Now showing items 1-20 of 11372

    • Multiple uses of circulating tumor cells in lung cancer?

      Dive, Caroline; CRUK Manchester Institute Biomarker Sciences Centre, Manchester (2020)
      Liquid biopsies are increasingly being used in clinical studies as prognostic, predictive, and pharmacodynamics biomarkers, as surrogates of tumor response, to detect minimal residual disease after treatment with curative intent and to inform on mechanisms of treatment resistance and treatment switching. There is also steady progress in the development of liquid biopsies for early detection of cancers. The advantages of liquid biopsies are that they are minimally invasive and readily repeatable. The liquid biopsy that has been most widely adopted is circulating tumor DNA (ctDNA) as it is readily measured without specialist equipment in most molecular biology laboratories. Circulating tumor cells (CTCs) are technically more challenging and have yet to realize their full potential as biomarkers in clinic. However, CTC technology is constantly improving, and CTCs have several exciting applications beyond ctDNA that, once optimized, will assist personalized cancer medicine, including their use as cultures for real-time therapy testing and their utility, in some cancer types, to derive mouse models. I will discuss the use of CTCs from patients with lung cancer in this presentation. CTCs in both non-small cell lung cancer (NSCLC) and SCLC enumerated by CellSearch (EpCAM and cytokerin positive, CD45 negative) hold prognostic information. However, while CellSearch CTCs are scarce in NSCLC, most likely due to epithelial-to-mesenchymal transition (EMT) that leads to downrgulation of the EpCAM surface marker used to capture them for enumeration, they are prevalent in SCLC. Single CTC copy number analysis has led to the development of classifier that, with further validation studies, could predict response to chemotherapy alongside ctDNA analysis for therapy monitoring. We have exploited SCLC CTC prevalence to derive mouse models in immune-incompetent mice (termed CDX) that allow us to explore biology and test new therapeutics. I will also update on our research using our biobank of 46 CDX models, exploring inter and intratumoral heterogeneity. The most important aspect of this approach is the ability to generate pre- and post-therapy CDX models allowing interrogation of therapy resistance mechanisms and the biology of progressing disease in a tumor type where tumor evolution is rapid and where serial tumor biopsies are rarely obtained. I will also describe our approaches to study mechanisms of tumor dissemination, including vasculogenic mimicry and new models of brain metastasis. More recently, we are developing direct CTC cultures that may allow real-time therapy testing with reporting to the clinic. I will report on our NSCLC CTC studies within the UK TRACERx consortium to study tumor evolution. We have explored the potential of CTCs found in the pulmonary draining vein of stage I-IIIa patients at surgery with curative intent to predict risk of disease recurrence and shown in a case study that a lethal subclone that gives rise to metastasis 10 months later was identified in the pulmonary vein at surgery. In summary, this presentation will exemplify utility of CTCs in lung cancer that are distinct from but complement the implementation of ctDNA.
    • The genomic and epigenomic evolutionary history of papillary renal cell carcinomas

      Zhu, B; Poeta, ML; Costantini, M; Zhang, T; Shi, J; Sentinelli, S; Zhao, W; Pompeo, V; Cardelli, M; Alexandrov, BS; et al. (2020)
      Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and that targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.
    • Accurate MR image registration to anatomical reference space for diffuse glioma

