Now showing items 1-20 of 12098

    • Advanced small intestine well-differentiated neuroendocrine tumors (WD-SiNET): A survey of practice on 3rd line treatment

      Lamarca, Angela; Cives, M.; de Mestier, L.; Crona, J.; Spada, F.; Oberg, K.; Pavel, M.; Alonso-Gordoa, T.; The Christie NHS Foundation Trust, Manchester, (2021)
      Introduction: Selection of third-line treatment after somatostatin analogues (SSA) and Peptide Receptor Radionuclide Therapy (PRRT) for WD-SiNETs remains challenging. Aim(s): Understand current practice and rationale for decision-making in the 3rd-line setting after SSA and PRRT. Materials and methods: An online survey (replies collected between 5/8/2020 and 21/9/2020) was built. Weighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored. Results: A total of 28 replies; medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from ENETS CoE (57.1%), who followed ENETS guidelines (82.1%). Overall, 3rd-line treatment for WD-SiNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%) or personal experience (22.2%). EVE was likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3rd-line setting (WA 3.23/4); irrespective of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was chosen if rapid progression (within 6 months) (WA 3.35/4), Ki-67 10-20% (WA 2.77/4), negative SSTR2 imaging (WA 2.65/4) or high tumor burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-FU (57.7%), FOLFOX (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4). Conclusion: Selection of 3rd line therapy is based on multiple factors mainly Ki-67, rate of progression, CS and tumor burden; decisions should be made within a multidisciplinary setting
    • Systemic and intracranial efficacy of brigatinib vs.crizotinib: updated results from the ALTA-1L Trial

      Popat, S.; Kim, H. R.; Ahn, M. J.; Yang, J. C. H.; Han, J. Y.; Hochmair, M.; Lee, K. H.; Delmonte, A.; Campelo, M. R. G.; Kim, D. W.; et al. (2021)
      Background: At ALTA-1L (NCT02737501) first interim analysis (IA1), brigatinib demonstrated superior BIRC-assessed PFS and iPFS vs crizotinib. We report IA2 results, planned at w75% of 198 expected PFS events. Methods: Patients with TKI-naive advanced ALK+ NSCLC were randomized 1:1 to brigatinib 180 mg qd (7-day lead-in at 90 mg) or crizotinib 250 mg bid. Endpoints: Primary, BIRC-assessed PFS (RECIST v1.1); secondary included confirmed ORR and iORR, and iPFS (BIRC). Results: 275 patients were randomized (brigatinib/crizotinib, n¼137/ 138); median age, 58/60 years; prior chemotherapy, 26%/27%; baseline brain metastases (BIRC), 34%/36%; brain radiotherapy, 13%/ 14% (WBRT/SRS balanced across arms). At data cutoff (28 June 2019, median follow-up [brigatinib/crizotinib], 24.9/15.2 months, 150 PFS events): BIRC-assessed PFS HR, 0.49 (95% CI, 0.35e0.68, log-rank P<0.0001); brigatinib mPFS, 24.0 months (95% CI, 18.5eNE) vs crizotinib 11.0 months (9.2e12.9). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31e0.61, median 29.4 vs 9.2 months). OS was immature (total events: 33/37, brigatinib/crizotinib). In patients with baseline brain metastases, PFS HR was 0.25; data were less mature in brigatinib patients without brain metastases. Additional results in Table. Radiological overall disease progression occurred in (brigatinib vs crizotinib) 54 (39%) vs 74 (54%) patients (BIRC) and 50 (36%) vs 84 (61%) (investigator); of these, brain was first site of progression more frequently with crizotinib vs brigatinib: 31 (42%) vs 17 (31%) patients (BIRC); 22 (26%) vs 7 (14%) (investigator). Most common TEAEs grade 3: brigatinib: increased CPK (24.3%) and lipase (14.0%), hypertension (11.8%); crizotinib: increased ALT (10.2%), AST (6.6%), lipase (6.6%). Brigatinib significantly delayed median time to deterioration vs crizotinib for global health score/QoL (log-rank P¼0.0485), emotional and social functioning, fatigue, nausea and vomiting, appetite loss, constipation. Conclusions: Brigatinib demonstrated superior systemic and intracranial efficacy vs crizotinib in all patients with TKInaive ALK+ NSCLC and in patients with baseline brain metastases.
    • Molecular profiling of well-differentiated neuroendocrine tumors: Role of ctDNA

