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3.
Colorectal Dis ; 2020 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-32307808

RESUMO

AIM: The aim was to determine the presentation, management and outcomes of MUTYH-associated polyposis (MAP). METHOD: A prospectively maintained database was used to identify patients with MAP. Demographic data and data on germline mutation, surgical management, histopathology of tumours and endoscopic surveillance were collected. RESULTS: In all, 134 patients with MAP were identified. The majority presented symptomatically (n = 83). Sixty-eight patients developed cancer (seven synchronous, 12 metachronous). The median age at diagnosis of first colorectal cancer was 47 years (range 33-74 years). Cancers occurred in the context of a few adenomas (< 10). The majority of patients (n = 108) had surgery as the first line management. One patient received palliative care. Twenty-five patients had endoscopic surveillance as first line management; no cancers occurred in this group. Patients who had segmental resection and postoperative surveillance still appeared to be at risk of metachronous cancer (5/30, 17%). CONCLUSIONS: MUTYH testing should be considered even in the context of cancers occurring with fewer than 10 adenomas. In cases of primary colorectal cancers, extended surgery should be considered if patients do not have access to high quality endoscopic surveillance postoperatively. For some patients, endoscopic therapy is an appropriate and safe option in expert hands.

4.
Nat Ecol Evol ; 4(4): 659, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32157252

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

5.
Eur J Cancer ; 128: 7-16, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32109852

RESUMO

BACKGROUND: Concurrent chemoradiotherapy is the standard treatment for anal cancer. Following national UK implementation of intensity-modulated radiotherapy (IMRT), this prospective, national cohort evaluates the one-year oncological outcomes and patient-reported toxicity outcomes (PRO) after treatment. MATERIALS AND METHODS: A national cohort of UK cancer centers implementing IMRT was carried out between February to July 2015. Cancer centers provided data on oncological outcomes, including survival, and disease and colostomy status at one-year. EORTC-QLQ core (C30) and colorectal (CR29) questionnaires were completed at baseline and one-year followup. The PRO scores at baseline and one year were compared. RESULTS: 40 UK Cancer Centers returned data with a total of 187 patients included in the analysis. 92% received mitomycin with 5-fluorouracil or capecitabine. One-year overall survival was 94%; 84% were disease-free and 86% colostomy-free at one-year followup. At one year, PRO results found significant improvements in buttock pain, blood and mucus in stools, pain, constipation, appetite loss, and health anxiety compared to baseline. No significant deteriorations were reported in diarrhea, bowel frequency, and flatulence. Urinary symptom scores were low at one year. Moderate impotence symptoms at baseline remained at one year, and a moderate deterioration in dyspareunia reported. CONCLUSIONS: With national anal cancer IMRT implementation, at this early pre-defined time point, one-year oncological outcomes were reassuring and resulted in good disease-related symptom control. one-year symptomatic complications following CRT for anal cancer using IMRT techniques appear to be relatively mild. These PRO results provide a basis to benchmark future studies.

6.
Obes Sci Pract ; 5(5): 408-415, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31687166

RESUMO

Introduction: Intuitive eating (IE) has emerged as a weight-neutral approach to health promotion for those with overweight/obesity. This weight-neutral paradigm has some support, although research thus far has often neglected to control for potential confounds (i.e. objective weight status and demographics) and foundational studies are lacking. The objective of the current study was to observe the unique association of IE with physical health indicators in a sample of adults, independent of objective weight status. Methods: Participants were 248 adults (32 ± 14 years old, 73% female, 64% White) of all weight categories (18.2-55.3 kg m-2), with an average body mass index (BMI) of 30 ± 8 kg m-2. IE was measured with the Intuitive Eating Scale-2 (IES-2). BMI was objectively measured in-lab. Health indicators included blood pressure (BP) and fasting glucose. Results: A series of hierarchical linear regressions revealed no significant associations between IE and systolic BP (ß = -0.076, P = 0.256), diastolic BP (DBP; ß = -0.122, P = 0.073) or fasting glucose (ß = 0.047, P = 0.500) after controlling for BMI. All effects sizes were small or below (f 2 = 0.00 to -0.04). Sensitivity analyses revealed significantly lower DBP in high intuitive eaters versus low when analysed with a t-test, t(111.651) = 3.602, P < 0.001, Levene corrected; however, after controlling for relevant covariates (i.e. BMI and demographics), analysis of covariance revealed no difference in DBP between groups, F(1, 116) = 0.330, P = 0.567. No significant differences in systolic BP or fasting glucose were observed between low and high intuitive eaters before or after considering covariates. Conclusions: In sum, this study investigated associations between IE and common indicators of physical health after controlling for objective weight status. Findings revealed no unique relationship between IE and physical health, and any IE-physical health relationships that were observed were accounted for BMI and/or demographic factors.

