet for twelve months. Feasibility was measured by patient participation, retention and adherence. Changes in weight, body mass index (BMI), heart rate, blood pressure, glucose markers and blood lipids were assessed using longitudinal Generalized Estimating Equation regression models with 95% confidence intervals. Of 56 heart and 60 lung transplant recipients, 52 (45%) consented, 41 were randomised and 39 (95%) completed the study with good adherence to randomized diets. After 12 months, changes in many risk factors were seen in the Mediterranean and low-fat diet groups respectively including mean BMI (-0.5 vs. 0.0kg/m2 ), systolic/diastolic blood pressure +0.5/+0.1 vs -4.4/-3.5 mmHg; fasting glucose -0.26 vs -0.27 mmol/L; total cholesterol -0.56 vs -0.40 mmol/L. Changes in BMI and systolic/diastolic blood pressure in 49 eligible patients who did not take part were +0.7 kg/m2 and +2.5/+1.8 mmHg. Thus such dietary interventions in cardiothoracic transplant patients are feasible, and potentially beneficial. A definitive nutritional intervention study in these high-risk patients is warranted.
  • Large extracellular vesicles can be characterised by multiplex labelling using imaging flow cytometry

    Johnson, Suzanne M; Banyard, Antonia; Smith, Christopher; Mironov, A.; McCabe, Martin G; Children's Cancer Group, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, University of Manchester, Oglesby Cancer Research Building, Manchester Academic Health Science Centre, Manchester Cancer Research Centre, Manchester M20 4GJ, UK. (2020)
    Extracellular vesicles (EVs) are heterogeneous in size (30 nm-10 µm), content (lipid, RNA, DNA, protein), and potential function(s). Many isolation techniques routinely discard the large EVs at the early stages of small EV or exosome isolation protocols. We describe here a standardised method to isolate large EVs from medulloblastoma cells and examine EV marker expression and diameter using imaging flow cytometry. Our approach permits the characterisation of each large EVs as an individual event, decorated with multiple fluorescently conjugated markers with the added advantage of visualising each event to ensure robust gating strategies are applied. Methods: We describe step-wise isolation and characterisation of a subset of large EVs from the medulloblastoma cell line UW228-2 assessed by fluorescent light microscopy, transmission electron microscopy (TEM) and tunable resistance pulse sensing (TRPS). Viability of parent cells was assessed by Annexin V exposure by flow cytometry. Imaging flow cytometry (Imagestream Mark II) identified EVs by direct fluorescent membrane labelling with Cell Mask Orange (CMO) in conjunction with EV markers. A stringent gating algorithm based on side scatter and fluorescence intensity was applied and expression of EV markers CD63, CD9 and LAMP 1 assessed. Results: UW228-2 cells prolifically release EVs of up to 6 µm. We show that the Imagestream Mark II imaging flow cytometer allows robust and reproducible analysis of large EVs, including assessment of diameter. We also demonstrate a correlation between increasing EV size and co-expression of markers screened. Conclusions: We have developed a labelling and stringent gating strategy which is able to explore EV marker expression (CD63, CD9, and LAMP1) on individual EVs within a widely heterogeneous population. Taken together, data presented here strongly support the value of exploring large EVs in clinical samples for potential biomarkers, useful in diagnostic screening and disease monitoring.
  • Antagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade

    Bonavita, Eduardo; Bromley, Christian P; Jonsson, G.; Pelly, Victoria S; Sahoo, Sudhakar; Walwyn-Brown, K.; Mensurado, S.; Moeini, Agrin; Flanagan, Eimear; Bell, Charlotte R; et al. (2020)
    Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.
  • Randomized comparisons of bevacizumab(B) and irinotecan(I),added to temozolomide(T), in children with relapsed/refractory high-risk neuroblastoma(RR-HRNB); survival results of the ITCC-SIOPEN beacon-neuroblastoma phase 2 trial

