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PURPOSE: The aim of the project was to evaluate intra-CSF etoposide administration in a palliative setting for children and young people with relapsed/refractory central nervous system (CNS) tumours, with the primary endpoints being overall survival and progression-free survival time. A safety endpoint was to assess the side effect profile and complications of intra-CSF etoposide. METHODS: Thirty-five patients under the age of 30 years (median age: 5.33 years) were enrolled onto the project. The cross-centre study was a service evaluation, with a data collection spreadsheet designed in Nottingham and completed by both Nottingham and Oxford centres. Data was analysed using SPSS, assessing the overall survival and progression-free survival times, as well as the 6-month and 1-year survival rates. RESULTS: The median overall survival and progression-free survival times were 10.97 and 5.91 months, respectively. The 6-month and 1-year overall survival rates were 67% and 48%, and the progression-free survival rates were 50% and 22%. Age at the start of intra-CSF therapy was significantly associated with overall survival (P = 0.046), with the 6 + age group having improved overall survival. Treatment type was significantly associated with overall survival (P = 0.012), with etoposide intra-CSF treatment being associated with improved overall survival. Treatment duration was significantly associated with both overall survival (P < 0.001) and progression-free survival (P < 0.001). CONCLUSION: Intra-CSF etoposide treatment has shown to increase both overall and progression-free survival significantly, whilst having few side effects and maintaining a good quality of life for patients, reflecting it as a beneficial therapy in the palliative setting.
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Neoplasias do Sistema Nervoso Central , Qualidade de Vida , Humanos , Criança , Adolescente , Pré-Escolar , Adulto , Etoposídeo , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Despite previous identification of pre-operative clinical and radiological predictors of post-operative paediatric cerebellar mutism syndrome (CMS), a unifying pre-operative risk stratification model for use during surgical consent is currently lacking. The aim of the project is to develop a simple imaging-based pre-operative risk scoring scheme to stratify patients in terms of post-operative CMS risk. METHODS: Pre-operative radiological features were recorded for a retrospectively assembled cohort of 89 posterior fossa tumour patients from two major UK treatment centers (age 2-23yrs; gender 28 M, 61 F; diagnosis: 38 pilocytic astrocytoma, 32 medulloblastoma, 12 ependymoma, 1 high grade glioma, 1 pilomyxoid astrocytoma, 1 atypical teratoid rhabdoid tumour, 1 hemangioma, 1 neurilemmoma, 2 oligodendroglioma). Twenty-six (29%) developed post-operative CMS. Based upon results from univariate analysis and C4.5 decision tree, stepwise logistic regression was used to develop the optimal model and generate risk scores. RESULTS: Univariate analysis identified five significant risk factors and C4.5 decision tree analysis identified six predictors. Variables included in the final model are MRI primary location, bilateral middle cerebellar peduncle involvement (invasion and/or compression), dentate nucleus invasion and age at imaging >12.4 years. This model has an accuracy of 88.8% (79/89). Using risk score cut-off of 203 and 238, respectively, allowed discrimination into low (38/89, predicted CMS probability <3%), intermediate (17/89, predicted CMS probability 3-52%) and high-risk (34/89, predicted CMS probability ≥52%). CONCLUSIONS: A risk stratification model for post-operative paediatric CMS could flag patients at increased or reduced risk pre-operatively which may influence strategies for surgical treatment of cerebellar tumours. Following future testing and prospective validation, this risk scoring scheme will be proposed for use during the surgical consenting process.