      Visser, M; Petr, J; Muller, DMJ; Eijgelaar, RS; Hendriks, EJ; Witte, M; Barkhof, F; van Herk, Marcel; Mutsaerts, H; Vrenken, H; et al. (2020)
      To summarize the distribution of glioma location within a patient population, registration of individual MR images to anatomical reference space is required. In this study, we quantified the accuracy of MR image registration to anatomical reference space with linear and non-linear transformations using estimated tumor targets of glioblastoma and lower-grade glioma, and anatomical landmarks at pre- and post-operative time-points using six commonly used registration packages (FSL, SPM5, DARTEL, ANTs, Elastix, and NiftyReg). Routine clinical pre- and post-operative, post-contrast T1-weighted images of 20 patients with glioblastoma and 20 with lower-grade glioma were collected. The 2009a Montreal Neurological Institute brain template was used as anatomical reference space. Tumors were manually segmented in the patient space and corresponding healthy tissue was delineated as a target volume in the anatomical reference space. Accuracy of the tumor alignment was quantified using the Dice score and the Hausdorff distance. To measure the accuracy of general brain alignment, anatomical landmarks were placed in patient and in anatomical reference space, and the landmark distance after registration was quantified. Lower-grade gliomas were registered more accurately than glioblastoma. Registration accuracy for pre- and post-operative MR images did not differ. SPM5 and DARTEL registered tumors most accurate, and FSL least accurate. Non-linear transformations resulted in more accurate general brain alignment than linear transformations, but tumor alignment was similar between linear and non-linear transformation. We conclude that linear transformation suffices to summarize glioma locations in anatomical reference space. Keywords: computer-assisted; glioma; image processing; linear registration; magnetic resonance imaging; non-linear registration.
    • The automated bone scan index as a predictor of response to prostate radiotherapy in men with newly diagnosed metastatic prostate cancer: an exploratory analysis of STAMPEDE's 'M1|RT comparison'

      Ali, Adnan; Hoyle, Alex P; Parker, CC; Brawley, CD; Cook, A; Amos, C; Calvert, J; Douis, H; Mason, MD; Attard, G; et al. (2020)
      Background: Prostate radiotherapy (RT) is a first-line option for newly diagnosed men with low-burden metastatic prostate cancer. The current criterion to define this clinical state is based on manual bone metastasis counts, but enumeration of bone metastases is limited by interobserver variations, and it does not account for metastasis volume or lesional coalescence. The automated bone scan index (aBSI) is a quantitative method of evaluating bone metastatic burden in a standardised and reproducible manner. Objective: To evaluate whether aBSI has utility as a predictive imaging biomarker to define a newly diagnosed metastatic prostate cancer population that might benefit from the addition of prostate RT to standard of care (SOC) systemic therapy. Design, setting, and participants: This is an exploratory analysis of men with newly diagnosed metastatic prostate cancer randomised in a 1:1 ratio to either SOC or SOC + prostate RT within the STAMPEDE 'M1|RT comparison'. Intervention: The SOC was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December 2015. Men allocated RT received either a daily or a weekly schedule that was nominated before randomisation. Outcome measurements and statistical analysis: Baseline bone scans were evaluated retrospectively to calculate aBSI. We used overall (OS) and failure-free (FFS) survival as the end points. Treatment-aBSI interaction was evaluated using the multivariable fractional polynomial interaction (MFPI) and subpopulation treatment effect pattern plot. Further analysis was done in aBSI quartiles using Cox regression models adjusted for stratification factors. Results and limitations: Baseline bone scans for 660 (SOC: 323 and SOC + RT: 337) of 2061 men randomised within the 'M1|RT comparison' met the software requirements for aBSI calculation. The median age was 68 yr, median PSA was 100 ng/mL, median aBSI was 0.9, and median follow-up was 39 mo. Baseline patient characteristics including aBSI were balanced between the treatment groups. Using the MFPI procedure, there was evidence of aBSI-treatment interaction for OS (p = 0.04, MFPI procedure) and FFS (p < 0.01, MFPI procedure). Graphical evaluation of estimated treatment effect plots showed that the OS and FFS benefit from prostate RT was greatest in patients with a low aBSI. Further analysis in quartiles based on aBSI supported this finding. Conclusions: A low automated bone scan index is predictive of survival benefit associated with prostate RT in men with newly diagnosed metastatic prostate cancer. Patient summary: The widely used bone scan can be evaluated using an automated technique to potentially select men with newly diagnosed metastatic prostate cancer who might benefit from prostate radiotherapy. Keywords: Hormone naïve; Imaging; Metastatic; Radiotherapy.
    • Chronic expression of p16(INK4a) in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation

      Azazmeh, N; Assouline, B; Winter, E; Ruppo, S; Nevo, Y; Maly, A; Meir, K; Witkiewicz, AK; Cohen, J; Rizou, SV; et al. (2020)
      p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.
    • Does tamoxifen have a therapeutic role outside of breast cancer? A systematic review of the evidence

      Clifford, RE; Bowden, D; Blower, E; Kirwan, Cliona C; Vimalachandran, D; Institute of Cancer Medicine, The University of Liverpool, UK. (2020)
      Introduction: Tamoxifen is a widely used hormonal based therapy for breast cancer in the adjuvant and metastatic setting, prolonging overall and recurrence-free survival. There has been increasing interest in the potential for novel 'off-target' effects of tamoxifen and its metabolite N-desmethyltamoxifen across a number of cancer types. We aim to review the current literature regarding the potential use of tamoxifen in other primary malignancies. Method: A qualitative systematic review was performed according to the PRISMA guidelines using pre-set search criteria across the PubMed, Cochrane and Scopus databases from 1985 to 2019. Additional results were generated from included papers references. Results: A total of 324 papers were identified, of which 47 were included; a further 29 articles were obtained from additional referencing to give a total of 76 articles. Clinical trials have demonstrated benefits with the use of tamoxifen in isolation and combination, specifically in patients with advanced non-resectable malignancy, however results are not consistent across the literature. In vivo data consistently suggests that off target effects of tamoxifen are mediated through the ceramide pathway or through inhibition of protein kinase C (PKC). Conclusions: With increased focus upon the potential of repurposing drugs, tamoxifen may be a candidate for repurposing in the wider cancer setting. There is evidence to suggest that the ceramide or PKC pathway could act as a therapeutic target for tamoxifen or alternative chemotherapeutics and merits further investigation.
    • The relationship between tumour associated macrophage markers and tumour, demographic & behavioural factors in breast cancer

      Singh, U; Castle, J; Greenhalgh, S; Hussain, U; Descamps, Tine; Nash, S; Wilson, M; Hunt, R; Kirwan, CC; University of Manchester, Manchester (2020)
      BACKGROUND: Tumour associated macrophages (TAMs) are prognostic markers in breast cancer, however the influence of patient demographic and behavioural factors on these inflammatory markers has not been fully appreciated. METHODS: In 201 invasive breast cancer and 58 ductal carcinoma in-situ (DCIS) patients, TAM density (percentage % CD68 [IHC-immunohistochemistry] positive cells) was correlated with tumour factors (grade, proliferation (Ki67), ER, HER2); demographic factors (age, menopausal status, breast density, BMI, diabetes) and behavioural factors (smoking, alcohol). RESULTS: TAM density was increased in invasive breast cancer, compared to DCIS, and normal tissue distant from the tumour (59%, 41% and 6% respectively; p<0.001). In invasive cancer, TAM density increased with increasing tumour grade (Grade 1: 42%, Grade 2: 58%, Grade 3: 72%; p=0.006), high Ki67 (71% vs. 47%; p=0.004), ER negativity (70% vs. 51%; p=0.02) and HER2 (HER2 positive 77% vs. HER2 negative 55%; p=0.055). TAM density was higher in high compared to low/intermediate DCIS (44% % vs 31% respectively). In terms of demographic factors, TAM density did not correlate with age, menopausal status, breast density (BIRADs), BMI or history of diabetes. TAM density was not increased in patients who smoked; however, it was increased in patients who self-reported alcohol intake (non-drinker 43% vs. drinker 62%; p=0.01). CONCLUSION: TAM density shows utility in identifying aggressive breast cancer sub-types. The association reported between TAM density and alcohol intake suggests a possible mechanism for alcohol as a risk factor for breast cancer.
    • Topological features of integrin adhesion complexes revealed by multiplexed proximity biotinylation