    Wheatley, K.; Holt, G.; Owens, C.; Valteau-Couanet, D.; Gambart, M.; Castel, V.; Van Eijkelenburg, N.; Castellano, A.; Nysom, K.; Gerber, N.; et al. (2020)
    Background and Aims: BEACON is a randomized phase 2 trial assessing whether bevacizumab adds to chemotherapy and evaluating chemotherapy regimens for RR-HRNB. Methods: Patients with RR-HRNB underwent randomizations, in a 3x2 factorial design, to: T, IT or topotecan (To)-T, +/- B. Toxicity and response were already reported. Survival outcomes – progression-free (PFS) and overall (OS) – for the I and B randomizations are reported here (To rand continued). The B randomization used a relaxed alpha (1- sided p=0.2) for PFS as its phase 2 success criterion; the I randomiza- tion was Bayesian. Cox model hazard ratios (HR) <1.0 indicate benefit for I or B. Heterogeneity tests (HT) assessed interactions between B and I. Analysis was intention-to-treat. Results: From 2013-19, 160 patients were randomized to B v. no B, including 121 to I v. no I, with median follow-up 15.4 months. B ran- domization: HR (95%CI) for PFS and OS were 0.85(0.59-1.23) and 0.84(0.56-1.24) respectively. I randomization: HR (95%CI) for PFS and OS were 0.66(0.43-1.00) and 0.63(0.41-0.99). I improved PFS and OS (98% probability that true HR<1.0 for both) and B just met its success criterion (PFS: 1p=0.20; OS: 1p=0.19).There was some, but not conclu- sive, evidence of a positive interaction between B and I for both PFS (HT:p=0.06) and OS (HT:p=0.12). If real, this would suggest that adding either I (IT) or B (BT) to T does not improve outcome, but adding both BIT) does. Conclusions: The BEACON results show that single agent T is subopti- mal. Statistical uncertainty about an interaction between I and B means two further interpretations are possible: 1) IT and possibly BT are bet- ter than T; 2) IT and BT are not better than T, but I and B together (BIT) are better. Hence, a definitive conclusion on the best combination(s) to take forward is not currently possible and further randomized evalua- tion is needed
  • Final results of CA180-372/COG AALL1122 phase 2 trial of dasatinib and chemotherapy in pediatric patients with newly-diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (PH plus ALL)

    Hunger, S.; Saha, Vaskar; Devidas, M.; Valsecchi, M.; Gastier-Foster, J.; Cazzaniga, G.; Reshmi, S.; Borowitz, M.; Moorman, A.; Heerema, N.; et al. (2020)
    Background and Aims: We administered EsPhALL chemotherapy plus dasatinib 60 mg/m 2 (starting day 15) at COG (North America and Aus- tralia) and EsPhALL (Italy and UK) sites. Patients (>1-17.99 years) with MRD 0.05% following induction Ib or MRD-positive follow- ing three additional high-risk (HR) chemotherapy blocks were allo- cated to CR1 HSCT. The remaining patients received chemother- apy plus dasatinib for 2 years. Only CNS3 patients received cranial irradiation. Methods: Enrollment was 109 patients (3/2012-5/2014); 3 were ineli- gible and received no trial therapy. Results: All 106 treated-patients achieved CR. With database lock 6/29/19, 48/106 had events including 38 relapses (24 marrow, 4 CNS, 4 marrow+CNS, 4 other, 2 marrow+other), 9 treatment-related deaths (7 in chemotherapy-assigned patients, 2 post-HSCT), and one malignancy. Nineteen (17.9%) patients met HSCT criteria, 15 (14.2%) received CR1 HSCT with 9 remaining event-free, 2 transplant-related deaths (6 weeks, 7 months), and 4 relapses (3 alive, 1 died). Among the four not transplanted, 2 were event-free, 1 relapsed and died, and 1 had an astrocytoma. The remaining 87 patients were assigned to chemotherapy plus dasatinib, with 47 remaining event-free. Seven died in CR1, 5 on-therapy (3 in HR3, 1 reinduction 2, 1 continuation) and 2 post-therapy (21 and 31 months). Thirty-three relapsed, 3 on-therapy at 16-23 months (all alive) and 30 post-therapy (18 12 months, 12 >12 months; 22 alive and 8 deceased). The primary toxicities were febrile neutropenia and infection; one chemotherapy patient discon- tinued dasatinib (allergy) and one discontinued post-HSCT (myelosup- pression). Conclusions: Dasatinib plus EsPhALL chemotherapy is safe and effec- tive in pediatric Ph +ALL. With only 14% of patients undergoing CR1 HSCT, as compared to 81% in the EsPhALL 2004 and 38% in the EsPhALL2010 imatinib trials, this trial demonstrates similar outcomes with 5-year EFS 54.6% (95% CI, 44.5-63.6) and OS 81.7% (95% CI, 82.8-87.9) versus 60.3%/71.5% in EsPhALL 2004, and 57%/71.8% in EsPhALL 2010
  • An excess mortality risk analysis of proton beam versus optimal photon radiotherapy for mediastinal Hodgkin lymphoma: who may benefit most?