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Doenças Cerebelares/diagnóstico , Mutismo/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Período Pré-Operatório , Adolescente , Algoritmos , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/epidemiologia , Neoplasias Cerebelares/complicações , Neoplasias Cerebelares/cirurgia , Cerebelo/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Mutismo/diagnóstico por imagem , Mutismo/epidemiologia , Variações Dependentes do Observador , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/epidemiologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Reino Unido/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Time to diagnosis (TTD) of childhood soft tissue sarcoma (STS) is significantly associated with survival. This review aims to identify pre-diagnostic symptoms/signs to inform earlier diagnosis interventions. METHODS: Medline, Embase, Cochrane and Web-of-Science were searched between January 2010 and February 2021 for studies including children (<18 years) diagnosed with STS, with no language restrictions. Pooled proportions of symptoms/signs were calculated and subanalysed by tumour location and age. RESULTS: Fifty-nine eligible studies were identified, totalling 2462 cases. The most frequent symptoms were lump/swelling (38%, 95% CI 27% to 51%), pain (6%, 95% CI 3% to 10%), cutaneous changes (4%, 95% CI 0 to 9%), localised eye swelling (3%, 95% CI 0 to 7%), cranial nerve deficits (2%, 95% CI 0 to 5%) and constitutional symptoms (2%, 95% CI 0 to 5%).Symptoms varied by location and age. Localised eye swelling (20%, 95% CI 3% to 45%), cranial nerve deficits (14%, 95% CI 4% to 28%) and impaired visual function (6%, 95% CI 0 to 17%) were frequent in head and neck tumours. For abdomen/pelvic tumours, urinary symptoms (24%, 95% CI 5% to 15%), abdominal distension/discomfort (22%, 95% CI 4% to 47%), genital lump/swelling (16%, 95% CI 1% to 42%), constitutional symptoms (9%, 95% CI 0%] to 23%), vaginal bleeding (7%, 95%C I 0 to 21%) and bowel habit changes (6%, 95% CI 0 to 17%) were frequent.In <5 years, consumptive coagulopathy (16%, 95% CI 0 to 48%), cutaneous changes (5%, 95% CI 0 to 40%), genital lump/swelling (4%, 95% CI 0 to 14%), reduced mobility (3%, 95% CI 0 to 11%), vaginal bleeding (2%, 95% CI 0 to 11%) and bleeding/bruising/petechiae (2%, 95% CI 0 to 20%) were frequent compared with lump/swelling, constitutional symptoms, pain and headaches which were frequent among >11 years. CONCLUSIONS: For STS, pre-diagnostic symptoms differ by age and location, highlighting the need to tailor early diagnosis interventions.
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Contusões , Sarcoma , Criança , Feminino , Humanos , Sarcoma/diagnóstico , Sarcoma/epidemiologia , Sarcoma/patologia , Cefaleia , Hemorragia UterinaRESUMO
PURPOSE: Delayed diagnosis and poor awareness are significant barriers to the early intervention of pediatric brain tumors. This multicenter observational study aimed to evaluate the baseline routes and time to diagnosis for pediatric brain tumors in Tamil Nadu (TN), with the goal of promoting early diagnosis and timely referrals in the future. METHODS: A standard proforma was used to retrospectively collect information on demographics, diagnosis, referral pathways, and symptoms of incident pediatric brain tumor cases between January 2018 and October 2020 across eight tertiary hospitals in TN. Dates of symptom onset, first presentation of health care, and diagnosis were used to calculate total diagnostic interval (TDI), patient interval (PI), and diagnostic interval (DI). RESULTS: A total of 144 cases (mean age, 6.64 years; range, 0-15.1 years) were included in the analysis. Among those, 94% (135/144) were from city/district areas, 40% (55/144) were self-referred, and 90% (129/144) had one to three health care professional visits before diagnosis. Median TDI, PI, and DI were 3.5 (IQR, 1-9.3), 0.6 (IQR, 0.1-4.6), and 0.6 (IQR, 0-3.3) weeks, respectively. Low-grade gliomas had the longest median TDI (6.6 weeks), followed by medulloblastomas (4.6 weeks) and high-grade gliomas (3.3 weeks). Average number of symptoms recorded was 1.7 at symptom onset and 1.9 at diagnosis. CONCLUSION: Although there are some similarities with data from the United Kingdom, many low-grade and optic pathway tumors were unaccounted for in our study. DIs were relatively short, which suggests that infrastructure may not be a problem in this cohort. Increased training and establishment of proper cancer registries, combined with proper referral pathways, could enhance early diagnosis for these children.