7.
8.
Nat Ecol Evol ; 3(7): 1102-1109, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182814

RESUMO

Adaptive radiation illustrates links between ecological opportunity, natural selection and the generation of biodiversity. Central to adaptive radiation is the association between a diversifying lineage and the evolution of phenotypic variation that facilitates the use of new environments or resources. However, is not clear whether adaptive evolution or historical contingency is more important for the origin of key phenotypic traits in adaptive radiation. Here we use targeted sequencing of >250,000 loci across 46 species to examine hypotheses concerning the origin and diversification of key traits in the adaptive radiation of Antarctic notothenioid fishes. Contrary to expectations of adaptive evolution, we show that notothenioids experienced a punctuated burst of genomic diversification and evolved key skeletal modifications before the onset of polar conditions in the Southern Ocean. We show that diversifying selection in pathways associated with human skeletal dysplasias facilitates ecologically important variation in buoyancy among Antarctic notothenioid species, and demonstrate the sufficiency of altered trip11, col1a2 and col1a1a function in zebrafish (Danio rerio) to phenocopy skeletal reduction in Antarctic notothenioids. Rather than adaptation being driven by the cooling of the Antarctic, our results highlight the role of historical contingency in shaping the adaptive radiation of notothenioids. Understanding the historical and environmental context for the origin of key traits in adaptive radiations extends beyond reconstructing events that result in evolutionary innovation, as it also provides a context in forecasting the effects of climate change on the stability and evolvability of natural populations.


Assuntos
Adaptação Fisiológica , Peixes , Animais , Regiões Antárticas , Biodiversidade , Humanos , Filogenia
9.
Philos Trans R Soc Lond B Biol Sci ; 374(1769): 20180205, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30967083

RESUMO

The cuckoo catfish, Synodontis multipunctatus, is the only known obligate brood parasite among fishes, exploiting the parental care of mouthbrooding cichlids endemic to Lake Tanganyika. Comparisons of this system to brood parasitism in birds may reveal broader principles that underlie the evolution of this life-history strategy in vertebrates. However, little is known about the features of the cuckoo catfish that enable this species to successfully parasitize cichlids. Here, we examine early ontogeny of the cuckoo catfish and compare it to that of its cichlid hosts as well as a non-parasitic congener. We found that cuckoo catfish embryos develop and hatch in advance of host embryos, and begin feeding on cichlid young just as they start to hatch. Overall timing of ontogeny in the cuckoo catfish was found to be similar to that of the substrate-spawning congener Synodontis lucipinnis, suggesting that more rapid development of the cuckoo catfish relative to cichlids is not a unique adaptation to brood parasitism. However, we found that cuckoo catfish progeny exhibit extensive morphological differences from S. lucipinnis, which may represent adaptations to brood parasitism. These life-history observations reveal both similarities and differences between the cuckoo catfish system and brood parasitism in other lineages. This article is part of the theme issue 'The coevolutionary biology of brood parasitism: from mechanism to pattern'.


Assuntos
Peixes-Gato/fisiologia , Ciclídeos/parasitologia , Interações Hospedeiro-Parasita , Traços de História de Vida , Adaptação Biológica , África , Animais , Lagos
10.
Clin Oncol (R Coll Radiol) ; 31(2): 72-80, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30583927

