Now showing items 21-40 of 10365

    • Early detection of HPV-associated oropharyngeal cancer - Authors' reply

      Graham, Donna; Prue, G; Baker, P; Nutting, C; Greenhouse, P; Lawler, M; Christie NHS Foundation Trust, Manchester, UK (2019)
    • Organ preservation in bladder cancer: an opportunity for truly personalized treatment

      Song, Yee Pei; McWilliam, Alan; Hoskin, Peter J; Choudhury, Ananya; Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK (2019)
      Radical treatment of many solid tumours has moved from surgery to multimodal organ preservation strategies combining systemic and local treatments. Trimodality bladder-preserving treatment (TMT) comprises maximal transurethral resection of the bladder tumour followed by radiotherapy and concurrent radiosensitizing treatment, thereby sparing the urinary bladder. From the patient's perspective, the choice of maintaining quality of life without a negative effect on the chances of cure and long-term survival is attractive. In muscle-invasive bladder cancer (MIBC), the evidence shows comparable clinical outcomes between patients undergoing radical cystectomy and TMT. Despite this evidence, many patients continue to be offered radical surgery as the standard-of-care treatment. Improvements in radiotherapy techniques with adaptive radiotherapy and advances in imaging translate to increases in the accuracy of treatment delivery and reductions in long-term toxicities. With the advent of novel biomarkers promising improved prediction of treatment response, stratification of patients for different treatments on the basis of tumour biology could soon be a reality. The future of oncological treatment lies in personalized medicine with the combination of technological and biological advances leading to truly bespoke management for patients with MIBC.
    • Communicative constructions of person-centred and non-person-centred caring in nurse-led consultations

      Siouta, E; Farrell, Carole; Chan, E; Walshe, C; Molassiotis, A; Department of Neurobiology, Care Sciences and Society, Division of Nursing, Karolinska Institute, Stockholm, Sweden (2019)
      PURPOSE: Nursing is theorised to be a component of person-centred care. Communicative constructions of person-centred caring are a topic that needs to be studied in consultations. The study aimed to explore how person-centred caring and non-person- centred caring are verbally constructed in consultations between patients and nurse. METHOD: This study was qualitative using audio-recorded observations from consultations with advanced nurse practitioners in nurse-led chemotherapy clinics from four hospitals in the UK through purposive sampling. Discourse analysis was used to identify communicative patterns in 45 non-participant observations of nurse consultations. RESULTS: The dominant discourse was a non-person-centred oriented discourse framed by the biomedical model. It was also possible to identify fragments of an alternative discourse-a person-oriented discourse localising health problems within the patient's personal and sociocultural context. CONCLUSIONS: The prominent use of a non-person-oriented discourse focusing on the medical/technical aspects of a patient's assessment/evaluation in consultations may make it difficult for patients to raise questions and concerns from their daily lives during consultations. However, fragments of a person-oriented discourse show that it is possible for nurses to allow a person-centred approach to the consultation. The pedagogical implications have to do with raising nurses' awareness of the role of evaluative language in enhancing person-centred communication with patients in clinical interactions.
    • Time to change the limited-stage paradigm for small cell lung cancer? - In reply

      Salem, Ahmed; Faivre-Finn, Corinne; Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom (2019)
    • Novel phase I trial design to evaluate the addition of cediranib or selumetinib to preoperative chemoradiotherapy for locally advanced rectal cancer: the DREAMtherapy trial