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Neoplasias Encefálicas , Glioma , Criança , Humanos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Índia/epidemiologia , Encaminhamento e Consulta , Estudos Retrospectivos , Recém-Nascido , Lactente , Pré-Escolar , AdolescenteRESUMO
OBJECTIVES: To assess public awareness of the risks and symptoms of cancer in children, teenagers, and young adults (CTYA) aged <18 years in Great Britain. METHODS: A face-to-face computer-assisted opinion survey was conducted by Ipsos MORI. Participants were a population-based sample of 1000 adults (475 men, 525 women) aged >18 years, with 26% having children aged 6-15 in their households. Questions covered perception about cumulative cancer risk, confidence in recognising signs and symptoms, recognition and perceived urgency of classical signs and symptoms. RESULTS: Only 32% of respondents felt confident in recognising CTYA cancer signs and symptoms. Symptoms deemed to require medical assessment within 48 hours by over 50% of participants included seizures/fits, blood in urine or stool, and persistent vomiting. All symptoms except one were selected for assessment within 3 months. On average, respondents identified 10.6 out of 42 classical signs and symptoms. The most recognised symptoms included lump, swelling in pelvis, testicle or breast (46%), blood in urine or stool (44%), changes to moles (43%), lump/swelling in the chest wall or armpits (41%) and weight loss (40%). The least recognised symptoms were early/late puberty (10%), developmental delay in children aged <2 years (11%) and slow growth (13%), with 8%, 2% and 6%, respectively, perceiving no need to discuss them with a doctor. CONCLUSIONS: Public awareness of childhood cancer risks and symptoms is substantially lower compared with adult cancer awareness in Great Britain. These findings indicate knowledge and awareness gaps among the general public, highlighting the need for a child cancer awareness campaign.
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Conhecimentos, Atitudes e Prática em Saúde , Neoplasias , Masculino , Criança , Humanos , Feminino , Adolescente , Adulto Jovem , Reino Unido/epidemiologia , Estudos Transversais , Fatores de Risco , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The incidence of childhood cancer has risen by 15% since the 1990s. Early diagnosis is key to optimising outcomes, however diagnostic delays are widely reported. Presenting symptoms are often non-specific causing a diagnostic dilemma for clinicians. This Delphi consensus process was conducted to develop a new clinical guideline for children and young people presenting with signs/symptoms suggestive of a bone or abdominal tumour. METHODS: Invitation emails were sent to primary and secondary healthcare professionals to join the Delphi panel. 65 statements were derived from evidence review by a multidisciplinary team. Participants were asked to rank their level of agreement with each statement on a 9-point Likert scale (1=strongly disagree, 9=strongly agree), with responses ≥7 taken to indicate agreement. Statements not reaching consensus were rewritten and reissued in a subsequent round. RESULTS: All statements achieved consensus after two rounds. 96/133 (72%) participants responded to round 1 (R1) and 69/96 (72%) completed round 2 (R2). 62/65 (94%) statements achieved consensus in R1 with 29/65 (47%) gaining more than 90% consensus. Three statements did not reach consensus scoring between 61% and 69%. All reached numerical consensus at the end of R2. Strong consensus was reached on best practice of conducting the consultation, acknowledging parental instinct and obtaining telephone advice from a paediatrician to decide the timing and place of review, rather than adult cancer urgent referral pathways. Dissensus in statements was due to unachievable targets within primary care and valid concerns over a potential overinvestigation of abdominal pain. CONCLUSIONS: This consensus process has consolidated statements that will be included in a new clinical guideline for suspected bone and abdominal tumours for use in both primary and secondary care. This evidence base will be translated into awareness tools for the public as part of the Child Cancer Smart national awareness campaign.
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Neoplasias Abdominais , Adulto , Humanos , Criança , Adolescente , Consenso , Técnica Delphi , Dor Abdominal , Correio EletrônicoRESUMO
The impacts of the lack of skin tone diversity in medical education images on healthcare professionals (HCPs) and patients are not well studied. The aim of this study was to assess the diagnostic knowledge of HCPs and correlate this with confidence and training resources used. An online multiple choice quiz was developed. The participants' demographics, training resources and self-confidence in diagnosing skin conditions were collected. The differences in the results between the subgroups and the correlations between the respondents' experience, self-reported confidence and quiz results were assessed. The mean score of 432 international participants was 5.37 (SD 1.75) out of a maximum of 10 (highest score). Eleven percent (n = 47) reached the 80% pass mark. Subanalysis showed no difference by the continent (p = 0.270), ethnicity (p = 0.397), profession (p = 0.599), training resources (p = 0.198) or confidence (p = 0.400). A significance was observed in the specialty (p = 0.01). A weak correlation between experience and confidence (Spearman's ρ = 0.286), but no correlation between scores and confidence or experience (ρ = 0.087 and 0.076), was observed. Of diagnoses, eczema was recognised in 40% and meningococcal rash in 61%. This is the first study assessing the identification of paediatric skin conditions in different skin tones internationally. The correct identification of common/important paediatric conditions was poor, suggesting a possible difference in knowledge across skin tones. There is an urgent need to improve the representation of all skin tones to ensure equity in patient care.
