The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation.

Metabolic adaptation is essential for cell survival during nutrient deprivation. We report that eukaryotic elongation factor 2 kinase (eEF2K), which is activated by AMP-kinase (AMPK), confers cell survival under acute nutrient depletion by blocking translation elongation. Tumor cells exploit this pathway to adapt to nutrient deprivation by reactivating the AMPK-eEF2K axis. Adaptation of transformed cells to nutrient withdrawal is severely compromised in cells lacking eEF2K. Moreover, eEF2K knockdown restored sensitivity to acute nutrient deprivation in highly resistant human tumor cell lines. In vivo, overexpression of eEF2K rendered murine tumors remarkably resistant to caloric restriction. Expression of eEF2K strongly correlated with overall survival in human medulloblastoma and glioblastoma multiforme. Finally, C. elegans strains deficient in efk-1, the eEF2K ortholog, were severely compromised in their response to nutrient depletion. Our data highlight a conserved role for eEF2K in protecting cells from nutrient deprivation and in conferring tumor cell adaptation to metabolic stress. PAPERCLIP:

Delivered relative dose intensity in adolescent and young adult germ cell tumours in England: Assessment of data quality and consistency from clinical trials compared to national cancer registration data.

Adolescent and young adults (AYA) with germ cell tumours (GCT) have poorer survival rates than children and many older adults with the same cancers. There are several likely contributing factors to this, including the treatment received. The prognostic benefit of intended dose intensity is well documented in GCT from trials comparing regimens. However, evidence specific to AYA is limited by poor recruitment of AYA to trials and dose delivery outside trials not being well examined. We examined the utility of cancer registration data and a clinical trials dataset to investigate the delivery of relative dose intensity (RDI) in routine National Health Service practice in England, compared to within international clinical trials. Linked data from the Cancer Outcomes and Services Dataset (COSD) and the Systemic Anti-Cancer Therapy (SACT) dataset, and data from four international clinical trials were analysed. Survival over time was described using Kaplan-Meier estimation; overall, by age category, International Germ-Cell Cancer Collaborative Group (IGCCCG) classification, stage, tumour subtype, primary site, ethnicity and deprivation. Cox regression models were used to determine the fully adjusted effect of RDI on mortality risk. The quality of both datasets was critically evaluated and clinically enhanced. RDI was found to be well maintained in all datasets with higher RDIs associated with improved survival outcomes. Real-world data demonstrated several strengths, including population coverage and inclusion of sociodemographic variables and comorbidity. It is limited in GCT however, by the poor completion of data items enabling risk classification of patients and a higher proportion of missing data.

Emerging therapies in Ewing sarcoma.

PURPOSE OF REVIEW: There is an unmet need to improve outcomes for patients for Ewing sarcoma, a rare, aggressive sarcoma with a peak incidence in adolescents and young adults (AYA). Current therapy at diagnosis involves multiagent chemotherapy and local therapy, but despite intensification of treatment, those with metastases at diagnosis and recurrent disease have poor outcomes. RECENT FINDINGS: Improved understanding of Ewing sarcoma biology has identified novel targets with promising activity in Ewing sarcoma patients, including tyrosine kinase inhibitors that are now undergoing evaluation as combination and maintenance therapy. Other emerging therapies include those that target the EWSR1::FLI1 fusion oncoprotein, and act on DNA damage, cell cycle and apoptotic pathways. Immunotherapeutic approaches, particularly CAR-T-cell therapy directed at GD2, also hold promise. Recent collaborative clinical trials that have defined an international standard of care for patients with newly diagnosed Ewing sarcoma and novel platform studies with adaptive designs offer unique opportunities to investigate these therapies inclusive of all ages. SUMMARY: Close international collaboration between clinicians and biologists will allow us to prioritize promising emerging therapies and develop biomarkers to facilitate their incorporation into standard of care and more rapidly translate into benefit for Ewing sarcoma patients.

Protocol for the development of a Core Outcome Set (COS) for Adolescents and Young Adults (AYAs) with cancer.