      Chastney, MR; Lawless, C; Humphries, JD; Warwood, S; Jones, MC; Knight, D; Jorgensen, Claus; Humphries, MJ; Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. (2020)
      Integrin adhesion complexes (IACs) bridge the extracellular matrix to the actin cytoskeleton and transduce signals in response to both chemical and mechanical cues. The composition, interactions, stoichiometry, and topological organization of proteins within IACs are not fully understood. To address this gap, we used multiplexed proximity biotinylation (BioID) to generate an in situ, proximity-dependent adhesome in mouse pancreatic fibroblasts. Integration of the interactomes of 16 IAC-associated baits revealed a network of 147 proteins with 361 proximity interactions. Candidates with underappreciated roles in adhesion were identified, in addition to established IAC components. Bioinformatic analysis revealed five clusters of IAC baits that link to common groups of prey, and which therefore may represent functional modules. The five clusters, and their spatial associations, are consistent with current models of IAC interaction networks and stratification. This study provides a resource to examine proximal relationships within IACs at a global level.
    • In vitro and in vivo induction of fetal hemoglobin with a reversible and selective DNMT1 inhibitor

      Gilmartin, AG; Groy, A; Gore, ER; Atkins, C; Long, ER, 3rd; Montoute, MN; Wu, Z; Halsey, W; McNulty, DE; Ennulat, D; et al. (2020)
      Pharmacological induction of fetal hemoglobin (HbF) expression is an effective therapeutic strategy for the management of beta-hemoglobinopathies such as sickle cell disease. DNA methyltransferase (DNMT) inhibitors 5-azacytidine (5-aza) and 5-aza-2'-deoxycytidine (decitabine) have been shown to induce fetal hemoglobin expression in both preclinical models and clinical studies, but are not currently approved for the management of hemoglobinopathies. We report here the discovery of a novel class of orally bioavailable DNMT1-selective inhibitors as exemplified by GSK3482364. This molecule potently inhibits the methyltransferase activity of DNMT1, but not DNMT family members DNMT3A or DNMT3B. In contrast with cytidine analog DNMT inhibitors, the DNMT1 inhibitory mechanism of GSK3482364 does not require DNA incorporation and is reversible. In cultured human erythroid progenitor cells (EPCs), GSK3482364 decreased overall DNA methylation resulting in de-repression of the gamma globin genes HBG1 and HBG2 and increased HbF expression. In a transgenic mouse model of sickle cell disease, orally administered GSK3482364 caused significant increases in both HbF levels and in the percentage HbF-expressing erythrocytes, with good overall tolerability. We conclude that in these preclinical models, selective, reversible inhibition of DNMT1 is sufficient for the induction of HbF, and is well-tolerated. We anticipate that GSK3482364 will be a useful tool molecule for the further study of selective DNMT1 inhibition both in vitro and in vivo. Keywords: DNA methyltransferase; Fetal Hemoglobin; Hemoglobinopathies; Molecular Pharmacology; Sickle Cell Disease.
    • Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial

      Murray Brunt, A; Haviland, JS; Wheatley, DA; Sydenham, MA; Alhasso, A; Bloomfield, DJ; Chan, C; Churn, M; Cleator, S; Coles, CE; et al. (2020)
      Background: We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial. Methods: FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ?1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at, ISRCTN19906132. Findings: Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were -0·3% (-1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and -0·7% (-1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1-5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy. Interpretation: 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer.
    • Tailored functionalized magnetic nanoparticles to target breast cancer cells including cancer stem-like cells