      Marti-Marti, Francisca; Jayson, Gordon C; Manoharan, Prakash; O'Connor, James PB; Renehan, Andrew G; Backen, Alison C; Mistry, H; Ortega, F; Li, K; Simpson, Kathryn L; et al. (2019)
      BACKGROUND: The DREAMtherapy (Dual REctal Angiogenesis MEK inhibition radiotherapy) trial is a novel intertwined design whereby two tyrosine kinase inhibitors (cediranib and selumetinib) were independently evaluated with rectal chemoradiotherapy (CRT) in an efficient manner to limit the extended follow-up period often required for radiotherapy studies. PATIENTS AND METHODS: Cediranib or selumetinib was commenced 10 days before and then continued with RT (45 Gy/25#/5 wks) and capecitabine (825 mg/m2 twice a day (BID)). When three patients in the cediranib 15-mg once daily (OD) cohort were in the surveillance period, recruitment to the selumetinib cohort commenced. This alternating schedule was followed throughout. Three cediranib (15, 20 and 30 mg OD) and two selumetinib cohorts (50 and 75 mg BID) were planned. Circulating and imaging biomarkers of inflammation/angiogenesis were evaluated. RESULTS: In case of cediranib, dose-limiting diarrhoea, fatigue and skin reactions were seen in the 30-mg OD cohort, and therefore, 20 mg OD was defined as the maximum tolerated dose. Forty-one percent patients achieved a clinical or pathological complete response (7/17), and 53% (9/17) had an excellent clinical or pathological response (ECPR). Significantly lower level of pre-treatment plasma tumour necrosis factor alpha (TNF?) was found in patients who had an ECPR. In case of selumetinib, the 50-mg BID cohort was poorly tolerated (fatigue and diarrhoea); a reduced dose cohort of 75-mg OD was opened which was also poorly tolerated, and further recruitment was abandoned. Of the 12 patients treated, two attained an ECPR (17%). CONCLUSIONS: This novel intertwined trial design is an effective way to independently investigate multiple agents with radiotherapy. The combination of cediranib with CRT was well tolerated with encouraging efficacy. TNF? emerged as a potential predictive biomarker of response and warrants further evaluation.
    • Nothing is impossible: radiation induced angiosarcoma of breast in a male patient

      Tsapralis, Nikolaos; Vlachogiorgos, Apostolos; Pham, Hien; Mowatt, David J; Department of Reconstructive and Plastic Surgery, The Christie NHS Foundation Trust, Manchester M204BX, UK (2019)
      Breast cancer in men is rare and only about 390 men in the UK are diagnosed with breast cancer each year with an incidence rate in the UK of 1.5 cases per 100 000 men. In addition, the increased use of radiotherapy for management of breast cancer has led to a reported increase of radiation induced angiosarcomas (RIAS) with an incidence of 0.05-0.3%. Here we report a unique and extremely rare case of RIAS of breast in a male patient. To our knowledge this is the only case in the literature of a radiation induced angiosarcoma of the breast in a male.
    • Cysteine cathepsin protease inhibition: an update on its diagnostic, prognostic and therapeutic potential in cancer

      Soond, SM; Kozhevnikova, MV; Townsend, Paul A; Zamyatnin, AA; Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya str. 8-2, 119991 Moscow, Russia. (2019)
      In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic research in this area in a translational direction; recent findings have given rise to a number of exciting developments in the areas of cancer diagnosis; prognosis and therapeutic development. As a fast-moving area of research; the focus of this review brings together the latest findings and highlights the translational significance of these developments.
    • Letter to the editor in response to 'When to apply sunscreen: a consensus statement for Australia and New Zealand'

      Baldwin, L; Olsen, CM; Gordon, L; Green, Adele C; Aitken, J; Neale, R; Whiteman, D; Janda, M; Institute of Health and Biomedical Research, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Australia (2019)
    • REQUITE: a prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer

      Seibold, P; Webb, A; Aguado-Barrera, ME; Azria, D; Bourgier, C; Brengues, M; Briers, E; Bultijnck, R; Calvo-Crespo, P; Carballo, A; et al. (2019)
      PURPOSE: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. METHODS: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. RESULTS: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician- (47,025 forms) and patient- (54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n?=?4409) and PAXgene tubes (n?=?3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade ³2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). CONCLUSION: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. PATIENT SUMMARY: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short- and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity.
    • Addition of docetaxel to first-line long-term hormone therapy in prostate cancer (STAMPEDE): modelling to estimate long-term survival, quality-adjusted survival, and cost-effectiveness