    Ntentas, G.; Dedeckova, K.; Andrilik, M.; Shakir, R.; Aznar, Marianne Camille; Ramroth, J.; Begum, R.; Darby, S.; Mikhaeel, G.; Cutter, D.; et al. (2020)
    Purpose/Objective(s): Previous studies have shown that proton beam therapy (PBT) can reduce radiation exposure of normal tissues in patients with mediastinal lymphoma compared to photon radiotherapy (RT). However, most studies were small, did not use intensity modulated radiotherapy (IMRT) which avoids low dose bath and focused mainly on dosimetric endpoints. Our purpose was to compare PBT to best available photon RT in a large cohort to identify which patients benefited most from PBT both dosimetrically and in terms of predicted excess mortality risk (EMR) from cardiovascular disease (CVD) and second cancers (SC). Materials/Methods: Between 2015 and 2019, 80 supradiaphragmatic Hodgkin lymphoma patients with mediastinal disease were treated with pencil beam scanning PBT in deep inspiration breath hold (DIBH). We replanned this cohort using Butterfly-VMAT (BVMAT) in DIBH to provide a comparison between clinical PBT and “best-plan” photon RT. We predicted EMR from CVD and SC (breast, lung and esophagus) using established dose-response relationships and mean organ doses. Doses to cardiac substructures (left ventricle, valves) and to carotids were also included in the prediction of EMR from CVD, as was the chemotherapyrelated EMR. The two RT methods were compared using within-patient multiple regression. Results: Compared to BVMAT, PBT substantially reduced cardiac doses and EMR from CVD but only for those patients whose clinical target volume (CTV) overlapped longitudinally with the heart by >40% (n Z 23). For those with 40% overlap (n Z 57), there was no substantial difference between PBT and BVMAT. Mean lung dose and EMR from lung SC was reduced substantially for all patients with PBT, but an additional benefit was observed for those with axillary disease (n Z 25). The EMR from breast cancer was halved for female patients with axillary disease, but this was a small effect in absolute terms. (Table 1) The integral dose was doubled with BVMAT compared to PBT (4.7 Gy from 2.3 Gy). Conclusion: PBT reduced radiation exposure to normal tissues to varying degrees in different patients. Only patients with >40% longitudinal overlap of CTV with the heart received substantial reduction of EMR from CVD. EMR from lung SC was reduced for all patients, and those with axillary involvement received the greatest benefit in terms of EMR from lung and breast SC. The EMR from breast SC, however, was low for both methods, attributable to the excellent sparing of the female breasts with both RT techniques.
  • Phase 1 study of regorafenib in combination with vincristine and irinotecan in pediatric patients with recurrent or refractory solid tumors