      Lazaro-Carrillo, A; Calero, M; Aires, A; A, LC; Simoes, Bruno M; Latorre, A; Somoza, A; Clarke, Robert B; Miranda, R; Villanueva, A; et al. (2020)
      Nanotechnology-based approaches hold substantial potential to avoid chemoresistance and minimize side effects. In this work, we have used biocompatible iron oxide magnetic nanoparticles (MNPs) called MF66 and functionalized with the antineoplastic drug doxorubicin (DOX) against MDA-MB-231 cells. Electrostatically functionalized MNPs showed effective uptake and DOX linked to MNPs was more efficiently retained inside the cells than free DOX, leading to cell inactivation by mitotic catastrophe, senescence and apoptosis. Both effects, uptake and cytotoxicity, were demonstrated by different assays and videomicroscopy techniques. Likewise, covalently functionalized MNPs using three different linkers-disulfide (DOX-S-S-Pyr, called MF66-S-S-DOX), imine (DOX-I-Mal, called MF66-I-DOX) or both (DOX-I-S-S-Pyr, called MF66-S-S-I-DOX)-were also analysed. The highest cell death was detected using a linker sensitive to both pH and reducing environment (DOX-I-S-S-Pyr). The greatest success of this study was to detect also their activity against breast cancer stem-like cells (CSC) from MDA-MB-231 and primary breast cancer cells derived from a patient with a similar genetic profile (triple-negative breast cancer). In summary, these nanoformulations are promising tools as therapeutic agent vehicles, due to their ability to produce efficient internalization, drug delivery, and cancer cell inactivation, even in cancer stem-like cells (CSCs) from patients.
    • Hydroxychloroquine/ chloroquine as a treatment choice or prophylaxis for Covid-19 at the primary care level in developing countries: A Primum non Nocere dilemma

      Medina MT; Moncada, Salvador; Faculty of Medical Sciences, National Autonomous University of Honduras, WFN Regional Director for Latin America, Tegucigalpa, Honduras. (2020)
      The Food and Drug Administration (FDA) warned against the use of Hydroxychloroquine or chloroquine for Covid-19 outside of a hospital or a clinical trial setting due to the risk of QT interval prolongation, ventricular tachycardia and the increased risk of these complications when combined with some antibiotics such as azithromycin. Several studies have reported no benefit of Hydroxychloroquine or chloroquine, when used alone or with a macrolide in COVID-19 hospitalized patients. Despite these warnings, in several developing countries the official guidelines for treatment of Covid-19 patients at the primary care level recommend Hydroxychloroquine and azithromycin, among other treatments, as the first-choice for mild symptomatic Covid-19 patients, asymptomatic contacts or for prophylaxis. In our opinion there is a primum non nocere dilemma during this Covid-19 pandemic. In order to solve this bioethical problem, we strongly recommend that a randomized controlled trial in a primary care setting be carried out as a matter of urgency in these areas of the world. Keywords: Bioethics; Clinical trials; Developing countries; Hydroxychloroquine/ chloroquine; Primary care.
    • Variables associated with survival in patients with invasive bladder cancer with and without surgery.

      Longdon E; Mistry H; Pratt, O; Donnelly, A; O'Neill, S; Nachlappan, M; Darwin, L; Clarke, Noel W; Hartley, R; Nachiappan, M; et al. (2020)
      We recorded the survival of 141 patients assessed for radical cystectomy, which included cardiopulmonary exercise testing. The median Kaplan-Meier survival estimates were: 1540 days for the whole cohort; 2200 days after cystectomy scheduled (n = 108); and 843 days without surgery. The mortality hazard remained double that expected for a matched general population, but survival was better in patients scheduled for surgery than those who were not: the mortality hazard ratio (95%CI) after cystectomy was 0.43 (0.26-0.73) the mortality hazard without surgery, p = 0.001. The mortality hazard ratios for the three-variable Bayesian Model Averaging survival model for all 141 patients were: referral for surgery (0.5); haemoglobin concentration (0.98); and efficiency of carbon dioxide output (1.05). Efficiency of carbon dioxide output was the single variable in the postoperative model (n = 108), mortality hazard 1.08 (per unit increase). The ratio of observed to expected peak oxygen consumption associated best with mortality in 33 patients not referred for surgery, hazard ratio 0.001. Our results can inform consultations with patients with invasive bladder cancer and suggest that interventions to increase fitness and haemoglobin may improve survival in patients who do and who do not undergo radical cystectomy. Keywords: bladder cancer; cardiopulmonary exercise testing; radical cystectomy; survival; transitional cell carcinoma.
    • Anxiety and depression after diagnosis of high-risk primary cutaneous melanoma: a 4-year longitudinal study

