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North East and Cumbria

Cancer Organisations and Resources
Cancer News from the North East
Latest Research Publications from the North East

Cancer Organisations and Resources (17 links)

Cancer News from the North East (2 links)


    Latest Research Publications from the North East

    Sharma P, Mehta M, Dhanjal DS, et al.
    Emerging trends in the novel drug delivery approaches for the treatment of lung cancer.
    Chem Biol Interact. 2019; 309:108720 [PubMed] Related Publications
    Cancer is one of the major diseases that cause a high number of deaths globally. Of the major types of cancers, lung cancer is known to be the most chronic form of cancer in the world. The conventional management of lung cancer includes different medical interventions like chemotherapy, surgical removal, and radiation therapy. However, this type of approach lacks specificity and also harms the adjacent normal cells. Lately, nanotechnology has emerged as a promising intervention in the management and treatment of lung cancers. Nanotechnology has revolutionized the existing modalities and focuses primarily on reducing toxicity and improving the bioavailability of anticancer drugs to the target tumor cells. Nanocarrier systems are being currently used extensively to exploit and to overcome the obstructions induced by cancers in the lungs. The nano-carrier-loaded therapeutic drug delivery methods have shown promising potential in treating lung cancer as its target is to control the growth of tumor cells. In this review, various modes of nano drug delivery options like liposomes, dendrimers, quantum dots, carbon nanotubes and metallic nanoparticles have been discussed. Nano-carrier drug delivery systems emerge as a promising approach and thus is expected to provide newer and advanced avenues in cancer therapeutics.

    Mills SJ, Radon MR, Baird RD, et al.
    Utilization of volumetric magnetic resonance imaging for baseline and surveillance imaging in Neuro-oncology.
    Br J Radiol. 2019; 92(1098):20190059 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
    The acquisition of volumetric post-contrast MRI has clear advantages in the interpretation of neuro-oncology studies but has yet to find its way into routine clinical practice beyond planning scans for surgery and radiotherapy. This commentary briefly highlights the benefits of these techniques whilst dispelling some of the perceived disadvantages.

    Veal GJ, Amankwatia EB, Paludetto MN, et al.
    Pharmacodynamic Therapeutic Drug Monitoring for Cancer: Challenges, Advances, and Future Opportunities.
    Ther Drug Monit. 2019; 41(2):142-159 [PubMed] Related Publications
    In the modern era of cancer treatment, with targeted agents superseding more traditional cytotoxic chemotherapeutics, it is becoming increasingly important to use stratified medicine approaches to ensure that patients receive the most appropriate drugs and treatment schedules. In this context, there is significant potential for the use of pharmacodynamic biomarkers to provide pharmacological information, which could be used in a therapeutic drug monitoring setting. This review focuses on discussing some of the challenges faced to date in translating preclinical pharmacodynamic biomarker approaches to a clinical setting. Recent advances in important areas including circulating biomarkers and pharmacokinetic/pharmacodynamic modeling approaches are discussed, and selected examples of anticancer drugs where there is existing evidence to potentially advance pharmacodynamic therapeutic drug monitoring approaches to deliver more effective treatment are discussed. Although we may not yet be in a position to systematically implement therapeutic drug monitoring approaches based on pharmacodynamic information in a cancer patient setting, such approaches are likely to become more commonplace in the coming years. Based on ever-increasing levels of pharmacodynamic information being generated on newer anticancer drugs, facilitated by increasingly advanced and accessible experimental approaches available to researchers to collect these data, we can now look forward optimistically to significant advances being made in this area.