      Woods, BS; Sideris, E; Sydes, MR; Gannon, MR; Parmar, MKB; Alzouebi, M; Attard, G; Birtle, AJ; Brock, S; Cathomas, R; et al. (2019)
    • High EMSY expression defines a BRCA-like subgroup of high-grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum

      Hollis, RL; Churchman, M; Michie, CO; Rye, T; Knight, L; McCavigan, A; Perren, T; Williams, ARW; McCluggage, WG; Kaplan, RS; et al. (2019)
      BACKGROUND: Approximately half of high-grade serous ovarian carcinomas (HGSOCs) demonstrate homologous recombination repair (HR) pathway defects, resulting in a distinct clinical phenotype comprising hypersensitivity to platinum, superior clinical outcome, and greater sensitivity to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. EMSY, which is known to be amplified in breast and ovarian cancers, encodes a protein reported to bind and inactivate BRCA2. Thus, EMSY overexpression may mimic BRCA2 mutation, resulting in HR deficiency. However, to our knowledge, the phenotypic consequences of EMSY overexpression in HGSOC patients has not been explored. METHODS: Here we investigate the impact of EMSY expression on clinical outcome and sensitivity to platinum-based chemotherapy using available data from transcriptomically characterized HGSOC cohorts. RESULTS: High EMSY expression was associated with better clinical outcome in a cohort of 265 patients with HGSOC from Edinburgh (overall survival multivariable hazard ratio, 0.58 [95% CI, 0.38-0.88; P = .011] and progression-free survival multivariable hazard ratio, 0.62 [95% CI, 0.40-0.96; P = .030]). Superior outcome also was demonstrated in the Medical Research Council ICON7 clinical trial and multiple publicly available data sets. Patients within the Edinburgh cohort who had high EMSY expression were found to demonstrate greater rates of complete response to multiple platinum-containing chemotherapy regimens (radiological complete response rate of 44.4% vs 12.5% at second exposure; P = .035) and corresponding prolonged time to disease progression (median, 151.5 days vs 60.5 days after third platinum exposure; P = .004). CONCLUSIONS: Patients with HGSOCs demonstrating high EMSY expression appear to experience prolonged survival and greater platinum sensitivity, reminiscent of BRCA-mutant cases. These data are consistent with the notion that EMSY overexpression may render HGSOCs HR deficient.
    • Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial

      Judson, I; Morden, JP; Kilburn, L; Leahy, Michael G; Benson, C; Bhadri, V; Campbell-Hewson, Q; Cubedo, R; Dangoor, A; Fox, L; et al. (2019)
      BACKGROUND: Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS. METHODS: In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing. FINDINGS: Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34á3 months (IQR 23á7-55á6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was -8á3% (IQR -26á5 to 5á9) with cediranib versus 13á4% (IQR 1á1 to 21á3) with placebo (one-sided p=0á0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase. INTERPRETATION: Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors. FUNDING: Cancer Research UK and AstraZeneca.
    • 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial

      Earl, H; Hiller, L; Vallier, A; Loi, S; McAdam, K; Hughes-Davies, L; Harnett, A; Ah-See, M; Simcock, R; Rea, D; et al. (2019)
      BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5á4 years (IQR 3á6-6á7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89á4% (95% CI 87á9-90á7) in the 6-month group and 89á8% (88á3-91á1) in the 12-month group (hazard ratio 1á07 [90% CI 0á93-1á24], non-inferiority p=0á011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0á0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0á0001). INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial.
    • Antigen-specific immunotherapy with thyrotropin receptor peptides in Graves' hyperthyroidism: a phase I study

