This study used anonymized death certificate data to determine the contribution of specific infections to neonatal deaths in England and Wales between 2003 and 2005. Infection was recorded in 11% of ...deaths, with two-thirds occurring in premature neonates. Group B Streptococcus was indicated in 32% of death certificates that specified a bacterial infection and in 11% of all infection-related deaths.
For extracranial malignant germ cell tumours (MGCTs) in the UK, the GCII study used carboplatin-based chemotherapy (JEb) and demonstrated equivalent survival to cisplatin-containing protocols. GCIII, ...a single-arm observational study, used new risk stratification, replaced consolidation chemotherapy with a standard number of cycles and introduced surveillance for all stage I MGCTs. Pure teratomas were registered to understand their natural history.
Patients with MGCTs were stratified to three risk groups – low risk (LR), intermediate risk (IR) and high risk (HR), using stage and prognostic factors. Patients with alpha fetoprotein (AFP) >10,000 kU/L, stage IV disease (except testis <5 years and all germinomas) or stage II-IV mediastinal tumour were classified HR. Stage I tumours (LR) received chemotherapy only if disease progressed. IR and HR patients received 4 and 6 JEB cycles, respectively. Carboplatin dose was calculated using glomerular filtration rate to give an area under the curve of 7.9 ml/m2.min.
Eighty-six patients with MGCTs were enrolled from 2005 to 2009: 59% female, median age, 5.7 years. Twenty-five patients were LR, 21 IR and 38 HR. Seven LR patients had disease progression; all were successfully treated with chemotherapy. Overall survival (OS) for the whole group was 97%; 5-year event-free survival for JEb-treated patients was 92%, and OS, 95%. JEb was well tolerated with no observed significant hearing or renal side-effects. There was no discernible difference in carboplatin dose whether calculated by body surface area or creatinine clearance. Forty-seven patients with teratoma were managed with surgery and one had malignant transformation.
Carboplatin-based chemotherapy as part of a risk-stratified approach leads to excellent survival in paediatric MGCTs, minimising potential burden of long-term effects.
•Carboplatin is an effective treatment for paediatric extracranial germ cell tumours.•An n+2 strategy of consolidation chemotherapy is unnecessary.•Treatment can probably be safely de-escalated in germinomas.•Carboplatin dosing of 600 mg/m2/cycle is reasonable for most patients.
The reprogramming of a patient's immune system through genetic modification of the T cell compartment with chimeric antigen receptors (CARs) has led to durable remissions in chemotherapy-refractory B ...cell cancers. Targeting of solid cancers by CAR-T cells is dependent on their infiltration and expansion within the tumor microenvironment, and thus far, fewer clinical responses have been reported. Here, we report a phase 1 study (NCT02761915) in which we treated 12 children with relapsed/refractory neuroblastoma with escalating doses of second-generation GD2-directed CAR-T cells and increasing intensity of preparative lymphodepletion. Overall, no patients had objective clinical response at the evaluation point +28 days after CAR-T cell infusion using standard radiological response criteria. However, of the six patients receiving ≥10
/meter
CAR-T cells after fludarabine/cyclophosphamide conditioning, two experienced grade 2 to 3 cytokine release syndrome, and three demonstrated regression of soft tissue and bone marrow disease. This clinical activity was achieved without on-target off-tumor toxicity. Targeting neuroblastoma with GD2 CAR-T cells appears to be a valid and safe strategy but requires further modification to promote CAR-T cell longevity.