RESUMO

AIMS: To investigate the potential role for a biological boost in anal cancer by assessing whether subvolumes of high 18F-fluorodeoxyglucose (FDG) avidity, identified at outset, are spatially consistent during a course of chemoradiotherapy (CRT). MATERIALS AND METHODS: FDG-positron emission tomography (FDG-PET) scans from 21 patients enrolled into the ART study (NCT02145416) were retrospectively analysed. In total, 29 volumes including both primary tumours and involved nodes >2 cm were identified. FDG-PET scans were carried out before treatment and on day 8 or 9 of CRT. FDG subvolumes were created using a percentage of maximum FDG avidity at thresholds of 34%, 40%, 50%, on the pre-treatment scans, and 70% and 80% on the subsequent scans. Both FDG-PET scans were deformably registered to the planning computed tomography scan. The overlap fraction and the vector distance were calculated to assess spatial consistency. FDG subvolumes for further investigation had an overlap fraction >0.7, as this has been defined in previous publications as a 'good' correlation. RESULTS: The median overlap fractions between the diagnostic FDG-PET subvolumes 34%, 40% and 50% of maximum standardised uptake value (SUVmax) and subsequent FDG-PET subvolumes of 70% of SUVmax were 0.97, 0.92 and 0.81. The median overlap fraction between the diagnostic FDG-PET subvolumes 34%, 40% and 50% and subsequent FDG-PET subvolumes of 80% were 1.00, 1.00 and 0.92. The median (range) vector distance values between diagnostic FDG-PET subvolumes 34%, 40% and 50% and subsequent FDG-PET subvolumes of 80% were 0.74 mm (0.19-2.94) 0.74 mm (0.19-3.39) and 0.71 mm (0.2-3.29), respectively. Twenty of 29 volumes (69.0%) achieved a threshold > 0.7 between the FDG 50% subvolume on the diagnostic scan and the FDG 80% subvolume on the subsequent scan. CONCLUSION: FDG-avid subvolumes identified at baseline were spatially consistent during a course of CRT treatment. The subvolume of 50% of SUVmax on the pre-treatment scan could be considered as a potential target for dose escalation.


Assuntos
Neoplasias do Ânus/diagnóstico , Neoplasias do Ânus/radioterapia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/radioterapia , Quimiorradioterapia/métodos , Fluordesoxiglucose F18/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Idoso , Feminino , Fluordesoxiglucose F18/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
Colorectal Dis ; 20 Suppl 1: 65-75, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29878668

RESUMO

In patients with advanced and recurrent colorectal cancer, surgical resection with clear margins is the greatest challenge and is limited by known anatomical constraints. Preoperative or intra-operative assessment of the limits of surgical dissection may help to explore the possibility of improving resectability through either targeted external beam radiotherapy or intra-operative radiotherapy. Professor Chang reviews the evidence base and potential advantages and disadvantages of this approach, whilst the expert panel agree a consensus on the evidence for assessment and therapy of such patients.


Assuntos
Braquiterapia/métodos , Colectomia/métodos , Neoplasias Colorretais/radioterapia , Neoplasias Colorretais/cirurgia , Cuidados Intraoperatórios/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Consenso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Terapia Neoadjuvante/métodos , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Seleção de Pacientes , Cuidados Pré-Operatórios/métodos , Prognóstico , Dosagem Radioterapêutica , Medição de Risco , Análise de Sobrevida
12.
Colorectal Dis ; 20 Suppl 1: 61-64, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29878672

RESUMO

Approximately 10-15% of patients present with an advanced rectal cancer that extends beyond the conventional total mesorectal excision (TME) planes. In such cases extending the surgery to ensure resection with clear margins (R0 resection) is essential in order to achieve long-term cure. Professor Holm describes the techniques of beyond-TME exenterative surgery, the methods of patient selection and outcomes.


Assuntos
Atitude do Pessoal de Saúde , Margens de Excisão , Protectomia/métodos , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Consenso , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Mesocolo/cirurgia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Exenteração Pélvica , Prognóstico , Neoplasias Retais/mortalidade , Medição de Risco , Cirurgiões/psicologia , Análise de Sobrevida
13.
Clin Oncol (R Coll Radiol) ; 30(7): 418-426, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29602584