      Lamarca, Angela; Frizziero, Melissa; Barriuso, Jorge; Kapacee, Zainul Abedin; Mansoor, Was; McNamara, Mairead G; Hubner, Richard A; Valle, Juan W; The Christie NHS Foundation Trust, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, (2021)
      Introduction: Tumor molecular profiling has proven relevant for the clinical management of cancer. Circulating tumor DNA (ctDNA) may be a useful surrogate of tumor tissue when this is insufficient for analysis. Aim(s): Aims: Rate of test failure, detection rate of pathological alterations (PAs) and impact on management. Materials and methods: Patients (pts) with well-differentiated neuroendocrine tumors (WdNETs) underwent ctDNA-based molecular profiling (FoundationLiquid®); non-WdNETs (paraganglioma, goblet cell or poorly differentiated neuroendocrine carcinoma) were used for comparison. Results: Fifteen pts with WdNET (18 ctDNA samples) included: 8 female (53.33%), median age 63.2 years (range 23.5-86.8). Primary: small bowel (8;53.3%); pancreas (5;33.3%); gastric (1;6.7%) and unknown primary (1;6.7%); grade (G)1 (n=5;33.3%); G2 (9;60.0%) and G3 (1;6.7%); median Ki-67: 5% (range 1-30). Thirty pts with non-WdNETs pts (34 ctDNA samples) were included. Five WdNETs samples (27.78%) failed analysis (vs 17.65% in non-WdNETs; p 0.395). Of 13 WdNET samples with successful ctDNA, PAs were detected in 6 (46.15%) (vs 82.14% in non-WdNETs; p 0.018). In WdNETs, PA rate was independent of anti-cancer systemic therapy (2/7;28.57% vs 4/6;66.67%; p 0.286) at time of ctDNA: 4, 1 and 1 samples had 1, 2 and 3 PAs, respectively; these were: CDKN2A mutation (m) (1 sample), CHEK2m (1), TP53m (2), FGFR2amplif (1), IDH2m (1), CTNNB1m (1), NF1m (1), PALB2m (1); nontargetable (0%) or impacted management (0%). There was a trend towards lower maximum mutant allele frequency (mMAF) in WdNETs (mean 0.33) vs non-WdNETs (mean 26.99); p 0.0584. Conclusion: Although feasible, ctDNA molecular profiling was of limited clinical utility for advanced WdNETs. Identification of PAs and mMAF seem higher in non-WdNETs.
    • Incidence of brain metastases (BMs) and outcomes in patients (pts) with extrapulmonary neuroendocrine neoplasms (EP-NENs)

      Kapacee, Zainul Abedin; Dawod, Mohammed; Allison, Jennifer; Frizziero, Melissa; Chakrabarty, Bipasha; Manoharan, Prakash; McBain, Catherine A; Mansoor, Was; Lamarca, Angela; Hubner, Richard A; et al. (2021)
      Introduction: The incidence, management and outcomes of pts with EP-NENs and BMs are unclear. Aim(s): To investigate outcomes in pts with EP-NENs ± BMs. Materials and methods: A retrospective study of consecutive pts with EP-NENs and BMs treated at a single ENETS CoE was performed. Median (med) overall survival (OS)/survival from BM diagnosis were estimated (Kaplan Meier). Results: Between Aug 04-Feb 20, 730 pts with an EP-NEN diagnosis were identified: med age 64 yrs (15-90); 56% male, 67% had advanced disease (ADVD). In pts with ADVD, the primary NEN site were: small bowel 42%, pancreas 22%, unknown 14%, large bowel 10%, other 5%, stomach 4% and appendix <1%; 37%, 30% and 30% pts had grade (G)1, 2 and 3 EP-NENs respectively (no grading 3%). Med OS for pts with ADVD G1, 2 and 3 EP-NENs without BMs were 95.8 (95% C.I 77.0-177.1), 61.7 (95% C.I 50.1-124.4) and 11.3 (95% C.I 9.3-14.4) months (mo) respectively. 17 pts (2.3%) developed BMs; 2 at initial diagnosis, 15 metachronously; 5 pts (29%) had a solitary BM, 12 (71%) had multiple BMs. The primary sites of origin were: unknown 41%, oesophagus 18%, pancreas 17%, small bowel 12%, cervix 6% and bladder 6%; 6%, 24% and 70% had G1, G2 and G3 EP-NENs respectively. Most common presenting symptoms of pts with BMs were limb weakness and cognitive impairment. Pts with BMs received high dose steroids and best supportive care (35%), whole brain radiotherapy with steroids (29%), surgery (18%) and localised radiotherapy (6%). Med OS for pts with G1+2 EP-NENs and BMs was not reached. Med OS in pts with G3 EP-NENs and BMs was 9.0 mo (95% CI 6.0-12.1); med survival from BM diagnosis was 2.0 mo (95% CI 0.0-4.4). Conclusion: BMs in pts with EP-NENs are rare, predominant in G3 NENs, and have a poor prognosis. Improved therapeutic options are needed.
    • Assessing the management of bone metastases in patients diagnosed with neuroendocrine neoplasms: Re-audit of clinical practice

