Ferrari, A.
Chisholm, J.C.
Jenney, M.
Minard-Colin, V.
Orbach, D.
Casanova, M.
Guillen, G.
Glosli, H.
van Rijn, R.R.
Schoot, R.A.
Cameron, A.L.
Rogers, T.
Alaggio, R.
Ben-Arush, M.
Mandeville, H.C.
Devalck, C.
Defachelles, A.-.
Coppadoro, B.
Bisogno, G.
Merks, J.H.
(2022). Adolescents and young adults with rhabdomyosarcoma treated in the European paediatric Soft tissue sarcoma Study Group (EpSSG) protocols: a cohort study. The lancet. child & adolescent health,
,
p. S2352-4642(22)00121-3.
show abstract
Background
Adolescent and young adult patients with rhabdomyosarcoma often have poorer outcomes than do children. We aimed to compare the findings of adolescent and young adult patients with children enrolled in two prospective clinical protocols.
Methods
This retrospective observational analysis was based on data from the European paediatric Soft tissue sarcoma Study Group (EpSSG) rhabdomyosarcoma 2005 trial (phase 3 randomised trial for localised rhabdomyosarcoma, open from April, 2006, to December, 2016) and the EpSSG MTS 2008 protocol (prospective, observational, single-arm study for metastatic rhabdomyosarcoma, open from June, 2010, to December, 2016), which involved 108 centres from 14 different countries in total. For this analysis, patients were categorised according to their age into children (age 0-14 years) and adolescents and young adults (age 15-21 years). For the analysis of adherence to treatment and toxicity, only patients with high-risk localised rhabdomyosarcoma included in the randomised part of the rhabdomyosarcoma 2005 study were considered. The primary outcome of event-free survival (assessed in all participants) was defined as the time from diagnosis to the first event (eg, tumour progression, relapse) or to the latest follow-up. Secondary outcomes were overall survival, response to chemotherapy, and toxicity.
Findings
Our analysis included 1977 patients, 1720 children (median age 4·7 years; IQR 2·6-8·4) and 257 adolescents and young adults (16·6 years; 15·8-18·0). 1719 patients were from the EpSSG rhabdomyosarcoma 2005 study (1523 aged <15 years and 196 aged 15-21 years) and 258 patients were from the EPSSG MTS 2008 study (197 aged <15 years and 61 aged 15-21 years). Adolescent and young adult patients were more likely than were children to have metastatic tumours (61 [23·7%] of 257 vs 197 [11·5%] of 1720; p<0·0001), unfavourable histological subtypes (119 [46·3%] vs 451 [26·2%]; p<0·0001), tumours larger than 5 cm (177 [68·9%] vs 891 [51·8%]; p<0·0001), and regional lymph node involvement (109 [42·4%] vs 339 [19·7%]; p<0·0001). Adolescent and young adult patients had lower 5-year event-free survival (52·6% [95% CI 46·3-58·6] vs 67·8% [65·5-70·0]; p<0·0001) and lower 5-year overall survival (57·1% [50·4-63·1] vs 77·9% [75·8-79·8]; p<0·0001) than did children. The multivariable analysis confirmed the inferior prognosis of patients aged 15-21 years (hazard ratios 1·48 [95% CI 1·20-1·83; p=0·0002] for poorer event-free survival and 1·73 [1·37-2·19; p<0·0001] for poorer overall survival). Modifications of administered chemotherapy occurred in 13 (15·3%) of 85 adolescents and young adults, and in 161 (21·4%) of 754 children. Grade 3-4 haematological toxicity and infection were observed more frequently in children than in adolescent and young adult patients.
Interpretation
This study found better outcomes for adolescent and young adult patients than those reported in epidemiological studies (eg, the EUROCARE-5 study reported 5-year overall survival of 39·6% for patients aged 15-19 years in the 2000-07 study period), suggesting that adolescent and young adult patients, at least up to age 21 years, can be treated with intensive paediatric therapies with no major tolerability issues and should be included in paediatric rhabdomyosarcoma trials. However, the inferior outcomes in adolescent and young adult patients compared with those in children, despite receiving similar therapy, suggest that a tailored and intensive treatment strategy might be warranted for these patients.
Funding
Fondazione Città della Speranza..
Sjoberg Bexelius, T.
Chisholm, J.C.
Okoye, B.
Cecil, T.
Angelini, P.
Dayal, S.
(2021). Hyperthermic intraperitoneal chemotherapy (HIPEC) as another treatment modality for desmoplastic round cell tumour patients: first paediatric experience from UK. Bmj case reports,
Vol.14
(1),
pp. e234876-e234876.
show abstract
We present the first young paediatric patient with desmoplastic small round cell tumour (DSRCT) treated in UK with hyperthermic intraperitoneal chemotherapy (HIPEC). A 7-year-old girl was diagnosed with abdominal DSRCT with peritoneal and liver metastases. After six cycles of chemotherapy she obtained a partial response, including almost complete resolution of the two liver metastases. It was decided to pursue cytoreductive surgery (CRS) combined with HIPEC, a procedure commonly performed in adults, but seldom in a child. The surgery was macroscopically complete and the HIPEC uncomplicated. She continued treatment without delays, including whole abdomino-pelvic radiotherapy and maintenance chemotherapy (cyclophosphamide/vinorelbine for 12 months). She is currently in complete remission 4 months after end of treatment and 26 months after diagnosis. HIPEC was made possible by successful collaboration between multiple teams. CRS-HIPEC proved to be safe and feasible and could be offered to other children with diagnoses of peritoneal malignancies across the UK..
Bergeron, C.
Jenney, M.
De Corti, F.
Gallego, S.
Merks, H.
Glosli, H.
Ferrari, A.
Ranchère-Vince, D.
De Salvo, G.L.
Zanetti, I.
Chisholm, J.
Minard-Colin, V.
Rogers, T.
Bisogno, G.
Rose, A.
Devalck, C.
Ferman, S.
Mudry, P.
Bergeron, C.
Arush, M.W.
Bisogno, G.
Glosli, H.
Sejnova, D.
Cesen, M.
Gallego, S.
Merks, J.H.
Jenney, M.
(2021). Embryonal rhabdomyosarcoma completely resected at diagnosis: The European paediatric Soft tissue sarcoma Study Group RMS2005 experience. European journal of cancer,
Vol.146,
pp. 21-29.
Stankunaite, R.
George, S.L.
Gallagher, L.
Jamal, S.
Shaikh, R.
Yuan, L.
Hughes, D.
Proszek, P.Z.
Carter, P.
Pietka, G.
Heide, T.
James, C.
Tari, H.
Lynn, C.
Jain, N.
Portela, L.R.
Rogers, T.
Vaidya, S.J.
Chisholm, J.C.
Carceller, F.
Szychot, E.
Mandeville, H.
Angelini, P.
Jesudason, A.B.
Jackson, M.
Marshall, L.V.
Gatz, S.A.
Anderson, J.
Sottoriva, A.
Chesler, L.
Hubank, M.
(2021). Circulating tumour DNA sequencing to determine therapeutic response and identify tumour heterogeneity in patients with paediatric solid tumours. European journal of cancer (oxford, england : 1990),
.
show abstract
Objective
Clinical diagnostic sequencing of circulating tumour DNA (ctDNA) is well advanced for adult patients, but application to paediatric cancer patients lags behind.
Methods
To address this, we have developed a clinically relevant (67 gene) NGS capture panel and accompanying workflow that enables sensitive and reliable detection of low-frequency genetic variants in cell-free DNA (cfDNA) from children with solid tumours. We combined gene panel sequencing with low pass whole-genome sequencing of the same library to inform on genome-wide copy number changes in the blood.
Results
Analytical validity was evaluated using control materials, and the method was found to be highly sensitive (0.96 for SNVs and 0.97 for INDEL), specific (0.82 for SNVs and 0.978 for INDEL), repeatable (>0.93 [95% CI: 0.89-0.95]) and reproducible (>0.87 [95% CI: 0.87-0.95]). Potential for clinical application was demonstrated in 39 childhood cancer patients with a spectrum of solid tumours in which the single nucleotide variants expected from tumour sequencing were detected in cfDNA in 94.4% (17/18) of cases with active extracranial disease. In 13 patients, where serial samples were available, we show a close correlation between events detected in cfDNA and treatment response, demonstrate that cfDNA analysis could be a useful tool to monitor disease progression, and show cfDNA sequencing has the potential to identify targetable variants that were not detected in tumour samples.
Conclusions
This is the first pan-cancer DNA sequencing panel that we know to be optimised for cfDNA in children for blood-based molecular diagnostics in paediatric solid tumours..
Drabbe, C.
Benson, C.
Younger, E.
Zaidi, S.
Jones, R.L.
Judson, I.
Chisholm, J.
Mandeville, H.
Fisher, C.
Thway, K.
Al Muderis, O.
Messiou, C.
Strauss, D.
Husson, O.
Miah, A.
Van der Graaf, W.T.
(2020). Embryonal and Alveolar Rhabdomyosarcoma in Adults: Real-Life Data From a Tertiary Sarcoma Centre. Clinical oncology,
Vol.32
(1),
pp. e27-e35.
Bexelius, T.S.
Wasti, A.
Chisholm, J.C.
(2020). Mini-Review on Targeted Treatment of Desmoplastic Small Round Cell Tumor. Frontiers in oncology,
Vol.10,
pp. 518-?.
show abstract
Desmoplastic small round cell tumor (DSRCT) is a devastating disease which most commonly affects adolescents, with a male predominance. Despite the best multimodality treatment efforts, most patients will ultimately not survive more than 3-5 years after diagnosis. Some research trials in soft-tissue sarcoma and Ewing sarcoma include DSRCT patients but few studies have been tailored to the specific clinical needs and underlying cytogenetic abnormalities characterizing this disease such as the typical EWSR1-WT1 gene fusion. Downstream activation of EWSR1-WT1 gene fusion includes signaling pathways of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and insulin growth factor (IGF)-1. Other biological pathways that are activated and expressed in DSRCT cells include endothelial growth factor receptor (EGFR), androgen receptor pathway, c-KIT, MET, and transforming growth factor (TGF) beta. Investigation of somatic mutations, copy number alterations (CNA), and chromosomes in DSRCT samples suggests that deregulation of mesenchymal-epithelial reverse transition (MErT)/epithelial-mesenchymal transition (EMT) and DNA damage repair (DDR) may be important in DSRCT. This mini review looks at known druggable targets in DSRCT and existing clinical evidence for targeted treatments, particularly multityrosine kinase inhibitors such as pazopanib, imatinib, and sorafenib alone or in combination with other agents such as mTOR (mammalian target of rapamycin) inhibitors. The aim is to increase shared knowledge about current available treatments and identify gaps in research to further efforts toward clinical development of targeted agents..
Ferrari, A.
Merks, J.H.
Chisholm, J.C.
Orbach, D.
Brennan, B.
Gallego, S.
van Noesel, M.M.
McHugh, K.
van Rijn, R.R.
Gaze, M.N.
Martelli, H.
Bergeron, C.
Corradini, N.
Minard-Colin, V.
Bisogno, G.
Geoerger, B.
Caron, H.N.
De Salvo, G.L.
Casanova, M.
(2020). Outcomes of metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) treated within the BERNIE study: a randomised, phase II study evaluating the addition of bevacizumab to chemotherapy. European journal of cancer,
Vol.130,
pp. 72-80.
Amoroso, L.
Castel, V.
Bisogno, G.
Casanova, M.
Marquez-Vega, C.
Chisholm, J.C.
Doz, F.
Moreno, L.
Ruggiero, A.
Gerber, N.U.
Fagioli, F.
Hingorani, P.
Melcón, S.G.
Slepetis, R.
Chen, N.
le Bruchec, Y.
Simcock, M.
Vassal, G.
(2020). Phase II results from a phase I/II study to assess the safety and efficacy of weekly nab-paclitaxel in paediatric patients with recurrent or refractory solid tumours: A collaboration with the European Innovative Therapies for Children with Cancer Network. European journal of cancer,
Vol.135,
pp. 89-97.
Bate, J.
Borrow, R.
Chisholm, J.
Clarke, S.C.
Dixon, E.
Faust, S.N.
Galanopoulou, A.
Goldblatt, D.
Heath, P.T.
Maishman, T.
Mapstone, S.
Patel, S.R.
Williams, A.P.
Gray, J.C.
(2020). Thirteen-Valent Pneumococcal Conjugate Vaccine in Children With Acute Lymphoblastic Leukemia: Protective Immunity Can Be Achieved on Completion of Treatment. Clinical infectious diseases,
Vol.71
(5),
pp. 1271-1280.
show abstract
Abstract
Background
Children with acute lymphoblastic leukemia (ALL) are at increased risk of developing invasive pneumococcal disease. This study describes the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13) during and after chemotherapy.
Methods
Children with ALL were allocated to study groups and received a single dose of PCV13: group 1, maintenance chemotherapy; group 2, end of chemotherapy; group 3, 6 months after chemotherapy. A protective vaccine response was defined as at least 10 of 12 serotypes (or >83% of serotypes with data) achieving postvaccination serotype-specific immunoglobulin G ≥0.35 µg/mL and ≥4-fold rise, compared to prevaccination at 1 and 12 months.