      Beesley, VL; Hughes, MCB; Smithers, BM; Khosrotehrani, K; Malt, MK; von Schuckmann, LA; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. (2020)
      Purpose: To quantify the prevalence of anxiety or depression (overall; melanoma-related) among people with high-risk primary melanoma, their related use of mental health services and medications, and factors associated with persistent new-onset symptoms across 4 years post-diagnosis. Methods: A longitudinal study of 675 patients newly diagnosed with tumor-stage 1b-4b melanoma. Participants completed the Hospital Anxiety and Depression Scale and answered questions about fear of cancer recurrence, use of medication, and support, serially over 4 years. We identified anxiety and depression trajectories with group-based trajectories models and factors associated with persistent symptoms with logistic regression. Results: At diagnosis, 93 participants (14%) had melanoma-related anxiety or depression, and 136 (20%) were affected by anxiety and/or depression unrelated to melanoma. After 6 months, no more than 27 (5%) reported melanoma-related anxiety or depression at any time, while the point prevalence of anxiety and depression unrelated to melanoma was unchanged (16-21%) among the disease-free. Of 272 participants reporting clinical symptoms of any cause, 34% were taking medication and/or seeing a psychologist or psychiatrist. Of the participants, 11% (n = 59) had new-onset symptoms that persisted; these participants were more likely aged < 70. Conclusions: Melanoma-related anxiety or depression quickly resolves in high-risk primary melanoma patients after melanoma excision, while prevalence of anxiety or depression from other sources remains constant among the disease-free. However, one-in-ten develop new anxiety or depression symptoms (one-in-twenty melanoma-related) that persist. Implications for cancer survivors: Chronic stress has been linked to melanoma progression. Survivors with anxiety and depression should be treated early to improve patient and, potentially, disease outcomes. Keywords: Anxiety; Depression; Distress; Fear of recurrence; Melanoma.
    • The proportion of cancers attributable to social deprivation: A population-based analysis of Australian health data

      Wilson, LF; Green, Adèle C; Jordan, SJ; Neale, RE; Webb, PM; Whiteman, DC; Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, 4006, Australia; (2020)
      Background: Cancer is a major disease burden globally and people who are socioeconomically disadvantaged have a higher incidence of many types of cancer. We investigated the potential to reduce socioeconomic disparities in cancer incidence in Australia by lowering the prevalence of exposure to four modifiable causes: smoking, alcohol, overweight/obesity and physical inactivity. Methods: We used cancer incidence data from the Australian Cancer Database and risk factor prevalence data from the Australian National Health Survey to estimate the proportions of cancers attributable to the four factors, by area-level socioeconomic disadvantage. For the three risk factors where prevalence was lowest among the least disadvantaged (smoking, overweight/obesity, physical inactivity), we also estimated the potential impact of reducing prevalence in the most disadvantaged areas to that in the least disadvantaged areas. Results: The proportion of cancer attributable to the four factors in combination ranged from 22 % in the most disadvantaged areas to 14 % in the least disadvantaged areas. If the prevalence of tobacco smoking, overweight/obesity and physical inactivity in the more disadvantaged areas were the same as that in the least disadvantaged, an estimated 19,500 cancers (4 % of all cancers diagnosed) could have been prevented in Australia between 2009 and 2013. Conclusions: Reducing the prevalence of key causal factors in areas of greater social disadvantage would prevent many cases of cancer. Strategies to achieve this in highly disadvantaged areas are needed. Keywords: Alcohol; Cancer; Obesity; Physical inactivity; Population attributable fraction; Potential impact fraction; Socioeconomic disadvantage; Tobacco smoking.
    • Technical evaluation of commercial mutation analysis platforms and reference materials for liquid biopsy profiling