BACKGROUND: Adolescents and young adults (AYAs) with cancer, defined as individuals aged 15-39 years at initial cancer diagnosis, form a unique population; they face age-specific issues as they transition to adulthood. This paper presents the protocol for the development of a core outcome set (COS) for AYAs with cancer. METHODS: The methodological standards from the Core Outcome Measures in Effectiveness Trials (COMET) and the International Consortium for Health Outcomes Measurement (ICHOM) for COS development will guide the development of the COS for AYAs with cancer. The project will consist of the following phases: (1) define the scope of the COS; (2) establish the need for a COS in this field (3) assemble an international, multi-stakeholder working group; (4) develop a detailed protocol; (5) determine "what to measure" (i.e., outcomes); (6) determine "how to measure" (i.e., measures); and (7) determine "case-mix" variables. CONCLUSIONS: The development of a COS for AYAs with cancer will facilitate the implementation of efficient and relevant standards for data collection, both for clinical trials and in routine healthcare, thereby increasing the usefulness of these data to improve the value of the care given to these underserved young cancer patients.

Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification.

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/ß-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

International variation in childhood cancer mortality rates from 2001 to 2015: Comparison of trends in the International Cancer Benchmarking Partnership countries.

Despite improved survival rates, cancer remains one of the most common causes of childhood death. The International Cancer Benchmarking Partnership (ICBP) showed variation in cancer survival for adults. We aimed to assess and compare trends over time in cancer mortality between children, adolescents and young adults (AYAs) and adults in the six countries involved in the ICBP: United Kingdom, Denmark, Australia, Canada, Norway and Sweden. Trends in mortality between 2001 and 2015 in the six original ICBP countries were examined. Age standardised mortality rates (ASR per million) were calculated for all cancers, leukaemia, malignant and benign central nervous system (CNS) tumours, and non-CNS solid tumours. ASRs were reported for children (age 0-14 years), AYAs aged 15 to 39 years and adults aged 40 years and above. Average annual percentage change (AAPC) in mortality rates per country were estimated using Joinpoint regression. For all cancers combined, significant temporal reductions were observed in all countries and all age groups. However, the overall AAPC was greater for children (-2.9; 95% confidence interval = -4.0 to -1.7) compared to AYAs (-1.8; -2.1 to -1.5) and adults aged >40 years (-1.5; -1.6 to -1.4). This pattern was mirrored for leukaemia, CNS tumours and non-CNS solid tumours, with the difference being most pronounced for leukaemia: AAPC for children -4.6 (-6.1 to -3.1) vs AYAs -3.2 (-4.2 to -2.1) and over 40s -1.1 (-1.3 to -0.8). AAPCs varied between countries in children for all cancers except leukaemia, and in adults over 40 for all cancers combined, but not in subgroups. Improvements in cancer mortality rates in ICBP countries have been most marked among children aged 0 to 14 in comparison to 15 to 39 and over 40 year olds. This may reflect better care, including centralised service provision, treatment protocols and higher trial recruitment rates in children compared to older patients.

Severity of COVID-19 in children with cancer: Report from the United Kingdom Paediatric Coronavirus Cancer Monitoring Project.

BACKGROUND: Children with cancer are frequently immunocompromised. While children are generally thought to be at less risk of severe SARS-CoV-2 infection than adults, comprehensive population-based evidence for the risk in children with cancer is unavailable. We aimed to produce evidence of the incidence and outcomes from SARS-CoV-2 in children with cancer attending all hospitals treating this population across the UK. METHODS: Retrospective and prospective observational study of all children in the UK under 16 diagnosed with cancer through data collection from all hospitals providing cancer care to this population. Eligible patients tested positive for SARS-CoV-2 on reverse transcription polymerase chain reaction (RT-PCR). The primary end-point was death, discharge or end of active care for COVID-19 for those remaining in hospital. RESULTS: Between 12 March 2020 and 31 July 2020, 54 cases were identified: 15 (28%) were asymptomatic, 34 (63%) had mild infections and 5 (10%) moderate, severe or critical infections. No patients died and only three patients required intensive care support due to COVID-19. Estimated incidence of hospital identified SARS-CoV-2 infection in children with cancer under 16 was 3%. CONCLUSIONS: Children with cancer with SARS-CoV-2 infection do not appear at increased risk of severe infection compared to the general paediatric population. This is reassuring and supports the continued delivery of standard treatment.