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Background: Medical images are invaluable in facilitating recognition of clinical signs. Recent studies highlight a lack of diversity of skin tone images used within medical education. However, there is a paucity of data on the impact of this on patient care. Aims: To investigate diversity in training resources used by users of an International online teaching platform and self-confidence in diagnosing skin conditions in all skin tones. Methods: Users of an online teaching platform (www.dftbskindeep.com) were invited to participate in a survey evaluating key points including geographical location, ethnicity, profession, specialty, years of experience, training resources and confidence in diagnosing skin conditions. Data analyses were performed using SPSS. Categorical variables were presented as proportions. Chi-squared or Fisher's exact tests were used to compare the distribution between groups as appropriate. Results: Of 600 participants, 74% reported training resources featuring predominantly white skin. Participants were "generally uncertain" in 43% cases, "sometimes uncertain but clinically safe" (52%), and "confident across a range of skin tones" in a minority (5%). Self-confidence was associated with location [higher in Africa (29%) and Latin America (11%), (p < 0.001)]; diversity of training resources [higher with a mix (10%) or darker tones (20%) (p < 0.001)]; clinical experience [6-10 (5%) or >10 years of practice (11%) (p < 0.001)] and specialty [highest in dermatologists (53%, p < 0.001)]. Self-confidence was lowest among pediatricians, emergency medicine and pediatric emergency medicine specialists (<5%). Conclusions: These data provide preliminary evidence that training resources used by healthcare professionals on a global scale may lack enough diversity on representation of skin images, and a lack of self-confidence in diagnosing pediatric skin conditions. Further work is needed to understand the impact on knowledge and patient care to ensure equitable healthcare for all.
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INTRODUCTION: Childhood cancer is diagnosed in 400 000 children and young people (CYP) aged 0-19 years worldwide annually. In the UK, a child's cumulative cancer risk increases from 1 in 4690 from birth to aged 1, to 1 in 470 by age 15. Once diagnosed, access to treatments offers survival to adulthood for over 80%. Tumour diagnoses are at a later stage and mortality is higher when compared with those in other parts of Europe. This means higher risk, more intensive therapies for a cure. Some CYPs are known to experience delays to diagnosis which may further contribute to poor outcomes. This study aims to understand the current pathway of childhood cancer referrals and diagnosis and quantify diagnostic intervals in the UK. METHODS AND ANALYSIS: This is a prospective multicentre observational study including all tertiary childhood cancer treatment centres in the UK. CYP (0-18 years) with a new diagnosis of cancer over the study period will be invited to participate. Data will be collected at initial diagnosis and 5 years after diagnosis. Data will include demographic details, clinical symptoms, tumour location, stage and clinical risk group. In addition, key diagnostic dates and referral routes will be collected to calculate the diagnostic intervals. At 5 years' follow-up, data will be collected on refractory disease, relapse and 1-year and 5-year survival. Population characteristics will be presented with descriptive analyses with further analyses stratified by age, geographical region and cancer type. Associations between diagnostic intervals/delay and risk factors will be explored using multiple regression and logistic regression. ETHICS: The study has favourable opinion from the York and Humber, Leeds West REC (19/YH/0416). DISSEMINATION: Results will be presented at academic conferences, published in peer-reviewed journals and disseminated through public messaging in collaboration with our charity partners through a national awareness campaign (ChildCancerSmart). STUDY REGISTRATION: researchregistry.com (researchregistry5313).
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Neoplasias , Adolescente , Adulto , Criança , Europa (Continente) , Humanos , Neoplasias/terapia , Estudos Prospectivos , Encaminhamento e Consulta , Reino Unido/epidemiologiaRESUMO
Background: The SARS-CoV-2 pandemic and initial public health response led to significant changes in health service delivery, access and utilisation. However, SARS-CoV-2 illness burden in children and young people (CYP) is low. To inform effective child public health interventions, we aimed to compare patterns of paediatric emergency department presentation during the initial pandemic response with a previous non-pandemic period. Methods: Retrospective review of attendances (0-18 years) over the initial pandemic (2 March 2020-3 May 2020) compared with 2019. Outcome measures included number of attendances, referral source, presenting complaint, discharge diagnosis and disposal. Descriptive statistics with subgroup analysis by age/sex/ethnicity and pandemic time periods (pre-lockdown, lockdown weeks 1-3 and lockdown weeks 4-6) was performed. Results: 4417 attendances (57% illness and 43% injuries) occurred, compared with 8813 (57% illness and 43% injuries), a reduction of 50%, maximal in lockdown week 2 (-73%). Ranking of top three illness presentations changed across the pandemic weeks. Breathing difficulty dropped from first (300, 25%) to second (117, 21%) to third (59, 11%) (p<0.001). Abdominal pain rose from the third pre-lockdown (87, 7%) and lockdown weeks 1-3 (37, 7%) to second in weeks 4-6 (62, 12%; p=0.004). Fever ranked second (235, 19%) in pre-lockdown and first in weeks 1-3 (134, 24%) and weeks 4-6 (94, 18%; p=0.035). Conclusions: Despite a 50% reduction, there was no significant change in acuity of illness. Rank of illness presentations changed, with abdominal pain ranking second and fever first, an important change from previous, which should prompt further research into causes. CYP-specific public health messaging and guidance for primary care are required in this second wave to ensure access to appropriate emergency services.