Results
One hundred eighteen children were recruited. Only 12.8% (5/39; 95% confidence interval [CI], 4.3%–27.4%) of patients vaccinated during maintenance (group 1) achieved a protective response at 1 month postvaccination and none had a protective response at 12 months. For group 2 patients, 59.5% (22/37; 95% CI, 42.1%–75.3%) achieved a response at 1 month and 37.9% (11/29; 95% CI, 20.7%–57.7%) maintained immunity at 12 months. For group 3 patients, 56.8% (21/37; 95% CI, 39.5%–72.9%) achieved a protective response at 1 month and 43.3% (13/30; 95% CI, 25.5%–62.6%) maintained immunity at 12 months.
Conclusions
This study demonstrated that the earliest time point at which protective immunity can be achieved in children with ALL is on completion of chemotherapy. This is earlier than current recommendations and may improve protection during a period when children are most susceptible to infection.
Clinical Trials Registration
EudraCT 2009-011587-11.
.
Bernauer, C.
Man, Y.K.
Chisholm, J.C.
Lepicard, E.Y.
Robinson, S.P.
Shipley, J.M.
(2020). Hypoxia and its therapeutic possibilities in paediatric cancers. British journal of cancer,
.
show abstract
In tumours, hypoxia-a condition in which the demand for oxygen is higher than its availability-is well known to be associated with reduced sensitivity to radiotherapy and chemotherapy, and with immunosuppression. The consequences of hypoxia on tumour biology and patient outcomes have therefore led to the investigation of strategies that can alleviate hypoxia in cancer cells, with the aim of sensitising cells to treatments. An alternative therapeutic approach involves the design of prodrugs that are activated by hypoxic cells. Increasing evidence indicates that hypoxia is not just clinically significant in adult cancers but also in paediatric cancers. We evaluate relevant methods to assess the levels and extent of hypoxia in childhood cancers, including novel imaging strategies such as oxygen-enhanced magnetic resonance imaging (MRI). Preclinical and clinical evidence largely supports the use of hypoxia-targeting drugs in children, and we describe the critical need to identify robust predictive biomarkers for the use of such drugs in future paediatric clinical trials. Ultimately, a more personalised approach to treatment that includes targeting hypoxic tumour cells might improve outcomes in subgroups of paediatric cancer patients..
Bate, J.
Baker, S.
Breuer, J.
Chisholm, J.C.
Gray, J.
Hambleton, S.
Houlton, A.
Jit, M.
Lowis, S.
Makin, G.
O’Sullivan, C.
Patel, S.R.
Phillips, R.
Ransinghe, N.
Ramsay, M.E.
Skinner, R.
Wheatley, K.
Heath, P.T.
(2019). PEPtalk2: results of a pilot randomised controlled trial to compare VZIG and aciclovir as postexposure prophylaxis (PEP) against chickenpox in children with cancer. Archives of disease in childhood,
Vol.104
(1),
pp. 25-29.
show abstract
ObjectiveTo determine the likely rate of patient randomisation and to facilitate sample size calculation for a full-scale phase III trial of varicella zoster immunoglobulin (VZIG) and aciclovir as postexposure prophylaxis against chickenpox in children with cancer.DesignMulticentre pilot randomised controlled trial of VZIG and oral aciclovir.SettingEngland, UK.PatientsChildren under 16 years of age with a diagnosis of cancer: currently or within 6 months of receiving cancer treatment and with negative varicella zoster virus (VZV) serostatus at diagnosis or within the last 3 months.InterventionsStudy participants who have a significant VZV exposure were randomised to receive PEP in the form of VZIG or aciclovir after the exposure.Main outcome measuresNumber of patients registered and randomised within 12 months of the trial opening to recruitment and incidence of breakthrough varicella.ResultsThe study opened in six sites over a 13-month period. 482 patients were screened for eligibility, 32 patients were registered and 3 patients were randomised following VZV exposure. All three were randomised to receive aciclovir and there were no cases of breakthrough varicella.ConclusionsGiven the limited recruitment to the PEPtalk2 pilot, it is unlikely that the necessary sample size would be achievable using this strategy in a full-scale trial. The study identified factors that could be used to modify the design of a definitive trial but other options for defining the best means to protect such children against VZV should be explored.Trial registration numberISRCTN48257441, EudraCT number: 2013-001332-22, sponsor: University of Birmingham..
Masters, E.
Weston, C.
Chisholm, J.
Soanes, L.
(2019). Role of the Advanced Nurse Practitioner Within Teenage and Young Adult Oncology What is the Impact on Patient and Staff Experience of a New Nurse Practitioner Role to a Teenage and Young Adult Service?. Journal of adolescent and young adult oncology,
Vol.8
(6),
pp. 668-673.
Gatz, S.A.
Aladowicz, E.
Casanova, M.
Chisholm, J.C.
Kearns, P.R.
Fulda, S.
Geoerger, B.
Schäfer, B.W.
Shipley, J.M.
(2019). A Perspective on Polo-Like Kinase-1 Inhibition for the Treatment of Rhabdomyosarcomas. Frontiers in oncology,
Vol.9,
pp. 1271-?.
show abstract
Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers..
Vaarwerk, B.
Schoot, R.A.
Maurice-Stam, H.
Slater, O.
Hartley, B.
Saeed, P.
Gajdosova, E.
van den Brekel, M.W.
Balm, A.J.
Hol, M.L.
van Jaarsveld, S.
Kremer, L.C.
Ronckers, C.M.
Mandeville, H.C.
Pieters, B.R.
Gaze, M.N.
Davila Fajardo, R.
Strackee, S.D.
Dunaway, D.
Smeele, L.E.
Chisholm, J.C.
Caron, H.N.
Grootenhuis, M.A.
Merks, J.H.
(2019). Psychosocial well-being of long-term survivors of pediatric head-neck rhabdomyosarcoma. Pediatric blood & cancer,
Vol.66
(2),
pp. e27498-e27498.
Roy Moulik, N.
Vaidya, S.
Mandeville, H.
Chisholm, J.C.
(2019). Managing peritoneal involvement in children and young people with rhabdomyosarcoma: A single‐center experience from the United Kingdom. Pediatric blood & cancer,
Vol.66
(9).
Bisogno, G.
De Salvo, G.L.
Bergeron, C.
Gallego Melcón, S.
Merks, J.H.
Kelsey, A.
Martelli, H.
Minard-Colin, V.
Orbach, D.
Glosli, H.
Chisholm, J.
Casanova, M.
Zanetti, I.
Devalck, C.
Ben-Arush, M.
Mudry, P.
Ferman, S.
Jenney, M.
Ferrari, A.
European paediatric Soft tissue sarcoma Study Group,
(2019). Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial. The lancet. oncology,
Vol.20
(11),
pp. 1566-1575.
show abstract
Background For more than three decades, standard treatment for rhabdomyosarcoma in Europe has included 6 months of chemotherapy. The European paediatric Soft tissue sarcoma Study Group (EpSSG) aimed to investigate whether prolonging treatment with maintenance chemotherapy would improve survival in patients with high-risk rhabdomyosarcoma.Methods RMS 2005 was a multicentre, open-label, randomised, controlled, phase 3 trial done at 102 hospitals in 14 countries. We included patients aged 6 months to 21 years with rhabdomyosarcoma who were considered to be at high risk of relapse: those with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring at unfavourable sites with unfavourable age (≥10 years) or tumour size (>5 cm), or both; those with any non-metastatic rhabdomyosarcoma with nodal involvement; and those with non-metastatic alveolar rhabdomyosarcoma but without nodal involvement. Patients in remission after standard treatment (nine cycles of ifosfamide, vincristine, dactinomycin with or without doxorubicin, and surgery or radiotherapy, or both) were randomly assigned (1:1) to stop treatment or continue maintenance chemotherapy (six cycles of intravenous vinorelbine 25 mg/m 2 on days 1, 8, and 15, and daily oral cyclophosphamide 25 mg/m 2 , on days 1-28). Randomisation was done by use of a web-based system and was stratified (block size of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary outcome was disease-free survival in the intention-to-treat population. Secondary outcomes were overall survival and toxicity. This trial is registered with EudraCT, number 2005-000217-35, and ClinicalTrials.gov, number NCT00339118, and follow-up is ongoing.Findings Between April 20, 2006, and Dec 21, 2016, 371 patients were enrolled and randomly assigned to the two groups: 186 to stop treatment and 185 to receive maintenance chemotherapy. Median follow-up was 60·3 months (IQR 32·4-89·4). In the intention-to-treat population, 5-year disease-free survival was 77·6% (95% CI 70·6-83·2) with maintenance chemotherapy versus 69·8% (62·2-76·2) without maintenance chemotherapy (hazard ratio [HR] 0·68 [95% CI 0·45-1·02]; p=0·061), and 5-year overall survival was 86·5% (95% CI 80·2-90·9) with maintenance chemotherapy versus 73·7% (65·8-80·1) without (HR 0·52 [95% CI 0·32-0·86]; p=0·0097). Toxicity was manageable in patients who received maintenance chemotherapy: 136 (75%) of 181 patients had grade 3-4 leucopenia, 148 (82%) had grade 3-4 neutropenia, 19 (10%) had anaemia, two (1%) had thrombocytopenia, and 56 (31%) had an infection. One (1%) patient had a grade 4 non-haematological toxicity (neurotoxicity). Two treatment-related serious adverse events occurred: one case of inappropriate antidiuretic hormone secretion and one of a severe steppage gait with limb pain, both of which resolved.Interpretation Adding maintenance chemotherapy seems to improve survival for patients with high-risk rhabdomyosarcoma. This approach will be the new standard of care for patients with high-risk rhabdomyosarcoma in future EpSSG trials.Funding Fondazione Città della Speranza, Association Léon Berard Enfant Cancéreux, Clinical Research Hospital Program (French Ministry of Health), and Cancer Research UK..
George, S.L.
Izquierdo, E.
Campbell, J.
Koutroumanidou, E.
Proszek, P.
Jamal, S.
Hughes, D.
Yuan, L.
Marshall, L.V.
Carceller, F.
Chisholm, J.C.
Vaidya, S.
Mandeville, H.
Angelini, P.
Wasti, A.
Bexelius, T.
Thway, K.
Gatz, S.A.
Clarke, M.
Al-Lazikani, B.
Barone, G.
Anderson, J.
Tweddle, D.A.
Gonzalez, D.
Walker, B.A.
Barton, J.
Depani, S.
Eze, J.
Ahmed, S.W.
Moreno, L.
Pearson, A.
Shipley, J.
Jones, C.
Hargrave, D.
Jacques, T.S.
Hubank, M.
Chesler, L.
(2019). A tailored molecular profiling programme for children with cancer to identify clinically actionable genetic alterations. European journal of cancer (oxford, england : 1990),
Vol.121,
pp. 224-235.
show abstract
BACKGROUND:For children with cancer, the clinical integration of precision medicine to enable predictive biomarker-based therapeutic stratification is urgently needed. METHODS:We have developed a hybrid-capture next-generation sequencing (NGS) panel, specifically designed to detect genetic alterations in paediatric solid tumours, which gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. In this study, we offered an NGS panel, with clinical reporting via a molecular tumour board for children with solid tumours. Furthermore, for a cohort of 12 patients, we used a circulating tumour DNA (ctDNA)-specific panel to sequence ctDNA from matched plasma samples and compared plasma and tumour findings. RESULTS:A total of 255 samples were submitted from 223 patients for the NGS panel. Using FFPE tissue, 82% of all submitted samples passed quality control for clinical reporting. At least one genetic alteration was detected in 70% of sequenced samples. The overall detection rate of clinically actionable alterations, defined by modified OncoKB criteria, for all sequenced samples was 51%. A total of 8 patients were sequenced at different stages of treatment. In 6 of these, there were differences in the genetic alterations detected between time points. Sequencing of matched ctDNA in a cohort of extracranial paediatric solid tumours also identified a high detection rate of somatic alterations in plasma. CONCLUSION:We demonstrate that tailored clinical molecular profiling of both tumour DNA and plasma-derived ctDNA is feasible for children with solid tumours. Furthermore, we show that a targeted NGS panel-based approach can identify actionable genetic alterations in a high proportion of patients..
Vaarwerk, B.
Bisogno, G.
McHugh, K.
Brisse, H.J.
Morosi, C.
Corradini, N.
Jenney, M.
Orbach, D.
Chisholm, J.C.
Ferrari, A.
Zanetti, I.
De Salvo, G.L.
van Rijn, R.R.
Merks, J.H.