Adolescents and Young Adults Living With an Uncertain or Poor Cancer Prognosis: The "New" Lost Tribe.

Historically, adolescent and young adult (AYA) patients with cancer, diagnosed for the first time at age 15 through 39 years, have often been identified as a "lost tribe" without a medical "home"; neither pediatric nor adult oncology services were able to provide age-appropriate care to this specific group. Internationally, AYA care programs are being established to bridge the gap between the age-defined healthcare worlds and to address the specific needs of AYAs with cancer. However, AYA care programs mostly focus on improving cure rates and addressing survivorship issues, and direct less attention to the unique needs of those living with an uncertain and/or poor cancer prognosis. Additionally, palliative care services are typically poorly equipped to address the age-specific needs of this group. Given that increasingly more AYAs with an uncertain and/or poor cancer prognosis are gaining life years because of novel treatments, and sometimes even face the prospect of long-term disease control, AYA care programs should address the unique palliative care needs of this "new" lost tribe within AYA oncology. This report provides a definition and description of the AYA population living with an uncertain and/or poor cancer prognosis in terms of epidemiologic, clinical, and psychosocial characteristics and challenges, and provides perspectives for future research and care initiatives. It also highlights the need to comprehensively examine the experience of AYAs who are living with uncertain and/or poor cancer prognosis to adjust best care practices for this unique group.

Oral etoposide as a single agent in childhood and young adult cancer in England: Still a poorly evaluated palliative treatment.

BACKGROUND: Oral etoposide is commonly used in palliative treatment of childhood and young adult cancer without robust evidence. We describe a national, unselected cohort of young people in England treated with oral etoposide using routinely collected, population-level data. METHODS: Patients aged under 25 years at cancer diagnosis (1995-2017) with a treatment record of single-agent oral etoposide in the Systemic AntiCancer Dataset (SACT, 2012-2018) were identified, linked to national cancer registry data using NHS number and followed to 5 January 2019. Overall survival (OS) was estimated for all tumours combined and by tumour group. A Cox model was applied accounting for age, sex, tumour type, prior and subsequent chemotherapy. RESULTS: Total 115 patients were identified during the study period. Mean age was 11.8 years at cancer diagnosis and 15.5 years at treatment with oral etoposide. Median OS was 5.5 months from the start of etoposide; 13 patients survived beyond 2 years. Survival was shortest in patients with osteosarcoma (median survival 3.6 months) and longest in CNS embryonal tumours (15.5 months). Across the cohort, a median of one cycle (range one to nine) of etoposide was delivered. OS correlated significantly with tumour type and prior chemotherapy, but not with other variables. CONCLUSIONS: This report is the largest series to date of oral etoposide use in childhood and young adult cancer. Most patients treated in this real world setting died quickly. Despite decades of use, there are still no robust data demonstrating a clear benefit of oral etoposide for survival.

EORTC SPECTA-AYA: A unique molecular profiling platform for adolescents and young adults with cancer in Europe.

For most adolescent and young adult (AYA) cancers, age-specific molecular features are poorly understood. EORTC-SPECTA, an academic translational research infrastructure for biomaterial collection, will explicitly recruit AYA patients and will therefore collect empirical data to bridge the molecular gap between pediatric and adult oncology. The initial pilot study, activated in February 2019 across Europe, will recruit 100 AYA patients (aged 12-29 years) with newly diagnosed or relapsed high-grade gliomas and high-grade bone and soft tissue sarcomas. The primary objective of the pilot is to determine feasibility and recruitment rates. Formalin-fixed tumor tissue and whole blood from study participants will be prospectively collected with clinical data and stored centrally at the Integrated BioBank of Luxembourg. Whole exome sequencing of matched tumor and blood, and tumor RNA sequencing and DNA methylation profiling will be performed at the German Cancer Research Center, Heidelberg, Germany. Virtual central pathology review of scanned diagnostic slides will be undertaken by an international expert panel, and diagnostic material returned to the participating centers. A multidisciplinary molecular tumor board will release a clinically validated report to referring clinicians within 4-6 weeks after biopsy. SPECTA-AYA constitutes a major opportunity to gain knowledge about the tumor biology of this unique age group. It incorporates notable innovative aspects: AYA specificity, pan-European academic collaboration, centralized biobanking, comprehensive molecular profiling and virtual central pathology review, among others. SPECTA-AYA will help untangle the tumor particularities of AYAs with cancer and aims to improve their access to novel drugs and personalized medicine.