      Weber, S; Spiegl, B; Perakis, SO; Ulz, CM; Abuja, PM; Kashofer, K; Leest, PV; Azpurua, MA; Tamminga, M; Brudzewsky, D; et al. (2020)
      Molecular profiling from liquid biopsy, in particular cell-free DNA (cfDNA), represents an attractive alternative to tissue biopsies for the detection of actionable targets and tumor monitoring. In addition to PCR-based assays, Next Generation Sequencing (NGS)-based cfDNA assays are now commercially available and are being increasingly adopted in clinical practice. However, the validity of these products as well as the clinical utility of cfDNA in the management of patients with cancer has yet to be proven. Within framework of the Innovative Medicines Initiative (IMI) program CANCER-ID we evaluated the use of commercially available reference materials designed for ctDNA testing and cfDNA derived from Diagnostic Leukaphereses (DLA) for inter- and intra-assay as well as intra- and inter-laboratory comparisons. In three experimental setups, a broad range of assays including ddPCR, MassARRAY and various NGS-based assays were tested. We demonstrate that both reference materials with predetermined VAFs and DLA samples are extremely useful for the performance assessment of mutation analysis platforms. Moreover, our data indicate a substantial variability of NGS assays with respect to sensitivity and specificity highlighting the importance of extensive validation of the test performance before offering these tests in clinical routine practice. Keywords: assay validation; cell-free DNA; cfDNA; circulating tumor DNA; ctDNA; diagnostic leukaphereses; molecular profiling; mutation analysis; performance assessment; reference material.
    • An evaluation of continuous subcutaneous infusions across seven NHS acute hospitals: is there potential for 48-hour infusions?

      Baker J; Dickman, A; Mason, S; Bickerstaff, M; Jackson, R; McArdle, A; Lawrence, I; Stephenson, F; Paton, Nina; Kirk, J; et al. (2020)
      Background: Continuous subcutaneous infusions (CSCIs) are commonly used in the United Kingdom as a way of administering medication to patients requiring symptom control when the oral route is compromised. These infusions are typically administered over 24 h due to currently available safety data. The ability to deliver prescribed medication by CSCI over 48 h may have numerous benefits in both patient care and health service resource utilisation. This service evaluation aims to identify the frequency at which CSCI prescriptions are altered at NHS Acute Hospitals. Methods: Pharmacists or members of palliative care teams at seven acute NHS hospitals recorded anonymised prescription data relating to the drug combination(s), doses, diluent and compatibility of CSCIs containing two or more drugs on a daily basis for a minimum of 2 days, to a maximum of 7 days. Results: A total of 1301 prescriptions from 288 patients were recorded across the seven sites, yielding 584 discrete drug combinations. Of the 584 combinations, 91% (n = 533) included an opioid. The 10 most-common CSCI drug combinations represented 37% of the combinations recorded. Median duration of an unchanged CSCI prescription across all sites was 2 days. Conclusion: Data suggests medication delivered by CSCI over 48 h may be a viable option. Before a clinical feasibility study can be undertaken, a pharmacoeconomic assessment and robust chemical and microbiological stability data will be required, as will the assessment of the perceptions from clinical staff, patients and their families on the acceptability of such a change in practice. Keywords: CSCI; Palliative therapy; Subcutaneous infusions.
    • Construction of the immune landscape of durable response to checkpoint blockade therapy by integrating publicly available datasets