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COVID-19 , Adolescente , Criança , Controle de Doenças Transmissíveis , Serviço Hospitalar de Emergência , Humanos , Estudos Retrospectivos , SARS-CoV-2 , Reino Unido/epidemiologiaRESUMO
Paediatric ependymomas are aggressive, treatment-resistant tumours with a tendency towards relapse, consistent with a sub-population of therapy-resistant cancer stem cells. These cells are believed to derive from brain lipid binding protein (BLBP)-expressing radial glia, hence we proposed that BLBP may be a marker for ependymoma therapy resistance. BLBP protein expression correlated with reduced overall survival (OS) in patients from two trials (CNS9204, a chemotherapy-led infant trial-5 y OS 45% vs. 80%, p = 0.011-and CNS9904, a radiotherapy-led trial-OS 38% vs. 85%, p = 0.002). All ependymoma cell lines examined by qRT-PCR expressed BLBP, with expression elevated in stem cell-enriched neurospheres. Modulation of BLBP function in 2D and 3D assays, using either peroxisome proliferator activated receptor (PPAR) antagonists or BLBP's fatty acid substrate docosahexaneoic acid (DHA), potentiated chemotherapy response and reduced cell migration and invasion in ependymoma cell lines. BLBP is therefore an independent predictor of poor survival in paediatric ependymoma, and treatment with PPAR antagonists or DHA may represent effective novel therapies, preventing chemotherapy resistance and invasion in paediatric ependymoma patients.
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BACKGROUND: The aim of the project was to identify risk factors associated with visual progression and treatment indications in pediatric patients with neurofibromatosis type 1 associated optic pathway glioma (NF1-OPG). METHODS: A multidisciplinary expert group consisting of ophthalmologists, pediatric neuro-oncologists, neurofibromatosis specialists, and neuro-radiologists involved in therapy trials assembled a cohort of children with NF1-OPG from 6 European countries with complete clinical, imaging, and visual outcome datasets. Using methods developed during a consensus workshop, visual and imaging data were reviewed by the expert team and analyzed to identify associations between factors at diagnosis with visual and imaging outcomes. RESULTS: Eighty-three patients (37 males, 46 females, mean age 5.1â ±â 2.6 y; 1-13.1 y) registered in the European treatment trial SIOP LGG-2004 (recruited 2004-2012) were included. They were either observed or treated (at diagnosis/after follow-up).In multivariable analysis, factors present at diagnosis associated with adverse visual outcomes included: multiple visual signs and symptoms (adjusted odds ratio [adjOR]: 8.33; 95% CI: 1.9-36.45), abnormal visual behavior (adjOR: 4.15; 95% CI: 1.20-14.34), new onset of visual symptoms (adjOR: 4.04; 95% CI: 1.26-12.95), and optic atrophy (adjOR: 3.73; 95% CI: 1.13-12.53). Squint, posterior visual pathway tumor involvement, and bilateral pathway tumor involvement showed borderline significance. Treatment appeared to reduce tumor size but improved vision in only 10/45 treated patients. Children with visual deterioration after primary observation are more likely to improve with treatment than children treated at diagnosis. CONCLUSIONS: The analysis identified the importance of symptomatology, optic atrophy, and history of vision loss as predictive factors for poor visual outcomes in children with NF1-OPG.