    Ayakannu T, Taylor AH, Marczylo TH, Konje JC
    New Insights of Uterine Leiomyoma Pathogenesis: Endocannabinoid System.
    Med Sci Monit Basic Res. 2019; 25:76-87 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
    BACKGROUND The aim of this study was to determine if components of the endocannabinoid system are modulated in uterine leiomyomas (fibroids). Components studied included cannabinoid receptors 1 (CB1) and 2 (CB2); the G protein-coupled receptor GPR55; transient potential vanilloid receptor 1 (TRPV1) and the endocannabinoid modulating enzymes N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), and their N-acylethanolamine (NAE) ligands: N-arachidonylethanolamine (AEA), N-oleoylethanolamine (OEA), and N-palmityolethanaolamine (PEA). MATERIAL AND METHODS Transcript levels of CB1, CB2, TRPV1, GPR55, NAPE-PLD, and FAAH were measured using RT-PCR and correlated with the tissue levels of the 3 NAEs in myometrial tissues. The tissues studied were: 1) fibroids, 2) myometrium adjacent/juxtaposed to the fibroid lesions, and 3) normal myometrium. Thirty-seven samples were processed for NAE measurements and 28 samples were used for RT-PCR analyses. RESULTS FAAH expression was significantly lower in fibroids, resulting in a NAPE-PLD: FAAH ratio that favors higher AEA levels in pre-menopausal tissues, whilst PEA levels were significantly lower, particularly in post-menopausal women, suggesting PEA protects against fibroid pathogenesis. The CB1: CB2 ratio was lower in fibroids, suggesting that loss of CB1 expression affects the fibroid cell phenotype. Significant correlations between reduced FAAH, CB1, and GPR55 expression and PEA in fibroids indicate that the loss of these endocannabinoid system components are biomarkers of leiomyomata. CONCLUSIONS Loss of expression of CB1, FAAH, GPR55, and PEA production are linked to the pathogenesis of uterine fibroids and further understanding of this might eventually lead to better disease indicators or the development of therapeutic potentials that might eventually be used in the management of uterine fibroids.

    Bartneck M, Schrammen PL, Möckel D, et al.
    The CCR2
    Cell Mol Gastroenterol Hepatol. 2019; 7(2):371-390 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
    BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) typically arises in fibrotic or cirrhotic livers, which are characterized by pathogenic angiogenesis. Myeloid immune cells, specifically tumor-associated macrophages (TAMs), may represent potential novel therapeutic targets in HCC, complementing current ablative or immune therapies. However, the detailed functions of TAM subsets in hepatocarcinogenesis have remained obscure.
    METHODS: TAM subsets were analyzed in-depth in human HCC samples and a combined fibrosis-HCC mouse model, established by i.p. injection with diethylnitrosamine after birth and repetitive carbon tetrachloride (CCl
    RESULTS: We show that human CCR2
    CONCLUSIONS: The HCC microenvironment in human patients and mice is characterized by functionally distinct macrophage populations, of which the CCR2

    Lyerly HK, Ren J, Canetta R, et al.
    Global Development of Anticancer Therapies for Rare Cancers, Pediatric Cancers, and Molecular Subtypes of Common Cancers.
    J Glob Oncol. 2018; 4:1-11 [PubMed] Related Publications
    Advances in genetic sequencing and other diagnostic technologies have enabled the use of precision medicine in clinical cancer care, as well as the development of novel therapies that are targeted to specific molecular drivers of cancer. Developing these new agents and making them accessible to patients requires global clinical studies and regulatory review and approval by different national regulatory agencies. Whereas these global trials present challenges for drug developers who conduct them and regulatory agencies who oversee them, they also raise practical issues about patients with low-frequency cancers who need these therapies. A lack of uniform standards in both regulatory approval for marketing and reimbursement for approved agents across countries may make the newly developed agent either unavailable or inaccessible to patients in certain countries or regions, even if patients from those countries or regions participated in the clinical research that established the safety and efficacy of the agent. In an effort to further understand and address this need, we convened an international workshop in 2017 in North Bethesda, MD. After presentations of the individual regulatory pathways for marketing approval and reimbursement for individual nations, participants discussed expedited pathways and specific challenges for uncommon cancers. As a matter of justice, agents being developed for rare cancers, pediatric cancers, or uncommon molecular subsets of common cancers need a pragmatic, science-based regulatory policy framework to clearly specify the type and quantity of evidence needed to demonstrate efficacy from these trials and evidence to support accessibility.

    Kim S, Wang M, Tyrer JP, et al.
    A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants.
    Int J Cancer. 2019; 144(9):2192-2205 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
    As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10

    Shah V, Johnson DC, Sherborne AL, et al.
    Blood. 2018; 132(23):2465-2469 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
    Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of