Large Extracellular Vesicles Can be Characterised by Multiplex Labelling Using Imaging Flow Cytometry.

Extracellular vesicles (EVs) are heterogeneous in size (30 nm-10 µm), content (lipid, RNA, DNA, protein), and potential function(s). Many isolation techniques routinely discard the large EVs at the early stages of small EV or exosome isolation protocols. We describe here a standardised method to isolate large EVs from medulloblastoma cells and examine EV marker expression and diameter using imaging flow cytometry. Our approach permits the characterisation of each large EVs as an individual event, decorated with multiple fluorescently conjugated markers with the added advantage of visualising each event to ensure robust gating strategies are applied. METHODS: We describe step-wise isolation and characterisation of a subset of large EVs from the medulloblastoma cell line UW228-2 assessed by fluorescent light microscopy, transmission electron microscopy (TEM) and tunable resistance pulse sensing (TRPS). Viability of parent cells was assessed by Annexin V exposure by flow cytometry. Imaging flow cytometry (Imagestream Mark II) identified EVs by direct fluorescent membrane labelling with Cell Mask Orange (CMO) in conjunction with EV markers. A stringent gating algorithm based on side scatter and fluorescence intensity was applied and expression of EV markers CD63, CD9 and LAMP 1 assessed. RESULTS: UW228-2 cells prolifically release EVs of up to 6 µm. We show that the Imagestream Mark II imaging flow cytometer allows robust and reproducible analysis of large EVs, including assessment of diameter. We also demonstrate a correlation between increasing EV size and co-expression of markers screened. CONCLUSIONS: We have developed a labelling and stringent gating strategy which is able to explore EV marker expression (CD63, CD9, and LAMP1) on individual EVs within a widely heterogeneous population. Taken together, data presented here strongly support the value of exploring large EVs in clinical samples for potential biomarkers, useful in diagnostic screening and disease monitoring.

Risk of subsequent primary neoplasms in survivors of adolescent and young adult cancer (Teenage and Young Adult Cancer Survivor Study): a population-based, cohort study.

BACKGROUND: Few studies have investigated the risks of subsequent primary neoplasms after adolescent and young adult (AYA) cancer. We investigated the risks of specific subsequent primary neoplasms after each of 16 types of AYA cancer. METHODS: The Teenage and Young Adult Cancer Survivor Study is a population-based cohort of 200 945 survivors of cancer diagnosed when aged 15-39 years in England and Wales from Jan 1, 1971, to Dec 31, 2006. The cohort was established using cancer registrations from the Office for National Statistics and the Welsh Cancer registry. Follow-up was from 5-year survival until the first occurrence of death, emigration, or study end date (Dec 31, 2012). In this analysis, we focus on the risk of specific subsequent primary neoplasms after 16 types of AYA cancer: breast; cervical; testicular; Hodgkin lymphoma (female); Hodgkin lymphoma (male); melanoma; CNS (intracranial); colorectal; non-Hodgkin lymphoma; thyroid; soft-tissue sarcoma; ovarian; bladder; other female genital; leukaemia; and head and neck cancer. We report absolute excess risks (AERs; per 10 000 person-years) and cumulative incidence of specific types of subsequent primary neoplasm after each type of AYA cancer. FINDINGS: During the 2 631 326 person-years of follow-up (median follow-up 16·8 years, IQR 10·5-25·2), 12 321 subsequent primary neoplasms were diagnosed in 11 565 survivors, most frequently among survivors of breast cancer, cervical cancer, testicular cancer, and Hodgkin lymphoma. AERs of any subsequent primary neoplasms were 19·5 per 10 000 person-years (95% CI 17·4-21·5) in survivors of breast cancer, 10·2 (8·0-12·4) in survivors of cervical cancer, 18·9 (16·6-21·1) in survivors of testicular cancer, 55·7 (50·4-61·1) in female survivors of Hodgkin lymphoma, and 29·9 (26·3-33·6) in male survivors of Hodgkin lymphoma. The cumulative incidence of all subsequent primary neoplasms 35 years after diagnosis was 11·9% (95% CI 11·3-12·6) in survivors of breast cancer, 15·8% (14·8-16·7) in survivors of cervical cancer, 20·2% (18·9-21·5) in survivors of testicular cancer, 26·6% (24·7-28·6) in female survivors of Hodgkin lymphoma, and 16·5% (15·2-18·0) in male survivors of Hodgkin lymphoma. In patients who had survived at least 30 years from diagnosis of cervical cancer, testicular cancer, Hodgkin lymphoma in women, breast cancer, and Hodgkin lymphoma in men, we identified a small number of specific subsequent primary neoplasms that account for 82%, 61%, 58%, 45%, and 41% of the total excess number of neoplasms, respectively. Lung cancer accounted for a notable proportion of the excess number of neoplasms across all AYA groups investigated. INTERPRETATION: Our finding that a small number of specific subsequent primary neoplasms account for a large percentage of the total excess number of neoplasms in long-term survivors of cervical, breast, and testicular cancer, and Hodgkin lymphoma provides an evidence base to inform priorities for clinical long-term follow-up. The prominence of lung cancer after each of these AYA cancers indicates the need for further work aimed at preventing and reducing the burden of this cancer in future survivors of AYA cancer. FUNDING: Cancer Research UK, National Institute for Health Research, Academy of Medical Sciences, and Children with Cancer UK.