(2019). Indeterminate Pulmonary Nodules at Diagnosis in Rhabdomyosarcoma: Are They Clinically Significant? A Report From the European Paediatric Soft Tissue Sarcoma Study Group. Journal of clinical oncology,
Vol.37
(9),
pp. 723-730.
show abstract
Purpose To evaluate the clinical significance of indeterminate pulmonary nodules at diagnosis (defined as ≤ 4 pulmonary nodules < 5 mm or 1 nodule measuring ≥ 5 and < 10 mm) in patients with pediatric rhabdomyosarcoma (RMS). Patients and Methods We selected patients with supposed nonmetastatic RMS treated in large pediatric oncology centers in the United Kingdom, France, Italy, and the Netherlands, who were enrolled in the European Soft Tissue Sarcoma Study Group (E pSSG) RMS 2005 study. Patients included in the current study received a diagnosis between September 2005 and December 2013, and had chest computed tomography scans available for review that were done at time of diagnosis. Local radiologists were asked to review the chest computed tomography scans for the presence of pulmonary nodules and to record their findings on a standardized case report form. In the E pSSG RMS 2005 Study, patients with indeterminate pulmonary nodules were treated identically to patients without pulmonary nodules, enabling us to compare event-free survival and overall survival between groups by log-rank test. Results In total, 316 patients were included; 67 patients (21.2%) had indeterminate pulmonary nodules on imaging and 249 patients (78.8%) had no pulmonary nodules evident at diagnosis. Median follow-up for survivors (n = 258) was 75.1 months; respective 5-year event-free survival and overall survival rates (95% CI) were 77.0% (64.8% to 85.5%) and 82.0% (69.7% to 89.6%) for patients with indeterminate nodules and 73.2% (67.1% to 78.3%) and 80.8% (75.1% to 85.3%) for patients without nodules at diagnosis ( P = .68 and .76, respectively). Conclusion Our study demonstrated that indeterminate pulmonary nodules at diagnosis do not affect outcome in patients with otherwise localized RMS. There is no need to biopsy or upstage patients with RMS who have indeterminate pulmonary nodules at diagnosis. .
Vaarwerk, B.
van der Lee, J.H.
Breunis, W.B.
Orbach, D.
Chisholm, J.C.
Cozic, N.
Jenney, M.
van Rijn, R.R.
McHugh, K.
Gallego, S.
Glosli, H.
Devalck, C.
Gaze, M.N.
Kelsey, A.
Bergeron, C.
Stevens, M.C.
Oberlin, O.
Minard-Colin, V.
Merks, J.H.
(2018). Prognostic relevance of early radiologic response to induction chemotherapy in pediatric rhabdomyosarcoma: A report from the International Society of Pediatric Oncology Malignant Mesenchymal Tumor 95 study. Cancer,
Vol.124
(5),
pp. 1016-1024.
Chisholm, J.C.
Suvada, J.
Dunkel, I.J.
Casanova, M.
Zhang, W.
Ritchie, N.
Choi, Y.
Park, J.
Das Thakur, M.
Simko, S.
Wan Rachel Tam, N.
Ferrari, A.
(2018). BRIM-P: A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF
mutation-positive melanoma. Pediatric blood & cancer,
Vol.65
(5),
pp. e26947-e26947.
Gallego, S.
Zanetti, I.
Orbach, D.
Ranchère, D.
Shipley, J.
Zin, A.
Bergeron, C.
de Salvo, G.L.
Chisholm, J.
Ferrari, A.
Jenney, M.
Mandeville, H.C.
Rogers, T.
Merks, J.H.
Mudry, P.
Glosli, H.
Milano, G.M.
Ferman, S.
Bisogno, G.
(2018). Fusion status in patients with lymph node‐positive (N1) alveolar rhabdomyosarcoma is a powerful predictor of prognosis: Experience of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG). Cancer,
Vol.124
(15),
pp. 3201-3209.
Bisogno, G.
Jenney, M.
Bergeron, C.
Gallego Melcón, S.
Ferrari, A.
Oberlin, O.
Carli, M.
Stevens, M.
Kelsey, A.
De Paoli, A.
Gaze, M.N.
Martelli, H.
Devalck, C.
Merks, J.H.
Ben-Arush, M.
Glosli, H.
Chisholm, J.
Orbach, D.
Minard-Colin, V.
De Salvo, G.L.
European paediatric Soft tissue sarcoma Study Group,
(2018). Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): a multicentre, open-label, randomised controlled, phase 3 trial. The lancet. oncology,
Vol.19
(8),
pp. 1061-1071.
show abstract
Background Rhabdomyosarcoma is an aggressive tumour that can develop in almost any part of the body. Doxorubicin is an effective drug against rhabdomyosarcoma, but its role in combination with an established multidrug regimen remains controversial. Therefore, we aimed to evaluate the possible benefit of early dose intensification with doxorubicin in patients with non-metastatic rhabdomyosarcoma.Methods We did a multicentre, open-label, randomised controlled, phase 3 trial involving 108 hospitals from 14 countries. We included patients older than 6 months but younger than 21 years with a pathologically proven diagnosis of rhabdomyosarcoma. We assigned each patient to a specific subgroup according to the EpSSG stratification system. Those with embryonal rhabdomyosarcoma incompletely resected and localised at unfavourable sites with or without nodal involvement, or those with alveolar rhabdomyosarcoma without nodal involvement were considered at high risk of relapse. These high-risk patients were randomly assigned (1:1) to receive either nine cycles of IVA (ifosfamide 3 g/m 2 given as a 3-h intravenous infusion on days 1 and 2, vincristine 1·5 mg/m 2 weekly during the first 7 weeks then only on day 1 of each cycle [given as a single intravenous injection], and dactinomycin 1·5 mg/m 2 on day 1 given as a single intravenous injection) or four cycles of IVA with doxorubicin 30 mg/m 2 given as a 4-h intravenous infusion on days 1 and 2 followed by five cycles of IVA. The interval between cycles was 3 weeks. Randomisation was done using a web-based system and was stratified (block sizes of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary endpoint was 3-year event-free survival assessed by the investigator at each centre in the intention-to-treat population. Patients who received at least one dose of study treatment were considered in the safety analysis. In agreement with the independent data monitoring committee, the study was closed to patient entry on Dec 16, 2013, after futility analysis. This trial is registered with EudraCT, number 2005-000217-35, and is currently in follow-up.Findings Between Oct 1, 2005, and Dec 16, 2013, 484 patients were randomly assigned to receive each chemotherapy regimen (242 in the IVA group and 242 in the IVA plus doxorubicin group). Median follow-up was 63·9 months (IQR 44·6-78·9). The 3-year event-free survival was 67·5% (95% CI 61·2-73·1) in the IVA plus doxorubicin group and 63·3% (56·8-69·0) in the IVA group (hazard ratio 0·87, 95% CI 0·65-1·16; p=0·33). Grade 3-4 leucopenia (232 [93%] of 249 patients in the IVA plus doxorubicin group vs 194 [85%] of 227 in the IVA group; p=0·0061), anaemia (195 [78%] vs 111 [49%]; p<0·0001), thrombocytopenia (168 [67%] vs 59 [26%]; p<0.0001), and gastrointestinal adverse events (78 [31%] vs 19 [8%]; p<0·0001) were significantly more common in the IVA plus doxorubicin group than in the IVA group. Grade 3-5 infections (198 [79%] vs 128 [56%]; p<0·0001) were also significantly more common in the IVA plus doxorubicin group than in the IVA group, in which one patient had grade 5 infection. Two treatment-related deaths were reported (one patient developed septic shock and one affected by Goldenhar syndrome developed intractable seizures) in the IVA plus doxorubicin group, both occurring after the first cycle of treatment, and none were reported in the IVA group.Interpretations The addition of dose-intensified doxorubicin to standard IVA chemotherapy did not show a significant improvement in the outcome of patients with high-risk non-metastatic rhabdomyosarcoma. Therefore, the IVA chemotherapy regimen should remain the standard of care for patients with localised rhabdomyosarcoma in Europe.Funding Fondazione Città della Speranza, Italy, and the Association Léon Berard Enfant Cancéreux, France..
Moreno, L.
Casanova, M.
Chisholm, J.C.
Berlanga, P.
Chastagner, P.B.
Baruchel, S.
Amoroso, L.
Gallego Melcón, S.
Gerber, N.U.
Bisogno, G.
Fagioli, F.
Geoerger, B.
Glade Bender, J.L.
Aerts, I.
Bergeron, C.
Hingorani, P.
Elias, I.
Simcock, M.
Ferrara, S.
Le Bruchec, Y.
Slepetis, R.
Chen, N.
Vassal, G.
(2018). Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer. European journal of cancer (oxford, england : 1990),
Vol.100,
pp. 27-34.
show abstract
Background nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported.Patients and methods Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m 2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).Results Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m 2 and grade 4 neutropenia >7 days at 270 mg/m 2 . The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m 2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m 2 . Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST.Conclusions nab-Paclitaxel 240 mg/m 2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103.Eudract 2013-000144-26..
Ali, A.
Mohamed, M.
Chisholm, J.
Thway, K.
(2017). Solid-Pattern Desmoplastic Small Round Cell Tumor. International journal of surgical pathology,
Vol.25
(2),
pp. 158-161.
show abstract
Desmoplastic small round cell tumor (DSRCT) is an aggressive small round cell sarcoma that typically occurs intra-abdominally in adolescents and young adults, and is characterized by a recurrent t(11;22)(p13;q12) translocation leading to generation of the EWSR1-WT1 fusion gene, which codes for a chimeric protein with transcriptional regulatory activity. DSRCT has a characteristic histologic appearance of nests of uniform small cells within prominent fibroblastic stroma and immunohistochemically it shows multidirectional differentiation, with expression of epithelial, neural, and muscle markers. We illustrate a case of DSRCT that presented as a large intra-abdominal mass, which harbored EWSR1 rearrangement by fluorescence in situ hybridization and EWSR1-WT1 fusion transcripts by reverse transcription-polymerase chain reaction (RT-PCR), and which histologically had an entirely solid morphology, lacking evidence of desmoplastic stroma. This purely solid variant emphasizes that even when occurring at a typical location, DSRCT may be difficult to recognize when lacking nonclassical morphology. This is of clinical relevance, as DSRCT with this pattern could be misdiagnosed as Ewing sarcoma if RT-PCR is not performed, with resulting prognostic and therapeutic implications..
Ferrari, A.
Trama, A.
De Paoli, A.
Bergeron, C.
Merks, J.H.
Jenney, M.
Orbach, D.
Chisholm, J.C.
Gallego, S.
Glosli, H.
De Salvo, G.L.
Botta, L.
Gatta, G.
Bisogno, G.
Grp, R.W.
(2017). Access to clinical trials for adolescents with soft tissue sarcomas: Enrollment in European pediatric Soft tissue sarcoma Study Group (EpSSG) protocols. Pediatric blood & cancer,
Vol.64
(6).
Ferrari, A.
Trama, A.
De Paoli, A.
Bergeron, C.
Merks, J.H.
Jenney, M.
Orbach, D.
Chisholm, J.C.
Gallego, S.
Glosli, H.
De Salvo, G.L.
Botta, L.
Gatta, G.
Bisogno, G.
RARECAREnet Working Group,
(2017). Access to clinical trials for adolescents with soft tissue sarcomas: Enrollment in European pediatric Soft tissue sarcoma Study Group (EpSSG) protocols. Pediatric blood & cancer,
Vol.64
(6).
show abstract
Background Adolescents with cancer are enrolled in clinical trials at far lower rates than children. This report compares the number of adolescents (15-19-year-olds) and children (0-14-year-olds) enrolled in the protocols of the European pediatric Soft tissue sarcoma Study Group (EpSSG) with the number of cases expected to occur.Methods The observed-to-expected (O/E) ratio was detected in the EpSSG countries contributing most of the cases, that is, Italy, France, Spain, the Netherlands, United Kingdom, and Ireland. The observed cases included patients enrolled in any of the EpSSG protocols from October 2008 to October 2015, when all EpSSG protocols were open in these countries. The number of expected cases was calculated from the incidence rates estimated throughout the RARECAREnet database in the countries' population-based cancer registries.Results In the countries considered, 2,118 cases aged 0-19 years were enrolled in the EpSSG trials from 2008 to 2015: 82.8% were children and 17.2% were adolescents. The O/E ratio was 0.30 among patients 15-19 years old, as opposed to 0.64 for those 0-14 years old. The O/E ratio differed for the different subtypes: in adolescents, it was 0.64 and 0.18 for rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), respectively; in children, it was 0.77 and 0.50, respectively. The O/E ratios differed across the countries considered.Conclusions Adolescents were less well represented than children on the EpSSG protocols, with better enrolment for RMS than for NRSTS for all age groups..
Selfe, J.
Olmos, D.
Al-Saadi, R.
Thway, K.
Chisholm, J.
Kelsey, A.
Shipley, J.
(2017). Impact of fusion gene status versus histology on risk-stratification for rhabdomyosarcoma: Retrospective analyses of patients on UK trials. Pediatric blood & cancer,
Vol.64
(7).
show abstract
Background Long-term toxicities from current treatments are a major issue in paediatric cancer. Previous studies, including our own, have shown prognostic value for the presence of PAX3/7-FOXO1 fusion genes in rhabdomyosarcoma (RMS). It is proposed to introduce PAX3/7-FOXO1 positivity as a component of risk stratification, rather than alveolar histology, in future clinical trials.Procedure To assess the potential impact of this reclassification, we have determined the changes to risk category assignment of 210 histologically reviewed patients treated in the UK from previous malignant mesenchymal tumour clinical trials for non-metastatic RMS based on identification of PAX3/7-FOXO1 by fluorescence in situ hybridisation and/or reverse transcription PCR.Results Using fusion gene positivity in the current risk stratification would reassign 7% of patients to different European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) risk groups. The next European trial would have 80% power to detect differences in event-free survival of 15% over 10 years and 20% over 5 years in reassigned patients. This would decrease treatment for over a quarter of patients with alveolar histology tumours that lack PAX3/7-FOXO1.Conclusions Fusion gene status used in stratification may result in significant numbers of patients benefitting from lower treatment-associated toxicity. Prospective testing to show this reassignment maintains current survival rates is now required and is shown to be feasible based on estimated recruitment to a future EpSSG trial. Together with developing novel therapeutic strategies for patients identified as higher risk, this may ultimately improve the outcome and quality of life for patients with RMS..