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Neurofibromatose 1 , Glioma do Nervo Óptico , Criança , Pré-Escolar , Estudos de Coortes , Europa (Continente) , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neurofibromatose 1/complicações , Neurofibromatose 1/epidemiologia , Neurofibromatose 1/terapia , Glioma do Nervo Óptico/complicações , Glioma do Nervo Óptico/epidemiologia , Glioma do Nervo Óptico/terapia , Fatores de RiscoRESUMO
Background: The COVID-19 pandemic led to changes in patterns of presentation to emergency departments. Child health professionals were concerned that this could contribute to the delayed diagnosis of life-threatening conditions, including childhood cancer (CC) and type 1 diabetes (T1DM). Our multicentre, UK-based service evaluation assessed diagnostic intervals and disease severity for these conditions. Methods: We collected presentation route, timing and disease severity for children with newly diagnosed CC in three principal treatment centres and T1DM in four centres between 1 January and 31 July 2020 and the corresponding period in 2019. Total diagnostic interval (TDI), patient interval (PI), system interval (SI) and disease severity across different time periods were compared. Results: For CCs and T1DM, the route to diagnosis and severity of illness at presentation were unchanged across all time periods. Diagnostic intervals for CCs during lockdown were comparable to that in 2019 (TDI 4.6, PI 1.1 and SI 2.1 weeks), except for an increased PI in January-March 2020 (median 2.7 weeks). Diagnostic intervals for T1DM during lockdown were similar to that in 2019 (TDI 16 vs 15 and PI 14 vs 14 days), except for an increased PI in January-March 2020 (median 21 days). Conclusions: There is no evidence of diagnostic delay or increased illness severity for CC or T1DM, during the first phase of the pandemic across the participating centres. This provides reassuring data for children and families with these life-changing conditions.
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COVID-19 , Diabetes Mellitus Tipo 1 , Neoplasias , Criança , Controle de Doenças Transmissíveis , Diagnóstico Tardio , Diabetes Mellitus Tipo 1/diagnóstico , Humanos , Neoplasias/diagnóstico , Pandemias , SARS-CoV-2 , Reino Unido/epidemiologiaRESUMO
The UK incidence of prostate cancer has been increasing in men aged < 60 years. Migrant studies and global and secular variation in incidence suggest that modifiable factors, including a high-fat diet, may contribute to prostate cancer risk. The aim of the present study was to investigate the role of dietary fat intake and its derivatives on early-onset prostate cancer risk. During 1999-2004, a population-based case-control study with 512 cases and 838 controls was conducted. Cases were diagnosed with prostate cancer when < or = 60 years. Controls were sourced from UK GP practice registers. A self-administered FFQ collected data on typical past diet. A nutritional database was used to calculate daily fat intake. A positive, statistically significant risk estimate for the highest v. lowest quintile of intake of total fat, SFA, MUFA and PUFA was observed when adjusted for confounding variables: OR 2.53 (95 % CI 1.72, 3.74), OR 2.49 (95 % CI 1.69, 3.66), OR 2.69 (95 % CI 1.82, 3.96) and OR 2.34 (95 % CI 1.59, 3.46), respectively, with all P for trend < 0.001. In conclusion, there was a positive statistically significant association between prostate cancer risk and energy-adjusted intake of total fat and fat subtypes. These results potentially identify a modifiable risk factor for early-onset prostate cancer.
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Gorduras na Dieta/efeitos adversos , Neoplasias da Próstata/etiologia , Estudos de Casos e Controles , Inquéritos sobre Dietas , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade , Razão de Chances , Neoplasias da Próstata/epidemiologia , Reino Unido/epidemiologiaRESUMO
BACKGROUND: HeadSmart, a public and professional awareness campaign, was launched to enhance awareness of brain tumour symptomatology identified in the Royal College of Paediatrics and Child Health, National Institute for Health and Care Excellence-accredited guideline. Quality improvement data showed a reduction in diagnostic interval nationally. To reach the government target of 4 weeks, we need to identify subgroups with ongoing delays. METHODS: Incident cases of brain tumours (0-18) diagnosed between January 2011 and May 2013 across 18 UK centres were included. Anonymised data including demographics, diagnosis and date of symptom onset/presentation were collected. Key outcome measures, total diagnostic interval (TDI), patient interval (PI) and system interval (SI) were calculated. Subanalysis by age, tumour grade and location was also performed. RESULTS: Young children (0-5 years) accounted for 38% of cases, with a peak age at diagnosis of 2 years. Central tumours experienced longest intervals with a median TDI of 10.5 weeks, PI of 3.2 weeks and SI of 2.9 weeks. Craniopharyngioma, low-grade glioma and optic pathway gliomas had the longest TDIs with a median of 15.1, 11.9 and 10.4 weeks, respectively. The greatest proportion of delay was in the SI. The 12-18 age group had a median TDI of 12.1 weeks, compared with 8 weeks for the 5-11 age group and 6 weeks for the 0-5 age group (p<0.001). CONCLUSIONS: Clear patterns of intervals for different age groups and anatomical locations have been demonstrated. Tailoring education and awareness strategies to ensure earlier diagnosis for central tumours and young people is crucial to minimise brain injury, subsequent disability and late effects of treatment for 70% of survivors.