EANO-EURACAN clinical practice guideline for diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma.

The European Association of Neuro-Oncology (EANO) and EUropean RAre CANcer (EURACAN) guideline provides recommendations for the diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma. The guideline is based on the 2016 WHO classification of tumours of the CNS and on scientific developments published since 1980. It aims to provide direction for diagnostic and management decisions, and for limiting unnecessary treatments and cost. In view of the scarcity of data in adults with medulloblastoma, we base our recommendations on adult data when possible, but also include recommendations derived from paediatric data if justified. Our recommendations are a resource for professionals involved in the management of post-pubertal and adult patients with medulloblastoma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.

Is the cancer survival improvement in European and American adolescent and young adults still lagging behind that in children?

Improvements during 1978 to 2006 in the 5-year survival rate of adolescents and young adults (AYAs, age 15-39) and children with cancers common to both age groups were evaluated for 1978 to 2006 in Europe and the USA. AYAs had absolute survival increases of 25% and 15% in Europe and the USA, respectively, but in both cases, AYA 5-year survival was, as of 2006, 4% lower than those in children. Acute lymphoblastic leukemia (ALL) explained most of the survival difference between AYAs and children on both the continents. In the USA, 20- to 39-year-olds with ALL have had less survival improvement than those in Europe.

Discussing factors associated with quality of life in cancer follow-up appointments: a preliminary test of a pragmatic model for clinical practice.

OBJECTIVE:: The aim of this study is to perform a preliminary test of a practical, evidence-based model to enable discussions around quality of life-related concerns during cancer follow-up appointments. DESIGN:: Cross-sectional study measuring quality of life, illness perceptions, emotional distress, fatigue, and subjective cognitive complaints. SETTING:: Cancer outpatient follow-up clinics in four National Health Services in the United Kingdom. PARTICIPANTS:: Working-age post-treatment cancer patients, treated with curative intent. INTERVENTIONS:: Not applicable. MAIN MEASURES:: European Organisation for the Research and Treatment of Cancer - Quality of Life Questionnaire - Core 30, Illness Perceptions Questionnaire - Revised, Hospital Anxiety and Depression Scale, Chalder Fatigue Scale, and Cognitive Failures Questionnaire. RESULTS:: Fifty-seven cancer patients, with a mean age of 36 years and on average 2.75 years post treatment, returned the completed questionnaires. Anxiety partially mediated the association between subjective cognitive complaints and illness identity (60%) and timeline (25%). Cognitive complaints mediated the relationships between quality of life and anxiety (45%), depression (30%), and fatigue (62%). Depression mediated the relationships between quality of life and illness identity (48%) and timeline (40%). CONCLUSION:: Our study provides a preliminary test of an evidence-based model to help elicit quality of life-related concerns during cancer follow-up appointments. Illness perceptions are associated with quality of life through the mediation of other cancer-relevant factors. Discussing the type, origin, and expected duration of symptoms may elicit other concerns, such as emotional distress, fatigue, or cognitive complaints, which explained a significant amount of the relationship between illness perceptions and quality of life.