RESUMO

AIMS: Gastrointestinal toxicity impedes dose escalation in chemoradiotherapy for hepatobiliary malignancies. Toxicity risk depends on clinical and radiotherapy metrics. We aimed to identify predictive factors using data from two prospective phase II clinical trials of locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Ninety-one patients with available data from the ARCII (59.4 Gy in 33 fractions with gemcitabine, cisplatin and nelfinavir, n = 23) and SCALOP (50.4 Gy in 28 fractions with capecitabine or gemcitabine, n = 74) trials were studied. The independent variables analysed comprised age, sex, performance status, baseline symptoms, tumour size, weight loss, chemotherapy regimen and dose-volume histogram of stomach and duodenum in 5 Gy bins. The outcome measures used were Common Terminology Criteria of Adverse Events (CTCAE) grade and risk of CTCAE grade ≥2 acute upper gastrointestinal toxicity (anorexia, pain, nausea and/or vomiting). The risk of CTCAE grade ≥2 events was modelled using multivariable logistic regression and prediction of severity grade using ordinal regression. RESULTS: CTCAE grade ≥2 symptoms occurred in 38 patients (42%). On univariate analysis, stomach V35-45Gy was predictive of risk (odds ratio 1.035, 95% confidence interval 1.007-1.063) and grade (1.023, 1.003-1.044) of toxicity. The area under the curve was 0.632 (0.516-0.747) with toxicity risk 33/66 (50%) above and 5/25 (20%) below the optimal discriminatory threshold (7.1 cm3). Using a threshold of 30 cm3, risk was 13/20 (65%) versus 25/71 (35%). The optimal multivariable logistic regression model incorporated patient sex, chemotherapy regimen and stomach V35-45Gy. Receiving gemcitabine rather than capecitabine (odds ratio 3.965, 95% confidence interval 1.274-12.342) and weight loss during induction chemotherapy (1.216, 1.043-1.419) were significant predictors for the SCALOP cohort, whereas age predicted toxicity risk in ARCII only (1.344, 1.015-1.780). Duodenum dose-volume did not predict toxicity risk or severity in any cohort. CONCLUSIONS: In chemoradiotherapy for LAPC the volume of stomach irradiated to a moderately high dose (35-45 Gy) predicts the incidence and severity of acute toxicity. Other predictive factors can include age, sex, recent weight loss and concomitant chemotherapy agents.


Assuntos
Neoplasias Pancreáticas/terapia , Lesões por Radiação , Radioterapia/efeitos adversos , Estômago/efeitos da radiação , Idoso , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Estudos de Coortes , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Gastroenteropatias/epidemiologia , Gastroenteropatias/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Nelfinavir/administração & dosagem , Nelfinavir/efeitos adversos , Estudos Prospectivos , Lesões por Radiação/epidemiologia , Lesões por Radiação/etiologia , Radioterapia/métodos , Fatores de Risco
14.
Contemp Clin Trials ; 66: 20-27, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29274893

RESUMO

Obesity is a global epidemic, yet successful interventions are rare. Up to 60% of people fail to achieve clinically meaningful, short-term weight loss (5-10% of start weight), whereas up to 72% are unsuccessful at achieving long-term weight loss (5-10% loss for ≥5years). Understanding how biological, cognitive, and self-regulatory factors work together to promote or to impede weight loss is clearly needed to optimize obesity treatment. This paper describes the methodology of the Cognitive and Self-regulatory Mechanisms of Obesity Study (the COSMOS trial). COSMOS is the first randomized controlled trial to investigate how changes in multiple biopsychosocial and cognitive factors relate to weight loss and one another across two weight loss treatments. The specific aims are to: 1) Confirm that baseline obesity-related physiological dysregulation is linked to cognitive deficits and poorer self-regulation, 2) Evaluate pre- to post-treatment change across time to assess individual differences in biomarkers, cognition, and self-regulation, and 3) Evaluate whether the acceptance-based treatment (ABT) group has greater improvements in outcomes (e.g., greater weight loss and less weight regain, improvements in biomarkers, cognition, and self-regulation), than the standard behavioral treatment group (SBT) from pre- to post-treatment and 1-year follow-up. The results of COSMOS will provide critical information about how dysregulation in biomarkers, cognition, and/or self-regulation is related to weight loss and whether weight loss treatments are differentially associated with these factors. This information will be used to identify promising treatment targets that are informed by biological, cognitive, and self-regulatory factors in order to advance obesity treatment.


Assuntos
Terapia de Aceitação e Compromisso/métodos , Cognição , Obesidade/terapia , Autocontrole , Programas de Redução de Peso/métodos , Adulto , Terapia Comportamental/métodos , Biomarcadores/metabolismo , Glicemia/metabolismo , Pressão Sanguínea , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/psicologia , Resultado do Tratamento , Ganho de Peso
15.
Clin Oncol (R Coll Radiol) ; 30(1): 5-14, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29033164

RESUMO

Six UK studies investigating stereotactic ablative radiotherapy (SABR) are currently open. Many of these involve the treatment of oligometastatic disease at different locations in the body. Members of all the trial management groups collaborated to generate a consensus document on appropriate organ at risk dose constraints. Values from existing but older reviews were updated using data from current studies. It is hoped that this unified approach will facilitate standardised implementation of SABR across the UK and will allow meaningful toxicity comparisons between SABR studies and internationally.