      Pearce, S; Dayan, C; Wraith, D; Barrell, K; Olive, N; Jansson, L; Walker-Smith, T; Carnegie, C; Martin, K; Boelaert, K; et al. (2019)
      Background: Graves' disease is one of the most common autoimmune conditions, but treatment remains imperfect. This study explores the first-in-human use of antigen-specific immunotherapy with a combination of two thyrotropin receptor (TSHR) peptides (termed ATX-GD-59) in Graves' hyperthyroidism. Methods: Twelve participants (11 female) with previously untreated mild to moderate Graves' hyperthyroidism were enrolled in a Phase I open label trial to receive 10 doses of ATX-GD-59 administered intradermally over an 18-week period. Adverse events, tolerability, changes in serum free thyroid hormones, and TSHR autoantibodies were measured. Results: Ten subjects received all 10 doses of ATX-GD-59, five (50%) of whom had free triiodothyronine within the reference interval by the 18-week visit. Two further subjects had improved free thyroid hormones by the end of the study (7/10 responders), whereas three subjects showed worsening thyrotoxicosis during the study. Serum TSHR autoantibody concentrations reduced during the study and correlated with changes in free thyroid hormones (r?=?0.85, p?=?0.002 for TSHR autoantibody vs. free triiodothyronine). Mild injection-site swelling and pain were the most common adverse events. Conclusions: These preliminary data suggest that ATX-GD-59 is a safe and well-tolerated treatment. The improvement in free thyroid hormones in 70% of subjects receiving the medication suggests potential efficacy as a novel treatment for Graves' hyperthyroidism.
    • Assessment of the spatial heterogeneity of breast cancers: associations between computed tomography and immunohistochemistry

      Woolf, David K; Li, S; Detre, S; Liu, A; Gogbashian, A; Simcock, I; Stirling, J; Kosmin, M; Cook, G; Siddique, M; et al. (2019)
      Background: Tumour heterogeneity is considered an important mechanism of treatment failure. Imaging-based assessment of tumour heterogeneity is showing promise but the relationship between these mathematically derived measures and accepted 'gold standards' of tumour biology such as immunohistochemical measures is not established. Methods: A total of 20 women with primary breast cancer underwent a research dynamic contrast-enhanced computed tomography prior to treatment with data being available for 15 of these. Texture analysis was performed of the primary tumours to extract 13 locoregional and global parameters. Immunohistochemical analysis associations were assessed by the Spearman rank correlation. Results: Hypoxia-inducible factor-1? was correlated with first-order kurtosis (r?=?-0.533, P?=?.041) and higher order neighbourhood grey-tone difference matrix coarseness (r?=?0.54, P?=?.038). Vascular maturity-related smooth muscle actin was correlated with higher order grey-level run-length long-run emphasis (r?=?-0.52, P?=?.047), fractal dimension (r?=?0.613, P?=?.015), and lacunarity (r?=?-0.634, P?=?.011). Micro-vessel density, reflecting angiogenesis, was also associated with lacunarity (r?=?0.547, P?=?.035). Conclusions: The associations suggest a biological basis for these image-based heterogeneity features and support the use of imaging, already part of standard care, for assessing intratumoural heterogeneity
    • Safety and efficacy of the addition of lapatinib to perioperative chemotherapy for resectable HER2-positive gastroesophageal adenocarcinoma: a randomized phase 2 clinical trial