Clonal selection drives genetic divergence of metastatic medulloblastoma.

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.

Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The Teenage and Young Adult Cancer Survivor Study.

BACKGROUND: Survivors of teenage and young adult cancer are acknowledged as understudied. Little is known about their long-term adverse health risks, particularly of cardiac disease that is increased in other cancer populations where cardiotoxic treatments have been used. METHODS: The Teenage and Young Adult Cancer Survivor Study cohort comprises 200 945 5-year survivors of cancer diagnosed at 15 to 39 years of age in England and Wales from 1971 to 2006, and followed to 2014. Standardized mortality ratios, absolute excess risks, and cumulative risks were calculated. RESULTS: Two thousand sixteen survivors died of cardiac disease. For all cancers combined, the standardized mortality ratios for all cardiac diseases combined was greatest for individuals diagnosed at 15 to 19 years of age (4.2; 95% confidence interval, 3.4-5.2) decreasing to 1.2 (95% confidence interval, 1.1-1.3) for individuals aged 35 to 39 years (2P for trend <0.0001). Similar patterns were observed for both standardized mortality ratios and absolute excess risks for ischemic heart disease, valvular heart disease, and cardiomyopathy. Survivors of Hodgkin lymphoma, acute myeloid leukaemia, genitourinary cancers other than bladder cancer, non-Hodgkin lymphoma, lung cancer, leukaemia other than acute myeloid, central nervous system tumour, cervical cancer, and breast cancer experienced 3.8, 2.7, 2.0, 1.7, 1.7, 1.6, 1.4, 1.3 and 1.2 times the number of cardiac deaths expected from the general population, respectively. Among survivors of Hodgkin lymphoma aged over 60 years, almost 30% of the total excess number of deaths observed were due to heart disease. CONCLUSIONS: This study of over 200 000 cancer survivors shows that age at cancer diagnosis was critical in determining subsequent cardiac mortality risk. For the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 and 39 years have been derived from a large population-based cohort with prolonged follow-up. The evidence here provides an initial basis for developing evidence-based follow-up guidelines.

Toxicity profile of bevacizumab in the UK Neurofibromatosis type 2 cohort.

Bevacizumab is considered an established part of the treatment strategies available for schwannomas in patients with Neurofibromatosis type 2 (NF2). In the UK, it is available through NHS National Specialized Commissioning to NF2 patients with a rapidly growing target schwannoma. Regrowth of the tumour on suspension of treatment is often observed resulting in prolonged periods of exposure to bevacizumab to control the disease. Hypertension and proteinuria are common events with bevacizumab use and there are concerns with regards to the long-term risks of prolonged treatment. Dosing, demographic and adverse event (CTCAE 4.03) data from the UK NF2 bevacizumab cohort are reviewed with particular consideration of renal and cardiovascular complications. Eighty patients (48 male:32 female), median age 24.5 years (range 11-66 years), were followed for a median of 32.7 months (range 12.0-60.2 months). The most common adverse events were fatigue, hypertension and infection. A total of 19/80 patients (24 %) had either a grade 2 or grade 3 hypertension event and 14/80 patients (17.5 %) had proteinuria. Of 36 patients followed for 36 months, 78 % were free from hypertension and 86 % were free of proteinuria. Logistic regression modeling identified age and induction dosing regime to be independent predictors of development of hypertension with dose of 7.5 mg/kg 3 weekly and age >30years having higher rates of hypertension. Proteinuria persisted in one of three patients after cessation of bevacizumab. One patient developed congestive heart failure and the details of this case are described. Further work is needed to determine optimal dosing regimes to limit toxicity without impacting on efficacy.

Interventions for preventing oral mucositis in patients with cancer receiving treatment: cytokines and growth factors.