      Garcia-Torralba, E; Lim, Kok Haw Jonathan; Barriuso, Jorge; McNamara, Mairead G; Hubner, Richard A; Mansoor, Was; Valle, Juan W; Lamarca, Angela; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, (2021)
      Introduction: There remains no global consensus on the optimal management of bone metastases in patients with neuroendocrine neoplasms (BM-NEN). Aim(s): To re-audit the clinical management of BM-NEN following the incorporation of institutional guidelines (TC-BM Guid) established in 2018 (PMID: 31639796). Materials and methods: Retrospective study of all patients with BM-NEN diagnosed from Jan-Dec 2019 following TC-BM Guid. Characteristics of BM-NEN and treatment received were evaluated against TC-BM Guid. Statistical analysis was performed using STATA v14. Results: Of 354 patients, 40 (11%) had BM (gastrointestinal: 53%, N=21; lung: 15%, N=6; unknown primary: 12%, N=5; other: 20%, N=8). BM were “widespread” in 80% (N=32). Compared to the cohort prior to TC-BM Guid implementation (2002-2018, N=85), incidence of symptoms (any), pain/hypercalcemia, and skeletal-related events were lower (45%, N=18 vs 78%, N=66; 40%, N=16 vs 64%, N=54; 13%, N=5 vs 20%, N=17, respectively). Use of analgesia for symptomatic BMs (80%, N=32 vs 44%, N=37) and use of bisphosphonates (33%, N=13 vs 22%, N=19) were higher. Use of radiotherapy and surgery were similar (23%, N=9 and 3%, N=1 respectively). The re-audit showed that management adhered to TC-BM Guid in the majority of patients (95%, N=38), including 4 patients who received best supportive care due to poor performance status (PS) and short prognosis (<3 months), which was not previously detailed in the guidelines. Conclusion: TC-BM Guid are deliverable, and current management of BM-NEN mostly adhered to these. Following this, TC-BM Guid were updated to reflect recommendations for symptomatic management only (best supportive care) for patients with poor PS/short life-expectancy.
    • Empowerment survey for patients with neuroendocrine tumors - A pilot study in Spanish population

      Hernando, J.; Sampedro-Nunez, M.; de Nova, J. L. M.; Trivino, E. M.; Vazquez, G.; Hernandez, X.; Fernandez, E.; Cusido, E.; Guaras, B.; Olmo-Garcia, M.; et al. (2021)
      Introduction: Quality of life is very important in patients with neuroendocrine tumors (NET), but other aspects such as satisfaction and empowerment of patients have been less studied. In Spain, there is a lack of validated cancer empowerment questionnaires. Aim(s): The aim of the present study is to conduct a pilot test with an online survey of patient’s empowerment in NET in the Spanish population. Materials and methods: The Spanish survey was designed with previous general health empowerment questionnaires (Health Education Impact Questionnaire, Maunsell 2014), internal hospital satisfaction scores, and direct feedback from NET-España Patient Advocacy group. The final survey was approved by GETNE Academy taskforce. Anonymous online survey was conducted between August and November 2020 in NET patients from NET-España association in Spain. Results: 67 NET patients answered (95.5% completed all questions). Scale internal consistency was good. Most patients had medium or high levels of general empowerment-related to NET. We identified two main areas where most patients had a low level of empowerment, including psychological support and patient's self-management groups. Specific questions related to NET characteristics and NET-specific treatments reflect the situation of NET management in Spain and reveals a high knowledge about the biology of the disease and current available therapies. Conclusion: This NET empowerment survey is understandable, easy to answer, and useful to measure the empowerment of the Spanish population with NET. After this initial pilot experience, a larger study in an unselected population is necessary for the validation of this questionnaire.
    • To determine the true incidence of brain metastases in atypical lung neuroendocrine tumors and explore factors that increase the risk of intracranial disease