      Smyth, E; Rowley, S; Cafferty, F; Allum, W; Grabsch, H; Stenning, S; Wotherspoon, A; Alderson, D; Crosby, T; Mansoor, Was; et al. (2019)
      Importance: Perioperative chemotherapy and surgery are a standard of care for operable gastroesophageal adenocarcinoma. Anti-HER2 therapy improves survival in patients with advanced HER2-positive disease. The safety and feasibility of adding lapatinib to perioperative chemotherapy should be assessed. Objectives: To assess the safety of adding lapatinib to epirubicin, cisplatin, and capecitabine (ECX) chemotherapy and to establish a recommended dose regimen for a phase 3 trial. Design, Setting, and Participants: Phase 2 randomized, open-label trial comparing standard ECX (sECX: 3 preoperative and 3 postoperative cycles of ECX with modified ECX plus lapatinib (mECX+L). This multicenter national trial was conducted in 29 centers in the United Kingdom in patients with histologically proven, HER2-positive, operable gastroesophageal adenocarcinoma. Registration for ERBB/HER2 testing took place from February 25, 2013, to April 19, 2016, and randomization took place between May 24, 2013, and April 21, 2016. Data were analyzed May 10, 2017, to May 25, 2017. Interventions: Patients were randomized 1:1 open-label to sECX (3 preoperative and 3 postoperative cycles of 50 mg/m2 of intravenous epirubicin on day 1, 60 mg/m2 intravenous cisplatin on day 1, 1250 mg/m2 of oral capecitabine on days 1 through 21) or mECX+L (ECX plus lapatinib days 1 through 21 in each cycle and as 6 maintenance doses). The first 10 patients in the mECX+L arm were treated with 1000 mg/m2 of capecitabine and 1250 mg of lapatinib per day, after which preoperative toxic effects were reviewed according to predefined criteria to determine doses for subsequent patients. Main Outcomes and Measures: Proportion of patients experiencing grade 3 or 4 diarrhea with mECX+L. A rate of 20% or less was considered acceptable. No formal comparison between arms was planned. Results: Between February 2013, and April 2016, 441 patients underwent central HER2 testing and 63 (14%) were classified as HER2 positive. Forty-six patients were randomized; 44 (24 sECX, 20 mECX+L) are included in this analysis. Two of the first 10 patients in the mECX+L arm reported preoperative grade 3 diarrhea; thus, no dose increase was made. The primary endpoint of preoperative grade 3 or 4 diarrhea rates were 0 of 24 in the sECX arm (0%) and 4 of 20 in the mECX+L arm (21%). One of 24 in the sECX arm and 3 of 20 in the mECX+L arm stopped preoperative treatment early, and for 4 of 19 in the mECX+L arm, lapatinib dose was reduced. Postoperative complication rates were similar in each arm. Conclusions and Relevance: Administration of 1250 mg of lapatinib per day in combination with ECX chemotherapy was feasible with some increase in toxic effects, which did not compromise operative management.
    • This is a platform alteration: a trial management perspective on the operational aspects of adaptive and platform and umbrella protocols

      Schiavone, F; Bathia, R; Letchemanan, K; Masters, L; Amos, C; Bara, A; Brown, L; Gilson, C; Pugh, C; Atako, N; et al. (2019)
      BACKGROUND: There are limited research and literature on the trial management challenges encountered in running adaptive platform trials. This trial design allows both (1) the seamless addition of new research comparisons when compelling clinical and scientific research questions emerge, and (2) early stopping of accrual to individual comparisons that do not show sufficient activity without affecting other active comparisons. Adaptive platform design trials also offer many potential benefits over traditional trials, from faster time to accrual to contemporaneously recruiting multiple research comparisons, added flexibility to focus on more promising research comparisons via pre-planned interim analyses and potentially shorter time to primary results. We share here our experiences from a trial management perspective, highlighting the challenges and successes. METHODS: We evaluated the operational aspects of making changes to these adaptive platform trials and identified both common and trial-specific challenges. The operational steps and challenges linked to both the addition of new research comparisons and stopping recruitment following pre-planned interim analysis were considered in our evaluation. RESULTS: Specific operational challenges in these adaptive platform protocols, additional to those in traditional two-arm trials, were identified. Key lessons are presented describing some of the solutions and considerations over conducting these trials. Careful consideration on the practicality of the protocol structure (modular versus single protocol), the longevity and continuity of trial oversight committees, and having clear clinical and scientific criteria for the addition of new research comparisons were identified as some of the most common challenges. CONCLUSIONS: Understanding the operational complexities associated with running adaptive platform protocols is paramount for their conduct, adaptive platform trials offer an efficient model to run randomised controlled trials and we are continuing to work to reduce further the effort required from an operational perspective.
    • Non-linear registration improves statistical power to detect hippocampal atrophy in aging and dementia