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Neoplasias Encefálicas/diagnóstico , Detecção Precoce de Câncer , Adolescente , Neoplasias Encefálicas/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Melhoria de Qualidade , Estudos Retrospectivos , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Management of unresectable pediatric low-grade glioma and glioneuronal tumor (LGG/LGGNT) is controversial. There are no validated prognostic features to guide use of radiation therapy (RT). Our study aimed to identify negative prognostic features in patients treated with RT using clinicopathologic and molecular data and validate these findings in an external dataset. METHODS: Children with non-metastatic, biopsy-proven unresectable LGG/LGGNT treated with RT at a single institution between 1997 and 2017 were identified. Recursive partitioning analysis (RPA) was used to stratify patients into low- and high-risk prognostic groups based on overall survival (OS). CNS9702 data were used for validation. RESULTS: One hundred and fifty patients met inclusion criteria. Median follow-up was 11.4 years. RPA yielded low- and high-risk groups with 10-year OS of 95.6% versus 76.4% (95% CI: 88.7%-98.4% vs 59.3%-87.1%, P = 0.003), respectively. These risk groups were validated using CNS9702 dataset (n = 48) (4-year OS: low-risk vs high-risk: 100% vs 64%, P < 0.001). High-risk tumors included diffuse astrocytoma or location within thalamus/midbrain. Low-risk tumors included pilocytic astrocytoma/ganglioglioma located outside of the thalamus/midbrain. In the subgroup with known BRAF status (n = 49), risk stratification remained prognostic independently of BRAF alteration (V600E or fusion). Within the high-risk group, delayed RT, defined as RT after at least one line of chemotherapy, was associated with a further decrement in overall survival (P = 0.021). CONCLUSION: A high-risk subgroup of patients, defined by diffuse astrocytoma histology or midbrain/thalamus tumor location, have suboptimal long-term survival and might benefit from timely use of RT. These results require validation.
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Astrocitoma , Neoplasias Encefálicas , Glioma , Adolescente , Astrocitoma/patologia , Astrocitoma/radioterapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Criança , Pré-Escolar , Feminino , Glioma/patologia , Glioma/radioterapia , Humanos , Lactente , Masculino , Prognóstico , Medição de Risco , Adulto JovemRESUMO
PURPOSE: The chemopreventive activity of aspirin in colorectal neoplasia may be explained in part by its effect on polyamine metabolism. The ornithine decarboxylase (ODC) G316A polymorphism affects polyamine metabolism through altered expression of ODC. We investigated the influence of ODC G316A on the chemopreventive activity of aspirin in colorectal adenoma (CRA) recurrence. EXPERIMENTAL DESIGN: We genotyped ODC G316A in 546 individuals in the United Kingdom Colorectal Adenoma Prevention trial of aspirin for CRA recurrence prevention and pooled our findings with data from two other randomized intervention trials. RESULTS: The United Kingdom Colorectal Adenoma Prevention participants with homozygous ODC 316AA genotype were at reduced CRA recurrence risk [relative risk (RR), 0.43; 95% confidence interval (95% CI), 0.16-1.15], particularly if also exposed to aspirin (RR, 0.24; 95% CI, 0.03-1.71). In the pooled analysis of 2,207 individuals, those with homozygous ODC 316AA genotype were at significantly reduced CRA recurrence risk (RR, 0.68; 95% CI, 0.47-0.99). Following stratification by genotype and aspirin exposure, individuals with homozygous wild-type or heterozygous genotypes derived modest benefit from aspirin (RR, 0.85; 95% CI, 0.72-1.01), whereas in those with both ODC 316AA genotype and aspirin exposure recurrence risk was halved (RR, 0.52; 95% CI, 0.29-0.91). CONCLUSION: The ODC G316A genotype is prognostic for CRA recurrence and predictive of an enhanced response to aspirin in preventing recurrence. This variant has the potential to be a clinically useful genetic marker to identify individuals likely to derive the greatest benefit from aspirin chemoprevention.
