Darren Hargrave - Academia.edu (original) (raw)
Papers by Darren Hargrave
Journal of pediatric endocrinology & metabolism: JPEM
Either your web browser doesn't support Javascript or it is currently turned off. In the latt... more Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page. ... Consensus and perspectives on treatment strategies in childhood craniopharyngioma: results of a ...
British Journal of Neurosurgery
The decision to biopsy diffuse pontine gliomas in children remains controversial. There have been... more The decision to biopsy diffuse pontine gliomas in children remains controversial. There have been many publications over the last 30 years aiming to address this issue. The prognosis for these patients remains extremely poor regardless of treatment and many authors advocate that biopsy carries significant risk for little or no clinical benefit. However, with an increasing knowledge of tumour biology and genetics there is the potential for specific treatments tailored for individual tumours based on their biological or genetic characteristics. The progress of such science in the first instance requires histological diagnosis as part of well conducted clinical trials, then, when treatments have been developed, biopsy samples will be needed to identify the tumours that may respond to such treatments. The authors believe that there is an increasing need for performing a biopsy of these lesions.
Pediatric blood & cancer, Jan 8, 2015
The efficacy of hybrid 18F-Fluroethyl-Choline (FEC) positron emission tomography (PET)/magnetic r... more The efficacy of hybrid 18F-Fluroethyl-Choline (FEC) positron emission tomography (PET)/magnetic resonance imaging (MRI) was investigated as an imaging modality for diagnosis and assessment of treatment response and remission status in four patients with proven or suspected intracranial non-germinomatous germ cell tumours (NGGCT). In two patients faint or absent choline avidity correlated with negative histology, whereas in other two patients, persistent choline avidity in the residual mass was suggestive of presence of viable tumour, subsequently confirmed histologically. We conclude that FEC-PET/MRI may be an effective imaging tool in detecting viable residual tumour in patients with intracranial NGGCT post treatment. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.
Medicine, science, and the law, 1992
The child homicides which were notified to the Leeds University Department of Forensic Medicine b... more The child homicides which were notified to the Leeds University Department of Forensic Medicine between 1970 and 1989 were studied. There were 131 cases, and information regarding age of victim, mode of death and post-mortem evidence of previous abuse was noted. The incidences of child homicide varied between 3 and 11 cases per year; the first three years of life providing the majority of cases. Blunt injury accounted for almost half of the deaths, whilst 34 per cent of cases showed evidence of previous physical or sexual abuse. In infant homicide (i.e. under one year of age) a pattern emerged which has previously been described as the 'shaken baby syndrome'.
Journal of pediatric endocrinology & metabolism : JPEM, 2006
Craniopharyngiomas are classified as histologically benign tumours that are usually treated by su... more Craniopharyngiomas are classified as histologically benign tumours that are usually treated by surgery alone or in combination with radiotherapy. However, the difficulty in managing recurrent tumours and the desire to try to avoid treatment-related morbidity from both surgery and irradiation has led to exploration of the role of chemotherapy in this tumour. In the majority of cases this has involved the application of intratumoral bleomycin in cystic craniopharyngiomas. This review reports the published experience of this type of local chemotherapy, including delivery, scheduling, outcomes and toxicity. In addition, the rarely reported use of systemic chemotherapy is discussed.
CNS Oncology, 2012
Pediatric diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis that has not seen a chan... more Pediatric diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis that has not seen a change in outcome despite multiple clinical trials. Possible reasons for failure to make progress in this aggressive childhood brain tumor include: poor understanding of the underlying molecular biology due to lack of access to tumor material; absence of accurate and relevant DIPG preclinical models for drug development; ill-defined therapeutic targets for novel agents; and inadequate drug delivery to the brainstem. This review will demonstrate that systematic studies to identify solutions for each of these barriers is starting to deliver progress that can turn pessimism to optimism in DIPG.