Chisholm, J.C.
Merks, J.H.
Casanova, M.
Bisogno, G.
Orbach, D.
Gentet, J.-.
Thomassin-Defachelles, A.-.
Chastagner, P.
Lowis, S.
Ronghe, M.
McHugh, K.
van Rijn, R.R.
Hilton, M.
Bachir, J.
Fürst-Recktenwald, S.
Geoerger, B.
Oberlin, O.
European paediatric Soft tissue sarcoma Study Group (EpSSG) and the European Innovative Therapies for Children with Cancer (ITCC) Consortium,
(2017). Open-label, multicentre, randomised, phase II study of the EpSSG and the ITCC evaluating the addition of bevacizumab to chemotherapy in childhood and adolescent patients with metastatic soft tissue sarcoma (the BERNIE study). European journal of cancer (oxford, england : 1990),
Vol.83,
pp. 177-184.
show abstract
Purpose We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or non-rhabdomyosarcoma 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 + five cycles of IVA, ±bevacizumab), surgery and/or radiotherapy, followed by maintenance chemotherapy (12 cycles of low-dose cyclophosphamide + vinorelbine, ±bevacizumab). 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 = 80) or with bevacizumab (n = 74). At the data cut-off for the primary efficacy analysis, median EFS was 14.9 months (95% confidence interval [CI]: 10.8-35.9) with chemotherapy and 20.6 months (95% CI: 15.2-24.9) with bevacizumab plus chemotherapy (stratified hazard ratio [HR] = 0.93; 95% CI: 0.61-1.41; P = 0.72). The HR for EFS in patients with RMS (n = 103) was 1.24 (95% CI: 0.73-2.09) versus 0.64 (95% CI: 0.32-1.26) for those with NRSTS (n = 49). Objective response rate was 36.0% (95% CI: 25.2-47.9) with chemotherapy and 54.0% (95% CI: 40.9-66.6) with bevacizumab plus chemotherapy (difference of 18.0%; 95% CI: 0.6-35.3). 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..
Kieran, M.W.
Chisholm, J.
Casanova, M.
Brandes, A.A.
Aerts, I.
Bouffet, E.
Bailey, S.
Leary, S.
MacDonald, T.J.
Mechinaud, F.
Cohen, K.J.
Riccardi, R.
Mason, W.
Hargrave, D.
Kalambakas, S.
Deshpande, P.
Tai, F.
Hurh, E.
Geoerger, B.
(2017). Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma. Neuro-oncology,
Vol.19
(11),
pp. 1542-1552.
show abstract
Background Sonidegib (LDE225) is a potent, selective hedgehog (Hh) inhibitor of Smoothened. This study explored the safety and pharmacokinetics of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response.Methods Pediatric patients aged ≥1 to <18 years were included according to a Bayesian design starting at 372 mg/m2 of continuous once daily oral sonidegib. Tumor samples were analyzed for Hh pathway activation using a validated 5-gene Hh signature assay. In phase II, pediatric patients were treated at the recommended phase II dose (RP2D) while adults received 800 mg daily.Results Sixteen adult (16 MB) and 60 pediatric (39 MB, 21 other) patients with an age range of 2-17 years were enrolled. The RP2D of sonidegib in pediatric patients was established at 680 mg/m2 once daily. The phase II study was closed prematurely. The 5-gene Hh signature assay showed that the 4 complete responders (2 pediatric and 2 adult) and 1 partial responder (adult) all had Hh-activated tumors, while 5 patients with activated Hh had either stable disease (n = 3) or progressive disease (n = 2). No patient with an Hh-negative signature (n = 50) responded. The safety profile for pediatric patients was generally consistent with the one established for adult patients; however, growth plate changes were observed in prepubertal pediatric patients.Conclusions Sonidegib was well tolerated and the RP2D in pediatric patients was 680 mg/m2 once daily. Five of the 10 MB patients with activated Hh pathway demonstrated complete or partial responses..
Clement, S.C.
Schoot, R.A.
Slater, O.
Chisholm, J.C.
Abela, C.
Balm, A.J.
van den Brekel, M.W.
Breunis, W.B.
Chang, Y.C.
Davila Fajardo, R.
Dunaway, D.
Gajdosova, E.
Gaze, M.N.
Gupta, S.
Hartley, B.
Kremer, L.C.
van Lennep, M.
Levitt, G.A.
Mandeville, H.C.
Pieters, B.R.
Saeed, P.
Smeele, L.E.
Strackee, S.D.
Ronckers, C.M.
Caron, H.N.
van Santen, H.M.
Merks, J.H.
(2016). Endocrine disorders among long-term survivors of childhood head and neck rhabdomyosarcoma. European journal of cancer,
Vol.54,
pp. 1-10.
Veal, G.J.
Errington, J.
Sastry, J.
Chisholm, J.
Brock, P.
Morgenstern, D.
Pritchard-Jones, K.
Chowdhury, T.
(2016). Adaptive dosing of anticancer drugs in neonates: facilitating evidence-based dosing regimens. Cancer chemotherapy and pharmacology,
Vol.77
(4),
pp. 685-692.
Herd, F.
Bate, J.
Chisholm, J.
Johnson, E.
Phillips, B.
(2016). Variation in practice remains in the UK management of paediatric febrile neutropenia. Archives of disease in childhood,
Vol.101
(4),
pp. 410-411.
Carceller, F.
Bautista, F.J.
Fowkes, L.A.
Marshall, L.V.
Sirvent, S.I.
Chisholm, J.C.
Pearson, A.D.
Koh, D.-.
Moreno, L.
(2016). Response Assessment in Paediatric Phase I Trials According to RECIST Guidelines: Survival Outcomes, Patterns of Progression and Relevance of Changes in Tumour Measurements. Pediatric blood & cancer,
Vol.63
(8),
pp. 1400-1406.
Phillips, R.S.
Sung, L.
Amman, R.A.
Riley, R.D.
Castagnola, E.
Haeusler, G.M.
Klaassen, R.
Tissing, W.J.
Lehrnbecher, T.
Chisholm, J.
Hakim, H.
Ranasinghe, N.
Paesmans, M.
Hann, I.M.
Stewart, L.A.
(2016). Predicting microbiologically defined infection in febrile neutropenic episodes in children: global individual participant data multivariable meta-analysis. British journal of cancer,
Vol.114
(6),
pp. 623-630.
Thway, K.
Chisholm, J.
Hayes, A.
Swansbury, J.
Fisher, C.
(2015). Pediatric low-grade fibromyxoid sarcoma mimicking ossifying fibromyxoid tumor: adding to the diagnostic spectrum of soft tissue tumors with a bony shell. Hum pathol,
Vol.46
(3),
pp. 461-466.
show abstract
We describe a case of superficial low-grade fibromyxoid sarcoma (LGFMS) in a 12-year-old boy, confirmed by the detection of FUS-CREB3L2 fusion transcripts by reverse-transcription polymerase chain reaction and FUS rearrangement with fluorescence in situ hybridization, which had morphological features similar to ossifying fibromyxoid tumor (OFMT), including an almost complete rim of mature, metaplastic bone. LGFMS and OFMT can appear morphologically similar, with bland ovoid cells within a fibrous to myxoid matrix. Both can occur superficially; and whereas MUC4 immunoreactivity is characteristic of LGFMS, this can also be seen in some OFMTs. As the morphological spectrum of LGFMS is wide, we highlight the potential for diagnostic confusion with OFMT, which is clinically pertinent as most OFMTs behave in a benign manner whereas LGFMS is a malignant neoplasm with a propensity for local recurrence and a significant metastatic rate. .
Schoot, R.A.
Slater, O.
Ronckers, C.M.
Zwinderman, A.H.
Balm, A.J.
Hartley, B.
van den Brekel, M.W.
Gupta, S.
Saeed, P.
Gajdosova, E.
Pieters, B.R.
Gaze, M.N.
Mandeville, H.C.
Fajardo, R.D.
Chang, Y.C.
Gains, J.E.
Strackee, S.D.
Dunaway, D.
Abela, C.
Mason, C.
Smeele, L.E.
Chisholm, J.C.
Levitt, G.A.
Kremer, L.C.
Grootenhuis, M.A.
Maurice-Stam, H.
Stiller, C.A.
Hammond, P.
Caron, H.N.
Merks, J.H.
(2015). Adverse events of local treatment in long-term head and neck rhabdomyosarcoma survivors after external beam radiotherapy or AMORE treatment. European journal of cancer,
Vol.51
(11),
pp. 1424-1434.
Norman, G.
Fayter, D.
Lewis-Light, K.
Chisholm, J.
McHugh, K.
Levine, D.
Jenney, M.
Mandeville, H.
Gatz, S.
Phillips, B.
(2015). An emerging evidence base for PET-CT in the management of childhood rhabdomyosarcoma: systematic review. Bmj open,
Vol.5
(1),
p. e006030.
show abstract
INTRODUCTION: Rhabdomyosarcoma (RMS) management depends on risk stratification at diagnosis and treatment response. Assessment methods include CT, MRI, bone scintigraphy, histological analysis and bone marrow biopsy. Advanced functional imaging (FI) has potential to improve staging accuracy and management strategies. METHODS AND ANALYSIS: We conducted a systematic review (PROSPERO 2013:CRD42013006128) of diagnostic accuracy and clinical effectiveness of FI in histologically proven paediatric RMS. PRISMA guidance was followed. We searched 10 databases to November 2013. Studies with ≥10 patients with RMS which compared positron emission tomography (PET), PET-CT or diffusion-weighted imaging (DWI) MRI to conventional imaging at any treatment stage were included. Study quality was assessed. Limited, heterogeneous effectiveness data required narrative synthesis, illustrated by plotting sensitivity and specificity in receiver operating curve (ROC) space. RESULTS: Eight studies (six PET-CT, two PET) with 272 RMS patients in total were included. No DWI-MRI studies met inclusion criteria. Pooled estimates were not calculated due to sparseness of data. Limited evidence indicated initial PET-CT results were predictive of survival. PET-CT changed management of 7/40 patients. Nodal involvement PET-CT: sensitivity ranged from 80% to 100%; specificity from 89% to 100%. Distant metastatic involvement: PET-CT sensitivity ranged from 95% to 100%; specificity from 80% to100%. Data on metastases in different sites were sparse. Limited data were found on outcome prediction by PET-CT response. DISSEMINATION AND ETHICS: PET/PET-CT may increase initial staging accuracy in paediatric RMS, specifically in the detection of nodal involvement and distant metastatic spread. There is a need to further assess PET-CT for this population, ideally in a representative, unbiased and transparently selected cohort of patients..
Gatz, S.A.
Thway, K.
Mandeville, H.
Kerawala, C.
MacVicar, D.
Chisholm, J.
(2015). Chemotherapy responsiveness in a patient with multiply relapsed ameloblastic fibro‐odontosarcoma of the maxilla. Pediatric blood & cancer,
Vol.62
(11),
pp. 2029-2032.
Morgenstern, D.A.
Hargrave, D.
Marshall, L.V.
Gatz, S.A.
Barone, G.
Crowe, T.
Pritchard-Jones, K.
Zacharoulis, S.
Lancaster, D.L.
Vaidya, S.J.
Chisholm, J.C.
Pearson, A.D.
Moreno, L.
(2014). Toxicity and outcome of children and adolescents participating in phase I/II trials of novel anticancer drugs: the Royal Marsden experience. J pediatr hematol oncol,
Vol.36
(3),
pp. 218-223.
show abstract
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. .
Calton, E.A.
Le Doare, K.
Appleby, G.
Chisholm, J.C.
Sharland, M.
Ladhani, S.N.
Participants, C.A.
(2014). Invasive Bacterial and Fungal Infections in Paediatric Patients with Cancer: Incidence, Risk Factors, Aetiology and Outcomes in aUK Regional Cohort 2009-2011. Pediatric blood & cancer,
Vol.61
(7),
pp. 1239-1245.
Schoot, R.A.
Slater, O.
Ronckers, C.M.
Zwinderman, A.H.
Balm, A.J.
Hartley, B.
van de Brekel, M.
Gupta, S.
Saeed, P.
Gajdosova, E.
Pieters, B.R.
Gaze, M.N.
Mandeville, H.C.
Fajardo, R.D.
Chang, Y.-.
Strackee, S.D.
Dunaway, D.
Abela, C.
Mason, C.
Smeele, L.E.
Chisholm, J.C.
Levitt, G.
Kremer, L.C.
Grootenhuis, M.A.
Maurice-Stam, H.
Stiller, C.A.
Hammond, P.
Caron, H.N.
Merks, J.H.
(2014). ADVERSE EVENTS OF LOCAL TREATMENT IN HEAD AND NECK RHABDOMYOSARCOMA SURVIVORS AFTER EXTERNAL BEAM RADIOTHERAPY OR AMORE TREATMENT. Pediatric blood & cancer,
Vol.61,
pp. S311-S311.
Norman, G.
Fayter, D.
Light-Lewis, K.
Chisholm, J.
Mandeville, H.
Gatz, S.
Levine, D.
Jenney, M.
McHugh, K.
Phillips, B.
(2014). THE ROLE OF PET-CT IN THE MANAGEMENT OF CHILDHOOD RHABDOMYOSARCOMA: SYSTEMATIC REVIEW. Pediatric blood & cancer,
Vol.61,
pp. S133-S133.
Bisogno, G.
De Salvo, G.L.
Bergeron, C.
Carli, M.
Ferrari, A.
Jenney, M.
Mercks, H.
Kelsey, A.
Gallego, S.
Chisholm, J.
Orbach, D.
Martelli, H.
Oberlin, O.
Stevens, M.
(2014). THE ROLE OF DOXORUBICIN IN THE TREATMENT OF RHABDOMYOSARCOMA: PRELIMINARY RESULTS FROM THE EPSSG RMS2005 RANDOMIZED TRIAL. Pediatric blood & cancer,
Vol.61,
pp. S133-S134.
Dommett, R.
Chisholm, J.
Turner, M.
Bajaj-Elliott, M.
Klein, N.J.
(2013). Mannose-binding lectin genotype influences frequency and duration of infectious complications in children with malignancy. J pediatr hematol oncol,
Vol.35
(1),
pp. 69-75.
show abstract
Children with cancer receiving identical treatment differ in their experience of infection, suggesting that variations in immunity may influence susceptibility to infection. Studies of the influence of mannose-binding lectin (MBL), an important component of the innate immune system, in children with febrile neutropenia (FN) have yielded conflicting results. We examined the role of MBL in infection susceptibility in the largest cohort of children with cancer reported to date. MBL levels were measured and genotyping performed on children (≤16 y) receiving chemotherapy for cancer in London, UK. Clinical data from FN episodes were recorded prospectively. MBL status was assessed in 269 children; 513 episodes of FN were captured from 211 patients. Patients with MBL2 polymorphisms experienced more FN episodes than wildtype genotype (median 2 vs. 1, respectively; P = 0.074) and more episodes with documented infection (P = 0.045). Patients experiencing multiple FN episodes had lower MBL levels (P = 0.036). MBL genotype influenced duration of episode in some groups: high-risk MBL-deficient patients spent up to 5 nights longer/episode in hospital than equivalent wildtypes. These results indicate that MBL deficiency influences both susceptibility to and outcome of FN episodes and may be most important in those patients at higher risk of complications of FN..
Bate, J.
Gibson, F.
Selwood, K.
Skinner, R.
Phillips, B.
Chisholm, J.C.
(2013). A reaudit of current febrile neutropenia practice in UK paediatric oncology centres prior to implementation of NICE guidance. Archives of disease in childhood,
Vol.98
(4),
pp. 315-316.
Bate, J.
Gibson, F.
Johnson, E.
Selwood, K.
Skinner, R.
Chisholm, J.
(2013). Neutropenic sepsis: prevention and management of neutropenic sepsis in cancer patients (NICE Clinical Guideline CG151). Archives of disease in childhood-education and practice edition,
Vol.98
(2),
pp. 73-75.
Gibson, F.
Chisholm, J.
Blandford, E.
Donachie, P.
Hartley, J.
Lane, S.
Selwood, K.
Skinner, R.
Phillips, R.
CCLG Supportive Care Group,
(2013). Developing a national 'low risk' febrile neutropenia framework for use in children and young people's cancer care. Support care cancer,
Vol.21
(5),
pp. 1241-1251.
show abstract
PURPOSE: A Delphi study was undertaken to develop a framework guidance that would rationalise and standardise the care of children with febrile neutropenia (FNP) across the UK. METHODS: A mailed Delphi survey was undertaken with health professionals working in children's cancer units. The survey employed two rounds of feedback on 22 practice statements drawn from a systematic review of clinical evidence. Consensus was assumed for any statement where 80+ % of respondents indicated that they "agreed" or "strongly agreed". RESULTS: Consensus was reached on 21 of the 22 practice statements in round 1 that were categorised into six areas: definition of fever and neutropenia, initial management and choice of antibiotic, defining low-risk patients, strategy in low-risk patients and alternative approaches. Consensus could not be reached on whether patients needed to be afebrile to be suitable for discharge and the required length of outpatient antibiotic treatment. CONCLUSIONS: A Delphi survey allowed the successful development of a national framework for identification and management of children with FNP. The use of an existing well-functioning professional network was key in this project's success..
Rousseau, R.
Geoerger, B.
Chisholm, J.
Casanova, M.
Merks, J.
Monnet, A.
Dhalluin, C.
Oberlin, O.
(2013). THE BERNIE STUDY: A PHASE II STUDY EVALUATING ADDITION OF BEVACIZUMAB TO CHEMOTHERAPY IN CHILDREN AND ADOLESCENTS WITH METASTATIC RHABDOMYOSARCOMA AND NON-RHABDOMYOSARCOMA SOFT TISSUE SARCOMA. Pediatric blood & cancer,
Vol.60,
pp. 92-92.
Orbach, D.
Mosseri, V.
Stevens, M.
Rey, A.
Gallelo, S.
Kelsey, A.
Christine, D.
Brenann, B.
Van Noesel, M.
Gaze, M.
Minard-Collin, V.
Merks, H.
Bergeron, C.
Rechnitzer, C.
Jenney, M.
Chisholm, J.
Scopinaro, M.
Martelli, H.
Oberlin, O.
(2013). NON PARAMENINGEAL HEAD-AND-NECK RHABDOMYOSARCOMA IN CHILDREN AND ADOLESCENT: A VERY LONG TERM EXPERIENCE OF THE INTERNATIONAL SOCIETY OF PEDIATRIC ONCOLOGY MALIGNANT MESENCHYMAL TUMOR (SIOP-MMT) COMMITTEE. Pediatric blood & cancer,
Vol.60,
pp. 36-36.
Schoot, R.A.
McHugh, K.
van Rijn, R.R.
Kremer, L.C.
Chisholm, J.C.
Caron, H.N.
Merks, J.H.
(2013). Response assessment in pediatric rhabdomyosarcoma: can response evaluation criteria in solid tumors replace three-dimensional volume assessments?. Radiology,
Vol.269
(3),
pp. 870-878.
show abstract
PURPOSE: To investigate (a) interobserver variability for three-dimensional (3D) (based on European Pediatric Soft-Tissue Sarcoma Study Group [EpSSG] guidelines) and one-dimensional (1D) (based on Response Evaluation Criteria in Solid Tumors [RECIST]) response assessments, (b) intermethod variability between EpSSG guidelines and RECIST, and (c) clinically relevant consequences of interobserver and intermethod variability in pediatric patients with rhabdomyosarcoma. MATERIALS AND METHODS: The study was approved by the Academic Medical Center Ethics Committee and the Great Ormond Street Hospital Ethics Committee; both committees waived the requirement for informed consent because of the retrospective nature of the study. Data were analyzed from 124 consecutive male and female children and young adults (age range, 1-18 years) with rhabdomyosarcoma at two institutions (1999-2009) with relevant imaging studies. Tumors were measured by two radiologists (1D and 3D measurements) at diagnosis and after induction chemotherapy. Interobserver variability was analyzed by using three different tests, and the intermethod variation was calculated. RESULTS: Sixty-four eligible patients were included (median age, 4.6 years). Agreement between observers for EpSSG guidelines and RECIST was moderate (κ = 0.565 and 0.592, respectively); interobserver variation led to different potential treatment decisions in nine (14%) and 11 (17%) of the 64 patients, respectively. Comparison of EpSSG guidelines and RECIST resulted in 13 discrepant response classifications (20%), which were equally distributed (under- and overestimation of response) and led to consequences for treatment choice in five patients (8%). CONCLUSION: EpSSG guidelines and RECIST are not interchangeable; neither technique demonstrated superiority in this study. These findings should be taken into account in future study protocol design. Online supplemental material is available for this article..
Williamson, D.
Missiaglia, E.
Chisholm, J.
Shipley, J.
(2012). Inconvenience of convenience cohorts--letter. Cancer epidemiol biomarkers prev,
Vol.21
(8),
p. 1388.
Chisholm, J.
Phillips, P.
Sutton, A.
Riley, R.
Picton, S.
Stewart, L.
(2012). Predicting Infectious Complications in Neutropenic Children and young people with Cancer Optimizing risk predictive strategies in febrile neutropenic episodes in children and young people undergoing treatment for malignant disease. Systematic reviews in pharmacy,
.
Bate, J.
Chisholm, J.
Skinner, R.
Breuer, J.
Ramsay, M.
Wheatley, K.
Hambleton, S.
Heath, P.T.
(2012). Varicella post-exposure prophylaxis in children with cancer: urgent need for a randomised controlled trial. Archives of disease in childhood,
Vol.97
(9),
pp. 853-854.
Missiaglia, E.
Williamson, D.
Chisholm, J.
Wirapati, P.
Pierron, G.
Petel, F.
Concordet, J.-.
Thway, K.
Oberlin, O.
Pritchard-Jones, K.
Delattre, O.
Delorenzi, M.
Shipley, J.
(2012). PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J clin oncol,
Vol.30
(14),
pp. 1670-1677.
show abstract
PURPOSE: To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data. PATIENTS AND METHODS: Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated. RESULTS: We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme. CONCLUSION: Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS..
Missiaglia, E.
Williamson, D.
Chisholm, J.
Wirapati, P.
Pierron, G.
Petel, F.
Concordet, J.-.
Thway, K.
Oberlin, O.
Pritchard-Jones, K.
Delattre, O.
Delorenzi, M.
Shipley, J.
(2012). Questionable Universal Validity of PAX3/FOXO1 Fusion Gene Status As Molecular Marker for Improvement of Risk Stratification in Rhabdomyosarcoma Therapy Reply. Journal of clinical oncology,
Vol.30
(32),
pp. 4040-4041.
George, S.L.
Broster, S.
Chisholm, J.C.
Brock, P.
(2012). Docetaxel in the treatment of children with refractory or relapsed hepatoblastoma. J pediatr hematol oncol,
Vol.34
(7),
pp. e295-e297.
show abstract
We report on the use of single-agent docetaxel (100 mg/m(2) in children >10 kg, 3.3 mg/kg in children <10 kg), given as a 1-hour infusion at 21-day intervals in 5 children with relapsed or refractory hepatoblastoma. One patient achieved complete remission of pulmonary metastases after 2 courses of docetaxel and remains well 10 years later, after completion of 13 courses of docetaxel and whole-lung radiotherapy. One patient showed a partial response to docetaxel based on α-fetoprotein measurements. Docetaxel shows some activity in progressive hepatoblastoma in this small case series and is a potential drug for future study in this disease..
Lehrnbecher, T.
Aplenc, R.
Rivas Pereira, F.
Lassaletta, A.
Caselli, D.
Kowalczyk, J.
Chisholm, J.
Sung, L.
Grp, S.I.
(2012). Variations in non-pharmacological anti-infective measures in childhood leukemia - results of an international survey. Haematologica-the hematology journal,
Vol.97
(10),
pp. 1548-1552.
Morgenstern, D.
Hargrave, D.
Marshall, L.V.
Gatz, S.A.
Barone, G.
Crowe, T.
Pritchard-Jones, K.
Zacharoulis, S.
Lancaster, D.L.
Vaidya, S.J.
Chisholm, J.C.
Pearson, A.
Moreno, L.
(2012). EARLY PHASE CLINICAL TRIALS IN PAEDIATRIC ONCOLOGY THE ROYAL MARSDEN EXPERIENCE. Pediatric blood & cancer,
Vol.59
(6),
pp. 1091-1091.
Geoerger, B.
Aerts, I.
Casanova, M.
Chisholm, J.
Hargrave, D.
Leary, S.E.
Ashley, D.
Bouffet, E.
MacDonald, T.
Di Giannatale, A.
Hurh, E.
Dey, J.
Kalambakas, S.
Teasdale, T.
Kieran, M.
(2012). UPDATED RESULTS FROM A PHASE I STUDY OF LDE225, A SMOOTHENED ANTAGONIST, IN PEDIATRIC PATIENTS WITH RECURRENT MEDULLOBLASTOMA OR OTHER SOLID TUMORS. Pediatric blood & cancer,
Vol.59
(6),
pp. 980-980.
Patel, S.R.
Bate, J.
Mathews, R.
Chisholm, J.
Heath, P.T.
(2012). VACCINATION STATUS OF CHILDREN WITH CANCER AFTER COMPLETION OF STANDARD-DOSE CHEMOTHERAPY AND AFTER HAEMATOPOIETIC STEM CELL TRANSPLANT. Pediatric blood & cancer,
Vol.59
(6),
pp. 1116-1116.
Chisholm, J.C.
Marandet, J.
Rey, A.
Scopinaro, M.
de Toledo, J.S.
Merks, J.H.
O'Meara, A.
Stevens, M.C.
Oberlin, O.
(2011). Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy. J clin oncol,
Vol.29
(10),
pp. 1319-1325.
show abstract
PURPOSE: Previous studies suggest poor outcome in children with relapsed rhabdomyosarcoma (RMS). A better understanding is needed of which patients can be salvaged after first relapse. PATIENTS AND METHODS: The analysis included children with nonmetastatic RMS and embryonal sarcoma enrolled onto the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumor (MMT) 84, 89, and 95 studies who relapsed after achieving complete local control with primary therapy. All patients included in the analysis had follow-up for ≥ 3.0 years after the last event. The clinical features, initial treatment characteristics, and features of the relapse were correlated with survival in univariate and multivariate analyses. RESULTS: In all, 474 eligible patients were identified for the study. At ≥ 3.0 years from the last event, 176 (37%) were alive ("cured"). In a full-model multivariate analysis, the factors identified at first relapse that most strongly associated with poor outcome were metastatic relapse (odds ratio [OR], 4.19; 95% CI, 2.0 to 8.5), prior radiotherapy treatment (OR, 3.64; 95% CI, 2.1 to 6.4), initial tumor size > 5 cm (OR, 2.53; 95% CI, 1.5 to 4.1), and time of relapse < 18 months from diagnosis (OR, 2.20; 95% CI, 1.3 to 3.6). Unfavorable primary disease site, nodal involvement at diagnosis, alveolar histology, and previous three- or six-drug chemotherapy were also independently associated with poor outcome. To estimate chance of cure for individual patients, a nomogram was developed, which allowed for weighting of these significant factors. CONCLUSION: Some children with relapsed RMS remain curable. It is now possible to estimate the chance of salvage for individual children to direct therapy appropriately toward cure, use of experimental therapies, and/or palliation..
Geoerger, B.
Chisholm, J.
Le Deley, M.-.
Gentet, J.-.
Zwaan, C.M.
Dias, N.
Jaspan, T.
Mc Hugh, K.
Couanet, D.
Hain, S.
Devos, A.
Riccardi, R.
Cesare, C.
Boos, J.
Frappaz, D.
Leblond, P.
Aerts, I.
Vassal, G.
European Consortium Innovative Therapies for Children with Cancer (ITCC),
(2011). Phase II study of gemcitabine combined with oxaliplatin in relapsed or refractory paediatric solid malignancies: An innovative therapy for children with Cancer European Consortium Study. Eur j cancer,
Vol.47
(2),
pp. 230-238.
show abstract
AIM: To assess objective response rates after 4 cycles of gemcitabine in combination with oxaliplatin in children and adolescents with relapsed or refractory solid tumours. METHODS: This multicentre, non-randomised Phase II study included five strata: neuroblastoma, osteosarcoma, medulloblastoma and other CNS tumours strata with two-stage Simon designs and a miscellaneous, extra-cranial solid tumour stratum with descriptive design. Eligibility criteria included: age 6 months to 21 years; measurable, relapsed or refractory solid malignancy; no more than one previous salvage therapy. Gemcitabine was administered intravenously at 1000 mg/m(2) over 100 min followed by oxaliplatin at 100mg/m(2) over 120 min on Day 1 of a 14-d cycle. Tumour response was assessed every 4 cycles according to WHO criteria. RESULTS: Ninety-three out of 95 patients enrolled in 25 centres received treatment: 12 neuroblastoma; 12 osteosarcoma; 14 medulloblastoma; 13 other CNS tumours and 42 miscellaneous non-CNS solid tumours. Median age was 11.7 years (range, 1.3-20.8 years). Tumour control (CR+PR+SD) at 4 cycles was obtained in 30/93 evaluable patients (32.3%; 95% confidence interval (CI), 22.9-42.7%), including four PR: 1/12 patients with osteosarcoma, 1/12 with medulloblastoma, 1/12 with rhabdomyosarcoma and 1/4 with other sarcoma. Five out of 12 eligible patients with neuroblastoma experienced stable disease. During a total of 481 treatment cycles (median 4, range 1-24 per patient), the most common treatment-related toxicities were haematologic (leukopenia, neutropenia, thrombocytopenia) and neurological (dysesthesia, paresthesia). CONCLUDING STATEMENT: The gemcitabine-oxaliplatin combination administered in a bi-weekly schedule has acceptable safety profile with limited activity in children with relapsed or refractory solid tumours..
Slade, I.
Bacchelli, C.
Davies, H.
Murray, A.
Abbaszadeh, F.
Hanks, S.
Barfoot, R.
Burke, A.
Chisholm, J.
Hewitt, M.
Jenkinson, H.
King, D.
Morland, B.
Pizer, B.
Prescott, K.
Saggar, A.
Side, L.
Traunecker, H.
Vaidya, S.
Ward, P.
Futreal, P.A.
Vujanic, G.
Nicholson, A.G.
Sebire, N.
Turnbull, C.
Priest, J.R.
Pritchard-Jones, K.
Houlston, R.
Stiller, C.
Stratton, M.R.
Douglas, J.
Rahman, N.
(2011). DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J med genet,
Vol.48
(4),
pp. 273-278.
show abstract
BACKGROUND: Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB). AIM: To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer. METHODS AND RESULTS: The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional DICER1 mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli-Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli-Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. DICER1 mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli-Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from DICER1 mutation-positive patients showed universal retention of the wild-type allele. DICER1 truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations. CONCLUSION: Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli-Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which DICER1 mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition 'DICER1 syndrome'. ACCESSION NUMBERS: The cDNA Genbank accession number for the DICER1 sequence reported in this paper is NM_030621.2..
Bate, J.
Chisholm, J.
Heath, P.T.
Breuer, J.
Skinner, R.
Manley, S.
Patel, S.
Wheatley, K.
Ramsay, M.
Kearns, P.R.
Hambleton, S.
(2011). PEPtalk: postexposure prophylaxis against varicella in children with cancer. Archives of disease in childhood,
Vol.96
(9),
pp. 841-845.
Lehrnbecher, T.
Aplenc, R.
Pereira, F.R.
Lassaletta, A.
Caselli, D.
Kowalczyk, J.
Chisholm, J.
Sung, L.
(2011). INSTITUTIONAL VARIATIONS IN NON-PHARMACOLOGICAL ANTI-INFECTIVE MEASURES - RESULTS OF AN INTERNATIONAL SURVEY. Pediatric blood & cancer,
Vol.57
(5),
pp. 847-847.
Bate, J.
Patel, S.R.
Chisholm, J.
Heath, P.T.
CCLG,
(2010). Immunisation Practices of Paediatric Oncology and Shared Care Oncology Consultants: A United Kingdom Survey. Pediatric blood & cancer,
Vol.54
(7),
pp. 941-946.
Jorgensen, M.
Bate, J.
Gatscher, S.
Chisholm, J.C.
(2010). Invasive pneumococcal disease following treatment for choroid plexus carcinoma. Support care cancer,
Vol.18
(5),
pp. 647-650.
show abstract
INTRODUCTION: A 13-month-old child was treated for choroid plexus carcinoma with partial embolisation, complete surgical excision and chemotherapy. The patient's course was complicated by the presence of chronic bilateral subdural collections. CASE REPORT: Four months from completing treatment, the child presented with an empyema in the subdural space caused by Streptococcus pneumoniae subtype 6A. DISCUSSION: The case highlights a number of questions about pneumococcal immunisation after standard chemotherapy. Evidence-based guidelines are required urgently to direct best practice..
Rees, H.
Andrews, M.
Broster, S.
Nicholson, J.
Skinner, R.
Chisholm, J.
Canc, S.C.
(2010). Influenza vaccination during cancer therapy. Archives of disease in childhood,
Vol.95
(7).
Chisholm, J.
Marandet, J.
Rey, A.
Oberlin, O.
(2010). PROGNOSTIC FACTORS AFTER RELAPSE IN NON-METASTATIC RHABDOMYOSARCOMA: WHO CAN BE SALVAGED?. Pediatric blood & cancer,
Vol.55
(5),
pp. 836-836.
Schoot, R.
McHugh, K.
van Rijn, R.
Chisholm, J.
Merks, J.
(2010). ARE THE RECIST CRITERIA USEFUL IN ASSESSING RESPONSE IN PAEDIATRIC RHABDOMYOSARCOMA?. Pediatric blood & cancer,
Vol.55
(5),
pp. 901-902.
Chisholm, J.C.
Casanova, M.
Geoerger, B.
Merks, J.H.
Massimini, G.
Moore, N.
Rooney, I.A.
Viviers, L.
Oberlin, O.
(2010). A phase II study evaluating addition of bevacizumab to chemotherapy in childhood and adolescent patients presenting with metastatic rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma soft tissue sarcoma (NRSTS). Journal of clinical oncology,
Vol.28
(15).
Gibson, F.
Hartley, J.
Lane, S.
Phillips, R.
Selwood, K.
Skinner, R.
Chisholm, J.
(2009). Reaching A National Consensus On An Approach To Low Risk Febrile Neutropenia: The Challenges of A Delphi Survey. European journal of oncology nursing,
Vol.13
(1),
pp. 63-63.
Thomas, L.
Baggen, L.
Chisholm, J.
Sharland, M.
(2009). Diagnosis and treatment of aspergillosis in children. Expert review of anti-infective therapy,
Vol.7
(4),
pp. 461-472.
Bate, J.
Ladhani, S.
Sharland, M.
Chisholm, J.
Lamagni, T.
Ramsay, M.
Johnson, A.
Pebody, R.
(2009). Infection-Related Mortality in Children With Malignancy in England and Wales, 2003-2005. Pediatric blood & cancer,
Vol.53
(3),
pp. 371-374.
Dommett, R.
Geary, J.
Freeman, S.
Hartley, J.
Sharland, M.
Davidson, A.
Tulloh, R.
Taj, M.
Stoneham, S.
Chisholm, J.C.
(2009). Successful introduction and audit of a step-down oral antibiotic strategy for low risk paediatric febrile neutropaenia in a UK, multicentre, shared care setting. European journal of cancer,
Vol.45
(16),
pp. 2843-2849.
Patel, S.R.
Chisholm, J.C.
Heath, P.T.
(2008). Vaccinations in children treated with standard-dose cancer therapy or hematopoietic stem cell transplantation. Pediatric clinics of north america,
Vol.55
(1),
pp. 169-+.
Laddie, J.
Chisholm, J.
(2007). A survey of parent and staff views on management by risk stratification in children with febrile neutropenia (FN). Pediatric blood & cancer,
Vol.49
(4),
pp. 508-509.
Phillips, R.
Skinner, R.
Chisholm, J.C.
(2007). Treating low-risk febrile neutropenia: Jenny's story. Archives of disease in childhood,
Vol.92
(1),
pp. 7-8.
Chisholm, J.C.
(2007). Reimmunization after therapy for childhood cancer. Clinical infectious diseases,
Vol.44
(5),
pp. 643-645.
Andrews, M.
Chisholm, J.
Nicholson, J.
Broster, S.
Rees, H.
(2007). Cross-sectional survey of influenza vaccination uptake in children with cancer. Pediatric blood & cancer,
Vol.49
(4),
pp. 509-509.
Phillips, B.
Selwood, K.
Lane, S.M.
Skinner, R.
Gibson, F.
Chisholm, J.C.
(2007). Variation in policies for the management of febrile neutropenia in United Kingdom Children's Cancer Study Group centres. Archives of disease in childhood,
Vol.92
(6),
pp. 495-498.
Chisholm, J.C.
Machin, D.
McDowell, H.
McHugh, K.
Ellershaw, C.
Jenney, M.
Foot, A.B.
Children's Cancer and Leukaemia Group (CCLG; formerly United Kingdom Children's Cancer Study Group),
(2007). Efficacy of carboplatin given in a phase II window study to children and adolescents with newly diagnosed metastatic soft tissue sarcoma. Eur j cancer,
Vol.43
(17),
pp. 2537-2544.
show abstract
AIM: The activity of carboplatin was evaluated in a phase II window study in previously untreated children with metastatic soft tissue sarcoma. METHODS: Children with poor-risk metastatic disease (over 10 years and/or with bone/bone marrow involvement) treated in the SIOP MMT 98 study were scheduled to receive two courses of intravenous carboplatin (area under curve [AUC] of 10), 21 days apart. RESULTS: Sixteen eligible patients were entered into the rhabdomyosarcoma (RMS) group. Response (complete remission or partial remission) was seen in five children (31%, 95% confidence interval (CI) 14-56%). Ten eligible patients with other soft tissue sarcomas were recruited into the non-RMS group. Two responses (20%, 95% CI 6-51%) were seen. Toxicity in both groups was predictable nausea, vomiting and marrow suppression and there were no toxic deaths. CONCLUSION: Single-agent carboplatin at AUC of 10 has an acceptable toxicity profile but only moderate efficacy in poor-risk metastatic soft tissue sarcoma..
