BACKGROUND: Paediatric High Grade Gliomas (HGG) have poor outcomes with conventional treatment. HGG in association with constitutional DNA mismatch repair deficiency (CMMRD) are hypermutated and have shown dramatic response to checkpoint inhibitors. Salvage following progression or failure to respond to check point inhibitors has rarely been reported. We describe a successful alternative therapeutic approach targeting the activated pathway (mTOR) in a hypermutated HGG. CASE SUMMARY: A 6-year-old girl presenting with seizures was diagnosed with left frontal lobe HGG with concurrent neck mass (Pilomatrixoma). Presence of synchronous tumours raised the possibility of cancer predisposition; the HGG was hypermutated with germline PMS2 mutation confirming diagnosis of CMMRD. Near total resection was undertaken followed by focal radiotherapy 54 Gy, with 1 cycle of concomitant CCNU. MRI post radiotherapy showed tumour progression. Anti-PDl inhibitor Nivolumab was commenced. CTLA-4 antibody, Ipilimumab was added after 4 cycles of Nivolumab due to poor response. Tumour response was seen, but dual therapy had to be discontinued due to toxicity. The tumour progressed following further single agent Nivolumab. In view of multiple mutations in the mTOR pathway (NF1, PIK3/PTEN, TSC1, TSC2), a mTOR inhibitor, Everolimus was commenced. There was 25% tumour reduction after 4 weeks treatment and further reduction after 6 months. Resection of residual tumour showed necrotic tissue only. There continues to be a sustained response to Everolimus for over 12 months. DISCUSSION: Approximately a third of CMMRD HGG respond to checkpoint inhibitors. For those that don’t, these hypermutated tumours offers the possibility of targeting specific molecular pathways. Response to Everolimus in HGG harbouring mTOR aberrations have been described. To our knowledge this is the first report of successful use of mTOR inhibitor in CMMRD HGG. CONCLUSION: Targeted molecular treatment for patients with CMMRD hypermutated brain tumours should be considered according to the mutated pathways.

Background and Objectives: Swallowing disorders lead to chronic lung aspiration.Early detection and treatment of aspiration in children with dysphagia are important to prevent lung damage. Diagnosis of aspiration, which may be silent, requires an instrumental study such as fiberoptic endoscopic evaluation of swallowing (FEES).Despite its usefulness, it is rarely practiced by pediatric pulmonologists. This study aimed to evaluate the feasibility and utility of FEES performed in the pediatric respiratory unit of a tertiary hospital, analyze the clinical characteristics, endoscopic findings and proposed treatments, and identify the factors associated with penetration or aspiration.Methods: Medical records of 373 children with suspected aspiration who were referred to the pediatric respiratory unit for FEES were reviewed retrospectively. Clinical characteristics, FEES findings, and the proposed treatments were analyzed.Results: Laryngeal penetration/aspiration was seen in 47.9% of the patients. The most common associated conditions were neurological disease and prematurity. The most frequently observed endoscopic finding was altered laryngeal sensitivity (36.5%). Intervention was recommended in 54.2% of the patients. Complications were not seen during any of the procedures. The multivariate logistic regression model revealed an independent association between aspiration and alterations in laryngeal sensitivity (odds ratio [OR], 5.68), pharyngeal pooling (OR, 11.47), and post-swallowing food residues (OR, 8.08). Conclusions:The FEES procedure performed by pediatric pulmonologists is a reliable method for diagnosing aspiration in children. It can be safely executed by trained pulmonologists, and significant endoscopic signs other than aspiration can guide in the diagnosis and management recommendations.

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.

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Background and Objectives: Swallowing disorders lead to chronic lung aspiration. Early detection and treatment of aspiration in children with dysphagia is important to prevent lung damage. Diagnosis of aspiration, which may be silent, requires an instrumental study such as fiberoptic endoscopic evaluation of swallowing (FEES). Despite its usefulness, it is rarely practiced by pediatric pulmonologists. This study aimed to evaluate the feasibility and utility of FEES performed in the pediatric respiratory unit of a tertiary hospital, analyze the clinical characteristics, endoscopic findings and proposed treatments, and identify the factors associated with penetration or aspiration. Methods: Medical records of 373 children with suspected aspiration who were referred to the pediatric respiratory unit for FEES were reviewed retrospectively. Clinical characteristics, FEES findings, and the proposed treatments were analyzed. Results: Aspiration was seen in 47.9% of the patients. The most common associated conditions were neurological disease and prematurity. The most frequently observed endoscopic finding was altered laryngeal sensitivity (36.5%). Intervention was recommended in 54.2 % of the patients. Complications were not seen during any of the procedures. Conclusions: The FEES procedure performed by pediatric pulmonologists is a reliable method for diagnosing aspiration in children. It can be safely executed by trained pulmonologists, and significant endoscopic signs other than aspiration can guide in the diagnosis and management recommendations.