      Bartel, F; Visser, M; de Ruiter, M; Belderbos, J; Barkhof, F; Vrenken, H; de Munck, J; Van Herk, Marcel; Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands (2019)
      OBJECTIVE: To compare the performance of different methods for determining hippocampal atrophy rates using longitudinal MRI scans in aging and Alzheimer's disease (AD). BACKGROUND: Quantifying hippocampal atrophy caused by neurodegenerative diseases is important to follow the course of the disease. In dementia, the efficacy of new therapies can be partially assessed by measuring their effect on hippocampal atrophy. In radiotherapy, the quantification of radiation-induced hippocampal volume loss is of interest to quantify radiation damage. We evaluated plausibility, reproducibility and sensitivity of eight commonly used methods to determine hippocampal atrophy rates using test-retest scans. MATERIALS AND METHODS: Manual, FSL-FIRST, FreeSurfer, multi-atlas segmentation (MALF) and non-linear registration methods (Elastix, NiftyReg, ANTs and MIRTK) were used to determine hippocampal atrophy rates on longitudinal T1-weighted MRI from the ADNI database. Appropriate parameters for the non-linear registration methods were determined using a small training dataset (N?=?16) in which two-year hippocampal atrophy was measured using test-retest scans of 8 subjects with low and 8 subjects with high atrophy rates. On a larger dataset of 20 controls, 40 mild cognitive impairment (MCI) and 20? AD patients, one-year hippocampal atrophy rates were measured. A repeated measures ANOVA analysis was performed to determine differences between controls, MCI and AD patients. For each method we calculated effect sizes and the required sample sizes to detect one-year volume change between controls and MCI (NCTRL_MCI) and between controls and AD (NCTRL_AD). Finally, reproducibility of hippocampal atrophy rates was assessed using within-session rescans and expressed as an average distance measure DAve, which expresses the difference in atrophy rate, averaged over all subjects. The same DAve was used to determine the agreement between different methods. RESULTS: Except for MALF, all methods detected a significant group difference between CTRL and AD, but none could find a significant difference between the CTRL and MCI. FreeSurfer and MIRTK required the lowest sample sizes (FreeSurfer: NCTRL_MCI?=?115, NCTRL_AD?=?17 with DAve?=?3.26%; MIRTK: NCTRL_MCI?=?97, NCTRL_AD?=?11 with DAve?=?3.76%), while ANTs was most reproducible (NCTRL_MCI?=?162, NCTRL_AD?=?37 with DAve?=?1.06%), followed by Elastix (NCTRL_MCI?=?226, NCTRL_AD?=?15 with DAve?=?1.78%) and NiftyReg (NCTRL_MCI?=?193, NCTRL_AD?=?14 with DAve?=?2.11%). Manually measured hippocampal atrophy rates required largest sample sizes to detect volume change and were poorly reproduced (NCTRL_MCI?=?452, NCTRL_AD?=?87 with DAve?=?12.39%). Atrophy rates of non-linear registration methods also agreed best with each other. DISCUSSION AND CONCLUSION: Non-linear registration methods were most consistent in determining hippocampal atrophy and because of their better reproducibility, methods, such as ANTs, Elastix and NiftyReg, are preferred for determining hippocampal atrophy rates on longitudinal MRI. Since performances of non-linear registration methods are well comparable, the preferred method would mostly depend on computational efficiency.
    • Risk of melanoma recurrence After diagnosis of a high-risk primary tumor