Clinical Nuclear Medicine, 2015
Purpose: To examine the feasibility of simultaneous acquisition of 18 Ffluoroethylcholine ( 18 F-... more Purpose: To examine the feasibility of simultaneous acquisition of 18 Ffluoroethylcholine ( 18 F-choline) PET and functional MRI (standardized uptake value [SUV] max/mean and apparent diffusion coefficient [ADC] mean ), using a hybrid PET/MRI scanner, for diagnosis and response assessment in a cohort of children with astrocytic brain tumors. Methods: 18 F-choline PET/MRI scans were performed in 12 patients with proven astrocytic tumors.
Pediatric Blood & Cancer, 2013
Criteria for new drug approval include demonstration of efficacy. In neuro-oncology, this is dete... more Criteria for new drug approval include demonstration of efficacy. In neuro-oncology, this is determined radiographically utilizing tumor measurements on MRI scans. Limitations of this method have been identified where drug activity is not reflected in decreased tumor size. The RANO (Response Assessment in Neuro-Oncology) working group was established to address limitations in defining endpoints for clinical trials in adult neuro-oncology and to develop standardized response criteria. RAPNO was subsequently established to address unique issues in pediatric neuro-oncology. The aim of this paper is to delineate response criteria issues in pediatric clinical trials as a basis for subsequent recommendations.
The Lancet Oncology, 2013
Despite major progress in the past 40 years, 20% of children with cancer die from the disease, an... more Despite major progress in the past 40 years, 20% of children with cancer die from the disease, and 40% of survivors have late adverse effects. Innovative, safe, and effective medicines are needed. Although regulatory initiatives in the past 15 years in the USA and Europe have been introduced, new drug development for children with cancer is insufficient. Children and families face major inequity between countries in terms of access to innovative drugs in development. Hurdles and bottlenecks are well known-eg, small numbers of patients, the complexity of developing targeted agents and their biomarkers for selected patients, limitations of US and EU regulations for paediatric medicines, insufficient return on investment, and the global economic crisis facing drug companies. New drug development pathways could efficiently address the challenges with innovative methods and trial designs, investment in biology and preclinical research, new models of partnership and funding including public-private partnerships and precompetitive research consortia, improved regulatory requirements, initiatives and incentives that better address these needs, and increased collaboration between paediatric oncology cooperative groups worldwide. Increased cooperation between all stakeholders-academia, parents' organisations and advocacy groups, regulatory bodies, pharmaceutical companies, philanthropic organisations, and government-will be essential.
Journal of Pediatric Hematology/Oncology, 2014
Early phase trials are crucial in developing new therapies for poor prognosis childhood malignanc... more Early phase trials are crucial in developing new therapies for poor prognosis childhood malignancies. Outcomes and toxicities of children treated on phase I/II trials at the Royal Marsden, one of the largest pediatric oncology early phase trial units in Europe, were examined to provide a baseline dataset and generate hypotheses. All patients recruited over a 10-year period to December 2011 were included. Variables including baseline characteristics, time on study, survival, toxicities, and admissions were collected. Seventy-two patients were recruited to 21 trials (5 phase I, 16 phase II; overall 12 involved molecularly targeted agents). Median age at consent was 12.4 years. Dose-limiting toxicities were rare in phase I trial participants (2 of 15 evaluable patients, 13%); the most common reason for leaving trials was disease progression (76%), rather than drug toxicity (1.7%). Median time on trial was 1.3 months (phase I patients) and 3.3 months (phase II). Early phase trials in children are safe and unexpected toxic side effects are infrequent. Patients and their families are willing to travel to access novel therapies, although the overall prognosis for these individuals is poor. Continued expansion of the portfolio is needed ultimately to improve the outcomes for those with resistant disease.
Medical and pediatric oncology, 2003
Klinische Pädiatrie
The fast growing internet offers easy access to medical information. So far there are limited dat... more The fast growing internet offers easy access to medical information. So far there are limited data concerning the quality of this information. This study examined quality and readability of paediatric neuro-oncological information on the internet in german language.
Pediatric blood & cancer, 2004
Journal of neuro-oncology, 2006
Children with pontine glioma usually present classically with ataxia, motor deficits and cranial ... more Children with pontine glioma usually present classically with ataxia, motor deficits and cranial nerve palsies. The pons has generally not been regarded as a structure that mediates complex affective behaviour. However, we report nine children who either at the time of presentation or progression demonstrated marked behavioural changes manifesting as either "pathological laughter" or separation anxiety in the form of school refusal. A mechanism of how pontine lesions can cause such complex affective and cognitive behaviour has been suggested to consist of the disruption of a network of cerebro-ponto-cerebellar pathways and the evidence for this mechanism is discussed.
The lancet oncology, 2006
Diffuse intrinsic brainstem gliomas constitute 15-20% of all CNS tumours in children, and are the... more Diffuse intrinsic brainstem gliomas constitute 15-20% of all CNS tumours in children, and are the main cause of death in children with brain tumours. Many clinical trials have been done over the past three decades, but survival has remained static. More than 90% of children die within 2 years of diagnosis, and conventional fractionated radiation remains the standard treatment. However, median survival differs substantially between clinical trials, suggesting a survival benefit with some strategies. We appraised the consistency between protocols in terms of eligibility criteria, definition and assessment of response and progression, statistical design, and endpoints. Study designs varied substantially, which could explain the differences in outcome, and no treatment has shown a benefit over conventional radiotherapy. However, consistency between protocols (eg, eligibility criteria and outcome measures) is important to measure the progress in management of diffuse pontine gliomas.
Neuro-oncology, 2006
The Internet is now the single largest source of health information and is used by many patients ... more The Internet is now the single largest source of health information and is used by many patients and their families who are affected by childhood brain tumors. To assess the quality of pediatric neuro-oncology information on the Internet, we used search engines to look for information on five common tumor types (brain stem glioma, craniopharyngioma, ependymoma, low-grade glioma, and medulloblastoma). The Web sites were evaluated for content quality by using the validated DISCERN rating instrument. Breadth of content and its accuracy were also scored by a checklist tool. Readability statistics were computed on the highest-rated sites. Of 114 evaluated Web sites, the sources were as follows: institutional, 46%; commercial, 35%; charitable, 15%; support group, 2%; and alternative medicine, 2%. Good interobserver correlation was found for both ratings instruments. The DISCERN tool rated Web sites as excellent (4%), good (7%), fair (29%), poor (39%), or very poor (21%). Only 5% of the We...
Journal of pediatric endocrinology & metabolism: JPEM
Either your web browser doesn't support Javascript or it is currently turned off. In the latt... more Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page. ... Consensus and perspectives on treatment strategies in childhood craniopharyngioma: results of a ...
British Journal of Neurosurgery
The decision to biopsy diffuse pontine gliomas in children remains controversial. There have been... more The decision to biopsy diffuse pontine gliomas in children remains controversial. There have been many publications over the last 30 years aiming to address this issue. The prognosis for these patients remains extremely poor regardless of treatment and many authors advocate that biopsy carries significant risk for little or no clinical benefit. However, with an increasing knowledge of tumour biology and genetics there is the potential for specific treatments tailored for individual tumours based on their biological or genetic characteristics. The progress of such science in the first instance requires histological diagnosis as part of well conducted clinical trials, then, when treatments have been developed, biopsy samples will be needed to identify the tumours that may respond to such treatments. The authors believe that there is an increasing need for performing a biopsy of these lesions.
Pediatric blood & cancer, Jan 8, 2015
The efficacy of hybrid 18F-Fluroethyl-Choline (FEC) positron emission tomography (PET)/magnetic r... more The efficacy of hybrid 18F-Fluroethyl-Choline (FEC) positron emission tomography (PET)/magnetic resonance imaging (MRI) was investigated as an imaging modality for diagnosis and assessment of treatment response and remission status in four patients with proven or suspected intracranial non-germinomatous germ cell tumours (NGGCT). In two patients faint or absent choline avidity correlated with negative histology, whereas in other two patients, persistent choline avidity in the residual mass was suggestive of presence of viable tumour, subsequently confirmed histologically. We conclude that FEC-PET/MRI may be an effective imaging tool in detecting viable residual tumour in patients with intracranial NGGCT post treatment. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.