BACKGROUND: Oral mucositis is a side effect of chemotherapy, head and neck radiotherapy, and targeted therapy, affecting over 75% of high-risk patients. Ulceration can lead to severe pain and difficulty with eating and drinking, which may necessitate opioid analgesics, hospitalisation and supplemental nutrition. These complications may disrupt cancer therapy, which may reduce survival. There is also a risk of death from sepsis if pathogens enter the ulcers of immunocompromised patients. Ulcerative oral mucositis can be costly to healthcare systems, yet there are few preventive interventions proven to be beneficial. Cytokines and growth factors may help the regeneration of cells lining of the mouth, thus preventing or reducing oral mucositis and its negative effects. OBJECTIVES: To assess the effects of cytokines and growth factors for preventing oral mucositis in patients with cancer who are receiving treatment. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (searched 10 May 2017); the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 4) in the Cochrane Library (searched 10 May 2017); MEDLINE Ovid (1946 to 10 May 2017); Embase Ovid (7 December 2015 to 10 May 2017); CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 10 May 2017); and CANCERLIT PubMed (1950 to 10 May 2017). The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. SELECTION CRITERIA: We included parallel-design randomised controlled trials (RCTs) assessing the effects of cytokines and growth factors in patients with cancer receiving treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of electronic searches, extracted data and assessed risk of bias. For dichotomous outcomes, we reported risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, we reported mean differences (MD) and 95% CIs. We pooled similar studies in random-effects meta-analyses. We reported adverse effects in a narrative format. MAIN RESULTS: We included 35 RCTs analysing 3102 participants. Thirteen studies were at low risk of bias, 12 studies were at unclear risk of bias, and 10 studies were at high risk of bias.Our main findings were regarding keratinocyte growth factor (KGF) and are summarised as follows.There might be a reduction in the risk of moderate to severe oral mucositis in adults receiving bone marrow/stem cell transplantation after conditioning therapy for haematological cancers (RR 0.89, 95% CI 0.80 to 0.99; 6 studies; 852 participants; low-quality evidence). We would need to treat 11 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 6 to 112). There might be a reduction in the risk of severe oral mucositis in this population, but there is also some possibility of an increase in risk (RR 0.85, 95% CI 0.65 to 1.11; 6 studies; 852 participants; low-quality evidence). We would need to treat 10 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 5 to prevent the outcome to 14 to cause the outcome).There is probably a reduction in the risk of moderate to severe oral mucositis in adults receiving radiotherapy to the head and neck with cisplatin or fluorouracil (RR 0.91, 95% CI 0.83 to 1.00; 3 studies; 471 participants; moderate-quality evidence). We would need to treat 12 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 7 to infinity). It is very likely that there is a reduction in the risk of severe oral mucositis in this population (RR 0.79, 95% CI 0.69 to 0.90; 3 studies; 471 participants; high-quality evidence). We would need to treat 7 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 5 to 15).It is likely that there is a reduction in the risk of moderate to severe oral mucositis in adults receiving chemotherapy alone for mixed solid and haematological cancers (RR 0.56, 95% CI 0.45 to 0.70; 4 studies; 344 participants; moderate-quality evidence). We would need to treat 4 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 3 to 6). There might be a reduction in the risk of severe oral mucositis in this population (RR 0.30, 95% CI 0.14 to 0.65; 3 studies; 263 participants; low -quality evidence). We would need to treat 10 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 8 to 19).Due to the low volume of evidence, single-study comparisons and insufficient sample sizes, we found no compelling evidence of a benefit for any other cytokines or growth factors and there was no evidence on children. There did not appear to be any serious adverse effects of any of the interventions assessed in this review. AUTHORS' CONCLUSIONS: We are confident that KGF is beneficial in the prevention of oral mucositis in adults who are receiving: a) radiotherapy to the head and neck with cisplatin or fluorouracil; or b) chemotherapy alone for mixed solid and haematological cancers. We are less confident about a benefit for KGF in adults receiving bone marrow/stem cell transplant after conditioning therapy for haematological cancers because of multiple factors involved in that population, such as whether or not they received total body irradiation (TBI) and whether the transplant was autologous (the patients' own cells) or allogeneic (cells from a donor). KGF appears to be a relatively safe intervention.Due to limited research, we are not confident that there are any beneficial effects of other cytokines and growth factors. There is currently insufficient evidence to draw any conclusions about the use of cytokines and growth factors in children.