      Rudqvist, NP; Zappasodi, R; Wells, D; Thorsson, V; Cogdill, A; Monette, A; Najjar, Y; Sweis, R; Wennerberg, E; Bommareddy, P; et al. (2020)
      Background Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, long-term benefits are only achieved in a small fraction of patients. Understanding the mechanisms underlying ICB activity is key to improving the efficacy of immunotherapy. A major limitation to uncovering these mechanisms is the limited number of responders within each ICB trial. Integrating data from multiple studies of ICB would help overcome this issue and more reliably define the immune landscape of durable responses. Towards this goal, we formed the TimIOs consortium, comprising researchers from the Society for Immunotherapy of Cancer Sparkathon TimIOs Initiative, the Parker Institute of Cancer Immunotherapy, the University of North Carolina-Chapel Hill, and the Institute for Systems Biology. Together, we aim to improve the understanding of the molecular mechanisms associated with defined outcomes to ICB, by building on our joint and multifaceted expertise in the field of immuno-oncology. To determine the feasibility and relevance of our approach, we have assembled a compendium of publicly available gene expression datasets from clinical trials of ICB. We plan to analyze this data using a previously reported pipeline that successfully determined main cancer immune-subtypes associated with survival across multiple cancer types in TCGA.1 Methods RNA sequencing data from 1092 patients were uniformly reprocessed harmonized, and annotated with predefined clinical parameters. We defined a comprehensive set of immunogenomics features, including immune gene expression signatures associated with treatment outcome,1,2 estimates of immune cell proportions, metabolic profiles, and T and B cell receptor repertoire, and scored all compendium samples for these features. Elastic net regression models with parameter optimization done via Monte Carlo cross-validation and leave-one-out cross-validation were used to analyze the capacity of an integrated immunogenomics model to predict durable clinical benefit following ICB treatment. Results Our preliminary analyses confirmed an association between the expression of an IFN-gamma signature in tumor (1) and better outcomes of ICB, highlighting the feasibility of our approach. Conclusions In line with analysis of pan-cancer TCGA datasets using this strategy (1), we expect to identify analogous immune subtypes characterizing baseline tumors from patients responding to ICB. Furthermore, we expect to find that these immune subtypes will have different importance in the model predicting response and survival. Results of this study will be incorporated into the Cancer Research Institute iAtlas Portal, to facilitate interactive exploration and hypothesis testing.
    • Author Correction: The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition

      Kelly, Joanna; Martini, S; Brownlow, N; Joshi, D; Federico, S; Jamshidi, S; Kjaer, S; Lockwood, N; Rahman, KM; Fraternali, F; et al. (2020)
      The original version of this article contained an error in the spelling of the author Khondaker Miraz Rahman, which was incorrectly given as Khondaker Miraz Rahmen. This has now been corrected in the PDF and HTML versions of the article.
    • Technical Note: GATE-RTion: a GATE/Geant4 release for clinical applications in scanned ion beam therapy

      Grevillot, L; Boersma, DJ; Fuchs, H; Aitkenhead, Adam H; Elia, A; Bolsa, M; Winterhalter, Carla; Vidal, M; Jan, S; Pietrzyk, U; et al. (2020)
      Purpose: GATE-RTion is a validated version of GATE for clinical use in the field of light ion beam therapy. This paper describes the GATE-RTion project and illustrates its potential through clinical applications developed in three European centers delivering scanned proton and carbon ion treatments. Methods: GATE-RTion is a collaborative framework provided by the OpenGATE collaboration. It contains a validated GATE release based on a specific Geant4 version, a set of tools to integrate GATE into a clinical environment and a network for clinical users. Results: Three applications are presented: Proton radiography at the Centre Antoine Lacassagne (Nice, France); Independent dose calculation for proton therapy at the Christie NHS Foundation Trust (Manchester, UK); Independent dose calculation for protons and carbon ions at the MedAustron Ion Therapy center (Wiener Neustadt, Austria). Conclusions: GATE-RTion builds the bridge between researchers and clinical users from the OpenGATE collaboration in the field of Light Ion Beam Therapy. The applications presented in three European facilities using three completely different machines (three different vendors, cyclotron- and synchrotron-based systems, protons, and carbon ions) demonstrate the relevance and versatility of this project. Keywords: GATE; Geant4; Independent dose calculation; Monte Carlo simulation; clinical; ion beam therapy.