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Adenoma/genética , Anticarcinógenos/uso terapêutico , Aspirina/uso terapêutico , Neoplasias Colorretais/genética , Recidiva Local de Neoplasia/genética , Ornitina Descarboxilase/genética , Adenoma/enzimologia , Adenoma/mortalidade , Adenoma/prevenção & controle , Adulto , Idoso , Aspirina/efeitos adversos , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/prevenção & controle , Feminino , Genes APC , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/enzimologia , PrognósticoRESUMO
Three of the hallmarks of poor prognosis in paediatric ependymoma are drug resistance, local invasion and recurrence. We hypothesised that these hallmarks were due to the presence of a sub-population of cancer stem cells expressing the multi-drug efflux transporter ABCB1. ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p ≤ 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p ≤ 0.001) and invasion (p ≤ 0.001). We demonstrate that ABCB1 positive patients from an infant chemotherapy-led trial (CNS9204) had a shorter mean event free survival (EFS) (2.7 versus 8.6 years; p = 0.007 log-rank analysis) and overall survival (OS) (5.4 versus 12 years; p = 0.009 log-rank analysis). ABCB1 positivity also correlated with reduced event free survival in patients with incompletely resected tumours who received chemotherapy across CNS9204 and CNS9904 (a radiotherapy-led SIOP 1999-04 trial cohort; p = 0.03). ABCB1 is a predictive marker of chemotherapy response in ependymoma patients and vardenafil, currently used to treat paediatric pulmonary hypertension in children, could be repurposed to reduce chemoresistance, migration and invasion in paediatric ependymoma patients at non-toxic concentrations.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Ependimoma/patologia , Células-Tronco Neoplásicas/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Pré-Escolar , Sinergismo Farmacológico , Ependimoma/genética , Ependimoma/metabolismo , Etoposídeo/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Metotrexato/farmacologia , Invasividade Neoplásica , Prognóstico , Análise de Sobrevida , Regulação para Cima , Dicloridrato de Vardenafila/farmacologia , Verapamil/farmacologia , Vincristina/farmacologiaRESUMO
Vitamin D receptor (VDR) activation inhibits proliferation and angiogenesis in the colorectal epithelium, and inhibits metastasis of colorectal tumors. Polymorphisms in the VDR gene alter receptor cellular levels and functioning, and may confer altered susceptibility to colorectal neoplasia. We aimed to investigate the influence of VDR polymorphisms and dietary factors impacting on vitamin D metabolism on colorectal adenoma (CRA) recurrence. Data on dietary intakes of calcium, vitamin D and dairy products were collected from 853 participants in the United Kingdom Colorectal Adenoma Prevention trial, a randomized trial of aspirin and folate for CRA recurrence prevention. The VDR Cdx2, FokI, BsmI, ApaI and TaqI polymorphisms were genotyped in 546 participants with available DNA, and gene-diet interaction analyses performed in 480. Dairy product intake was inversely related to CRA recurrence risk independent of calcium and vitamin D [relative risk (RR) = 0.64; 95% confidence intervals (CIs): 0.47-0.88, for subjects in the highest compared to lowest intake tertile, p(trend) = 0.005]. Milk accounted for 60% of dairy product intake, and on analysis of milk and nonmilk dairy products separately recurrence risk in individuals in the highest tertile of milk intake was half that of lowest tertile individuals (RR = 0.52; 95% CI: 0.38-0.72, p(trend) = 3.2 x 10(-5)), whereas nonmilk dairy products did not influence recurrence. VDR polymorphism genotypes and haplotypes did not directly alter recurrence risk, but the reduction in risk associated with high dairy product intake was confined to individuals with ApaI aA/AA genotype (p(interaction) = 0.02). These findings indicate dairy products, and in particular milk, have chemopreventive activity against CRA recurrence.
Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Laticínios , Recidiva Local de Neoplasia/genética , Polimorfismo Genético , Receptores de Calcitriol/genética , Fatores de Transcrição/genética , Adenoma/diagnóstico , Adenoma/epidemiologia , Adenoma/prevenção & controle , Adulto , Idoso , Animais , Aspirina/uso terapêutico , Compostos de Cálcio/administração & dosagem , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Feminino , Ácido Fólico/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Leite , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Inquéritos e Questionários , Reino Unido , Vitamina D/administração & dosagemRESUMO
A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10(-17)). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction.