Stephen Lowis - Academia.edu (original) (raw)

Papers by Stephen Lowis

Journal of Neuropathology and Experimental Neurology, Sep 1, 2015

Pilocytic astrocytomas (PAs) are increasingly tested for KIAA1549-BRAF fusions. We used reverse t... more Pilocytic astrocytomas (PAs) are increasingly tested for KIAA1549-BRAF fusions. We used reverse transcription polymerase chain reaction for the 3 most common KIAA1549-BRAF fusions, together with BRAF V600E and histone H3.3 K27M analyses to identify relationships of these molecular characteristics with clinical features in a cohort of 32 PA patients. In this group, the overall BRAF fusion detection rate was 24 (75%). Ten (42%) of the 24 had the 16-9 fusion, 8 (33%) had only the 15-9 fusion, and 1 (4%) of the patients had only the 16-11 fusion. In the PAs with only the 15-9 fusion, 1 PA was in the cerebellum and 7 were centered in the midline outside of the cerebellum, that is, in the hypothalamus (n = 4), optic pathways (n = 2), and brainstem (n = 1). Tumors within the cerebellum were negatively associated with fusion 15-9. Seven (22%) of the 32 patients had tumor-related deaths and 25 of the patients (78%) were alive between 2 and 14 years after initial biopsy. Age, sex, tumor location, 16-9 fusion, and 15-9 fusion were not associated with overall survival. Thus, in this small cohort, 15-9 KIAA1549-BRAF fusion was associated with mid-line PAs located outside of the cerebellum; these tumors, which are generally difficult to resect, are prone to recurrence.

Oxford University Press eBooks, Oct 1, 2017

Embryonal tumours account for 20% of paediatric central nervous system (CNS) tumours. Medulloblas... more Embryonal tumours account for 20% of paediatric central nervous system (CNS) tumours. Medulloblastoma (MB), the most frequent, arises in the cerebellum. Clinical strategies have been based on series of multi-institutional trials since the 1970s. Recent understanding of the influence of molecular/biological factors has led to subdivision into four distinct subtypes with differing clinical and prognostic profiles, on which stratification is now based. Management of MB in adults is largely based on principles of managing children, modified according to differing clinical and toxicity profiles. Molecular analysis has led to the understanding that what was previously referred to as CNS-PNET comprise a heterogeneous group of tumours with a significant proportion representing other histologies. Atypical teratoid/rhabdoid tumour (AT/RT) carries mutations in the gene hSNF5/INI1 in most cases, with many now associated with an improved prospect of long-term survival. Pineal tumours have similar clinical presentations, comprising a heterogeneous mix of histologies from pineocytoma through to pineoblastoma.

Pediatric Pulmonology, Jun 8, 2020

Patients with pulmonary Langerhans cell histiocytosis (LCH) typically have a benign course but ma... more Patients with pulmonary Langerhans cell histiocytosis (LCH) typically have a benign course but may have extensive cystic lung disease with rare life‐threatening complications including multiple and recurrent pneumothoraces and respiratory failure. We report seven severely affected pediatric patients treated with chemotherapy, aggressive chest tube management, and pleurodesis of whom five survived. Patients with extraordinary amounts of pulmonary cystic disease and multiple pneumothoraces due to LCH can have remarkable, curative outcomes with early recognition, optimal LCH‐directed therapy, and supportive care.

Archives of Disease in Childhood, Aug 16, 2019

BackgroundThe National Institute for Health and Care Excellence (NICE) guidance for referral of c... more BackgroundThe National Institute for Health and Care Excellence (NICE) guidance for referral of children with suspected cancer was first published in 2005 and updated in 2015. The updated version relied on sparse primary care evidence and published without input from key stakeholders, for example, acute general paediatricians and paediatric haematologists/oncologists. This led to a document that fell short as a practical guide for referring physicians managing children with potentially life-threatening conditions. Following discussions between the Children’s Cancer and Leukaemia Group (CCLG, the UK multidisciplinary professional body for healthcare professionals caring for children with cancer) and NICE, it was agreed that a practical supplement should be produced for the 2015 guidance. A prerequisite was evidence gathering from tertiary care to balance the existing primary care evidence, and a Delphi consensus method was therefore convened.MethodsA CCLG NICE Guidance Committee formulated 25 draft statements for review. The CCLG emailed its paediatric haematologist/oncologist membership (n=179) and 88 responded (49%). To achieve consensus, statements required ≥70% agreement from ≥60% of actual respondents, from the denominator (n=88).ResultsFifteen of 25 original statements were accepted at the first round of voting. Three of 25 statements where >50% did not support were rejected outright. One statement could not be revised without replicating a previously accepted statement. The six remaining statements were revised and a second round of voting undertaken; all six revised statements were accepted. Overall, 21 of 25 statements (84%) met consensus criteria.ConclusionsThis expert opinion should help streamline suspected cancer referral in children and help optimise subsequent outcomes.

European Journal of Cancer, Sep 1, 2017

We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adol... more We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). Patients and methods: Eligible patients aged !6 months to <18 years were randomised to receive induction chemotherapy (four cycles of IVADo þ five cycles of IVA, AEbevacizumab), surgery and/or radiotherapy, followed by maintenance chemotherapy (12 cycles of low-dose cyclophosphamide þ vinorelbine, AEbevacizumab). The primary objective was event-free survival (EFS) evaluated by an independent radiological review committee. Results: One hundred and fifty-four patients were randomised to receive chemotherapy alone (n Z 80) or with bevacizumab (n Z 74). At the data cutoff for the primary efficacy analysis, median EFS was 14.9 months (95% confidence interval [CI]: 10.8e35.9) with chemotherapy and 20.6 months (95% CI: 15.2e24.9) with bevacizumab plus chemotherapy (stratified hazard ratio [HR] Z 0.93; 95% CI: 0.61e1.41; P Z 0.72). The HR for EFS in patients with RMS (n Z 103) was 1.24 (95% CI: 0.73e2.09) versus 0.64 (95% CI: 0.32e1.26) for those with NRSTS (n Z 49). Objective response rate was 36.0% (95% CI: 25.2e47.9) with chemotherapy and 54.0% (95% CI: 40.9e66.6) with bevacizumab plus chemotherapy (difference of 18.0%; 95% CI: 0.6e35.3). There were no treatment-related deaths and no increased incidence of grade 3/4 toxicities with bevacizumab. Conclusion: The addition of bevacizumab to chemotherapy appeared tolerable in children and adolescents with metastatic RMS/NRSTS, but the primary end-point of EFS did not show statistically significant improvement. Trial registration: ClinicalTrials.gov, NCT00643565.

Neuro-oncology, Oct 1, 2018

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, i... more Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management.Significance:Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related video: https://vimeo.com/438254885See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

Supplementary Figures and Legends

CRC Press eBooks, Oct 31, 2020

Current Paediatrics, Jun 1, 1993

CRC Press eBooks, Oct 29, 2014

CRC Press eBooks, Jul 30, 2004

Journal of Neuropathology and Experimental Neurology, Sep 1, 2015

Pilocytic astrocytomas (PAs) are increasingly tested for KIAA1549-BRAF fusions. We used reverse t... more Pilocytic astrocytomas (PAs) are increasingly tested for KIAA1549-BRAF fusions. We used reverse transcription polymerase chain reaction for the 3 most common KIAA1549-BRAF fusions, together with BRAF V600E and histone H3.3 K27M analyses to identify relationships of these molecular characteristics with clinical features in a cohort of 32 PA patients. In this group, the overall BRAF fusion detection rate was 24 (75%). Ten (42%) of the 24 had the 16-9 fusion, 8 (33%) had only the 15-9 fusion, and 1 (4%) of the patients had only the 16-11 fusion. In the PAs with only the 15-9 fusion, 1 PA was in the cerebellum and 7 were centered in the midline outside of the cerebellum, that is, in the hypothalamus (n = 4), optic pathways (n = 2), and brainstem (n = 1). Tumors within the cerebellum were negatively associated with fusion 15-9. Seven (22%) of the 32 patients had tumor-related deaths and 25 of the patients (78%) were alive between 2 and 14 years after initial biopsy. Age, sex, tumor location, 16-9 fusion, and 15-9 fusion were not associated with overall survival. Thus, in this small cohort, 15-9 KIAA1549-BRAF fusion was associated with mid-line PAs located outside of the cerebellum; these tumors, which are generally difficult to resect, are prone to recurrence.

Oxford University Press eBooks, Oct 1, 2017

Embryonal tumours account for 20% of paediatric central nervous system (CNS) tumours. Medulloblas... more Embryonal tumours account for 20% of paediatric central nervous system (CNS) tumours. Medulloblastoma (MB), the most frequent, arises in the cerebellum. Clinical strategies have been based on series of multi-institutional trials since the 1970s. Recent understanding of the influence of molecular/biological factors has led to subdivision into four distinct subtypes with differing clinical and prognostic profiles, on which stratification is now based. Management of MB in adults is largely based on principles of managing children, modified according to differing clinical and toxicity profiles. Molecular analysis has led to the understanding that what was previously referred to as CNS-PNET comprise a heterogeneous group of tumours with a significant proportion representing other histologies. Atypical teratoid/rhabdoid tumour (AT/RT) carries mutations in the gene hSNF5/INI1 in most cases, with many now associated with an improved prospect of long-term survival. Pineal tumours have similar clinical presentations, comprising a heterogeneous mix of histologies from pineocytoma through to pineoblastoma.

Pediatric Pulmonology, Jun 8, 2020

Patients with pulmonary Langerhans cell histiocytosis (LCH) typically have a benign course but ma... more Patients with pulmonary Langerhans cell histiocytosis (LCH) typically have a benign course but may have extensive cystic lung disease with rare life‐threatening complications including multiple and recurrent pneumothoraces and respiratory failure. We report seven severely affected pediatric patients treated with chemotherapy, aggressive chest tube management, and pleurodesis of whom five survived. Patients with extraordinary amounts of pulmonary cystic disease and multiple pneumothoraces due to LCH can have remarkable, curative outcomes with early recognition, optimal LCH‐directed therapy, and supportive care.

Archives of Disease in Childhood, Aug 16, 2019

BackgroundThe National Institute for Health and Care Excellence (NICE) guidance for referral of c... more BackgroundThe National Institute for Health and Care Excellence (NICE) guidance for referral of children with suspected cancer was first published in 2005 and updated in 2015. The updated version relied on sparse primary care evidence and published without input from key stakeholders, for example, acute general paediatricians and paediatric haematologists/oncologists. This led to a document that fell short as a practical guide for referring physicians managing children with potentially life-threatening conditions. Following discussions between the Children’s Cancer and Leukaemia Group (CCLG, the UK multidisciplinary professional body for healthcare professionals caring for children with cancer) and NICE, it was agreed that a practical supplement should be produced for the 2015 guidance. A prerequisite was evidence gathering from tertiary care to balance the existing primary care evidence, and a Delphi consensus method was therefore convened.MethodsA CCLG NICE Guidance Committee formulated 25 draft statements for review. The CCLG emailed its paediatric haematologist/oncologist membership (n=179) and 88 responded (49%). To achieve consensus, statements required ≥70% agreement from ≥60% of actual respondents, from the denominator (n=88).ResultsFifteen of 25 original statements were accepted at the first round of voting. Three of 25 statements where &gt;50% did not support were rejected outright. One statement could not be revised without replicating a previously accepted statement. The six remaining statements were revised and a second round of voting undertaken; all six revised statements were accepted. Overall, 21 of 25 statements (84%) met consensus criteria.ConclusionsThis expert opinion should help streamline suspected cancer referral in children and help optimise subsequent outcomes.

European Journal of Cancer, Sep 1, 2017

We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adol... more We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). Patients and methods: Eligible patients aged !6 months to <18 years were randomised to receive induction chemotherapy (four cycles of IVADo þ five cycles of IVA, AEbevacizumab), surgery and/or radiotherapy, followed by maintenance chemotherapy (12 cycles of low-dose cyclophosphamide þ vinorelbine, AEbevacizumab). The primary objective was event-free survival (EFS) evaluated by an independent radiological review committee. Results: One hundred and fifty-four patients were randomised to receive chemotherapy alone (n Z 80) or with bevacizumab (n Z 74). At the data cutoff for the primary efficacy analysis, median EFS was 14.9 months (95% confidence interval [CI]: 10.8e35.9) with chemotherapy and 20.6 months (95% CI: 15.2e24.9) with bevacizumab plus chemotherapy (stratified hazard ratio [HR] Z 0.93; 95% CI: 0.61e1.41; P Z 0.72). The HR for EFS in patients with RMS (n Z 103) was 1.24 (95% CI: 0.73e2.09) versus 0.64 (95% CI: 0.32e1.26) for those with NRSTS (n Z 49). Objective response rate was 36.0% (95% CI: 25.2e47.9) with chemotherapy and 54.0% (95% CI: 40.9e66.6) with bevacizumab plus chemotherapy (difference of 18.0%; 95% CI: 0.6e35.3). There were no treatment-related deaths and no increased incidence of grade 3/4 toxicities with bevacizumab. Conclusion: The addition of bevacizumab to chemotherapy appeared tolerable in children and adolescents with metastatic RMS/NRSTS, but the primary end-point of EFS did not show statistically significant improvement. Trial registration: ClinicalTrials.gov, NCT00643565.

Neuro-oncology, Oct 1, 2018

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, i... more Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management.Significance:Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related video: https://vimeo.com/438254885See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

Supplementary Figures and Legends

CRC Press eBooks, Oct 31, 2020

Current Paediatrics, Jun 1, 1993

CRC Press eBooks, Oct 29, 2014

CRC Press eBooks, Jul 30, 2004