Duncan, C.
Chisholm, J.C.
Freeman, S.
Riley, U.
Sharland, M.
Pritchard-Jones, K.
(2007). A prospective study of admissions for febrile neutropenia in secondary paediatric units in South East England. Pediatr blood cancer,
Vol.49
(5),
pp. 678-681.
show abstract
BACKGROUND: The Paediatric Oncology Centres (POCs) treating childhood cancer in South East England produce unified supportive care guidelines for use in the secondary pediatric (shared care) units. This study evaluated the adherence to current guidelines for febrile neutropenia (FN) and documented outcome in terms of bacterial isolates, antibiotic resistance patterns, length of hospital stay, and mortality. PROCEDURE: Prospective study of pediatric FN admissions between July 2001 and December 2002. RESULTS: Data were received on 433 eligible FN episodes in 212 patients. The recommended empirical antibiotics (piptazobactam + gentamicin) were used in 354 (82%) admissions. Blood cultures were positive in 129 episodes (30%). Gram-positive organisms predominated (120/149 organisms isolated) and the majority were coagulase-negative Staphylococci (95/120). There were 27 Gram-negative isolates and 1 fungal isolate. No Gram-negative isolate was resistant to both first-line antibiotics. Only one death was recorded in the study group. The median length of hospital stay was 5 days. CONCLUSIONS: We obtained data on a large number of shared care episodes of FN. The antibiotic guidelines were followed in most episodes. Bacteremia was common, but little resistance to first-line antibiotics was documented among Gram-negative isolates, confirming the safety of the strategy in our population..
Fowler, D.J.
Chisholm, J.
Roebuck, D.
Newman, L.
Malone, M.
Sebire, N.J.
(2006). Melanotic neuroectodermal tumor of infancy: clinical, radiological, and pathological features. Fetal pediatr pathol,
Vol.25
(2),
pp. 59-72.
show abstract
We present a case of a 4-month-old female infant with a maxillary melanotic neuroectodermal tumor of infancy (MNTI) and review the pooled data from previous publications on this entity. The literature to date comprises 378 reported cases from 1918 to the present, from which data on the presence or absence of metastatic disease was available in 311, and on the presence or absence of local recurrence in 165. These pooled data suggest a local recurrence rate of 36% with metastasis occurring in 7% of cases. At present, the optimal management includes complete surgical excision with clear margins, but there are no reliable histopathological or molecular features to predict the biological behavior in individual cases..
Fowler, D.J.
Malone, M.
Chisholm, J.
Roebuck, D.
Sebire, N.J.
(2006). Primary thoracic myxoid variant of extrarenal rhabdoid tumor in childhood. Fetal pediatr pathol,
Vol.25
(3),
pp. 159-168.
show abstract
Primary extrarenal rhabdoid tumors (RT) are now recognized as a specific entity in pediatric oncological pathology practice. We present an unusual case of a small cell myxoid variant of a thoracic RT in an infant and highlight the importance of recent molecular developments in the diagnosis of these tumors. An 8-month-old child presented with a short history of cough and shortness of breath. Imaging demonstrated a large mass occupying the majority of the thoracic cavity on the right side. A percutaneous needle biopsy of the mass showed fragments of tissue composed of malignant tumor with a predominant "small ovoid cell" phenotype and extensive myxoid change, with small nests and islands of tumor cells; occasional cells demonstrated open vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasmic inclusions. Immunohistochemical staining revealed focal strong cytoplasmic positivity for cytokeratin, focal strong paranuclear cytoplasmic vimentin positivity, and INI1 staining showed normal nuclear positivity in control tissues but was negative in tumor cell nuclei. Electron microscopy demonstrated characteristic paranuclear whorls of intermediate filaments confirming the diagnosis of extrarenal malignant RT. The diagnosis of malignant rhabdoid tumor may be difficult, particularly in cases, such as the present, with a predominant small-cell myxoid phenotype. The characteristic expression patterns of cytokeratin and vimentin provide strong clues to the diagnosis, and the use of INI1 antibody now makes definitive diagnosis possible even on needle core biopsies..
Chisholm, J.C.
Dommett, R.
(2006). The evolution towards ambulatory and day-case management of febrile neutropenia. Br j haematol,
Vol.135
(1),
pp. 3-16.
show abstract
Febrile neutropenia (FN) is only second to chemotherapy administration as a cause of hospital admission during treatment for cancer. As FN may signify serious or life-threatening infection, management protocols have focussed on trying to prevent adverse outcomes in these patients. However, it is now possible to identify a subset of patients with FN at low risk of life-threatening complications in whom duration of hospitalisation and intensity of therapy can be reduced safely. This review discusses how the management of FN has evolved to enable patients identified as low risk to be treated on specific low risk management strategies, with an emphasis on some of the practical considerations for the implementation of such strategies..
Chisholm, J.
Rubie, H.
Desfachalles, S.
Morland, B.
Munzer, C.
Valteau-Couanet, D.
Mosseri, V.
Bergeron, C.
Weston, C.
Coze, C.
Auvrignon, A.
Djafari, L.
Hobson, R.
Baunin, C.
Dickinson, F.
Brisse, H.
McHugh, K.
Biassoni, L.
Giammarile, F.
Vassal, G.
Societe Francaise des cancers de l'enfant,
United Kingdom Childrens Cancer Study Group - New Agents Group Study,
(2006). A Phase II study of Temozolomide in relapsed or refractory high-risk Neuroblastoma. Journal of clinical oncology,
(24(33)),
pp. 5259-5264.
Chisholm, J.
Howe, K.
Taj, M.
Zambon, M.
(2005). Influenza immunisation in children with solid tumours. European journal of cancer,
Vol.41
(15),
pp. 2280-2287.
Veal, G.J.
Cole, M.
Errington, J.
Parry, A.
Hale, J.
Pearson, A.D.
Howe, K.
Chisholm, J.C.
Beane, C.
Brennan, B.
Waters, F.
Glaser, A.
Hemsworth, S.
McDowell, H.
Wright, Y.
Pritchard-Jones, K.
Pinkerton, R.
Jenner, G.
Nicholson, J.
Elsworth, A.M.
Boddy, A.V.
Kingdom Children's Cancer Study Group Pharmacology Working Group,
(2005). Pharmacokinetics of dactinomycin in a pediatric patient population: a United Kingdom Children's Cancer Study Group Study. Clin cancer res,
Vol.11
(16),
pp. 5893-5899.
show abstract
PURPOSE: Dactinomycin (actinomycin D) is an antitumor antibiotic used routinely to treat certain pediatric and adult cancers. Despite concerns over the incidence of toxicity, little is known about the pharmacology of dactinomycin. A study was done to investigate dactinomycin pharmacokinetics in children. EXPERIMENTAL DESIGN: Dactinomycin was administered to 31 patients by bolus i.v. infusion, at doses of 0.70 to 1.50 mg/m2. Plasma concentrations were determined by liquid chromatography-mass spectrometry up to 24 hours after drug administration and National Cancer Institute Common Toxicity Criteria was assessed. RESULTS: Pharmacokinetic data analysis suggested that a three-compartment model most accurately reflected dactinomycin pharmacokinetics. However, there was insufficient data available to fully characterize this model. A median peak plasma concentration (Cmax) of 25.1 ng/mL (range, 3.2-99.2 ng/mL) was observed at 15 minutes after administration. The median exposure (AUC0-6), determined in 16 patients with sampling to 6 hours, was 2.67 mg/L.min (range, 1.12-4.90 mg/L.min). After adjusting for body size, AUC0-6 and Cmax were positively related to dose (P = 0.03 and P = 0.04, respectively). Patients who experienced any level of Common Toxicity Criteria grade had a 1.46-fold higher AUC0-6, 95% confidence interval (1.02-2.09). AUC0-6 was higher in patients <40 kg, possibly indicating a greater toxicity risk. CONCLUSIONS: Data presented suggest that dosing of dactinomycin based on surface area is not optimal, either in younger patients in whom the risk of toxicity is greater, or in older patients where doses are capped..
Tischkowitz, M.D.
Chisholm, J.
Gaze, M.
Michalski, A.
Rosser, E.M.
(2004). Medulloblastoma as a first presentation of fanconi anemia. J pediatr hematol oncol,
Vol.26
(1),
pp. 52-55.
show abstract
Fanconi anemia is a chromosomal instability syndrome associated with certain congenital abnormalities, defective hemopoiesis, and an increased risk of developing acute myeloid leukemia and some solid tumors. The diagnosis can be made at birth if congenital abnormalities are present but is often made in childhood when hematologic complications develop. The authors report a case of Fanconi anemia diagnosed in a child with no congenital abnormalities and normal bone marrow who first presented with a cerebellar medulloblastoma. The authors discuss diagnostic and therapeutic implications for such malignancies in Fanconi anemia..
Little, M.A.
Morland, B.
Chisholm, J.
Hole, A.
Shankar, A.
Devine, T.
Easlea, D.
Meyer, L.C.
Pinkerton, C.R.
(2002). A randomised study of prophylactic G-CSF following MRC UKALL XI intensification regimen in childhood ALL and T-NHL. Med pediatr oncol,
Vol.38
(2),
pp. 98-103.
show abstract
BACKGROUND: Despite the current widespread use of prophylactic G-CSF in children with solid tumours and leukaemia, its effectiveness has not been clearly demonstrated. This randomised study evaluates the role of G-CSF given after a 5-day intensification block in children with acute lymphoblastic leukaemia (ALL). PROCEDURE: Forty-six children with ALL or T-Cell non-Hodgkins lymphoma (NHL) treated on MRC ALL 97, UKALL XI or UKCCSG 9504 NHL protocols were randomised to receive granulocyte colony-stimulating factor following either the first or the second block of intensive chemotherapy in a cross-over study to determine if the prophylactic administration of G-CSF could reduce the rate of readmission to hospital for management of febrile neutropenia. RESULTS: There was a statistically significant difference in the rate of hospital admission in the group receiving prophylaxis, with 34 of 46 being admitted, compared to 42 of 46 patients in the control arm (74 vs. 91%; P=0.0386). There were no differences found in duration of hospital admission, haematological toxicity, neutrophil recovery or duration of supportive care between the two groups. There was no demonstrable cost benefit derived from the prophylactic administration of G-CSF. CONCLUSIONS: This study shows that the prophylactic administration of G-CSF following intensification chemotherapy for childhood ALL and T-NHL produces a significant reduction in the rate of readmission to hospital for the management of febrile neutropenia..
Chisholm, J.C.
Devine, T.
Charlett, A.
Pinkerton, C.R.
Zambon, M.
(2001). Response to influenza immunisation during treatment for cancer. Arch dis child,
Vol.84
(6),
pp. 496-500.
show abstract
AIMS: To assess the annual risk of influenza infection in children with cancer and the immunogenicity of a trivalent split virus influenza vaccine in these children. METHODS: Eighty four children with cancer were tested for susceptibility to the circulating strains of influenza virus in autumn 1995 and 1996. Non-immunised children were reassessed the following spring for serological evidence of natural infection. Forty two patients received two doses of influenza vaccine. These children were receiving continuing chemotherapy for acute lymphoblastic leukaemia or were within six months of completing chemotherapy. RESULTS: Among the 84 children tested for influenza virus susceptibility only 8% of patients were fully protected (antibody titres >/= 40) against all three of the prevalent influenza virus strains; 33% were susceptible to all three viruses. Evidence of acquired natural infection was seen in 30% of unimmunised patients. Among immunised susceptible patients, 66% made some protective response to the vaccine and 55% showed protective antibody titres to all three viral strains following vaccination. Older age was associated with increased response to the H1N1 and H3N2 vaccine components, but total white cell count or neutrophil count at immunisation, type of cancer, or length of time on treatment for acute lymphoblastic leukaemia did not affect response. CONCLUSIONS: Most children with cancer studied were at risk of influenza infection. A significant response to immunisation was seen, supporting annual influenza vaccination for children being treated for cancer..
Chisholm, J.
Devine, T.
Dick, G.
Mycroft, J.
Pinkerton, C.R.
(2000). Safety and tolerability of Amphotericin B Lipid Complex (Abelcet). International journal of pediatric hematology/oncology,
Vol.6
(6),
pp. 393-402.
Chisholm, J.
Devine, T.
Mycroft, J.
Pinkerton, C.R.
(1999). Liposomal amphotericin B (AmBisome) in children with febrile neutropenia and renal dysfunction. International journal of pediatric hematology/oncology,
Vol.6
(3),
pp. 173-182.
Veys, P.A.
Meral, A.
Hassan, A.
Goulden, N.
Chisholm, J.
New, H.
Armstrong, J.
Bennett-Rees, N.
Webb, D.
Gerritsen, B.
(1998). Improved outcome for blood and marrow transplantation in immunodeficiency. Bone marrow transplantation,
Vol.21,
pp. S128-S128.
Chisholm, J.C.
Devine, T.
Mycroft, J.
Pinkerton, C.R.
(1998). Tolerability of amphotericin B lipid complex (ABELCET) in children with malignant disease. Bone marrow transplantation,
Vol.21,
pp. S145-S145.
Vaarwerk, B.
Mallebranche, C.