    Casanova, M.; Bautista, F.; Campbell-Hewson, Q.; Makin, Guy W J; Marshall, L. V.; Verschuur, A.; Nieto, A. C.; Corradini, N.; Ploeger, B.; Mueller, U.; et al. (2020)
    Background and Aims: This phase 1 study evaluated regorafenib plus vincristine/irinotecan in pediatric patients with rhabdomyosarcoma (RMS) and other solid tumors. Methods: Patients with relapsed/refractory tumors received intra- venous vincristine (1.5 mg/m 2 , Days 1,8) and irinotecan (50 mg/m 2 /day, Days1–5) plus once-daily oral regorafenib (6–<24 months: 60 mg/m 2 escalating to 65 mg/m 2 ;2–<18 years: 72 mg/m 2 escalating to 82 mg/m 2) on either Days 1–14 (concomitant dosing) or Days 8–21 (sequential dosing) during each 21-day cycle. Per protocol, 50% of patients had to have RMS. Results: Of 21 treated patients (RMS, n=12; Ewing sarcoma, n=5; neuroblastoma, n=3; Wilms tumor, n=1), 2 received concomitant (72 mg/m 2 ) and 19 sequential (72 mg/m 2 ,n=6; 82 mg/m 2 ,n=13) dos-ing. Median age was 10 years (1.5–17.0). Median number of cycles was 3 (1–17); irinotecan dose reductions occurred in 62%. Grade 3 dose-limiting toxicities were reported with concomitant (periph- eral neuropathy and liver injury [1]; pain, vomiting, febrile aplasia [1]) and sequential (rash and elevated aspartate aminotransferase [1]; thrombocytopenia [1]) dosing. Concomitant dosing was discontinued Maximum tolerated dose and recommended phase 2 dose (RP2D) of regorafenib in sequential combination was 82 mg/m 2 . Most com-mon grade 3 toxicities were neutropenia (71%), thrombocytope- nia (33%), leukopenia (29%), anemia (24%), and alanine aminotrans-ferase increased (24%). Response rate was 38%, including 1 complete (RMS) and 7 partial responses (5 RMS, 2 Ewing sarcoma); 3 had prior irinotecan. Of 12 patients with RMS, 6 (4 with alveolar subtype) had a response. Nine patients (43%) had stable disease (maximum 17 cycles). After the cut-off, 2 additional patients (1 RMS, 1 Ewing sarcoma) had a partial response. Conclusions: Regorafenib can be combined at its single-agent RP2D of 82 mg/m 2 with standard-dose vincristine/irinotecan (with appropri- ate dose modifications) in pediatric patients with refractory/relapsed solid tumors in a sequential dosing schedule. Activity was observed in patients with sarcoma
  • Prognostic factors for survival with metastatic spinal cord compression in the SCORAD randomized trial