Assuntos
Radiocirurgia/métodos , Consenso , Guias como Assunto , Humanos , Reino Unido
17.
Int J Radiat Oncol Biol Phys ; 99(1): 51-60, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28816160

RESUMO

PURPOSE: The heart receives high radiation doses during radiation therapy of advanced-stage lung cancer. We have explored associations between overall survival, cardiac radiation doses, and electrocardiographic (ECG) changes in patients treated in IDEAL-CRT, a trial of isotoxically escalated concurrent chemoradiation delivering tumor doses of 63 to 73 Gy. METHODS AND MATERIALS: Dosimetric and survival data were analyzed for 78 patients. The whole heart, pericardium, AV node, and walls of left and right atria (LA/RA-Wall) and ventricles (LV/RV-Wall) were outlined on radiation therapy planning scans, and differential dose-volume histograms (dDVHs) were calculated. For each structure, dDVHs were approximated using the average dDVH and the 10 highest-ranked structure-specific principal components (PCs). ECGs at baseline and 6 months after radiation therapy were analyzed for 53 patients, dichotomizing patients according to presence or absence of "any ECG change" (conduction or ischemic/pericarditis-like change). All-cause death rate (DR) was analyzed from the start of treatment using Cox regression. RESULTS: 38% of patients had ECG changes at 6 months. On univariable analysis, higher scores for LA-Wall-PC6, Heart-PC6, "any ECG change," and larger planning target volume (PTV) were significantly associated with higher DR (P=.003, .009, .029, and .037, respectively). Heart-PC6 and LA-Wall-PC6 represent larger volumes of whole heart and left atrial wall receiving 63 to 69 Gy. Cardiac doses ≥63 Gy were concentrated in the LA-Wall, and consequently Heart-PC6 was highly correlated with LA-Wall-PC6. "Any ECG change," LA-Wall-PC6 scores, and PTV size were retained in the multivariable model. CONCLUSIONS: We found associations between higher DR and conduction or ischemic/pericarditis-like changes on ECG at 6 months, and between higher DR and higher Heart-PC6 or LA-Wall-PC6 scores, which are closely related to heart or left atrial wall volumes receiving 63 to 69 Gy in this small cohort of patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Coração/efeitos da radiação , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/radioterapia , Órgãos em Risco/efeitos da radiação , Lesões por Radiação/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Causas de Morte , Fracionamento da Dose de Radiação , Eletrocardiografia/efeitos da radiação , Feminino , Coração/diagnóstico por imagem , Coração/fisiologia , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/efeitos da radiação , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Órgãos em Risco/diagnóstico por imagem , Órgãos em Risco/fisiologia , Pericárdio/efeitos da radiação , Análise de Componente Principal , Estudos Prospectivos , Doses de Radiação , Lesões por Radiação/fisiopatologia , Planejamento da Radioterapia Assistida por Computador
18.
Genetics ; 207(2): 609-623, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28835471

RESUMO

Large-scale forward genetic screens have been instrumental for identifying genes that regulate development, homeostasis, and regeneration, as well as the mechanisms of disease. The zebrafish, Danio rerio, is an established genetic and developmental model used in genetic screens to uncover genes necessary for early development. However, the regulation of postembryonic development has received less attention as these screens are more labor intensive and require extensive resources. The lack of systematic interrogation of late development leaves large aspects of the genetic regulation of adult form and physiology unresolved. To understand the genetic control of postembryonic development, we performed a dominant screen for phenotypes affecting the adult zebrafish. In our screen, we identified 72 adult viable mutants showing changes in the shape of the skeleton as well as defects in pigmentation. For efficient mapping of these mutants and mutation identification, we devised a new mapping strategy based on identification of mutant-specific haplotypes. Using this method in combination with a candidate gene approach, we were able to identify linked mutations for 22 out of 25 mutants analyzed. Broadly, our mutational analysis suggests that there are key genes and pathways associated with late development. Many of these pathways are shared with humans and are affected in various disease conditions, suggesting constraint in the genetic pathways that can lead to change in adult form. Taken together, these results show that dominant screens are a feasible and productive means to identify mutations that can further our understanding of gene function during postembryonic development and in disease.


Assuntos
Desenvolvimento Ósseo/genética , Genes Dominantes , Mutagênese , Pigmentação da Pele/genética , Peixe-Zebra/genética , Animais , Haplótipos , Fenótipo , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/genética
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