Affinita, M.C.
van der Lee, J.H.
Ferrari, A.
Chisholm, J.C.
Defachelles, A.-.
De Salvo, G.L.
Corradini, N.
Minard-Colin, V.
Morosi, C.
Brisse, H.J.
McHugh, K.
Bisogno, G.
van Rijn, R.R.
Orbach, D.
Merks, J.H.
Is surveillance imaging in pediatric patients treated for localized rhabdomyosarcoma useful? The European experience. Cancer,
Vol.126
(4),
pp. 823-831.
show abstract
Background After the completion of therapy, patients with localized rhabdomyosarcoma (RMS) are subjected to intensive radiological tumor surveillance. However, the clinical benefit of this surveillance is unclear. This study retrospectively analyzed the value of off-therapy surveillance by comparing the survival of patients in whom relapse was detected by routine imaging (the imaging group) and patients in whom relapse was first suspected by symptoms (the symptom group). Methods This study included patients with relapsed RMS after the completion of therapy for localized RMS who were treated in large pediatric oncology hospitals in France, the United Kingdom, Italy, and the Netherlands and who were enrolled in the International Society of Paediatric Oncology Malignant Mesenchymal Tumor 95 (1995-2004) study, the Italian Paediatric Soft Tissue Sarcoma Committee Rhabdomyosarcoma 96 (1996-2004) study, or the European Paediatric Soft Tissue Sarcoma Study Group Rhabdomyosarcoma 2005 (2005-2013) study. The survival times after relapse were compared with a log-rank test between patients in the imaging group and patients in the symptom group. Results In total, 199 patients with relapsed RMS were included: 78 patients (39.2%) in the imaging group and 121 patients (60.8%) in the symptom group. The median follow-up time after relapse was 7.4 years (interquartile range, 3.9-11.5 years) for survivors (n = 86); the 3-year postrelapse survival rate was 50% (95% confidence interval [CI], 38%-61%) for the imaging group and 46% (95% CI, 37%-55%) for the symptom group (P = .7). Conclusions Although systematic routine imaging is the standard of care after RMS therapy, the majority of relapses were detected as a result of clinical symptoms. This study found no survival advantage for patients whose relapse was detected before the emergence of clinical symptoms. These results show that the value of off-therapy surveillance is controversial, particularly because repeated imaging may also entail potential harm..
Terwisscha van Scheltinga, S.E.
Wijnen, M.H.
Martelli, H.
Rogers, T.
Mandeville, H.
Gaze, M.N.
McHugh, K.
Corradini, N.
Orbach, D.
Jenney, M.
Kelsey, A.
Chisholm, J.
Gallego, S.
Glosli, H.
Ferrari, A.
Zanetti, I.
De Salvo, G.L.
Minard-Colin, V.
Bisogno, G.
van Noesel, M.M.
Merks, H.H.
Local staging and treatment in extremity rhabdomyosarcoma A report from the EpSSG-RMS2005 study. Cancer medicine,
Vol.9
(20),
pp. 7580-7589.
show abstract
Rhabdomyosarcoma of the extremities present with two main challenges: correct evaluation of initial regional nodal involvement and define adequate local treatment. Methods Pediatric patients with localized rhabdomyosarcoma of the extremity included in the EpSSG-RMS2005 study between 2005 and 2014 were evaluated for staging, treatment, and survival. The outcome was compared to the preceding European SIOP-MMT studies. Results Of the 162 patients included, histology was unfavorable in 113 (70%), 124 (77%) were younger than 10 years, 128 (79%) were IRS III, and 47 (29%) were node-positive. A regional node biopsy was performed in 97 patients (60%) and modified the lymph node stage in 15/97 (16%). Primary and delayed surgery was performed in 155 (96%) and radiotherapy delivered in 118 (73%) patients. Relapse occurred in 61 cases (38%), local in 14 (23%), regional in 13 (21%), distant in 22 (36%), and combined relapse in 12 (20%) with five progressive diseases (8%) and four secondary tumors (7%). Five-year event free (EFS) and overall survival (OS) were 58.4% (95%CI, 50.3-65.7) and 71.7% (63.6-78.4), respectively. In the previous studies MMT89 and MMT95, tumor surgery was performed in 32/53 (60%) and 74/82(90%), respectively, and radiotherapy delivered in 13/53 (25%) and 26/82 (30%), respectively. Five-year EFS and OS were 35.6%, and 50.3% in MMT89 and 54.3% and 68.2% in the MMT95 study. Conclusions Even if the lymph node staging was not always complete according to the RMS2005 protocol, node sampling changed lymph node status in a significant number of patients. Despite the higher rate of patients treated with locoregional radiotherapy, survival in RMS2005 did not improve compared to the previous European SIOP-MMT95 study..
Chisholm, J.
Optimising antimicrobial selection and duration in the treatment of febrile neutropenia in children. Journal of infection and drug resistance,
.
Chisholm, J.
Shipley, J.
Mandeville, H.
Non-parameningeal Head And Neck Rhabdomyosarcoma In Children, Adolescents, And Young Adults: Experience Of The European Paediatric Soft Tissue Sarcoma Study Group (Epssg) – Rms2005 Study. Eurpoean journal of cancer,
.
Chisholm, J.
Mandeville, H.
The Impact of Radiation Therapy in Children and Adolescents With Metastatic Rhabdomyosarcoma. International journal of radiation: oncology - biology - physics,
.
Chisholm, J.
Randomized phase 2 trial of the Vincristine-Irinotecan combination with or without Temozolomide, in children and adults with relapsed or refractory rhabdomyosarcoma: an EpSSG/ITCC trial. Journal of clinical oncology,
.
Shern, J.F.
Selfe, J.
Izquierdo, E.
Patidar, R.
Chou, H.-.
Song, Y.K.
Yohe, M.E.
Sindiri, S.
Wei, J.
Wen, X.
Rudzinski, E.R.
Barkauskas, D.A.
Lo, T.
Hall, D.
Linardic, C.M.
Hughes, D.
Jamal, S.
Jenney, M.
Chisholm, J.
Brown, R.
Jones, K.
Hicks, B.
Angelini, P.
George, S.
Chesler, L.
Hubank, M.
Kelsey, A.
Gatz, S.A.
Skapek, S.X.
Hawkins, D.S.
Shipley, J.M.
Khan, J.
Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium. Journal of clinical oncology : official journal of the american society of clinical oncology,
Vol.39
(26),
pp. 2859-2871.
show abstract
Purpose Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAX-FOXO1 fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome.Patients and methods Tumor samples collected from patients enrolled on Children's Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed.Results DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In FOXO1 fusion-negative cases, mutation of any RAS pathway member was found in > 50% of cases, and 21% had no putative driver mutation identified. BCOR (15%), NF1 (15%), and TP53 (13%) mutations were found at a higher incidence than previously reported and TP53 mutations were associated with worse outcomes in both fusion-negative and FOXO1 fusion-positive cases. Interestingly, mutations in RAS isoforms predominated in infants < 1 year (64% of cases). Mutation of MYOD1 was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database (ClinOmics), containing all genomic variants, and clinical annotation including survival data.Conclusion This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials..
Chisholm, J.
Role of 18F-FDG-PET/CT in the staging of metastatic rhabdomyosarcoma: A report from the European paediatric Soft tissue sarcoma Study Group. European journal of cancer,
.
Defachelles, A.-.
Bogart, E.
Casanova, M.
Merks, J.H.
Bisogno, G.
Calareso, G.
Gallego Melcon, S.
Gatz, S.A.
Le Deley, M.-.
McHugh, K.
Probst, A.
Rocourt, N.
van Rijn, R.R.
Wheatley, K.
Minard-Colin, V.
Chisholm, J.C.
Randomized Phase II Trial of Vincristine-Irinotecan With or Without Temozolomide, in Children and Adults With Relapsed or Refractory Rhabdomyosarcoma: A European Paediatric Soft Tissue Sarcoma Study Group and Innovative Therapies for Children With Cancer Trial. Journal of clinical oncology : official journal of the american society of clinical oncology,
Vol.39
(27),
pp. 2979-2990.
show abstract
Purpose The VIT-0910 trial was conducted to evaluate efficacy and safety of the vincristine-irinotecan combination with and without temozolomide (VIT and VI, respectively) in relapsed or refractory rhabdomyosarcoma (RMS). Methods In this randomized European phase II trial, patients age 0.5-50 years received 21-day cycles combining vincristine (1.5 mg/m 2 once a day on day 1 and day 8) and irinotecan (50 mg/m 2 once a day from day 1 to day 5) with and without temozolomide (125 mg/m 2 once a day from day 1 to day 5 and 150 mg/m 2 once a day from cycle 2), until progression or unacceptable toxicity. The primary end point was objective response rate after two cycles. Secondary end points included best response, progression-free survival, overall survival, and adverse events. A Simon 2-stage design was initially planned to separately analyze 40 patients/arm. After amendment, the trial sample size was increased to 120 and a comparison between arms, adjusted for confounding factors, was added to the statistical plan (ClinicalTrials.gov, NCT01355445). Results Overall, 120 patients (60 per arm) were recruited in 37 European centers. The median age was 11 years (range, 0.75-45); 89% of patients had a relapsed RMS. The objective response rate was 44% (24 of 55 evaluable patients) for VIT versus 31% (18 of 58) for VI (adjusted odds ratio, 0.50; 95% CI, 0.22 to 1.12; P = .09). The VIT arm achieved significantly better overall survival (adjusted hazard ratio, 0.55; 95% CI, 0.35 to 0.84; P = .006) compared with VI, with consistent progression-free survival results (adj-hazard ratio, 0.68; 95% CI, 0.46 to 1.01; P = .059). Overall, patients experienced adverse events ≥ grade 3 more frequently with VIT than VI (98% v 78%, respectively; P = .009), including a significant excess of hematologic toxicity (81% v 61%; P = .025). Conclusion The addition of temozolomide to VI improved chemotherapy efficacy for patients with relapsed RMS, with manageable increase in toxicity. VIT is considered the new standard treatment in these patients in the European paediatric Soft Tissue Sarcoma Group and will be the control arm in the next randomized trial..
Doz, F.
van Tilburg, C.M.
Geoerger, B.
Højgaard, M.
Øra, I.
Boni, V.
Capra, M.
Chisholm, J.
Chung, H.C.
DuBois, S.G.
Gallego-Melcon, S.
Gerber, N.U.
Goto, H.
Grilley-Olson, J.E.
Hansford, J.R.
Hong, D.S.
Italiano, A.
Kang, H.J.
Nysom, K.
Thorwarth, A.
Stefanowicz, J.
Tahara, M.
Ziegler, D.S.
Gavrilovic, I.T.
Norenberg, R.
Dima, L.
De La Cuesta, E.
Laetsch, T.W.
Drilon, A.
Perreault, S.
Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Neuro-oncology,
.
show abstract
Abstract Background Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. Methods Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). Results As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3–79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16–49) for all patients. In all patients, the 24-week disease control rate was 73% (95% CI: 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45–100), 56% (95% CI: 38–74), and 85% (95% CI: 71–99), respectively. Median time to response was 1.9 months (range 1.0–3.8 months). Duration of treatment ranged from 1.2–31.3+ months. Treatment-related adverse events were reported for 20 patients, with Grade 3–4 in 3 patients. No new safety signals were identified. Conclusions In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile..
Lyons, O.
Forbat, L.
Menson, E.
Chisholm, J.C.
Pryde, K.
Conlin, S.
Felton, V.
Ingle, S.
McKenzie, C.
Ramachandran, R.
Sayer, C.
Snowball, C.
Strachan-Gadsby, E.
Tisovszky, N.
Barclay, S.
Transforming training into practice with the conflict management framework: a mixed methods study. Bmj paediatrics open,
Vol.5
(1),
pp. e001088-e001088.
show abstract
ObjectiveTo implement and evaluate the use of the conflict management framework (CMF) in four tertiary UK paediatric services.DesignMixed methods multisite evaluation including prospective pre and post intervention collection of conflict data alongside semistructured interviews.SettingEight inpatient or day care wards across four tertiary UK paediatric services.InterventionsThe two-stage CMF was used in daily huddles to prompt the recognition and management of conflict.ResultsConflicts were recorded for a total of 67 weeks before and 141 weeks after implementation of the CMF across the four sites. 1000 episodes of conflict involving 324 patients/families across the four sites were recorded. After implementation of the CMF, time spent managing episodes of conflict around the care of a patient was decreased by 24% (p<0.001) (from 73 min to 55 min) and the estimated cost of this staff time decreased by 20% (p<0.02) (from £26 to £21 sterling per episode of conflict). This reduction occurred despite conflict episodes after implementation of the CMF having similar severity to those before implementation. Semistructured interviews highlighted the importance of broad multidisciplinary leadership and training to embed a culture of proactive and collaborative conflict management.ConclusionsThe CMF offers an effective adjunct to conflict management training, reducing time spent managing conflict and the associated staff costs..
Chisholm, J.
Metastatic rhabdomyosarcoma: results of the European paediatric Soft tissue sarcoma Study Group MTS 2008 study and pooled analysis with the concurrent BERNIE study. Journal of clinical oncology,
.