    Hoskin, Peter J; Lopes, A.; Hackshaw, A.; Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, (2020)
    Purpose/Objective(s): SCORAD randomized 686 patients with metastatic spinal cord compression (MSCC) to receive either a single dose of 8Gy or 20Gy in 5 fractions; no significant difference in survival, recovery of ambulatory status or pain control was seen (Hoskin et al, 2019). Survival with MSCC after radiotherapy is poor and variable. The aim of this study was to establish a prognostic model for predicting overall survival in patients with MSCC. Materials/Methods: The median overall survival in SCORAD is 13 weeks. This time point has been used for the analysis. SCORAD data was randomly divided into a training set (412, 60%) and a validation set (274, 40%) matched for key characteristics: treatment, ambulatory status, primary tumor and extent of metastases. Multivariable Cox analysis used twelve factors on the training set to select prognostic factors for overall survival: treatment, sex, extent of metastases, number of MSCC sites, baseline bowel and bladder function, prior chemotherapy, radiotherapy or hormonal status, baseline ambulatory status, primary tumor and location of MSCC. Using backward elimination with a significance level of 0.20 and keeping treatment in the model, five factors were retained as prognostic factors: sex, extent of metastases, primary tumor, baseline ambulatory status and location of MSCC. Receiver operating characteristic (ROC) analysis was performed to evaluate the accuracy of the reduced model in predicting 13-week overall survival. Specific cut-off values associated with sensitivity rates for fixed false positive rate values were identified. Results: The model indicates that, adjusted for treatment, females had decrease risk of death compared with males (HR:0.66: 95% CI 0.47 to 0.92, p Z 0.02) as well as patients with SCC located in L1-S2 (HR:0.69: 95% CI 0.52 to 0.92, p Z 0.01) and T6-L5 (HR:0.71:95% CI 0.44 to 1.16, p Z 0.17) compared with C1-T12. Poor survival was associated with presence of nonskeletal mets [HR: 1.31: 95%CI 1.04 to 1.65 , p Z 0.02], having lung (HR:3.98: 95% CI 2.85 to 5.54, p<0.001), gastrointestinal cancer (HR: 2.97, 95% CI 2.02 to 4.37, p<0.001) or a cancer other than prostate or breast cancer (HR:2.4: 95% CI 1.67 to 3.44, p<0.001). Patients classified with impaired ambulatory status at baseline were also at increased risk of death (grade 2, HR: 1.72: 95% CI 1.27 to 2.34, p Z p<0.001; grade 3, HR: 2.5, 95% CI 1.79 to 3.48, p<0.001; grade 4, HR: 2.04: 95%CI 1.3 to 3.2, p Z 0.002). The prognostic performance of the model was associated with a 13-weeks OS ROC area under the curve (AUC) of 0.75, 95%CI: 0.69 to 0.81. The risk score 0.996 for the 13- weeks OS had a false positive rate of 30% and corresponding sensitivity of 65.63%. Conclusion: The accuracy of this prognostic model developed in SCORAD is limited and is below the recommended level of AUC >0.85 for a strong prognostic performance. However, this model will guide patient management and provide the basis for stratification factors in further studies.
  • EARL: a multicentre phase III randomised trial to evaluate the efficacy of endobronchial electrocautery with autofluorescence bronchoscopy (AFB) surveillance versus AFB surveillance alone in high-grade bronchial dysplasia

    Kalinke, L.; Thakrar, R.; Daniels, H.; Rintoul, R.; Booton, R.; Hackshaw, Allan; Janes, S.; Lungs for Living Research Unit, London, United Kingdom (2020)
    Introduction: Bronchial pre-invasive lesions are precursors of squamous cell cancer. However, not every pre-invasive lesion is destined to this; some lesions may remain stable or even regress to normal epithelium. Performing surveillance with autofluorescence bronchoscopy (AFB), we have shown that 50% of high-grade lesions (HGLs), i.e. severe dysplasia/carcinoma in-situ, progress to cancer (unpublished). Their treatment remains controversial. Guidelines advocate surgical management. This carries inherent risk and its benefit has not been proven in a randomised trial; new lesions also develop, so a tissue-sparing strategy is needed. Methods: We are conducting a Cancer Research UK-funded, international multi-centre randomised trial to examine whether thermal ablation using bronchoscopic electrocautery of HGLs prevents their progression to cancer. Participants will be randomised to electrocautery and AFB surveillance or AFB surveillance alone. The trial will run across four centres (University College London Hospital, Wythenshawe, Papworth and VUmc, Amsterdam)and opens in December 2019. We aim to recruit 106 participants within 3 years. Referral criteria are: 1. Individuals with HGLs found incidentally on bronchial biopsy or at resection margins post-operatively (even if found up to one year previously) 2. Individuals with abnormal sputum cytology, but normal CT and/or bronchoscopy All participants will have a chest CT, pulmonary function tests and AFB at baseline, and then AFB at 6, 12, 24 and 36 months. Participants can receive two electrocautery treatments per year over the 3-year trial period. Results: The primary endpoint is the time to progression of any HGL in a patient to invasive lung cancer. Secondary outcomes are (i) cancer-free and overall survival, (ii) health-related quality of life and (iii) cost-effectiveness. Conclusion: The EARL trial is the first Phase III randomised trial of an endobronchial therapy for the prevention of lung cancer. If successful, it will address the unmet clinical need for a proven tissue-sparing therapy for this high-risk population.

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