Abstract BACKGROUND Optic nerve sheath meningiomas (ONSM) are rare, comprising 1-2% of paediatric CNS meningiomas. Despite slow growth, ONSM often lead to vision loss in the affected eye. Diagnosis ...is challenging due to the tumour’s proximity to the optic nerve, complicating biopsy or complete removal. METHODS We searched our Neuro-Oncology MDT database for patients treated for ONSM between Jan 2018 and Dec 2023. We retrospectively reviewed clinical presentation and diagnostic workup that led to the diagnosis of ONSM. RESULTS 6 children aged 3-15years (mean 9 years) were identified over 5 years. 3 children were treated at GOSH, 2 at UCLH and 1 at BCH. 3/6 patients were male. 2/6 underwent a biopsy. Presenting symptoms included headache, acute visual loss and eye pain. 2/6 patients presented with bilateral vision deterioration. The average time between onset of symptoms and presentation was 8 months (range 3–15 months). Identified causes of delayed diagnosis included delayed presentation related to COVID-19 pandemic (2 patients) and impaired quality of imaging due to dental braces (1 patient). Whilst awaiting diagnosis, 2 patients lost vision completely in their affected eye. Diagnostic workup included: optic disc examination (6 patients), lumbar puncture (2 patients), angiotensin-converting enzyme (sACE) (2 patients), MRI brain and spine (6 patients), CT scan (6 patients), PET-DOTATE scan (3 patients), NF2 genetic testing (4 patients). Two patients completed PBT therapy while 1 is undergoing radiotherapy. One patient underwent an enucleation, while the rest are under surveillance. CONCLUSIONS Paediatric ONSM diagnosis remains challenging despite advanced imaging. Our review highlights the added value of CT and PET-DOTATATE when a biopsy is high-risk. CT reveals calcification in 20-50% ONSM while the role of PET-DOTATATE is related to the expression of somatostatin receptor 2 in meningiomas. Despite optimal treatment, vision loss maybe unavoidable. Early multidisciplinary consultations are advised for enhanced outcomes.
BackgroundThis study reports how parents and young people who had an experience offebrile neutropenia (FN) improved the design of a trial to inform the management of this condition. Five parents, a ...young person who had completed treatment and three clinician-researchers contributed.MethodsThe group was formed after an invitation on social media and met via video conference. Many participants were from an existing childhood-cancer parent-involvement group. The initial questions asked during discussion were about the importance of the topic, the views on the need for a trial, which important outcomes should be measured and the practical aspects which would make it easier or more difficult for people to take part in it. The conversation occurred for an entire afternoon, was audio and video recorded, transcribed, analysed and checked by those involved. The fifth parent added to this via email.ResultsThe group altered the trial structure by proposing randomising of each child to one of the two management methods through the whole of their anti-cancer treatment, rather than randomising the study sites or the child at each visit. They felt that even if people declined taking part in the study in the first weeks of diagnosis, their views might change and they should be allowed to consent later. They also proposed methods of collecting important patient and family data, enriching the medical information gained in the study. Active follow-up, negotiated for each individual family, was also suggested.ConclusionTrials for improving the management of FN in children and young people who are undergoing anti-cancer treatments should consider individual-patient randomisation, collection of ‘quality of life’ and ‘experience of care’ aspects using digital and paper-based methods, engage families in shared decision-making about management options and ensure adequate supportive information is available and accessible to all patients regardless of background, geographical location or age.
For children with cancer, the clinical integration of precision medicine to enable predictive biomarker–based therapeutic stratification is urgently needed.
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.
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.
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.
•The hybrid-capture panel gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded tissue.•A tailored sequencing approach identifies ≥1 genetic alteration in 70% of samples and potentially actionable genetic alterations in 51% of patients.•In paired samples, from different treatment time points, there were differences in the genetic alterations detected.