    O'Reilly D, Fou L, Hasler E, et al.
    Diagnosis and management of pancreatic cancer in adults: A summary of guidelines from the UK National Institute for Health and Care Excellence.
    Pancreatology. 2018; 18(8):962-970 [PubMed] Related Publications
    To enable standardisation of care of pancreatic cancer patients and facilitate improvement in outcome, the United Kingdom's National Institute for Health and Care Excellence (NICE) developed a clinical guideline for the diagnosis and management of pancreatic cancer in adults. Systematic literature searches, systematic review and meta-analyses were undertaken. Recommendations were drafted on the basis of the group's interpretation of the best available evidence of clinical and cost effectiveness. There was patient involvement and public consultation. Recommendations were made on: diagnosis; staging; monitoring of inherited high risk; psychological support; pain; nutrition management; and the specific management of people with resectable-, borderline-resectable- and unresectable-pancreatic cancer. The guideline committee also made recommendations for future research into neoadjuvant therapy, cachexia interventions, minimally invasive pancreatectomy, pain management and psychological support needs. These NICE guidelines aim to promote best current practice and support and stimulate research and innovation in pancreatic cancer.

    Byrne J, Alessi D, Allodji RS, et al.
    The PanCareSurFup consortium: research and guidelines to improve lives for survivors of childhood cancer.
    Eur J Cancer. 2018; 103:238-248 [PubMed] Related Publications
    BACKGROUND: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF.
    METHODS: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public.
    RESULTS: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case-control studies of subsequent malignancies and cardiac disease in 5-year survivors.
    CONCLUSIONS: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health.

    Aden K, Bartsch K, Dahl J, et al.
    Epithelial RNase H2 Maintains Genome Integrity and Prevents Intestinal Tumorigenesis in Mice.
    Gastroenterology. 2019; 156(1):145-159.e19 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
    BACKGROUND & AIMS: RNase H2 is a holoenzyme, composed of 3 subunits (ribonuclease H2 subunits A, B, and C), that cleaves RNA:DNA hybrids and removes mis-incorporated ribonucleotides from genomic DNA through ribonucleotide excision repair. Ribonucleotide incorporation by eukaryotic DNA polymerases occurs during every round of genome duplication and produces the most frequent type of naturally occurring DNA lesion. We investigated whether intestinal epithelial proliferation requires RNase H2 function and whether RNase H2 activity is disrupted during intestinal carcinogenesis.
    METHODS: We generated mice with epithelial-specific deletion of ribonuclease H2 subunit B (H2b
    RESULTS: The H2b
    CONCLUSIONS: In analyses of mice with disruption of the ribonuclease H2 subunit B gene and colorectal tumors from patients, we provide evidence that RNase H2 functions as a colorectal tumor suppressor. H2b/p53

    Gomez-Rubio P, Piñero J, Molina-Montes E, et al.
    Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case-control approaches.
    Int J Cancer. 2019; 144(7):1540-1549 [PubMed] Related Publications
    Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene-disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case-control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58-0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21-0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19-0.89, and OR = 0.73, 95%CI 0.53-1.00, respectively). Several inflammatory-related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.

    Tingle SJ, Severs GR, Goodfellow M, et al.
    NARCA: A novel prognostic scoring system using neutrophil-albumin ratio and Ca19-9 to predict overall survival in palliative pancreatic cancer.
    J Surg Oncol. 2018; 118(4):680-686 [PubMed] Related Publications
    BACKGROUND AND OBJECTIVES: Several serum based-markers and ratios have been investigated for their prognostic value in pancreatic ductal adenocarcinoma (PDAC). This cohort study aimed to combine these into a novel prognostic scoring system.
    METHODS: A retrospective cohort study was performed on 145 patients with unresectable histologically-confirmed PDAC. Based on the existing literature the following markers were investigated: neutrophil-lymphocyte ratio (NLR), neutrophil-albumin ratio (NAR), platelet-lymphocyte ratio (PLR), fibrinogen, and Ca19-9. These values were dichotomized about their medians for Kaplan-Meier and Cox regression analysis.
    RESULTS: Univariate Cox regression revealed statistically significant prognostic value for: NLR, NAR, PLR, fibrinogen, and Ca19-9. When combining these using Cox regression analysis adjusting for other prognostic indicators, only NAR (hazard ratios [HR] = 3.174, P = 0.022) and Ca19-9 (HR = 2.697, P = 0.031) were independent predictors of survival. Combining NAR and Ca19-9 we split the cohort into three "NARCA" groups: NARCA0 = NAR ≤ 0.13 and Ca19-9 ≤ 770, NARCA1 = either NAR > 0.13 or Ca19-9 >770, NARCA2 = NAR > 0.13 and Ca19-9 > 770. Median survival was 20.5, 9.7 and 4.1 months in NARCA0, 1, and 2 respectively ( P < 0.0005, log-rank test). A separate validation cohort confirmed the prognostic significance of the score ( P = 0.048).
    CONCLUSIONS: Combining NAR and Ca19-9 into a prognostic score allows stratification of unresectable PDAC patients into groups with significantly different overall survival.