      Jones, J; Spurgeon, Laura; Shaheen, Fadhel; Lewis, Alexandra R; Mansoor, Was; Khan, Adeel; The Christie NHS Foundation Trust, Manchester (2021)
      Introduction: Lung neuroendocrine tumors (NETs) make up 25% of all NETs. Typical carcinoid (TC) and atypical carcinoid (AC) account for 2% and 0.2% of all lung NETs respectively, and AC tend to be more aggressive. Although both can metastasise, AC are more likely; common sites include bone and liver. Currently, brain imaging is not included in the work-up of TC/AC, as <5% of cases are thought to develop brain metastases (BM). However, evidence suggests this may be an underestimate. Identifying BM would inform management and could improve prognosis. Thus, evaluating the incidence in TC/AC is needed to ascertain whether there is justification for baseline brain imaging. Furthermore, Ki-67 could be useful as a predictive tool. Aim(s): To review the incidence of BM in TC/AC to determine whether there is justification for routine brain imaging and to explore factors which could increase the risk of BM. Materials and methods: Single site, retrospective analysis of 287 patients with TC/AC over a 13-year period. Incidence of BM (as detected on CT/MRI), at diagnosis or during the course of the disease, was reviewed. Results: None of the 215 TC patients developed BM, whereas 8 out of 72 (11.1%) with AC did; 50% of these were present at diagnosis. 13.04% of AC with BM had evidence of both bone and liver involvement. 75% of AC with BM had Ki-67 expression >15%. Conclusion: Over 10% of the AC developed BM, half of which were present at diagnosis. This provides convincing evidence of the need for baseline brain imaging in AC, particularly for patients with Ki-67 expression >15% or with bone and liver involvement, as these factors were associated with increased risk. Early detection and treatment of BM can improve outcomes
    • Predominantly solid hemangioblastoma presenting as an extra-axial cerebellopontine angle lesion

      Ahmed, Gasim; Sheikh, U.; Masri, S.; Joseph, J.; Sonwalker, H.; Radiology, Lancashire Teaching Hospital Foundation Trust, Presto (2021)
      Hemangioblastomas (HBs) are typically intra-axial, highly vascular tumors of the central nervous system and account for up to 2.5% of all intracranial tumors and up to 12% of posterior fossa neoplasms. Extra-axial HBs are rarely described in the literature. The radiological appearances of cerebellopontine angle (CPA) extra-axial HB can lead to a diagnostic conundrum as they may mimic the appearance of dural metastasis, vestibular schwannoma, or meningioma. Here, we describe a patient who presented with an extra-axial CPA HB and explore the literature of the condition.
    • Outcome of Stage IV completely necrotic wilms tumour and local stage III treated according to the SIOP 2001 protocol

      Dávila Fajardo, R.; Furtwängler, R.; van Grotel, M.; van Tinteren, H.; Pasqualini, C.; Pritchard-Jones, K.; Al-Saadi, R.; de Camargo, B.; Ramírez Villar, G. L.; Graf, N.; et al. (2021)
      Objective: Wilms tumour (WT) patients with a localised completely necrotic nephroblastoma after preoperative chemotherapy are a favourable outcome group. Since the introduction of the SIOP 2001 protocol, the SIOP- Renal Tumour Study Group (SIOP-RTSG) has omitted radiotherapy for such patients with low-risk, local stage III in an attempt to reduce treatment burden. However, for metastatic patients with local stage III, completely necrotic WT, the recommendations led to ambiguous use. The purpose of this descriptive study is to demonstrate the outcomes of patients with metastatic, completely necrotic and local stage III WT in relation to the application of radiotherapy or not. Methods and materials: all metastatic patients with local stage III, completely necrotic WT after 6 weeks of preoperative chemotherapy who were registered in the SIOP 2001 study were included in this analysis. The pattern of recurrence according to the usage of radiation treatment and 5 year event-free survival (EFS) and overall survival (OS) was analysed. Results: seven hundred and three metastatic WT patients were registered in the SIOP 2001 database. Of them, 47 patients had a completely necrotic, local stage III WT: 45 lung metastases (11 combined localisations), 1 liver/peritoneal, and 1 tumour thrombus in the renal vein and the inferior vena cava with bilateral pulmonary arterial embolism. Abdominal radiotherapy was administered in 29 patients (62%; 29 flank/abdominal irradiation and 9 combined with lung irradiation). Eighteen patients did not receive radiotherapy. Median follow-up was 6.6 years (range 1-151 months). Two of the 47 patients (4%) developed disease recurrence in the lung (one combined with abdominal relapse) and eventually died of the disease. Both patients had received abdominal radiotherapy, one of them combined with lung irradiation. Five-year EFS and OS were 95% and 95%, respectively. Conclusions: the outcome of patients with stage IV, local stage III, completely necrotic Wilms tumours is excellent. Our results suggest that abdominal irradiation in this patient category may not be of added value in first-line treatment, consistent with the current recommendation in the SIOP-RTSG 2016 UMBRELLA protocol.
    • Embryonic environmental niche reprograms somatic cells to express pluripotency markers and participate in adult chimaeras