Medicine, science, and the law, 1992
The child homicides which were notified to the Leeds University Department of Forensic Medicine b... more The child homicides which were notified to the Leeds University Department of Forensic Medicine between 1970 and 1989 were studied. There were 131 cases, and information regarding age of victim, mode of death and post-mortem evidence of previous abuse was noted. The incidences of child homicide varied between 3 and 11 cases per year; the first three years of life providing the majority of cases. Blunt injury accounted for almost half of the deaths, whilst 34 per cent of cases showed evidence of previous physical or sexual abuse. In infant homicide (i.e. under one year of age) a pattern emerged which has previously been described as the 'shaken baby syndrome'.
Journal of pediatric endocrinology & metabolism : JPEM, 2006
Craniopharyngiomas are classified as histologically benign tumours that are usually treated by su... more Craniopharyngiomas are classified as histologically benign tumours that are usually treated by surgery alone or in combination with radiotherapy. However, the difficulty in managing recurrent tumours and the desire to try to avoid treatment-related morbidity from both surgery and irradiation has led to exploration of the role of chemotherapy in this tumour. In the majority of cases this has involved the application of intratumoral bleomycin in cystic craniopharyngiomas. This review reports the published experience of this type of local chemotherapy, including delivery, scheduling, outcomes and toxicity. In addition, the rarely reported use of systemic chemotherapy is discussed.
CNS Oncology, 2012
Pediatric diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis that has not seen a chan... more Pediatric diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis that has not seen a change in outcome despite multiple clinical trials. Possible reasons for failure to make progress in this aggressive childhood brain tumor include: poor understanding of the underlying molecular biology due to lack of access to tumor material; absence of accurate and relevant DIPG preclinical models for drug development; ill-defined therapeutic targets for novel agents; and inadequate drug delivery to the brainstem. This review will demonstrate that systematic studies to identify solutions for each of these barriers is starting to deliver progress that can turn pessimism to optimism in DIPG.
Clinical Nuclear Medicine, 2015
Purpose: To examine the feasibility of simultaneous acquisition of 18 Ffluoroethylcholine ( 18 F-... more Purpose: To examine the feasibility of simultaneous acquisition of 18 Ffluoroethylcholine ( 18 F-choline) PET and functional MRI (standardized uptake value [SUV] max/mean and apparent diffusion coefficient [ADC] mean ), using a hybrid PET/MRI scanner, for diagnosis and response assessment in a cohort of children with astrocytic brain tumors. Methods: 18 F-choline PET/MRI scans were performed in 12 patients with proven astrocytic tumors.
Pediatric Blood & Cancer, 2013
Criteria for new drug approval include demonstration of efficacy. In neuro-oncology, this is dete... more Criteria for new drug approval include demonstration of efficacy. In neuro-oncology, this is determined radiographically utilizing tumor measurements on MRI scans. Limitations of this method have been identified where drug activity is not reflected in decreased tumor size. The RANO (Response Assessment in Neuro-Oncology) working group was established to address limitations in defining endpoints for clinical trials in adult neuro-oncology and to develop standardized response criteria. RAPNO was subsequently established to address unique issues in pediatric neuro-oncology. The aim of this paper is to delineate response criteria issues in pediatric clinical trials as a basis for subsequent recommendations.
The Lancet Oncology, 2013
Despite major progress in the past 40 years, 20% of children with cancer die from the disease, an... more Despite major progress in the past 40 years, 20% of children with cancer die from the disease, and 40% of survivors have late adverse effects. Innovative, safe, and effective medicines are needed. Although regulatory initiatives in the past 15 years in the USA and Europe have been introduced, new drug development for children with cancer is insufficient. Children and families face major inequity between countries in terms of access to innovative drugs in development. Hurdles and bottlenecks are well known-eg, small numbers of patients, the complexity of developing targeted agents and their biomarkers for selected patients, limitations of US and EU regulations for paediatric medicines, insufficient return on investment, and the global economic crisis facing drug companies. New drug development pathways could efficiently address the challenges with innovative methods and trial designs, investment in biology and preclinical research, new models of partnership and funding including public-private partnerships and precompetitive research consortia, improved regulatory requirements, initiatives and incentives that better address these needs, and increased collaboration between paediatric oncology cooperative groups worldwide. Increased cooperation between all stakeholders-academia, parents' organisations and advocacy groups, regulatory bodies, pharmaceutical companies, philanthropic organisations, and government-will be essential.