    Arkenau HT, Italiano A, Mak G, et al.
    An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours.
    Eur J Cancer. 2018; 103:17-23 [PubMed] Related Publications
    BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity.
    PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8.
    RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months.
    CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases.
    EUDRACT NUMBER: 2009-017817-31.

    Ostrom QT, Kinnersley B, Armstrong G, et al.
    Age-specific genome-wide association study in glioblastoma identifies increased proportion of 'lower grade glioma'-like features associated with younger age.
    Int J Cancer. 2018; 143(10):2359-2366 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
    Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18-53, 54-64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p

    Gaudet MM, Deubler EL, Kelly RS, et al.
    Blood levels of cadmium and lead in relation to breast cancer risk in three prospective cohorts.
    Int J Cancer. 2019; 144(5):1010-1016 [PubMed] Related Publications
    Cadmium and lead have been classified as carcinogens by the International Agency for Research on Cancer. However, their associations with breast cancer risk are unknown despite their persistence in the environment and ubiquitous human exposure. We examined associations of circulating levels of cadmium and lead with breast cancer risk in three case-control studies nested within the Cancer Prevention Study-II (CPS-II) LifeLink Cohort, European Prospective Investigation into Cancer and Nutrition - Italy (EPIC-Italy) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Metal levels were measured in stored erythrocytes from 1,435 cases and 1,433 controls using inductively coupled plasma-mass spectrometry. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models with each study result weighted by the within- and between-study variances. I

    den Bakker CM, Anema JR, Zaman AGNM, et al.
    Prognostic factors for return to work and work disability among colorectal cancer survivors; A systematic review.
    PLoS One. 2018; 13(8):e0200720 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
    BACKGROUND: Colorectal cancer is diagnosed progressively in employed patients due to screening programs and increasing retirement age. The objective of this study was to identify prognostic factors for return to work and work disability in patients with colorectal cancer.
    METHODS: The research protocol was published at PROSPERO with registration number CRD42017049757. A systematic review of cohort and case-control studies in colorectal cancer patients above 18 years, who were employed when diagnosed, and who had a surgical resection with curative intent were included. The primary outcome was return to work or work disability. Potentially prognostic factors were included in the analysis if they were measured in at least three studies. Risk of bias was assessed according to the QUality In Prognosis Studies tool. A qualitative synthesis analysis was performed due to heterogeneity between studies. Quality of evidence was evaluated according to Grading of Recommendation Assessment, Development and Evaluation.
    RESULTS: Eight studies were included with a follow-up period of 26 up to 520 weeks. (Neo)adjuvant therapy, higher age, and more comorbidities had a significant negative influence on return to work. A previous period of unemployment, extensive surgical resection and postoperative complications significantly increased the risk of work disability. The quality of evidence for these prognostic factors was considered very low to moderate.
    CONCLUSION: Health care professionals need to be aware of these prognostic factors to select patients eligible for timely intensified rehabilitation in order to optimize the return to work process and prevent work disability.

    Sturgess B, Brown M, Fraser F, Bailey S
    "They've got a lot of needs and I don't think they're being met fully": A qualitative study of the multi-professional team approach to the management of children with optic pathway gliomas.
    Pediatr Blood Cancer. 2018; 65(12):e27377 [PubMed] Related Publications
    BACKGROUND: Optic pathway gliomas (OPGs) are low-grade tumours of the visual pathway. Although survival rates are high, there is considerable morbidity and hence treatment focuses on preservation of vison and quality of life. The multiple, complex issues faced by these patients are often confounded by a concurrent diagnosis of neurofibromatosis type-1 (NF1). As there is a paucity of literature addressing the current practices of the multi-professional team (MPT) caring for children diagnosed with an OPG, individual professional experiences often guide the MPT's approach to the care of these children and their families.
    AIMS: This study aimed to gain views on the management of children with OPGs, from MPT members involved in their care, in order to inform recommendations on how to improve the service offered to these children and their families.
    METHODS: A qualitative design collected experiential data from MPT members via semi-structured interviews. MPT focus groups were used to validate the data.
    RESULTS: Data collected from 20 MPT members resulted in the overarching themes of Issues Faced by the Patient and Family and Challenges to the Holistic Care of the Patient. Four recommendations are suggested, namely (1) the production of an MPT training resource, (2) improved visual team links, (3) an OPG patient passport and (4) a joint NF1-OPG clinic.
    CONCLUSION: There are many challenges to MPT members providing holistic care to patients with OPGs. As no OPG clinical practice guidelines currently exist, it is suggested that the above recommendations be piloted with evaluation to validate their use.