      Żyżyńska-Galeńska, K.; Bernat, A.; Piliszek, A.; Karasiewicz, J.; Szablisty, E.; Sacharczuk, M.; Brewińska-Olchowik, M.; Bochenek, M.; Grabarek, Joanna; Modliński, J. A.; et al. (2021)
      The phenomenon of the reprogramming of terminally differentiated cells can be achieved by various means, like somatic cell nuclear transfer, cell fusion with a pluripotent cell, or the introduction of pluripotency genes. Here, we present the evidence that somatic cells can attain the expression of pluripotency markers after their introduction into early embryos. Mouse embryonic fibroblasts introduced between blastomeres of cleaving embryos, within two days of in vitro culture, express transcription factors specific to blastocyst lineages, including pluripotency factors. Analysis of donor tissue marker DNA has revealed that the progeny of introduced cells are found in somatic tissues of foetuses and adult chimaeras, providing evidence for cell reprogramming. Analysis of ploidy has shown that in the chimaeras, the progeny of introduced cells are either diploid or tetraploid, the latter indicating cell fusion. The presence of donor DNA in diploid cells from chimaeric embryos proved that the non-fused progeny of introduced fibroblasts persisted in chimaeras, which is evidence of reprogramming by embryonic niche. When adult somatic (cumulus) cells were introduced into early cleavage embryos, the extent of integration was limited and only cell fusion-mediated reprogramming was observed. These results show that both cell fusion and cell interactions with the embryonic niche reprogrammed somatic cells towards pluripotency.
    • Adolescents and young adults living with an uncertain or poor cancer prognosis: the 'new' lost tribe

      Burgers, V. W. G.; van der Graaf, W. T. A.; van der Meer, D. J.; McCabe, Martin G; Rijneveld, A. W.; van den Bent, M. J.; Husson, O.; Department of Psychosocial Research and Epidemiology, Netherlands Cancer Institute. Department of Medical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam (2021)
      Historically, adolescent and young adult (AYA) patients with cancer, diagnosed for the first time at age 15 through 39 years, have often been identified as a "lost tribe" without a medical "home"; neither pediatric nor adult oncology services were able to provide age-appropriate care to this specific group. Internationally, AYA care programs are being established to bridge the gap between the age-defined healthcare worlds and to address the specific needs of AYAs with cancer. However, AYA care programs mostly focus on improving cure rates and addressing survivorship issues, and direct less attention to the unique needs of those living with an uncertain and/or poor cancer prognosis. Additionally, palliative care services are typically poorly equipped to address the age-specific needs of this group. Given that increasingly more AYAs with an uncertain and/or poor cancer prognosis are gaining life years because of novel treatments, and sometimes even face the prospect of long-term disease control, AYA care programs should address the unique palliative care needs of this "new" lost tribe within AYA oncology. This report provides a definition and description of the AYA population living with an uncertain and/or poor cancer prognosis in terms of epidemiologic, clinical, and psychosocial characteristics and challenges, and provides perspectives for future research and care initiatives. It also highlights the need to comprehensively examine the experience of AYAs who are living with uncertain and/or poor cancer prognosis to adjust best care practices for this unique group
    • Developing tumor radiosensitivity signatures using LncRNAs