Journal of Pediatric Hematology/Oncology, 2014
Early phase trials are crucial in developing new therapies for poor prognosis childhood malignanc... more Early phase trials are crucial in developing new therapies for poor prognosis childhood malignancies. Outcomes and toxicities of children treated on phase I/II trials at the Royal Marsden, one of the largest pediatric oncology early phase trial units in Europe, were examined to provide a baseline dataset and generate hypotheses. All patients recruited over a 10-year period to December 2011 were included. Variables including baseline characteristics, time on study, survival, toxicities, and admissions were collected. Seventy-two patients were recruited to 21 trials (5 phase I, 16 phase II; overall 12 involved molecularly targeted agents). Median age at consent was 12.4 years. Dose-limiting toxicities were rare in phase I trial participants (2 of 15 evaluable patients, 13%); the most common reason for leaving trials was disease progression (76%), rather than drug toxicity (1.7%). Median time on trial was 1.3 months (phase I patients) and 3.3 months (phase II). Early phase trials in children are safe and unexpected toxic side effects are infrequent. Patients and their families are willing to travel to access novel therapies, although the overall prognosis for these individuals is poor. Continued expansion of the portfolio is needed ultimately to improve the outcomes for those with resistant disease.
Medical and pediatric oncology, 2003
Klinische Pädiatrie
The fast growing internet offers easy access to medical information. So far there are limited dat... more The fast growing internet offers easy access to medical information. So far there are limited data concerning the quality of this information. This study examined quality and readability of paediatric neuro-oncological information on the internet in german language.
Pediatric blood & cancer, 2004
Journal of neuro-oncology, 2006
Children with pontine glioma usually present classically with ataxia, motor deficits and cranial ... more Children with pontine glioma usually present classically with ataxia, motor deficits and cranial nerve palsies. The pons has generally not been regarded as a structure that mediates complex affective behaviour. However, we report nine children who either at the time of presentation or progression demonstrated marked behavioural changes manifesting as either "pathological laughter" or separation anxiety in the form of school refusal. A mechanism of how pontine lesions can cause such complex affective and cognitive behaviour has been suggested to consist of the disruption of a network of cerebro-ponto-cerebellar pathways and the evidence for this mechanism is discussed.
The lancet oncology, 2006
Diffuse intrinsic brainstem gliomas constitute 15-20% of all CNS tumours in children, and are the... more Diffuse intrinsic brainstem gliomas constitute 15-20% of all CNS tumours in children, and are the main cause of death in children with brain tumours. Many clinical trials have been done over the past three decades, but survival has remained static. More than 90% of children die within 2 years of diagnosis, and conventional fractionated radiation remains the standard treatment. However, median survival differs substantially between clinical trials, suggesting a survival benefit with some strategies. We appraised the consistency between protocols in terms of eligibility criteria, definition and assessment of response and progression, statistical design, and endpoints. Study designs varied substantially, which could explain the differences in outcome, and no treatment has shown a benefit over conventional radiotherapy. However, consistency between protocols (eg, eligibility criteria and outcome measures) is important to measure the progress in management of diffuse pontine gliomas.
Neuro-oncology, 2006
The Internet is now the single largest source of health information and is used by many patients ... more The Internet is now the single largest source of health information and is used by many patients and their families who are affected by childhood brain tumors. To assess the quality of pediatric neuro-oncology information on the Internet, we used search engines to look for information on five common tumor types (brain stem glioma, craniopharyngioma, ependymoma, low-grade glioma, and medulloblastoma). The Web sites were evaluated for content quality by using the validated DISCERN rating instrument. Breadth of content and its accuracy were also scored by a checklist tool. Readability statistics were computed on the highest-rated sites. Of 114 evaluated Web sites, the sources were as follows: institutional, 46%; commercial, 35%; charitable, 15%; support group, 2%; and alternative medicine, 2%. Good interobserver correlation was found for both ratings instruments. The DISCERN tool rated Web sites as excellent (4%), good (7%), fair (29%), poor (39%), or very poor (21%). Only 5% of the We...