    Kumar N, Patel RS, Wang SSY, et al.
    Factors influencing extended hospital stay in patients undergoing metastatic spine tumour surgery and its impact on survival.
    J Clin Neurosci. 2018; 56:114-120 [PubMed] Related Publications
    Metastatic spine tumour surgeries (MSTS) are indicated for preservation or restoration of neurological function, to provide mechanical stability and pain alleviation. The goal of MSTS is to improve the quality of life of the patients with spinal metastases and rarely for oncological control which is usually achieved by adjuvant therapies. Hence outcome measures such as length of stay (LOS) and rate of complications after MSTS are important indicators of quality but there is limited literature evidence for the same. We carried out a retrospective study to determine the incidence and the factors influencing normal (nLOS) and extended length of stay (eLOS) after MSTS. Data of 220 consecutive patients who underwent MSTS between 2005 and 2015 were retrieved from hospital electronic records. The preoperative, intraoperative and postoperative variables, discharge destinations as well as socioeconomic factors were analyzed. eLOS defined as positive when the LOS exceeded the 75th percentile for this cohort, was the key outcome indicator. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors of eLOS. The overall median LOS was 7 days (1-30 days) and 55 patients had eLOS (LOS ≥ 11 days). Multivariate analysis revealed that significant variables independently associated with eLOS were instrumentation >9 spinal segmental levels (OR 2.89, 95% CI 1.1-7.5, p = 0.032) and presence of postoperative complications (OR 3.68, 95% CI 1.85-7.30, p < 0.001). Metastatic tumours other than breast, prostate and lung have lesser risk of eLOS (OR 0.31, 95% CI 0.14-0.70, p = 0.004). Survival estimates show that patients with eLOS have shorter survival than patients with nLOS (Crude HR 1.81, 95% CI 1.13-2.89, p = 0.003).

    Radivoyevitch T, Dean RM, Shaw BE, et al.
    Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma.
    Leuk Res. 2018; 74:130-136 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
    BACKGROUND: Exposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
    METHODS: 9028 recipients of hematopoietic cell autotransplants (1995-2010) for Hodgkin lymphoma (HL; n = 916), non-Hodgkin lymphoma (NHL; n = 3546) and plasma cell myeloma (PCM; n = 4566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS.
    RESULTS: 335 MDS/AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HR = 4.0; 95% confidence interval [1.4, 11.6]) and NHL (HR = 2.5 [1.1, 2.5]); (2) ≥3 versus 1 line of chemotherapy for NHL (HR = 1.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005-2010 versus 1995-1999 (HR = 2.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/MDS in HL, NHL and PCM to be 5-10 times the background rate. In contrast, relative risks were 10-50 for AML and approximately 100 for MDS in the autotransplant cohort.
    CONCLUSIONS: There are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.

    Chari A, Stewart AK, Russell SD, et al.
    Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials.
    Blood Adv. 2018; 2(13):1633-1644 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
    Carfilzomib is a selective proteasome inhibitor approved for the treatment of relapsed and/or refractory multiple myeloma (RRMM). It has significantly improved outcomes, including overall survival (OS), and shown superiority vs standard treatment with lenalidomide plus dexamethasone and bortezomib plus dexamethasone. The incidence rate of cardiovascular (CV) events with carfilzomib treatment has varied across trials. This analysis evaluated phase 1-3 trials with >2000 RRMM patients exposed to carfilzomib to describe the incidence of CV adverse events (AEs). In addition, the individual CV safety data of >1000 patients enrolled in the carfilzomib arm of phase 3 studies were compared with the control arms to assess the benefit-risk profile of carfilzomib. Pooling data across carfilzomib trials, the CV AEs (grade ≥3) noted included hypertension (5.9%), dyspnea (4.5%), and cardiac failure (4.4%). Although patients receiving carfilzomib had a numeric increase in the rates of any-grade and grade ≥3 cardiac failure, dyspnea, and hypertension, the frequency of discontinuation or death due to these cardiac events was low and comparable between the carfilzomib and control arms. Serial echocardiography in a blinded cardiac substudy showed no objective evidence of cardiac dysfunction in the carfilzomib and control arms. Moreover, carfilzomib had no significant effect on cardiac repolarization. Our results, including the OS benefit, showed that the benefit of carfilzomib treatment in terms of reducing progression or death outweighed the risk for developing cardiac failure or hypertension in most patients. Appropriate carfilzomib administration and risk factor management are recommended for elderly patients and patients with underlying risk factors.