      Khan, Mairah T; Yang, Lingjian; More, Elisabet; Irlam-Jones, Joely J; Valentine, Helen R; Hoskin, Peter J; Choudhury, Ananya; West, Catharine M L; Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie NHS Foundation Trust Hospital, Manchester M20 4BX (2021)
      Long non-coding RNAs (lncRNAs) are involved in diverse biological processes, including DNA damage repair, and are of interest as potential biomarkers of radiosensitivity. We investigated whether lncRNA radiosensitivity signatures could be derived for use in cancer patients treated with radiotherapy. Signature development involved radiosensitivity measurements for cell lines and primary tumor samples, and patient outcome after radiotherapy. A 10-lncRNA signature trained on radiosensitivity measurements in bladder cell lines showed a trend towards independent validation. In multivariable analyses, patients with tumors classified as radioresistant by the lncRNA signature had poorer local relapse-free survival (P = 0.065) in 151 patients with muscle-invasive bladder cancer who underwent radiotherapy. An mRNA-based radiosensitivity index signature performed similarly to the lncRNA bladder signature for local relapse-free survival (P = 0.055). Pathway analysis showed the lncRNA signature associated with molecular processes involved in radiation responses. Knockdown of one of the lncRNAs in the signature showed a modest increase in radiosensitivity in one cell line. An alternative approach involved training on primary cervical tumor radiosensitivity or local control after radiotherapy. Both approaches failed to generate a cervix lncRNA radiosensitivity signature, which was attributed to the age of samples in our cohorts. Our work highlights challenges in validating lncRNA signatures as biomarkers in archival tissue from radiotherapy cohorts, but supports continued investigation of lncRNAs for a role in radiosensitivity.
    • Distribution and clinical role of KIT gene mutations in melanoma according to subtype: a study of 492 Spanish patients

      Millán-Esteban, D.; García-Casado, Z.; Manrique-Silva, E.; Virós, Amaya; Kumar, R.; Furney, S.; López-Guerrero, J. A.; Requena, C.; Bañuls, J.; Traves, V.; et al. (2021)
      Background: KIT mutations are primarily associated with acral and mucosal melanoma, and have been reported to show higher prevalence in chronic sun-damaged (CSD) than non-CSD melanomas. Objectives: To investigate the prevalence of KIT mutations in melanoma according to subtype, and determine the clinical role of such mutations. Material & methods: We present results from a study of a Spanish population of 492 melanomas, classified according to the latest World Health Organization (WHO) guidelines. We analysed the mutational status of KIT and correlated with different clinical variables related to sun exposure and family history. Results: KIT mutations were significantly more frequent in acral (3/36; 8.3%) and mucosal (4/8; 50%) melanomas than non-acral cutaneous melanomas. No significant difference was observed in KIT mutational status between CSD and non-CSD melanomas. Conclusion: Our results suggest that KIT mutations in melanoma tumours are unrelated to the development of nevi or chronic sun damage, but their presence is associated with aggressive melanomas which show ulceration, vascular invasiveness, and increased Breslow thickness. These findings are consistent with those reported by The Cancer Genome Atlas network.
    • Patient-reported outcomes with durvalumab by PD-L1 expression and prior chemoradiotherapy-related variables in unresectable stage III non-small-cell lung cancer

      Garassino, M. C.; Paz-Ares, L.; Hui, R.; Faivre-Finn, Corinne; Spira, A.; Planchard, D.; Özgüroğlu, M.; Daniel, D.; Vicente, D.; Murakami, S.; et al. (2021)
      Aim: We retrospectively investigated the impact of tumor PD-L1 expression and prior chemoradiotherapy (CRT)-related variables on patient-reported outcomes (PROs) from PACIFIC. Patients & methods: PACIFIC was a Phase III study of durvalumab versus placebo after CRT in patients with unresectable, stage III non-small-cell lung cancer. If available, pre-CRT tumor tissue was tested for PD-L1 tumor-cell expression, scored at prespecified (25%) and post-hoc (1%) cut-offs. PROs were assessed using EORTC QLQ C30/-LC13. Results: Similar to the intent-to-treat (ITT) population, most PROs remained stable over time across PD-L1 and CRT subgroups, with few clinically relevant differences between treatment arms. Time to deterioration was generally similar to the ITT population. Conclusion: Neither PD-L1 expression nor prior CRT-related variables influenced PROs with durvalumab therapy. Clinical trial registration: NCT02125461 (ClinicalTrials.gov).
    • A position statement on the utility of interval imaging in standard of care brain tumour management: defining the evidence gap and opportunities for future research