      von Schuckmann, LA; Hughes, MCB; Ghiasvand, R; Malt, M; van der Pols, JC; Beesley, VL; Khosrotehrani, K; Smithers, BM; Green, Adele C; Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia (2019)
      Importance: With emerging new systemic treatments for metastatic melanoma, early detection of disease recurrence is increasingly important. Objective: To investigate the risk of melanoma recurrence in patients with a localized melanoma at a high risk of metastasis. Design, Setting, and Participants: A total of 1254 patients with newly diagnosed, histologically confirmed tumor category T1b to T4b melanoma in Queensland, Australia, were recruited prospectively between October 1, 2010, and October 1, 2014, for participation in a cohort study. Data analysis was conducted from February 8, 2018, to February 20, 2019. We used Cox proportional hazards regression analysis to examine associations between patient and tumor factors and melanoma recurrence. Exposures: Disease-free survival (DFS) by melanoma tumor category defined by the 7th vs 8th editions of the AJCC Cancer Staging Manual (AJCC 7 vs AJCC 8). Main Outcomes and Measures: Melanoma recurrences were self-reported through follow-up questionnaires administered every 6 months and confirmed by histologic or imaging findings. Results: Of 1254 patients recruited, 825 individuals (65.8%) agreed to participate. Thirty-six were found to be ineligible after providing consent and a further 89 patients were excluded after reclassifying tumors using AJCC 8, leaving 700 participants with high-risk primary melanoma (mean [SD] age, 62.2 [13.5] years; 410 [58.6%] men). Independent predictors of recurrence were head or neck site of primary tumor, ulceration, thickness, and mitotic rate greater than 3/mm2 (hazard ratio, 2.36; 95% CI, 1.19-4.71). Ninety-four patients (13.4%) developed a recurrence within 2 years of diagnosis: 66 tumors (70.2%) were locoregional, and 28 tumors (29.8%) developed at distant sites. After surgery for locoregional disease, 37 of 64 patients (57.8%) remained disease free at 2 years, 7 patients (10.9%) developed new locoregional recurrence, and 20 patients (31.3%), developed distant disease. Two-year DFS was similar when comparing AJCC 7 and AJCC 8, for T1b (AJCC 7, 253 [93.3% DFS]; AJCC 8, 242 [93.0% DFS]) and T4b (AJCC 7 and AJCC 8, 50 [68.0% DFS] category tumors in both editions. Patients with T2a to T4a tumors who did not have a sentinel lymph node biopsy (SLNB) at diagnosis had lower DFS than patients with the same tumor category and a negative SLNB (T2a: 136 [91.1%; 95% CI, 86.4-95.9] vs 96 [96.9%; 95 % CI, 93.4-100.0]; T4a: 33 [78.8%; 95% CI, 64.8-92.7] vs 6 [83.3; 95% CI, 53.5-100.0]). Conclusions and Relevance: These findings suggest that 13.4% of patients with a high-risk primary melanoma will experience disease recurrence within 2 years. Head or neck location of initial tumor, SLNB positivity, and signs of rapid tumor growth may be associated with primary melanoma recurrence.
    • Optical coherence tomography to detect acute esophageal radiation-induced damage in mice: a validation study

      Jelvehgaran, P; de Bruin, DM; Khmelinskii, A; Borst, G; Steinberg, JD; Song, JY; de Vos, J; van Leeuwen, TG; Alderliesten, T; de Boer, JF; et al. (2019)
      Radiation therapy for patients with non-small-cell lung cancer is hampered by acute radiation-induced toxicity in the esophagus. This study aims to validate that optical coherence tomography (OCT), a minimally invasive imaging technique with high resolution (~10 ?m), is able to visualize and monitor acute radiation-induced esophageal damage (ARIED) in mice. We compare our findings with histopathology as the gold standard. Irradiated mice receive a single dose of 40 Gy at proximal and distal spots of the esophagus of 10.0 mm in diameter. We scan mice using OCT at two, three, and seven days post-irradiation. In OCT analysis we define ARIED as a presence of distorted esophageal layering, change in backscattering signal properties, or change in the esophageal wall thickness. The average esophageal wall thickness is 0.53 mm larger on OCT when ARIED is present based on histopathology. The overall sensitivity and specificity of OCT to detect ARIED compared to histopathology are 94 % and 47 %, respectively. However, the overall sensitivity of OCT to assess ARIED is 100% seven days post-irradiation. We validated the capability of OCT to detect ARIED induced by high doses in mice. Nevertheless, clinical studies are required to assess the potential role of OCT to visualize ARIED in humans. This article is protected by copyright. All rights reserved.