    Earp M, Tyrer JP, Winham SJ, et al.
    Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.
    PLoS One. 2018; 13(7):e0197561 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
    Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

    Abdallah FW, Cil T, MacLean D, et al.
    Too Deep or Not Too Deep?: A Propensity-Matched Comparison of the Analgesic Effects of a Superficial Versus Deep Serratus Fascial Plane Block for Ambulatory Breast Cancer Surgery.
    Reg Anesth Pain Med. 2018; 43(5):480-487 [PubMed] Related Publications
    BACKGROUND AND OBJECTIVES: Serratus fascial plane block can reduce pain following breast surgery, but the question of whether to inject the local anesthetic superficial or deep to the serratus muscle has not been answered. This cohort study compares the analgesic benefits of superficial versus deep serratus plane blocks in ambulatory breast cancer surgery patients at Women's College Hospital between February 2014 and December 2016. We tested the joint hypothesis that deep serratus block is noninferior to superficial serratus block for postoperative in-hospital (pre-discharge) opioid consumption and pain severity.
    METHODS: One hundred sixty-six patients were propensity matched among 2 groups (83/group): superficial and deep serratus blocks. The cohort was used to evaluate the effect of blocks on postoperative oral morphine equivalent consumption and area under the curve for rest pain scores. We considered deep serratus block to be noninferior to superficial serratus block if it were noninferior for both outcomes, within 15 mg morphine and 4 cm·h units margins. Other outcomes included intraoperative fentanyl requirements, time to first analgesic request, recovery room stay, and incidence of postoperative nausea and vomiting.
    RESULTS: Deep serratus block was associated with postoperative morphine consumption and pain scores area under the curve that were noninferior to those of the superficial serratus block. Intraoperative fentanyl requirements, time to first analgesic request, recovery room stay, and postoperative nausea and vomiting were not different between blocks.
    CONCLUSIONS: The postoperative in-hospital analgesia associated with deep serratus block is as effective (within an acceptable margin) as superficial serratus block following ambulatory breast cancer surgery. These new findings are important to inform both current clinical practices and future prospective studies.

    Kampen KR, Sulima SO, Verbelen B, et al.
    The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL.
    Leukemia. 2019; 33(2):319-332 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
    The R98S mutation in ribosomal protein L10 (RPL10 R98S) affects 8% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) cases, and was previously described to impair cellular proliferation. The current study reveals that RPL10 R98S cells accumulate reactive oxygen species which promotes mitochondrial dysfunction and reduced ATP levels, causing the proliferation defect. RPL10 R98S mutant leukemia cells can survive high oxidative stress levels via a specific increase of IRES-mediated translation of the anti-apoptotic factor B-cell lymphoma 2 (BCL-2), mediating BCL-2 protein overexpression. RPL10 R98S selective sensitivity to the clinically available Bcl-2 inhibitor Venetoclax (ABT-199) was supported by suppression of splenomegaly and the absence of human leukemia cells in the blood of T-ALL xenografted mice. These results shed new light on the oncogenic function of ribosomal mutations in cancer, provide a novel mechanism for BCL-2 upregulation in leukemia, and highlight BCL-2 inhibition as a novel therapeutic opportunity in RPL10 R98S defective T-ALL.

    Brock PR, Maibach R, Childs M, et al.
    Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss.
    N Engl J Med. 2018; 378(25):2376-2385 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
    BACKGROUND: Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival.
    METHODS: We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years.
    RESULTS: A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively.
    CONCLUSIONS: The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 number, NCT00652132 ; EudraCT number, 2007-002402-21 .).