      Booth, T. C.; Thompson, G.; Bulbeck, H.; Boele, F.; Buckley, C.; Cardoso, J.; Dos Santos Canas, L.; Jenkinson, D.; Ashkan, K.; Kreindler, J.; et al. (2021)
      Objectiv e: To summarise current evidence for the utility of interval imaging in monitoring disease in adult brain tumours, and to develop a position for future evidence gathering while incorporating the application of data science and health economics. Methods: Experts in 'interval imaging' (imaging at pre-planned time-points to assess tumour status); data science; health economics, trial management of adult brain tumours, and patient representatives convened in London, UK. The current evidence on the use of interval imaging for monitoring brain tumours was reviewed. To improve the evidence that interval imaging has a role in disease management, we discussed specific themes of data science, health economics, statistical considerations, patient and carer perspectives, and multi-centre study design. Suggestions for future studies aimed at filling knowledge gaps were discussed. Results: Meningioma and glioma were identified as priorities for interval imaging utility analysis. The "monitoring biomarkers" most commonly used in adult brain tumour patients were standard structural MRI features. Interval imaging was commonly scheduled to provide reported imaging prior to planned, regular clinic visits. There is limited evidence relating interval imaging in the absence of clinical deterioration to management change that alters morbidity, mortality, quality of life, or resource use. Progression-free survival is confounded as an outcome measure when using structural MRI in glioma. Uncertainty from imaging causes distress for some patients and their caregivers, while for others it provides an important indicator of disease activity. Any study design that changes imaging regimens should consider the potential for influencing current or planned therapeutic trials, ensure that opportunity costs are measured, and capture indirect benefits and added value. Conclusion: Evidence for the value, and therefore utility, of regular interval imaging is currently lacking. Ongoing collaborative efforts will improve trial design and generate the evidence to optimise monitoring imaging biomarkers in standard of care brain tumour management.
    • CUL2(LRR1) , TRAIP and p97 control CMG helicase disassembly in the mammalian cell cycle

      Villa, F.; Fujisawa, R.; Ainsworth, J.; Nishimura, K.; Lie-A-Ling, Michael; Lacaud, Georges; Labib, K. P.; The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee (2021)
      The eukaryotic replisome is disassembled in each cell cycle, dependent upon ubiquitylation of the CMG helicase. Studies of Saccharomyces cerevisiae, Caenorhabditis elegans and Xenopus laevis have revealed surprising evolutionary diversity in the ubiquitin ligases that control CMG ubiquitylation, but regulated disassembly of the mammalian replisome has yet to be explored. Here, we describe a model system for studying the ubiquitylation and chromatin extraction of the mammalian CMG replisome, based on mouse embryonic stem cells. We show that the ubiquitin ligase CUL2LRR1 is required for ubiquitylation of the CMG-MCM7 subunit during S-phase, leading to disassembly by the p97 ATPase. Moreover, a second pathway of CMG disassembly is activated during mitosis, dependent upon the TRAIP ubiquitin ligase that is mutated in primordial dwarfism and mis-regulated in various cancers. These findings indicate that replisome disassembly in diverse metazoa is regulated by a conserved pair of ubiquitin ligases, distinct from those present in other eukaryotes.
    • Contributions of embryonic hsc-independent hematopoiesis to organogenesis and the adult hematopoietic system

      Neo, W H; Lie-A-Ling, Michael; Fadlullah, Muhammad Z H; Lacaud, Georges; Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Macclesfield (2021)
      During ontogeny, the establishment of the hematopoietic system takes place in several phases, separated both in time and location. The process is initiated extra-embryonically in the yolk sac (YS) and concludes in the main arteries of the embryo with the formation of hematopoietic stem cells (HSC). Initially, it was thought that HSC-independent hematopoietic YS cells were transient, and only required to bridge the gap to HSC activity. However, in recent years it has become clear that these cells also contribute to embryonic organogenesis, including the emergence of HSCs. Furthermore, some of these early HSC-independent YS cells persist into adulthood as distinct hematopoietic populations. These previously unrecognized abilities of embryonic HSC-independent hematopoietic cells constitute a new field of interest. Here, we aim to provide a succinct overview of the current knowledge regarding the contribution of YS-derived hematopoietic cells to the development of the embryo and the adult hematopoietic system.
    • Metabolomic biomarkers for the detection of obesity-driven endometrial cancer