Abstract
Management of infant medulloblastoma remains a challenge. Front-line chemotherapy can successfully avoid radiation in low-risk infant medulloblastoma. Patients that do relapse can be ...salvaged long-term with radiotherapy. We report 4 cases of infants with medulloblastoma treated with chemotherapy (HIT2000 protocol) with residual or progressive disease. RESULTS: Four cases of infant medulloblastoma, all MBEN/nodular desmoplastic SHH type B, p53 WT, no MYC / MYCN amplification. CASE 1: 16 month old girl, metastatic lesions in the cerebellum and meningeal enhancement. Germline SUFU mutation. After 3 cycles of chemotherapy MRI showed more enhancement of the residual disease. To inform management, second look surgery was performed. Pathology showed fibrous tissue only, no malignant cells. The child continues to be treated as per HIT2000. CASE 2: 5 month old girl, metastatic lesions in the cerebellum. Germline SUFU mutation. 2 months after end of treatment, MRI demonstrated progression of cerebellar lesion. Surgical resection was performed, pathology showed differentiated mature neuronal tissue. No further treatment; remains in remission 1 year after suspected progression. CASE 3: 27 month old boy, metastatic lesions in cerebellum. Germline SUFU mutation. 1 month post-completion of treatment progressive prominent nodules along the cerebellum and cerebellar leptomeningeal enhancement. Biopsy not feasible so close MRI surveillance was initiated. MRI remains stable 1 year after suspected progression. CASE 4: 30 months old boy, non-metastatic disease. Complete resection. No germline mutation. End-of-treatment MRI showed subtle new intraspinal leptomeningeal deposits and a suspicious left optic tract nodule, subsequent MRI 8 weeks later showed clear progressive disease. Unfortunately, the child died before radiotherapy could be delivered. CONCLUSION: Salvage radiotherapy for infants with medulloblastoma who progress following chemotherapy treatment can be life-saving but risk significant cognitive impairment. Differentiation of medulloblastoma following radio/chemotherapy has been reported. We recommend considering tissue confirmation prior to embarking on further treatment for suspected relapse.
Abstract BACKGROUND For many patients, PLGG has a chronic disease course with potential for multiple and significant functional deficits and decreased Quality-of-Life (QOL). However, there have been ...limited large-cohort evaluations or prognostication studies of QOL & functional outcomes. AIMS 1. Large-cohort analysis of long-term PLGG survivor functional & QOL outcomes: combining clinical follow-up assessment with survivor-reported QOL & function. 2. Evaluation of prognostic associations between PLGG variables & functional/QOL outcomes. METHODS Demographic, tumour & treatment factors of PLGG patients diagnosed 1980-2021 at Great Ormond Street Hospital, UK, were retrospectively collected & evaluated prognostically with functional outcomes from last clinical follow-up.Cohort long-term survivors completed prospective QOL(PedsQl Core) & function(PESAT-PT) questionnaires.PedsQL scores were evaluated prognostically with patient/tumour/treatment factors using multivariate logistic regression.PedsQL scores were compared with healthy (N=649) & chronically-ill (N=137) reference populations. RESULTS PLGG cohort (N=814) OS was 94.3%,PFS 76% & median treatments 1 (0-21) at median follow-up 8 years. 42% had 1 functional deficit at last clinical follow-up. Diagnostic age, tumour location, surgical resection, & receipt chemo/radiotherapy were independently associated with functional outcomes. 122 long-term survivors completed prospective questionnaires at median follow-up 21 years. 87% reported dysfunction: physical 60%,visual 50%,neurocognitive 49%,social 25%, endocrine 23%,travel 21%,employment 18%,& hearing 11%. Mean PedsQl scores:Physical 82(0-100), Psychosocial 73(13-100), Total 76(9-100). PLGG survivors had significantly lower mean Total, Physical & Psychosocial PedsQl scores than healthy controls (p0.0001,p0.0003,p0.0001), but comparable to people with chronic illness (p0.60,p0.14,p0.21). No correlation identified between PedsQl scores & number of impaired functional domains. Favourable Total PedsQl scores were associated with surgical resection(OR-5.94,p0.02) & fewer treatment interventions on multivariate analysis(OR-2.8,p0.0005). Adverse PedsQl scores were associated with NF1 (OR-11.82,p0.04), BRAF-V600E mutation(OR-18.55,p0.04), OPGs(OR-12.1,p0.01), & seizures(OR-18.93,p<0.0001). CONCLUSIONS Prognostication of heterogeneous PLGG survivor functional and QOL outcomes is complex but possible, without clear correlation between QOL and functional outcomes. For many, PLGG is a lifelong disease that begins in childhood.
Sept 28 marks World Rabies Day, launched in 2007 to increase public health awareness and reduce the incidence of this fatal but preventable disease. 5 years on, our experience in Malawi suggests that ...rabies incidence is rising and control measures are inadequate.
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