    Walker BA, Mavrommatis K, Wardell CP, et al.
    Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma.
    Blood. 2018; 132(6):587-597 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
    Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including

    Eaton DJ, Lee J, Patel R, et al.
    Stereotactic radiosurgery for benign brain tumors: Results of multicenter benchmark planning studies.
    Pract Radiat Oncol. 2018 Sep - Oct; 8(5):e295-e304 [PubMed] Related Publications
    PURPOSE: Stereotactic radiosurgery (SRS) is strongly indicated for treatment of surgically inaccessible benign brain tumors. Various treatment platforms are available, but few comparisons have included multiple centers. As part of a national commissioning program, benchmark planning cases were completed by all clinical centers in the region.
    METHODS AND MATERIALS: Four benign cases were provided, with images and structures predelineated, including intracanalicular vestibular schwannoma (VS), larger VS, skull base meningioma, and secreting pituitary adenoma. Centers were asked to follow their local practice, and plans were reviewed centrally using metrics for target coverage, selectivity, gradient falloff, and normal tissue sparing.
    RESULTS: Sixty-eight plans were submitted using 18 different treatment platforms. Fourteen plans were subsequently revised following feedback, and review of 5 plans led to a restriction of service on 2 platforms (2 centers). Prescription doses were consistent for VS and meningioma submissions, but a wide range of doses were used for the pituitary case. All centers prioritized coverage, with the prescription isodose covering ≥95% of 78/82 target volumes. Lower values may be expected next to air cavities when using advanced algorithms, and in general may be acceptable for some benign lesions. Selectivity was much more variable, and in some cases this was combined with high gradient index and/or >1 mm margin, resulting in large volumes of normal tissue being irradiated. Normal tissue doses were more variable across linear accelerator (LINAC)-based plans than with Gamma Knife or CyberKnife, and dose spillage seemed independent of prescription isodose (inhomogeneity). This may reflect the variety of LINAC-based approaches represented or the necessary tradeoff between different objectives.
    CONCLUSIONS: These benchmarking exercises have highlighted areas of different clinical practice and priorities and potential for improvement. The subsequent sharing of plan data and margin philosophies between the neurosurgery and oncology communities allowed for meaningful comparison between centers and their peers.

    Offor UT, Akyea RK, Neequaye JE, et al.
    The changing clinical pattern of endemic Burkitt lymphoma in Western Africa: Experience from a tertiary center in Ghana.
    Pediatr Blood Cancer. 2018; 65(10):e27275 [PubMed] Related Publications
    BACKGROUND: Burkitt lymphoma (BL) is the most common childhood cancer in Ghana, where the endemic variant is the predominant subtype and historically presents as a highly chemo-sensitive jaw tumor. This study aimed to update the current epidemiological characteristics of childhood BL in our institution.
    PROCEDURE: Patient data for all children diagnosed with BL and seen at Korle Bu Teaching Hospital between January 2007 and December 2012 were retrospectively analyzed.
    RESULTS: BL was diagnosed in 173 children (<13 years) during the study period, with the abdomen as the most common tumor site (46%) followed by the jaw (31%). Abdominal tumors were associated with advanced/disseminated disease (P = 0.002), and were more likely to occur in females irrespective of tumor stage (relative risk = 1.56 [95% CI; 1.1-12.3]). Twenty-five percent (43/173) of the study cohort died and mortality was influenced by increasing age (P = 0.02) and advanced disease (P = 0.03). Treatment delay was experienced by nine in ten patients primarily due to familial financial constraint (75%). Treatment abandonment was observed as a first event in 94% of patients and two thirds of children in the study were eventually lost to follow-up.
    CONCLUSION: The predominance of primary abdominal tumors in our study cohort may indicate a changing epidemiological pattern of BL in Ghana. High rates of treatment delay and abandonment were evident and are likely to be contributing factors to the poor childhood cancer survival outcomes seen in resource-limited countries in Africa.

    Francis PA, Pagani O, Fleming GF, et al.
    Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer.
    N Engl J Med. 2018; 379(2):122-137 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
    BACKGROUND: In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials.
    METHODS: Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy.
    RESULTS: In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen-ovarian suppression group, and 32.3% of the exemestane-ovarian suppression group.
    CONCLUSIONS: Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group. (Funded by Pfizer and others; SOFT and TEXT numbers, NCT00066690 and NCT00066703 , respectively.).

    Fordham SE, Blair HJ, Elstob CJ, et al.
    Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase.
    Blood Adv. 2018; 2(10):1157-1169 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
    The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other hematologic malignancies.
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