      Njoku, K.; Campbell, A. E.; Geary, B.; MacKintosh, M. L.; Derbyshire, A. E.; Kitson, S. J.; Sivalingam, V. N.; Pierce, Andrew; Whetton, Anthony D; Crosbie, E. J.; et al. (2021)
      Endometrial cancer is the most common malignancy of the female genital tract and a major cause of morbidity and mortality in women. Early detection is key to ensuring good outcomes but a lack of minimally invasive screening tools is a significant barrier. Most endometrial cancers are obesity-driven and develop in the context of severe metabolomic dysfunction. Blood-derived metabolites may therefore provide clinically relevant biomarkers for endometrial cancer detection. In this study, we analysed plasma samples of women with body mass index (BMI) ≥30kg/m2 and endometrioid endometrial cancer (cases, n = 67) or histologically normal endometrium (controls, n = 69), using a mass spectrometry-based metabolomics approach. Eighty percent of the samples were randomly selected to serve as a training set and the remaining 20% were used to qualify test performance. Robust predictive models (AUC > 0.9) for endometrial cancer detection based on artificial intelligence algorithms were developed and validated. Phospholipids were of significance as biomarkers of endometrial cancer, with sphingolipids (sphingomyelins) discriminatory in post-menopausal women. An algorithm combining the top ten performing metabolites showed 92.6% prediction accuracy (AUC of 0.95) for endometrial cancer detection. These results suggest that a simple blood test could enable the early detection of endometrial cancer and provide the basis for a minimally invasive screening tool for women with a BMI ≥ 30 kg/m2.
    • Randomised controlled trial evidence questions the assumption that pulmonary metastasectomy benefits patients with colorectal cancer

      Batchelor, T.; Hasan, Jurjees; Macbeth, F.; Shackcloth, M.; Treasure, T.; Bristol Royal Infirmary, Bristol, UK. (2021)
      Pulmonary metastasectomy for sarcoma is surgery without proven benefit, and in the light of a randomized controlled trial examining pulmonary metastasectomy in colorectal cancer, it should be questioned.
    • Safety and activity of autologous T cells with enhanced NY-ESO-1-specific T-cell receptor (GSK3377794) in HLA-a*02(+) previously-treated and - untreated patients with advanced metastatic/unresectable synovial sarcoma: A master protocol study design (IGNYTE-ESO)

      D'Angelo, S. P.; Blay, J. Y.; Chow, W. A.; Demetri, G. D.; Thistlethwaite, Fiona C; Sen, S.; Razak, A. R. A.; Haanen, J.; Noujaim, J. C.; Johnson, M. L.; et al. (2020)
      Background: T cells modified to target NY-ESO-1 have shown encouraging activity in HLA-A*02+ patients with NY-ESO-1–positive synovial sarcoma. NY-ESO-1 is a cancer/testis antigen that is expressed across multiple tumor types and highly expressed in synovial sarcoma. NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR able to recognize NY-ESO-1 epitope in complex with HLA-A*02. Ongoing trials are evaluating GSK3377794 in multiple solid tumors and multiple myeloma. Methods: This study (NCT03967223) uses a Master Protocol design that allows investigation of GSK3377794 in multiple tumor types under the same protocol in separate substudies. The first two are single-arm substudies in patients with advanced metastatic or unresectable synovial sarcoma: treatment-naïve (1st line [1L], substudy 1; n = 10 planned) and progressing after anthracycline-based chemotherapy (2L+, substudy 2; n = 55 planned). Patients must be aged ≥10 years, have adequate organ function, ECOG performance status 0–1, measurable disease, and no central nervous system metastases. Excluded prior treatments include gene therapy with an integrating vector or NY-ESO-1–specific T cells, vaccine or targeting antibody, or allogeneic stem cell transplant. Patients will undergo leukapheresis and manufacture of GSK3377794; lymphodepletion then GSK3377794 infusion, followed by safety and disease assessments; and long-term follow-up for 15 years (under a separate protocol). The primary objective of substudy 2 is overall response rate per RECIST v1.1 by central independent review. Secondary objectives include time to response, duration of response, disease control rate, progression-free survival, overall survival, plus safety and tolerability. Exploratory objectives include assessment of the correlation of T-cell persistence with safety, clinical responses, and infused T-cell phenotype. Evaluation of quality of life and daily functioning of patients will also be assessed. Enrollment began in December 2019. These data are presented on behalf of the original authors with their permission. A similar presentation (P453) was presented at the SITC Annual Meeting, National Harbor, MD, USA, Nov 6–10, 2019. Funding: GlaxoSmithKline (208467) Clinical trial information: NCT03967223.